U.S. patent application number 14/526438 was filed with the patent office on 2015-03-05 for uses and compositions for treatment of rheumatoid arthritis.
The applicant listed for this patent is Mary A. Cifaldi, Jeffrey D. Kent, Hartmut Kupper, John L. Perez. Invention is credited to Mary A. Cifaldi, Jeffrey D. Kent, Hartmut Kupper, John L. Perez.
Application Number | 20150064194 14/526438 |
Document ID | / |
Family ID | 38610131 |
Filed Date | 2015-03-05 |
United States Patent
Application |
20150064194 |
Kind Code |
A1 |
Kupper; Hartmut ; et
al. |
March 5, 2015 |
Uses and Compositions for Treatment of Rheumatoid Arthritis
Abstract
The invention provides methods, uses and compositions for the
treatment of rheumatoid arthritis. The invention describes methods
and uses for treating rheumatoid arthritis wherein a TNF.alpha.
inhibitor, such as a human TNF.alpha. antibody, or antigen-binding
portion thereof. Also described are methods for determining the
efficacy of a TNF.alpha. inhibitor for treatment of rheumatoid
arthritis in a subject.
Inventors: |
Kupper; Hartmut;
(Mutterstadt, DE) ; Kent; Jeffrey D.; (Evanston,
IL) ; Cifaldi; Mary A.; (Gurnee, IL) ; Perez;
John L.; (Doylestown, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Kupper; Hartmut
Kent; Jeffrey D.
Cifaldi; Mary A.
Perez; John L. |
Mutterstadt
Evanston
Gurnee
Doylestown |
IL
IL
PA |
DE
US
US
US |
|
|
Family ID: |
38610131 |
Appl. No.: |
14/526438 |
Filed: |
October 28, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11786442 |
Apr 10, 2007 |
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14526438 |
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60909683 |
Apr 2, 2007 |
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60902427 |
Feb 21, 2007 |
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60899262 |
Feb 2, 2007 |
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60858376 |
Nov 10, 2006 |
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60815489 |
Jun 20, 2006 |
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60809770 |
May 30, 2006 |
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60790909 |
Apr 10, 2006 |
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Current U.S.
Class: |
424/142.1 |
Current CPC
Class: |
C07K 2317/76 20130101;
A61K 2039/505 20130101; A61P 19/02 20180101; C12N 2760/16034
20130101; G01N 33/15 20130101; Y02A 50/30 20180101; A61K 2039/545
20130101; Y02A 50/388 20180101; A61K 39/3955 20130101; A61K
2039/55516 20130101; C07K 16/241 20130101; A61K 2039/55 20130101;
C07K 2317/21 20130101; A61K 39/092 20130101; C12N 2760/16071
20130101; A61K 39/39558 20130101; A61K 39/39 20130101; A61K 2300/00
20130101; A61P 37/00 20180101; A61K 39/145 20130101; C07K 2317/30
20130101; A61K 2039/54 20130101; C12N 7/00 20130101 |
Class at
Publication: |
424/142.1 |
International
Class: |
A61K 39/39 20060101
A61K039/39; C12N 7/00 20060101 C12N007/00; A61K 39/145 20060101
A61K039/145; A61K 39/09 20060101 A61K039/09; A61K 39/395 20060101
A61K039/395 |
Claims
1-18. (canceled)
19. A method for enhancing immunization with a vaccine and treating
rheumatoid arthritis (RA) in a subject having RA, the method
comprising administering to the subject a vaccine comprising an
antigen and administering to the subject an antibody, or an
antigen-binding portion thereof, that binds to human Tumor Necrosis
Factor alpha (TNF.alpha.) in an amount sufficient to enhance
immunization with the vaccine and treat the RA in the subject,
wherein the anti-TNF.alpha. antibody, or an antigen-binding portion
thereof, comprises a light chain variable region (LCVR) having a
CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, a
CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5, and
a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 7;
and comprises a heavy chain variable region (HCVR) comprising a
CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, a
CDR2 domain comprising the amino acid sequence of SEQ ID NO: 6, and
a CDR1 domain comprising the amino acid sequence of SEQ ID NO:
8.
20. The method of claim 19, further comprising measuring the titer
of antibodies produced by the subject against the antigen.
21. The method of claim 19, wherein the vaccine is administered
after initial administration of and concurrently with the antibody
or antigen-binding portion thereof.
22. The method of claim 19, wherein the antigen is a bacterial
antigen or a viral antigen.
23. The method of claim 22, wherein the bacterial antigen is a
pneumococcal antigen.
24. The method of claim 22, wherein the viral antigen is an
influenza antigen.
25. The method of claim 19, wherein the vaccine is a subvirion
vaccine.
26. The method of claim 19, wherein the antigen is derived from a
host organism and is purified away from the host organism.
27. The method of claim 19, wherein the antibody, or
antigen-binding portion thereof, comprises a light chain variable
region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1
and comprises a heavy chain variable region (HCVR) comprising the
amino acid sequence of SEQ ID NO: 2.
28. The method of claim 19, wherein the antibody, or
antigen-binding portion thereof, is adalimumab.
29. The method of claim 28, wherein a 40 mg dose of adalimumab is
subcutaneously administered biweekly to the subject.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of priority to U.S.
provisional patent application No. 60/790,909 filed on Apr. 10,
2006; U.S. provisional patent application No. 60/809,770 filed on
May 30, 2006; U.S. provisional patent application No. 60/815,489
filed on Jun. 20, 2006; U.S. provisional patent application No.
60/858,376, filed on Nov. 10, 2006; U.S. provisional patent
application No. 60/902,427 filed on Feb. 21, 2007; U.S. provisional
patent application No. 60/899,268 file on Feb. 2, 2007; and U.S.
provisional patent application No. 60/909,683 filed on Apr. 2,
2007. The contents of all the above-mentioned priority applications
are hereby incorporated by reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] Rheumatoid arthritis (RA) is considered a chronic,
inflammatory autoimmune disorder. RA is a disabling and painful
inflammatory condition which can lead to the substantial loss of
mobility due to pain and joint destruction. RA leads to the
soft-tissue swelling of joints.
SUMMARY OF THE INVENTION
[0003] In one aspect, the invention provides a method of preventing
Pneumococcal disease and treating rheumatoid arthritis (RA) in a
subject comprising administering a pneumococcal vaccine and a human
TNF.alpha. antibody, or antigen-binding portion thereof, to the
subject, such that Pneumococcal disease is prevented and rheumatoid
arthritis is treated.
[0004] In one aspect, the invention provides the use of a human
TNF.alpha. antibody, or antigen-binding portion thereof, in the
manufacture of a medicament for the treatment of RA in a subject,
wherein the medicament is designed to be administered in
combination with a pneumococcal vaccine for the prevention of
Pneumococcal disease.
[0005] In another aspect, the invention provides a method of
treating late-onset RA comprising administering a human TNF.alpha.
antibody, or antigen-binding portion thereof, to a patient having
late-onset RA.
[0006] In another aspect, the invention provides the use of a human
TNF.alpha. antibody, or antigen-binding portion thereof, in the
manufacture of a medicament for the treatment of late-onset RA in a
subject.
[0007] In one embodiment, the subject is over 60 years old.
[0008] In another embodiment, the human TNF.alpha. antibody, or
antigen-binding portion thereof, is administered to the subject in
a biweekly dosing regimen. In another embodiment, the human
TNF.alpha. antibody, or antigen-binding portion thereof, is
administered to the subject in a dose of 40 mg. In one embodiment,
the human TNF.alpha. antibody, or antigen-binding portion thereof,
is administered to the subject subcutaneously.
[0009] In one aspect, the invention provides a method of
determining the efficacy of a TNF.alpha. inhibitor for treating RA
in a subject comprising determining an ACR20 response of a patient
population having RA and who was administered the TNF.alpha.
inhibitor, wherein an ACR20 response in at least about 80% of the
patient population indicates that the TNF.alpha. inhibitor is an
effective TNF.alpha. inhibitor for the treatment of RA in a
subject.
[0010] In one embodiment, an ACR20 response in at least about 85%
of the patient population indicates that the TNF.alpha. inhibitor
is an effective TNF.alpha. inhibitor for the treatment of RA in a
subject.
[0011] In another aspect, the invention provides a method of
determining the efficacy of a TNF.alpha. inhibitor for treating RA
in a subject comprising determining an ACR50 response of a patient
population having RA and who was administered the TNF.alpha.
inhibitor, wherein an ACR50 response in at least about 62% of the
patient population indicates that the TNF.alpha. inhibitor is an
effective TNF.alpha. inhibitor for the treatment of RA in a
subject.
[0012] In one embodiment, an ACR50 response in at least about 65%
of the patient population indicates that the TNF.alpha. inhibitor
is an effective TNF.alpha. inhibitor for the treatment of RA in a
subject. In another embodiment, the method further comprises
administering the effective TNF.alpha. inhibitor to a subject for
the treatment of RA.
[0013] In one aspect, the invention provides a method of treating
RA in a subject comprising administering an effective TNF.alpha.
inhibitor, wherein the effective TNF.alpha. inhibitor was
identified as providing an ACR20-response in at least about 80% of
a patient population who received the effective TNF.alpha.
inhibitor for the treatment of RA.
[0014] In one aspect, the invention provides the use of an
effective TNF.alpha. inhibitor in the manufacture of a medicament
for the treatment of RA in a subject, wherein the TNF.alpha.
inhibitor was identified as providing an ACR20 response in at least
about 80% of a patient population who received the effective
TNF.alpha. inhibitor for the treatment of RA.
[0015] In one aspect, the invention provides a method of treating
RA in a subject comprising administering an effective TNF.alpha.
inhibitor, wherein the effective TNF.alpha. inhibitor was
identified as providing an ACR50 response in at least about 62% of
a patient population who received the effective TNF.alpha.
inhibitor for the treatment of RA.
[0016] In one aspect, the invention provides the use of an
effective TNF.alpha. inhibitor in the manufacture of a medicament
for the treatment of RA in a subject, wherein the effective
TNF.alpha. inhibitor was identified as providing an ACR50 response
in at least about 62% of a patient population who received the
effective TNF.alpha. inhibitor for the treatment of RA.
[0017] In one aspect, the invention provides a method for
predicting the efficacy of a TNF.alpha. inhibitor for the treatment
of rheumatoid arthritis (RA) in a subject comprising using the
combination of a C-reactive protein (CRP) level of the subject and
a Patient Activity Score (PAS) of the subject, wherein an
improvement in the CRP level and the PAS score early in the
treatment of the patient with the TNF.alpha. inhibitor indicates
that the TNF.alpha. inhibitor is an effective TNF.alpha. inhibitor
for the treatment of RA in the subject.
[0018] In one embodiment, the improvement in the CRP level and the
PAS score early in the treatment of the subject occurs at about two
weeks following initiation of the treatment in the subject. In
another embodiment, the PAS score is determined using the Health
Assessment Questionnaire (HAQ) of the subject. In another
embodiment, the improvement in the CRP level is at least as
described in the Examples below. In another embodiment, the
improvement in the HAQ score is at least about 0.4.
[0019] In another aspect, the invention provides a method for
determining the efficacy of a TNF.alpha. inhibitor for the
treatment of rheumatoid arthritis (RA) in a subject comprising
determining a Simplified Disease Activity Score (SDAI) of a patient
population having RA and who was administered the TNF.alpha.
inhibitor, wherein a mean SDAI of no greater than about 3.3 in at
least about 11% of the patient population indicates that the
TNF.alpha. inhibitor is an effective TNF.alpha. inhibitor for
treating RA.
[0020] In one embodiment, the TNF.alpha. inhibitor is a TNF.alpha.
antibody, or antigen-binding portion thereof, or a TNF.alpha.
fusion protein. In one embodiment, the TNF.alpha. fusion protein is
etanercept. In one embodiment, the TNF.alpha. antibody, or
antigen-binding portion thereof, is an antibody selected from the
group consisting of a humanized antibody, a chimeric antibody, a
human antibody, and a multivalent antibody. In one embodiment, the
TNF.alpha. antibody, or antigen-binding portion thereof, is
infliximab or golimumab.
[0021] In another aspect, the invention provides a method for
determining the efficacy of a human TNF.alpha. antibody, or
antigen-binding portion thereof, for treating RA in a subject
comprising determining an ACR70 response of a patient population
having RA and who was administered the human TNF.alpha. antibody,
or antigen-binding portion thereof, wherein an ACR70 response in at
least about 20% of the patient population indicates that the human
TNF.alpha. antibody, or antigen-binding portion thereof, is an
effective human TNF.alpha. antibody, or antigen-binding portion
thereof, for the treatment of RA in a subject.
[0022] In one embodiment, an ACR70 response in at least about 25%
of the patient population indicates that the human TNF.alpha.
antibody, or antigen-binding portion thereof, is an effective human
TNF.alpha. antibody, or antigen-binding portion thereof, for the
treatment of RA in a subject. In one embodiment, an ACR70 response
in at least about 30% of the patient population indicates that the
human TNF.alpha. antibody, or antigen-binding portion thereof, is
an effective human TNF.alpha. antibody, or antigen-binding portion
thereof, for the treatment of RA in a subject. In another
embodiment, an ACR70 response in at least about 35% of the patient
population indicates that the human TNF.alpha. antibody, or
antigen-binding portion thereof, is an effective human TNF.alpha.
antibody, or antigen-binding portion thereof, for the treatment of
RA in a subject. In yet another embodiment, an ACR70 response in at
least about 40% of the patient population indicates that the human
TNF.alpha. antibody, or antigen-binding portion thereof, is an
effective human TNF.alpha. antibody, or antigen-binding portion
thereof, for the treatment of RA in a subject.
[0023] In one embodiment the method further comprises administering
the effective human TNF.alpha. antibody, or antigen-binding portion
thereof, to a subject for the treatment of RA.
[0024] In one aspect, the invention provides a method of treating
RA in a subject comprising administering an effective human
TNF.alpha. antibody, or antigen-binding portion thereof, for the
treatment of RA in a subject, wherein the effective human
TNF.alpha. antibody, or antigen-binding portion thereof, was
identified as achieving an ACR70 response in at least about 20% of
a patient population who was administered the human TNF.alpha.
antibody, or antigen-binding portion thereof.
[0025] In another aspect, the invention provides the use of an
effective human TNF.alpha. antibody, or antigen-binding portion
thereof, in the manufacture of a medicament for treating RA in a
subject, wherein the effective human TNF.alpha. antibody, or
antigen-binding portion thereof, was identified as achieving an
ACR70 response in at least about 20% of a patient population who
was administered the human TNF.alpha. antibody, or antigen-binding
portion thereof.
[0026] In one aspect, the invention provides a method for
determining the efficacy of a 33 human TNF.alpha. antibody, or
antigen-binding portion thereof, for treating RA in a subject
comprising determining a moderate EULAR response of a patient
population having RA and who was administered the human TNF.alpha.
antibody, or antigen-binding portion thereof, wherein a moderate
EULAR response in at least about 83% of the patient population
indicates that the human TNF.alpha. antibody, or antigen-binding
portion thereof, is an effective human TNF.alpha. antibody, or
antigen-binding portion thereof, for the treatment of RA.
[0027] In one embodiment, a moderate EULAR response in at least
about 85% of the patient population indicates that the human
TNF.alpha. antibody, or antigen-binding portion thereof, is an
effective human TNF.alpha. antibody, or antigen-binding portion
thereof, for the treatment of RA. In another embodiment, a moderate
EULAR response in at least about 90% of the patient population
indicates that the human TNF.alpha. antibody, or antigen-binding
portion thereof, is an effective human TNF.alpha. antibody, or
antigen-binding portion thereof, for the treatment of RA. In
another embodiment, a moderate EULAR response in at least about 92%
of the patient population indicates that the human TNF.alpha.
antibody, or antigen-binding portion thereof, is an effective human
TNF.alpha. antibody, or antigen-binding portion thereof, for the
treatment of RA.
[0028] In one embodiment the method further comprises administering
the effective human TNF.alpha. antibody, or antigen-binding portion
thereof, to a subject for the treatment of RA.
[0029] In one aspect, the invention provides a method of treating
RA in a subject comprising administering an effective human
TNF.alpha. antibody, or antigen-binding portion thereof, for the
treatment of RA in a subject, wherein the effective human
TNF.alpha. antibody, or antigen-binding portion thereof, was
identified as achieving a moderate EULAR response in at least about
83% of a patient population who was administered the human
TNF.alpha. antibody, or antigen-binding portion thereof.
[0030] In another aspect, the invention provides the use of an
effective human TNF.alpha. antibody, or antigen-binding portion
thereof, in the manufacture of a medicament for treating RA in a
subject, wherein the effective human TNF.alpha. antibody, or
antigen-binding portion thereof, was identified as achieving a
moderate EULAR response in at least about 83% of a patient
population who was administered the human TNF.alpha. antibody, or
antigen-binding portion thereof.
[0031] In one aspect, the invention provides a method for
determining the efficacy of a human TNF.alpha. antibody, or
antigen-binding portion thereof, for treating RA in a subject
comprising determining a good EULAR response of a patient
population having RA and who was administered the human TNF.alpha.
antibody, or antigen-binding portion thereof, wherein a good EULAR
response in at least about 35% of the patient population indicates
that the human TNF.alpha. antibody, or antigen-binding portion
thereof, is an effective human TNF.alpha. antibody, or
antigen-binding portion thereof, for the treatment of RA in a
subject.
[0032] In one embodiment, a good EULAR response in at least about
40% of the patient population indicates that the human TNF.alpha.
antibody, or antigen-binding portion thereof, is an effective human
TNF.alpha. antibody, or antigen-binding portion thereof, for the
treatment of RA in a subject.
[0033] In one aspect, the invention provides a method for
determining the efficacy of a human TNF.alpha. antibody, or
antigen-binding portion thereof, for treating RA in a subject who
has failed prior infliximab treatment comprising determining an
ACR20 response of a patient population having RA who has failed
previous infliximab treatment and who was administered the human
TNF.alpha. antibody, or antigen-binding portion thereof, wherein an
ACR20 response in at least about 50% of the patient population
indicates that the human TNF.alpha. antibody, or antigen-binding
portion thereof, is an effective human TNF.alpha. antibody, or
antigen-binding portion thereof, for the treatment of RA in a
subject who has failed prior infliximab treatment.
[0034] In one embodiment, an ACR20 response in at least about 50%
of the patient population indicates that the human TNF.alpha.
antibody, or antigen-binding portion thereof, is an effective human
TNF.alpha. antibody, or antigen-binding portion thereof, for the
treatment of RA in a subject who has failed prior infliximab
treatment. In another embodiment, an ACR20 response in at least
about 55% of the patient population indicates that the human
TNF.alpha. antibody, or antigen-binding portion thereof, is an
effective human TNF.alpha. antibody, or antigen-binding portion
thereof, for the treatment of RA in a subject who has failed prior
infliximab treatment. In another embodiment, an ACR20 response in
at least about 60% of the patient population indicates that the
human TNF.alpha. antibody, or antigen-binding portion thereof, is
an effective human TNF.alpha. antibody, or antigen-binding portion
thereof, for the treatment of RA in a subject who has failed prior
infliximab treatment. In yet another embodiment, an ACR20 response
in at least about 65% of the patient population indicates that the
human TNF.alpha. antibody, or antigen-binding portion thereof, is
an effective human TNF.alpha. antibody, or antigen-binding portion
thereof, for the treatment of RA in a subject who has failed prior
infliximab treatment. In one embodiment,
an ACR20 response in at least about 69% of the patient population
indicates that the human TNF.alpha. antibody, or antigen-binding
portion thereof, is an effective human TNF.alpha. antibody, or
antigen-binding portion thereof, for the treatment of RA in a
subject who has failed prior infliximab treatment.
[0035] In one embodiment, the method further comprises
administering the effective human TNF.alpha. antibody, or
antigen-binding portion thereof, to a subject to maintain treat
RA.
[0036] In another embodiment, the human TNF.alpha. antibody, or an
antigen-binding portion thereof, dissociates from human TNF.alpha.
with a K.sub.d of 1.times.10.sup.-8 M or less and a K.sub.off rate
constant of 1.times.10.sup.-3 s.sup.-1 or less, both determined by
surface plasmon resonance, and neutralizes human TNF.alpha.
cytotoxicity in a standard in vitro L929 assay with an IC.sub.50 of
1.times.10.sup.-7 M or less.
[0037] In one embodiment, the human TNF.alpha. antibody, or an
antigen-binding portion thereof, has the following
characteristics:
[0038] a) dissociates from human TNF.alpha. with a K.sub.off rate
constant of 1.times.10.sup.-3 s.sup.-1 or less, as determined by
surface plasmon resonance;
[0039] b) has a light chain CDR3 domain comprising the amino acid
sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single
alanine substitution at position 1, 4, 5, 7 or 8 or by one to five
conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8
and/or 9;
[0040] c) has a heavy chain CDR3 domain comprising the amino acid
sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single
alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or
by one to five conservative amino acid substitutions at positions
2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12.
[0041] In another embodiment, the human TNF.alpha. antibody, or an
antigen-binding portion thereof, comprises a light chain variable
region (LCVR) having a CDR3 domain comprising the amino acid
sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single
alanine substitution at position 1, 4, 5, 7 or 8, and comprises a
heavy chain variable region (HCVR) having a CDR3 domain comprising
the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID
NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6,
8, 9, 10 or 11. In another embodiment, the human TNF.alpha.
antibody, or an antigen-binding portion thereof, comprises a light
chain variable region (LCVR) comprising the amino acid sequence of
SEQ ID NO: 1 and a heavy chain variable region (HCVR) comprising
the amino acid sequence of SEQ ID NO: 2.
[0042] In one embodiment, the human TNF.alpha. antibody, or an
antigen-binding portion thereof, is adalimumab.
[0043] In another aspect, the invention provides an article of
manufacture comprising [0044] a) a packaging material; [0045] b) a
TNF.alpha. antibody, or antigen-binding portion thereof; and [0046]
c) a label or package insert indicating that patients with RA
receiving treatment with the TNF.alpha. antibody, or
antigen-binding portion thereof, can be administered a
pneumonococcal vaccine concurrently with the TNF.alpha. antibody,
or antigen-binding portion thereof.
[0047] In one embodiment, the pneumonococcal vaccine is a
pneumonococcal polysaccharide vaccine.
[0048] In another aspect, the invention provides an article of
manufacture comprising [0049] a) a packaging material; [0050] b)
pneumonococcal or influenza virus vaccine; and [0051] c) a label or
package insert contained within the packaging material indicating
that patients receiving the pneumonococcal or influenza virus
vaccine can be safely administered a TNF.alpha. inhibitor.
[0052] In another aspect, the invention provides an article of
manufacture comprising [0053] a) a packaging material; [0054] b) a
TNF.alpha. antibody, or antigen-binding portion thereof; and [0055]
c) a label or package insert contained within the packaging
material indicating that in studies of the TNF.alpha. antibody, or
antigen-binding portion thereof, observed malignancies included
melanoma and/or granulose cell tumor of the ovary.
[0056] In one embodiment, the TNF.alpha. antibody, or
antigen-binding portion thereof, is a human TNF.alpha. antibody, or
antigen-binding portion thereof, and dissociates from human
TNF.alpha. with a K.sub.d of 1.times.10.sup.-8 M or less and a
K.sub.off rate constant of 1.times.10.sup.-3 s.sup.-1 or less, both
determined by surface plasmon resonance, and neutralizes human
TNF.alpha. cytotoxicity in a standard in vitro L929 assay with an
IC.sub.50 of 1.times.10.sup.-7 M or less.
[0057] In another embodiment, the TNF.alpha. antibody, or an
antigen-binding portion thereof, has the following
characteristics:
[0058] a) dissociates from human TNF.alpha. with a K.sub.off rate
constant of 1.times.10.sup.-3 s.sup.-1 or less, as determined by
surface plasmon resonance;
[0059] b) has a light chain CDR3 domain comprising the amino acid
sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single
alanine substitution at position 1, 4, 5, 7 or 8 or by one to five
conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8
and/or 9;
[0060] c) has a heavy chain CDR3 domain comprising the amino acid
sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single
alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or
by one to five conservative amino acid substitutions at positions
2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12.
[0061] In another embodiment, the TNF.alpha. antibody, or an
antigen-binding portion thereof, comprises a light chain variable
region (LCVR) having a CDR3 domain comprising the amino acid
sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single
alanine substitution at position 1, 4, 5, 7 or 8, and comprises a
heavy chain variable region (HCVR) having a CDR3 domain comprising
the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID
NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6,
8, 9, 10 or 11. In yet another embodiment, the TNF.alpha. antibody,
or an antigen-binding portion thereof, comprises a light chain
variable region (LCVR) comprising the amino acid sequence of SEQ ID
NO: 1 and a heavy chain variable region (HCVR) comprising the amino
acid sequence of SEQ ID NO: 2.
[0062] In one embodiment, the human TNF.alpha. antibody, or an
antigen-binding portion thereof, is adalimumab.
[0063] In one embodiment of the invention, the subject having RA is
an adult patient (or subject) with moderately to severely active
disease.
[0064] The invention provides an article of manufacture comprising
a packaging material; a TNF.alpha. inhibitor; and a label or
package insert contained within the packaging material indicating
that the standardized mortality rate for the TNF.alpha. inhibitor
was calculated at about 0.67.
[0065] The invention also provides a method of treating a human
subject having rheumatoid arthritis (RA) comprising administering a
TNF.alpha. inhibitor to the subject, wherein the subject has
previously failed an anti-TNF.alpha. therapy comprising
administration of an alternate TNF.alpha. antagonist. In one
embodiment, the alternate TNF.alpha. antagonist is a biologic
agent. In one embodiment, the biologic agent comprises etanercept
or infliximab. In another embodiment, the alternate TNF.alpha.
antagonist was discontinued for a reason selected from the group
consisting of no response, lost efficacy, and intolerance.
[0066] The invention includes a method for monitoring the
effectiveness of a TNF.alpha. inhibitor for the treatment of
rheumatoid arthritis (RA) in a human subject comprising
administering the TNF.alpha. inhibitor to a preselected patient
population having RA; and determining the effectiveness of the
TNF.alpha. inhibitor using a baseline ACR score of the patient
population and an ACR score of the patient population following
administration of the TNF.alpha. inhibitor, wherein an ACR20
achieved in about 58-85% of the patient population indicates that
the TNF.alpha. inhibitor is effective at treating RA.
[0067] The invention also provides a method for monitoring the
effectiveness of a TNF.alpha. inhibitor for the treatment of RA in
a human subject comprising administering the TNF.alpha. inhibitor
to a preselected patient population having RA; and determining the
effectiveness of the TNF.alpha. inhibitor using a baseline ACR
score of the patient population and an ACR score of the patient
population following administration of the TNF.alpha. a inhibitor,
wherein an ACR50 achieved in about 30-62% of the patient population
indicates that the TNF.alpha. inhibitor is effective at treating
RA.
[0068] The invention also provides a method for monitoring the
effectiveness of a TNF.alpha. inhibitor for the treatment of RA in
a human subject comprising administering the TNF.alpha. inhibitor
to a preselected patient population having RA; and determining the
effectiveness of the TNF.alpha. inhibitor using a baseline ACR
score of the patient population and an ACR score of the patient
population following administration of the TNF.alpha. inhibitor,
wherein an ACR70 achieved in about 12-38% of the patient population
indicates that the TNF.alpha. inhibitor is effective at treating
RA. In one embodiment, preselected patient population has already
been administered the TNF.alpha. inhibitor.
[0069] The invention includes a method for monitoring the
effectiveness of a TNF.alpha. inhibitor for the treatment of RA in
a human subject comprising administering the TNF.alpha. inhibitor
to a preselected patient population having rheumatoid arthritis;
determining the effectiveness of the TNF.alpha. inhibitor using a
baseline Disease Activity Score (DAS)28 score of the patient
population and a DAS28 score of the patient population following
administration of the TNF.alpha. inhibitor, wherein a mean change
in the DAS28 score of between about -1.9 and -2.8 of the patient
population indicates that the TNF.alpha. inhibitor is effective at
treating RA. In one embodiment, the TNF.alpha. inhibitor has
already been administered to the pre-selected patient
population.
[0070] The invention includes an article of manufacture comprising
a packaging material; a TNF.alpha. inhibitor; and a label or
package insert contained within the packaging material indicating
that patients receiving treatment with the TNF.alpha. inhibitor can
be safely administered a pneumonococcal or influenza virus
vaccine.
[0071] The invention also includes an article of manufacture
comprising a packaging material; pneumonococcal or influenza virus
vaccine; and a label or package insert contained within the
packaging material indicating that patients receiving the
pneumonococcal or influenza virus vaccine can be safely
administered a TNF.alpha. inhibitor.
[0072] The invention provides a method for treating RA and
immunizing against a pneumonococcal or influenza virus antigen in a
human subject comprising administering a TNF.alpha. inhibitor to
the subject; and administering a pneumonococcal or influenza viral
vaccine to the subject.
[0073] The invention further provides an article of manufacture
comprising a packaging material; a TNF.alpha. inhibitor; and a
label or package insert contained within the packaging material
indicating that in studies of the TNF.alpha. inhibitor, observed
malignancies included melanoma and granulose cell tumor of the
ovary.
[0074] The invention includes a method of achieving an early
clinical response in a Hispanic human subject having RA comprising
administering a TNF.alpha. inhibitor such that an early clinical
response in the Hispanic human subject is achieved. In one
embodiment, the Hispanic human subject is Venezuelan. In one
embodiment, the early clinical response is determined using an
assessment test selected from the group consisting of DAS28, TJC28,
SJC28, HAQ, pain on VAS, ESR, and CRP. In another embodiment, the
invention includes the early clinical response occurs at about 2
weeks following administration of the TNF.alpha. inhibitor.
[0075] The invention provides a method of testing the efficacy of a
TNF.alpha. inhibitor for the rapid improvement of moderate to
severe RA in a Hispanic patient population comprising administering
the TNF.alpha. inhibitor to a preselected Hispanic patient
population having moderate to severe RA; determining the efficacy
of the TNF.alpha. inhibitor using a baseline Health Assessment
Questionnaire (HAQ) score of the patient population and an HAQ
score of the patient population following administration of the
TNF.alpha. inhibitor, wherein a decrease in the mean HAQ score of
at least about -0.5 indicates that the TNF.alpha. inhibitor is
efficacious for the rapid improvement of moderate to severe RA in a
Hispanic patient population. In one embodiment, the rapid
improvement occurs at about 2 weeks following administration of the
TNF.alpha. inhibitor. In one embodiment, the TNF.alpha. inhibitor
has already been administered to the pre-selected patient
population.
[0076] The invention provides an article of manufacture comprising
a packaging material; a TNF.alpha. inhibitor; and a label or
package insert contained within the packaging material indicating
that in studies of the TNF.alpha. inhibitor for the treatment of
juvenile rheumatoid arthritis (JRA) the most common adverse events
(AEs) were infections. In one embodiment, the infections include
mild upper respiratory infections.
[0077] In one embodiment, the TNF.alpha. inhibitor is administered
weekly. In another embodiment, the TNF.alpha. inhibitor is
administered every other week.
[0078] The invention further provides a package comprising a
TNF.alpha. inhibitor and a label, in a position which is visible to
prospective purchasers, comprising a printed statement which
informs prospective purchasers that the median apparent clearance
(CL/F) of the TNF.alpha. inhibitor ranges from about 13.2 to about
15.0 mL/hr. In one embodiment of the invention, the package further
informs prospective purchasers that concomitant therapy with either
immunosuppressant 6 mercaptopurine or azathioprine has slightly
lower or no impact on TNF.alpha. inhibitor CL/F. In one embodiment,
the anti-TNF.alpha. antibody, or antigen-binding portion thereof,
is a 40 mg dose.
[0079] The invention describes a package comprising a TNF.alpha.
inhibitor and a label, in a position which is visible to
prospective purchasers, comprising a printed statement which
informs prospective purchasers that TNF.alpha. inhibitor mean
steady-state trough concentrations of approximately 6-7 .mu.g/mL
and 7-9 .mu.g/mL were observed without and with methotrexate,
respectively.
[0080] The invention also includes a package comprising a
TNF.alpha. inhibitor, wherein the package contains, on the label
and in a position which is visible to prospective purchasers, a
printed statement which informs prospective purchasers that
available data suggest that the clinical response is usually
achieved within 12 weeks of treatment; and continued therapy should
be carefully reconsidered in a patient not responding within this
time period.
[0081] The invention provides a package comprising adalimumab,
wherein the package contains, on the label and in a position which
is visible to prospective purchasers, a printed statement which
informs prospective purchasers that the proportion of patients who
discontinued treatment due to adverse events during the
double-blind, controlled portion of Studies I-IX was 5.1% for
patients taking the adalimumab and 3.2% for control treated
patients.
[0082] The invention also provides a package comprising a
TNF.alpha. inhibitor, wherein the package contains, on the label
and in a position which is visible to prospective purchasers, a
printed statement which informs prospective purchasers that the
TNF.alpha. inhibitor has been shown to have an uncommon undesirable
effect in clinical studies selected from the group consisting of
vaginal infection (including fungal), hyperglycaemia, dysphonia,
pharyngeal erythema, wheezing, skin reaction, skin exfoliation,
spasm, rheumatoid nodule, shoulder pain, and feeling hot.
[0083] The invention further provides a package comprising
adalimumab, wherein the package contains, on the label and in a
position which is visible to prospective purchasers, a printed
statement which informs prospective purchasers of at least one of
the following notifications: in the nine controlled trials, 17% of
patients treated with adalimumab developed injection site reactions
(erythema and/or itching, haemorrhage, pain or swelling), compared
to 10% of patients receiving placebo or active control; in the nine
controlled trials, the rate of infection was 1.52 per patient year
in the adalimumab treated patients and 1.40 per patient year in the
placebo and active control-treated patients; in the nine controlled
trials, 29 malignancies were reported in 2370 adalimumab treated
patients with 1779 patient-years of exposure (16.3 per 1000 patient
years), and 6 malignancies were reported in 1309 control treated
patients observed with 872 patient-years of exposure (6.9 per 1000
patient years); this included 2 lymphomas in the adalimumab treated
patients (1.1 per 1000 patient years) and 1 lymphoma in the control
treated patients (1.1 per 1000 patient years); and two patients out
of 3834 treated with adalimumab in all rheumatoid arthritis,
psoriatic arthritis and ankylosing spondylitis studies developed
clinical signs suggestive of new-onset lupus-like syndrome.
[0084] In one embodiment of the invention, the TNF.alpha. inhibitor
is selected from the group consisting of an anti-TNF.alpha.
antibody, or an antigen-binding portion thereof, a TNF fusion
protein, or a recombinant TNF binding protein. In one embodiment,
the TNF fusion protein is etanercept. In another embodiment of the
invention, the anti-TNF.alpha. antibody, or antigen-binding portion
thereof, is selected from the group consisting of a chimeric
antibody, a humanized antibody, and a multivalent antibody.
[0085] In one embodiment of the invention, the anti-TNF.alpha.
antibody, or antigen-binding portion thereof, is a human
antibody.
[0086] In another embodiment, the anti-TNF.alpha. antibody, or
antigen-binding portion thereof, is an isolated human antibody that
dissociates from human TNF.alpha. with a K.sub.d of
1.times.10.sup.-8 M or less and a K.sub.off rate constant of
1.times.10.sup.-3 s.sup.-1 or less, both determined by surface
plasmon resonance, and neutralizes human TNF.alpha. cytotoxicity in
a standard in vitro L929 assay with an IC.sub.50 of
1.times.10.sup.-7 M or less.
[0087] In one embodiment of the invention, the anti-TNF.alpha.
antibody is an isolated human antibody, or antigen-binding portion
thereof, with the following characteristics:
[0088] a) dissociates from human TNF.alpha. with a K.sub.off rate
constant of 1.times.10.sup.-3 s.sup.-1 or less, as determined by
surface plasmon resonance;
[0089] b) has a light chain CDR3 domain comprising the amino acid
sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single
alanine substitution at position 1, 4, 5, 7 or 8 or by one to five
conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8
and/or 9;
[0090] c) has a heavy chain CDR3 domain comprising the amino acid
sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single
alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or
by one to five conservative amino acid substitutions at positions
2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12.
[0091] In one embodiment of the invention, the anti-TNF.alpha.
antibody is an isolated human antibody, or an antigen binding
portion thereof, with a light chain variable region (LCVR)
comprising the amino acid sequence of SEQ ID NO: 1 and a heavy
chain variable region (HCVR) comprising the amino acid sequence of
SEQ ID NO: 2. In one embodiment, the anti-TNF.alpha. antibody, or
antigen-binding portion thereof, is adalimumab.
[0092] In one embodiment, the anti-TNF.alpha. antibody, or
antigen-binding portion thereof, is a 40 mg dose.
[0093] In another embodiment, the anti-TNF.alpha. antibody, or
antigen-binding portion thereof, is administered
subcutaneously.
[0094] The another embodiment of the invention, the anti-TNF.alpha.
antibody, or antigen-binding portion thereof, is infliximab or
golimumab.
[0095] The invention provides a package comprising a TNF.alpha.
inhibitor and a label, in a position which is visible to
prospective purchasers, comprising a printed statement which
informs prospective purchasers that the median apparent clearance
(CL/F) of the TNF.alpha. inhibitor ranges from about 13.2 to about
15.0 mL/hr.
[0096] In one embodiment, the printed statement further informs
prospective purchasers that concomitant therapy with either
immunosuppressant 6 mercaptopurine or azathioprine has slightly
lower or no impact on TNF.alpha. inhibitor CL/F.
[0097] In one embodiment the TNF.alpha. inhibitor is a human
anti-TNF.alpha. antibody, or antigen-binding portion thereof. In
one embodiment of the invention, the anti-TNF.alpha. antibody, or
antigen-binding portion thereof, is an isolated human antibody that
dissociates from human TNF.alpha. with a K.sub.d of
1.times.10.sup.-8 M or less and a K.sub.off rate constant of
1.times.10.sup.-3 s.sup.-1 or less, both determined by surface
plasmon resonance, and neutralizes human TNF.alpha. cytotoxicity in
a standard in vitro L929 assay with an IC.sub.50 of
1.times.10.sup.-7 M or less.
[0098] In another embodiment the anti-TNF.alpha. antibody is an
isolated human antibody, or antigen-binding portion thereof, with
the following characteristics:
[0099] a) dissociates from human TNF.alpha. with a K.sub.off rate
constant of 1.times.10.sup.-3 s.sup.-1 or less, as determined by
surface plasmon resonance;
[0100] b) has a light chain CDR3 domain comprising the amino acid
sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single
alanine substitution at position 1, 4, 5, 7 or 8 or by one to five
conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8
and/or 9;
[0101] c) has a heavy chain CDR3 domain comprising the amino acid
sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single
alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or
by one to five conservative amino acid substitutions at positions
2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12.
[0102] In one embodiment, the anti-TNF.alpha. antibody is an
isolated human antibody, or an antigen binding portion thereof,
with a light chain variable region (LCVR) comprising the amino acid
sequence of SEQ ID NO: 1 and a heavy chain variable region (HCVR)
comprising the amino acid sequence of SEQ ID NO: 2
[0103] In one embodiment, the anti-TNF.alpha. antibody, or
antigen-binding portion thereof, is adalimumab.
[0104] In one embodiment, the anti-TNF.alpha. antibody, or
antigen-binding portion thereof, is a 40 mg dose.
[0105] The invention also includes a label which indicates warnings
and precautions regarding the use of the TNF.alpha. inhibitor. In
one embodiment, the information provided in the label describes
malignancies. In another embodiment, the label of the invention may
indicate during the controlled portions of TNF.alpha. inhibitor
trials in patients with rheumatoid arthritis, psoriatic arthritis,
ankylosing spondylitis, and Crohn's disease, malignancies, other
than lymphoma and non-melanoma skin cancer, were observed at a rate
(95% confidence interval) of 0.6 (0.3, 1.0)/100 patient-years among
2887 adalimumab-treated patients versus a rate of 0.4 (0.2,
1.1)/100 patient-years among 1570 control patients (median duration
of treatment of 5.7 months for adalimumab-treated patients and 5.5
months for control-treated patients). In another embodiment, the
label of the invention indicates that the size of the control group
and limited duration of the controlled portions of studies
precludes the ability to draw firm conclusions. In one embodiment,
the label indicates that in the controlled and uncontrolled
open-label portions of the clinical trials of the TNF.alpha.
inhibitor, the more frequently observed malignancies, other than
lymphoma and non-melanoma skin cancer, were breast, colon,
prostate, lung and melanoma. In one embodiment, the label indicates
that these malignancies in TNF.alpha. inhibitor treated and
control-treated patients were similar in type and number to what
would be expected in the general population. In a further
embodiment, the label indicates that during the controlled portions
of the TNF.alpha. inhibitor rheumatoid arthritis, psoriatic
arthritis, ankylosing spondylitis, and Crohn's disease trials, the
rate (95% confidence interval) of non-melanoma skin cancers was 0.8
(0.47, 1.24)/100 patient-years among adalimumab-treated patients
0.2 (0.05, 0.82)/100 patient-years among control patients. In one
embodiment, the label indicates that the potential role of TNF
blocking therapy in the development of malignancies is not known.
In one embodiment, the label indicates that in the controlled
portions of clinical trials of all the TNF-blocking agents, more
cases of lymphoma have been observed among patients receiving TNF
blockers compared to control patients. In one embodiment, the label
indicates that in controlled trials in patients with rheumatoid
arthritis, psoriatic arthritis, ankylosing spondylitis, and Crohn's
disease, 2 lymphomas were observed among 2887 HUMIRA-treated
patients versus 1 among 1570 control patients. In another
embodiment, the label of the invention indicates that in combining
the controlled and uncontrolled open-label portions of these
clinical trials with a median duration of approximately 2 years,
including 4843 patients and over 13,000 patient-years of therapy,
the observed rate of lymphomas is approximately 0.12/100
patient-years, and that this is approximately 3.5-fold higher than
expected in the general population.
[0106] The label of the invention may also contain information
regarding the drug interactions of the TNF.alpha. inhibitor, with
other drugs. In one embodiment, the label indicates that
methotrexate (MTX) reduced adalimumab apparent clearance after
single and multiple dosing by 29% and 44% respectively, in patients
with rheumatoid arthritis.
[0107] In one embodiment, the invention provides a method of
treating a human subject having rheumatoid arthritis (RA)
comprising administering a TNF.alpha. inhibitor to the subject,
wherein the subject has previously failed an anti-TNF.alpha.
therapy comprising administration of an alternate TNF.alpha.
antagonist, e.g. a biologic agent, such as the etanercept or
infliximab. In one embodiment, the alternate TNF.alpha. antagonist
was discontinued for a reason selected from the group consisting of
no response, lost efficacy, and intolerance.
[0108] The invention also provides a method for monitoring the
effectiveness of a TNF.alpha. inhibitor for the treatment of
rheumatoid arthritis (RA) in a human subject comprising
administering the TNF.alpha. inhibitor to a preselected patient
population having RA; and determining the effectiveness of the
TNF.alpha. inhibitor using a baseline ACR score of the patient
population and an ACR score of the patient population following
administration of the TNF.alpha. inhibitor, wherein an ACR20
achieved in about 58-85% of the patient population indicates that
the TNF.alpha. inhibitor is effective at treating RA.
[0109] The invention also provides a method for monitoring the
effectiveness of a TNF.alpha. inhibitor for the treatment of RA in
a human subject comprising administering the TNF.alpha. inhibitor
to a preselected patient population having RA; and determining the
effectiveness of the TNF.alpha. inhibitor using a baseline ACR
score of the patient population and an ACR score of the patient
population following administration of the TNF.alpha. inhibitor,
wherein an ACR50 achieved in about 30-62% of the patient population
indicates that the TNF.alpha. inhibitor is effective at treating
RA.
[0110] The invention also provides a method for monitoring the
effectiveness of a TNF.alpha. inhibitor for the treatment of RA in
a human subject comprising administering the TNF.alpha. inhibitor
to a preselected patient population having RA; and determining the
effectiveness of the TNF.alpha. inhibitor using a baseline ACR
score of the patient population and an ACR score of the patient
population following administration of the TNF.alpha. inhibitor,
wherein an ACR70 achieved in about 12-38% of the patient population
indicates that the TNF.alpha. inhibitor is effective at treating
RA.
[0111] The invention further provides a method for monitoring the
effectiveness of a TNF.alpha. inhibitor for the treatment of RA in
a human subject comprising administering the TNF.alpha. inhibitor
to a preselected patient population having rheumatoid arthritis;
determining the effectiveness of the TNF.alpha. inhibitor using a
baseline Disease Activity Score (DAS)28 score of the patient
population and a DAS28 score of the patient population following
administration of the TNF.alpha. inhibitor, wherein a mean change
in the DAS28 score of between about -1.9 and -2.8 of the patient
population indicates that the TNF.alpha. inhibitor is effective at
treating RA.
[0112] The invention also provides a method of achieving an early
clinical response in a Hispanic human subject having RA comprising
administering a TNF.alpha. inhibitor such that an early clinical
response in the Hispanic human subject is achieved. In one
embodiment, the Hispanic human subject is Venezuelan. In another
embodiment, the early clinical, response is determined using an
assessment test selected from the group consisting of DAS28, TJC28,
SJC28, HAQ, pain on VAS, ESR, and CRP. In another embodiment, the
early clinical response occurs at about 2 weeks following
administration of the TNF.alpha. inhibitor.
[0113] The invention also provides a method of testing the efficacy
of a TNF.alpha. inhibitor for the rapid improvement of moderate to
severe RA in a Hispanic patient population comprising administering
the TNF.alpha. inhibitor to a preselected Hispanic patient
population having moderate to severe RA; determining the efficacy
of the TNF.alpha. inhibitor using a baseline Health Assessment
Questionnaire (HAQ) score of the patient population and an HAQ
score of the patient population following administration of the
TNF.alpha. inhibitor, wherein a decrease in the mean HAQ score of
at least about -0.5 indicates that the TNF.alpha. inhibitor is
efficacious for the rapid improvement of moderate to severe RA in a
Hispanic patient population.
[0114] The invention further provides a method of testing the
efficacy of a in a Hispanic patient population comprising
administering the TNF.alpha. inhibitor to a preselected Hispanic
patient population having moderate to severe RA; determining the
efficacy of the TNF.alpha. inhibitor using a baseline Health
Assessment Questionnaire (HAQ) score of the patient population and
an HAQ score of the patient population following administration of
the TNF.alpha. inhibitor, wherein a decrease in the mean HAQ score
of at least about -0.5 indicates that the TNF.alpha. inhibitor is
efficacious for the rapid improvement of moderate to severe RA in a
Hispanic patient population.
[0115] The invention includes a method for predicting the efficacy
of a TNF.alpha. inhibitor for improving the quality of life of a
patient having rheumatoid arthritis (RA) in a patient comprising
comparing the baseline DAS28 score of the patient with a DAS28
score of the patient following treatment with the TNF.alpha.
inhibitor, wherein an improvement in the DAS28 indicates that the
TNF.alpha. inhibitor will be effective for improving the quality of
life in the patient. In one embodiment, the patient has severe
RA.
[0116] The invention also includes a method for predicting the
efficacy of a TNF.alpha. inhibitor for the treatment of rheumatoid
arthritis in a subject comprising using a mean baseline score
selected from the group consisting of a global assessment of the
patient's disease activity, pain, function, fatigue, and stiffness,
wherein an improvement selected from the group consisting of an
improvement of at least about 2.4 in the patient global score, an
improvement of at least about 2.8 in the pain score, an improvement
of at least about 2.7 in the function score, an improvement of at
least about 0.8 in the fatigue score, and an improvement of at
least about 1.2 in the stiffness score, at day 1 from baseline,
indicates that the TNF.alpha. inhibitor will be effective for
treating RA in the patient
[0117] The invention further provides an article of manufacture
comprising a packaging material; a TNF.alpha. inhibitor; and a
label or package insert contained within the packaging material
indicating that the standardized mortality rate for the TNF.alpha.
inhibitor was calculated at about 0.67.
[0118] In one embodiment, the invention provides methods, uses, and
compositions for reducing signs and symptoms of rheumatoid
arthritis in a subject. In another embodiment, the invention
provides methods, uses, and compositions for inducing major
clinical response of rheumatoid arthritis in a subject. In another
embodiment, the invention provides methods, uses, and compositions
for inhibiting the progression of structural damage associated with
RA in a subject. In one embodiment, the invention provides methods,
uses, and compositions for improving physical function in adult
patients with moderately to severely active disease.
BRIEF DESCRIPTION OF THE FIGURES
[0119] FIG. 1 graphically depicts Study A's design.
[0120] FIG. 2 shows ACR responses through 18 months in Study B.
[0121] FIG. 3 shows EULAR responses through 18 months in Study
B.
[0122] FIG. 4 shows median C-Reactive Protein Concentrations (mg/L)
over time for patients in the study of example 4.
[0123] FIG. 3 graphically depicts physician and patient assessments
of disease activity and pain over time through 18 months for
patients in the study of example 4.
[0124] FIG. 6 graphically depicts physician and patient assessments
of disease activity and pain over time through 18 months for
patients in the study of example 4.
[0125] FIG. 7 graphically depicts physician and patient assessments
of disease activity and pain over time through 18 months for
patients in the study of example 4.
[0126] FIG. 8 graphically depicts the disposition of patients
treated with adalimumab 40 mg eow for patients in the study of
example 5.
[0127] FIG. 9 graphically depicts the percent of patients
continuing on adalimumab treatment from first dose for patients in
the study of example 5.
[0128] FIG. 10 shows disease activity and functional disability
scores (TJC68 and SJC66) by ACR20 response for patients in the
study of example 5.
[0129] FIG. 11 shows disease activity and functional disability
scores (DAS28 and HAQ Disability Index) by ACR20 response for
patients in the study of example 5.
[0130] FIG. 12 shows disease activity and functional disability
scores (CRP) by ACR20 response for patients in the study of example
5.
[0131] FIG. 13 shows ACR response rates for patients in the study
of example 5.
[0132] FIG. 14 shows the study design of the study in example
6.
[0133] FIG. 15 shows Median Tender Joint Count (TJC28) through week
12 by DMARD combinations with adalimumab for patients in the study
of example 9.
[0134] FIG. 16 shows Median Swollen Joint Count (SJC28) at week 12
by DMARD combinations with adalimumab for patients in the study of
example 9.
[0135] FIG. 17 shows Study C's Design.
[0136] FIG. 18 shows the disposition of the study for patients in
the study of example 11.
[0137] FIG. 19 depicts the Model Pathway.
[0138] FIG. 20 graphically depicts the study design of the study
described in example 12.
[0139] FIG. 21 describes an overview of the Study D design
study.
[0140] FIG. 22 describes the study disposition.
[0141] FIG. 23 shows the time course of mean change in e-diary
assessments to week 12.
[0142] FIG. 24 shows the effect of adalimumab treatment on patient
pain,
[0143] FIG. 25 shows the effect of adalimumab treatment on
functional disability.
[0144] FIG. 26 shows the effect of adalimumab treatment on
fatigue.
[0145] FIG. 27 shows the effect of adalimumab treatment on morning
stiffness severity.
[0146] FIG. 28 shows the effect of adalimumab treatment on patient
global.
[0147] FIG. 29 shows the enrollment of study participants.
[0148] FIG. 30 shows the correlation of RADAI and DAS28 Scores
after 6 Months of Adalimumab Therapy (N=100).
[0149] FIG. 31 depicts the composition of the study population with
regard to preceding dose-finding studies. *Only study DE011/DE026
comprised 26 weeks; other studies had different durations before
enrollment in DE033.
[0150] FIG. 32 depicts the change from baseline in Functional
Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue)
scores in the DE026 subgroup over 3 years (n=99). *P<0.001 vs.
baseline. .sup..dagger.P<0.01 vs. placebo. Last observation
carried forward, eow=every other week; MCID=minimum clinically
important difference; SEM=standard error of the mean.
[0151] FIG. 33 depicts the change from baseline in health utility
index (HUI3) scores in the DE026 subgroup over 3 years (n=99).
*P<0.001 vs. baseline. .sup..dagger.P<0.05 vs. placebo. Last
observation carried forward. eow=every other week; MCID=minimum
clinically important difference; SEM=standard error of the
mean.
DETAILED DESCRIPTION OF THE INVENTION
I. Definitions
[0152] The term "human TNF.alpha." (abbreviated herein as
hTNF.alpha., or simply hTNF), as used herein, is intended to refer
to a human cytokine that exists as a 17 kD secreted form and a 26
kD membrane associated form, the biologically active form of which
is composed of a trimer of noncovalently bound 17 kD molecules. The
structure of hTNF.alpha. is described further in, for example,
Pennica, D., et al. (1984) Nature 312:724-729; Davis, J. M., et al.
(1987) Biochemistry 26:1322-1326; and Jones, E. Y., et al. (1989)
Nature 338:225-228. The term human TNF.alpha. is intended to
include recombinant human TNF.alpha. (rhTNF.alpha.), which can be
prepared by standard recombinant expression methods or purchased
commercially (R & D Systems, Catalog No. 210-TA, Minneapolis,
Minn.). TNF.alpha. is also referred to as TNF.
[0153] The term "TNF.alpha. inhibitor" includes agents which
interfere with TNF.alpha. activity. The term also includes each of
the anti-TNF.alpha. human antibodies and antibody portions
described herein as well as those described in U.S. Pat. Nos.
6,090,382; 6,258,562; 6,509,015, and in U.S. patent application
Ser. Nos. 09/801,185 and 10/302,356. In one embodiment, the
TNF.alpha. inhibitor used in the invention is an anti-TNF.alpha.
antibody, or a fragment thereof, including infliximab
(Remicade.RTM., Johnson and Johnson; described in U.S. Pat. No.
5,656,272, incorporated by reference herein), CDP571 (a humanized
monoclonal anti-TNF-alpha IgG4 antibody), CDP 870 (a humanized
monoclonal anti-TNF-alpha antibody fragment), an anti-TNF dAb
(Peptech), CNTO 148 (golimumab; Medarex and Centocor, see WO
02/12502), and adalimumab (HUMIRA.RTM. Abbott Laboratories, a human
anti-TNF mAb, described in U.S. Pat. No. 6,090,382 as D2E7).
Additional TNF antibodies which may be used in the invention are
described in U.S. Pat. Nos. 6,593,458; 6,498,237; 6,451,983; and
6,448,380, each of which is incorporated by reference herein. In
another embodiment, the TNF.alpha. inhibitor is a TNF fusion
protein, e.g., etanercept (Enbrel.RTM., Amgen; described in WO
91/03553 and WO 09/406476, incorporated by reference herein). In
another embodiment, the TNF.alpha. inhibitor is a recombinant TNF
binding protein (r-TBP-1) (Serono).
[0154] The term "antibody", as used herein, is intended to refer to
immunoglobulin molecules comprised of four polypeptide chains, two
heavy (H) chains and two light (L) chains inter-connected by
disulfide bonds. Each heavy chain is comprised of a heavy chain
variable region (abbreviated herein as HCVR or VH) and a heavy
chain constant region. The heavy chain constant region is comprised
of three domains, CH1, CH2 and CH3. Each light chain is comprised
of a light chain variable region (abbreviated herein as LCVR or VL)
and a light chain constant region. The light chain constant region
is comprised of one domain, CL. The VH and VL regions can be
further subdivided into regions of hypervariability, termed
complementarity determining regions (CDR), interspersed with
regions that are more conserved, termed framework regions (FR).
Each VH and VL is composed of three CDRs and four FRs, arranged
from amino-terminus to carboxy-terminus in the following order:
FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The antibodies of the
invention are described in further detail in U.S. Pat. Nos.
6,090,382; 6,258,562; and 6,509,015, each of which is incorporated
herein by reference in its entirety.
[0155] The term "antigen-binding portion" or "antigen-binding
fragment" of an antibody (or simply "antibody portion"), as used
herein, refers to one or more fragments of an antibody that retain
the ability to specifically bind to an antigen (e.g., hTNF.alpha.).
It has been shown that the antigen-binding function of an antibody
can be performed by fragments of a full-length antibody. Binding
fragments include Fab, Fab', F(ab').sub.2, Fabc, Fv, single chains,
and single-chain antibodies. Examples of binding fragments
encompassed within the term "antigen-binding portion" of an
antibody include (i) a Fab fragment, a monovalent fragment
consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab').sub.2
fragment, a bivalent fragment comprising two Fab fragments linked
by a disulfide bridge at the hinge region; (iii) a Fd fragment
consisting of the VH and CH1 domains; (iv) a Fv fragment consisting
of the VL and VH domains of a single arm of an antibody, (v) a dAb
fragment (Ward et al. (1989) Nature 341:544-546), which consists of
a VH domain; and (vi) an isolated complementarity determining
region (CDR). Furthermore, although the two domains of the Fv
fragment, VL and VH, are coded for by separate genes, they can be
joined, using recombinant methods, by a synthetic linker that
enables them to be made as a single protein chain in which the VL
and VH regions pair to form monovalent molecules (known as single
chain Fv (scFv); see e.g., Bird et al. (1988) Science 24:423-426;
and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883).
Such single chain antibodies are also intended to be encompassed
within the term "antigen-binding portion" of an antibody. Other
forms of single chain antibodies, such as diabodies are also
encompassed. Diabodies are bivalent, bispecific antibodies in which
VH and VL domains are expressed on a single polypeptide chain, but
using a linker that is too short to allow for pairing between the
two domains on the same chain, thereby forcing the domains to pair
with complementary domains of another chain and creating two
antigen binding sites (see e.g., Holliger et al. (1993) Proc. Natl.
Acad. Sci. USA 90:6444-6448; Poljak et al. (1994) Structure
2:1121-1123). The antibody portions of the invention are described
in further detail in U.S. Pat. Nos. 6,090,382, 6,258,562,
6,509,015, each of which is incorporated herein by reference in its
entirety.
[0156] Still further, an antibody or antigen-binding portion
thereof may be part of a larger immunoadhesion molecules, formed by
covalent or noncovalent association of the antibody or antibody
portion with one or more other proteins or peptides. Examples of
such immunoadhesion molecules include use of the streptavidin core
region to make a tetrameric scFv molecule (Kipriyanov, S. M., et
al. (1995) Human Antibodies and Hybridoma 6:93-101) and use of a
cysteine residue, a marker peptide and a C-terminal polyhistidine
tag to make bivalent and biotinylated scFv molecules (Kipriyanov,
S. M., et al. (1994) Mol. Immunol. 31:1047-1058). Antibody
portions, such as Fab and F(ab').sub.2 fragments, can be prepared
from whole antibodies using conventional techniques, such as papain
or pepsin digestion, respectively, of whole antibodies. Moreover,
antibodies, antibody portions and immunoadhesion molecules can be
obtained using standard recombinant DNA techniques, as described
herein.
[0157] A "conservative amino acid substitution", as used herein, is
one in which one amino acid residue is replaced with another amino
acid residue having a similar side chain. Families of amino acid
residues having similar side chains have been defined in the art,
including basic side chains (e.g., lysine, arginine, histidine),
acidic side chains (e.g. aspartic acid, glutamic acid), uncharged
polar side chains (e.g., glycine, asparagine, glutamine, serine,
threonine, tyrosine, cysteine), nonpolar side chains (e.g.,
alanine, valine, leucine, isoleucine, proline, phenylalanine,
methionine, tryptophan), beta-branched side chains (e.g.,
threonine, valine, isoleucine) and aromatic side chains (e.g.,
tyrosine, phenylalanine, tryptophan, histidine).
[0158] "Chimeric antibodies" refers to antibodies wherein one
portion of each of the amino acid sequences of heavy and light
chains is homologous to corresponding sequences in antibodies
derived from a particular species or belonging to a particular
class, while the remaining segment of the chains is homologous to
corresponding sequences from another species. In one embodiment,
the invention features a chimeric antibody or antigen-binding
fragment, in which the variable regions of both light and heavy
chains mimics the variable regions of antibodies derived from one
species of mammals, while the constant portions are homologous to
the sequences in antibodies derived from another species. In a
preferred embodiment of the invention, chimeric antibodies are made
by grafting CDRs from a mouse antibody onto the framework regions
of a human antibody.
[0159] "Humanized antibodies" refer to antibodies which comprise at
least one chain comprising variable region framework residues
substantially from a human antibody chain (referred to as the
acceptor immunoglobulin or antibody) and at least one
complementarity determining region (CDR) substantially from a
non-human-antibody (e.g., mouse). In addition to the grafting of
the CDRs, humanized antibodies typically undergo further
alterations in order to improve affinity and/or immunogenicity.
[0160] The term "multivalent antibody" refers to an antibody
comprising more than one antigen recognition site. For example, a
"bivalent" antibody has two antigen recognition sites, whereas a
"tetravalent" antibody has four antigen recognition sites. The
terms "monospecific", "bispecific", "trispecific", "tetraspecific",
etc. refer to the number of different antigen recognition site
specificities (as opposed to the number of antigen recognition
sites) present in a multivalent antibody. For example, a
"monospecific" antibody's antigen recognition sites all bind the
same epitope. A "bispecific" or "dual specific" antibody has at
least one antigen recognition site that binds a first epitope and
at least one antigen recognition site that binds a second epitope
that is different from the first epitope. A "multivalent
monospecific" antibody has multiple antigen recognition sites that
all bind the same epitope. A "multivalent bispecific" antibody has
multiple antigen recognition sites, some number of which bind a
first epitope and some number of which bind a second epitope that
is different from the first epitope
[0161] The term "human antibody", as used herein, is intended to
include antibodies having variable and constant regions derived
from human germline immunoglobulin sequences. The human antibodies
of the invention may include amino acid residues not encoded by
human germline immunoglobulin sequences (e.g., mutations introduced
by random or site-specific mutagenesis in vitro or by somatic
mutation in vivo), for example in the CDRs and in particular CDR3.
However, the term "human antibody", as used herein, is not intended
to include antibodies in which CDR sequences derived from the
germline of another mammalian species, such as a mouse, have been
grafted onto human framework sequences.
[0162] The term "recombinant human antibody", as used herein, is
intended to include all human antibodies that are prepared,
expressed, created or isolated by recombinant means, such as
antibodies expressed using a recombinant expression vector
transfected into a host cell (described further below), antibodies
isolated from a recombinant, combinatorial human antibody library
(described further below), antibodies isolated from an animal
(e.g., a mouse) that is transgenic for human immunoglobulin genes
(see e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287) or
antibodies prepared, expressed, created or isolated by any other
means that involves splicing of human immunoglobulin gene sequences
to other DNA sequences. Such recombinant human antibodies have
variable and constant regions derived from human germline
immunoglobulin sequences. In certain embodiments, however, such
recombinant human antibodies are subjected to in vitro mutagenesis
(or, when an animal transgenic for human Ig sequences is used, in
vivo somatic mutagenesis) and thus the amino acid sequences of the
VH and VL regions of the recombinant antibodies are sequences that,
while derived from and related to human germline VH and VL
sequences, may not naturally exist within the human antibody
germline repertoire in vivo.
[0163] Such chimeric, humanized, human, and dual specific
antibodies can be produced by recombinant DNA techniques known in
the art, for example using methods described in PCT International
Application No. PCT/US86/02269; European Patent Application No.
184,187; European Patent Application No. 171,496; European Patent
Application No. 173,494; PCT International Publication No. WO
86/01533; U.S. Pat. No. 4,816,567; European Patent Application No.
125,023; Better et al. (1988) Science 240:1041-1043; Liu et al.
(1987) Proc. Natl. Acad. Sci. USA 84:3439-3443; Liu et al. (1987)
J. Immunol. 139:3521-3526; Sun et al. (1987) Proc. Natl. Acad. Sci.
USA 84:214-218; Nishimura et al. (1987) Cancer Res. 47:999-1005;
Wood et al. (1985) Nature 314:446-449; Shaw et al. (1988) J. Natl.
Cancer Inst. 80:1553-1559); Morrison (1985) Science 229:1202-1207;
Oi et al. (1986) BioTechniques 4:214; U.S. Pat. No. 5,225,539;
Jones et al. (1986) Nature 321:552-525; Verhoeyan et al. (1988)
Science 239:1534; and Beidler et al. (1988) J. Immunol.
141:4053-4060, Queen et al., Proc. Natl. Acad. Sci. USA
86:10029-10033 (1989), U.S. Pat. No. 5,530,101, U.S. Pat. No.
5,585,089, U.S. Pat. No. 5,693,761, U.S. Pat. No. 5,693,762, Selick
et al., WO 90/07861, and Winter, U.S. Pat. No. 5,225,539.
[0164] An "isolated antibody", as used herein, is intended to refer
to an antibody that is substantially free of other antibodies
having different antigenic specificities (e.g., an isolated
antibody that specifically binds hTNF.alpha. is substantially free
of antibodies that specifically bind antigens other than
hTNF.alpha.). An isolated antibody that specifically binds
hTNF.alpha. may, however, have cross-reactivity to other antigens,
such as TNF.alpha. molecules from other species. Moreover, an
isolated antibody may be substantially free of other cellular
material and/or chemicals.
[0165] A "neutralizing antibody", as used herein (or an "antibody
that neutralized hTNF.alpha. activity"), is intended to refer to an
antibody whose binding to hTNF.alpha. results in inhibition of the
biological activity of hTNF.alpha.. This inhibition of the
biological activity of hTNF.alpha. can be assessed by measuring one
or more indicators of hTNF.alpha. biological activity, such as
hTNF.alpha.-induced cytotoxicity (either in vitro or in vivo),
hTNF.alpha.-induced cellular activation and hTNF.alpha. binding to
hTNF.alpha. receptors. These indicators of hTNF.alpha. biological
activity can be assessed by one or more of several standard in
vitro or in vivo assays known in the art (see U.S. Pat. No.
6,090,382). Preferably, the ability of an antibody to neutralize
hTNF.alpha. activity is assessed by inhibition of
hTNF.alpha.-induced cytotoxicity of L929 cells. As an additional or
alternative parameter of hTNF.alpha. activity, the ability of an
antibody to inhibit hTNF.alpha. t-induced expression of ELAM-1 on
HUVEC, as a measure of hTNF.alpha.-induced cellular activation, can
be assessed.
[0166] The term "surface plasmon resonance", as used herein, refers
to an optical phenomenon that allows for the analysis of real-time
biospecific interactions by detection of alterations in protein
concentrations within a biosensor matrix, for example using the
BIAcore system (Pharmacia Biosensor AB, Uppsala, Sweden and
Piscataway, N.J.). For further descriptions, see Example 1 of U.S.
Pat. No. 6,258,562 and Jonsson et al. (1993) Ann. Biol. Clin.
51:19; Jonsson et al. (1991) Biotechniques 11:620-627; Johnsson et
al. (1995) J. Mol. Recognit. 8:125; and Johnnson et al. (1991)
Anal. Biochem. 198:268.
[0167] The term "K.sub.off", as used herein, is intended to refer
to the off rate constant for dissociation of an antibody from the
antibody/antigen complex.
[0168] The term "K.sub.d", as used herein, is intended to refer to
the dissociation constant of a particular antibody-antigen
interaction.
[0169] The term "IC.sub.50" as used herein, is intended to refer to
the concentration of the inhibitor required to inhibit the
biological endpoint of interest, e.g., neutralize cytotoxicity
activity.
[0170] The term "dose," as used herein, refers to an amount of
TNF.alpha. inhibitor which is administered to a subject.
[0171] The term "dosing", as used herein, refers to the
administration of a substance (e.g., an anti-TNF.alpha. antibody)
to achieve a therapeutic objective (e.g., treatment of rheumatoid
arthritis).
[0172] A "dosing regimen" describes a treatment schedule for a
TNF.alpha. inhibitor, e.g., a treatment schedule over a prolonged
period of time and/or throughout the course of treatment, e.g.
administering a first dose of a TNF.alpha. inhibitor at week 0
followed by a 20 second dose of a TNF.alpha. inhibitor on a
biweekly dosing regimen.
[0173] The terms "biweekly dosing regimen", "biweekly dosing", and
"biweekly administration", as used herein, refer to the time course
of administering a substance (e.g., an anti-TNF.alpha. antibody) to
a subject to achieve a therapeutic objective, e.g, throughout the
course of treatment. The biweekly dosing regimen is not intended to
include a weekly dosing regimen. Preferably, the substance is
administered every 9-19 days, more preferably, every 11-17 days,
even more preferably, every 13-15 days, and most preferably, every
14 days. In one embodiment, the biweekly dosing regimen is
initiated in a subject at week 0 of treatment. In another
embodiment, a maintenance dose is administered on a biweekly dosing
regimen. In one embodiment, both the loading and maintenance doses
are administered according to a biweekly dosing regimen. In one
embodiment, biweekly dosing includes a dosing regimen wherein doses
of a TNF.alpha. inhibitor are administered to a subject every other
week beginning at week 0. In one embodiment, biweekly dosing
includes a dosing regimen where doses of a TNF.alpha. inhibitor are
administered to a subject every other week consecutively for a
given time period, e.g., 4 weeks, 8 weeks, 16, weeks, 24 weeks, 26
weeks, 32 weeks, 36 weeks, 42 weeks, 48 weeks, 52 weeks, 56 weeks,
etc. Biweekly dosing methods are also described in US 20030235585,
incorporated by reference herein.
[0174] The term "combination" as in the phrase "a first agent in
combination with a second agent" includes co-administration of a
first agent and a second agent, which for example may be dissolved
or intermixed in the same pharmaceutically acceptable carrier, or
administration of a first agent, followed by the second agent, or
administration of the second agent, followed by the first agent.
The present invention, therefore, includes methods of combination
therapeutic treatment and combination pharmaceutical
compositions.
[0175] The term "concomitant" as in the phrase "concomitant
therapeutic treatment" includes administering an agent in the
presence of a second agent. A concomitant therapeutic treatment
method includes methods in which the first, second, third, or
additional agents are co-administered. A concomitant therapeutic
treatment method also includes methods in which the first or
additional agents are administered in the presence of a second or
additional agents, wherein the second or additional agents, for
example, may have been previously administered. A concomitant
therapeutic treatment method may be executed step-wise by different
actors. For example, one actor may administer to a subject a first
agent and a second actor may to administer to the subject a second
agent, and the administering steps may be executed at the same
time, or nearly the same time, or at distant times, so long as the
first agent (and additional agents) are after administration in the
presence of the second agent (and additional agents). The actor and
the subject may be the same entity (e.g., human).
[0176] The term "combination therapy", as used herein, refers to
the administration of two or more therapeutic substances, e.g., an
anti-TNF.alpha. antibody and another drug. The other drug(s) may be
administered concomitant with, prior to, or following the
administration of an anti-TNF.alpha. antibody.
[0177] The term "treatment," as used within the context of the
present invention, is meant to include therapeutic treatment, as
well as prophylactic or suppressive measures, for the treatment of
rheumatoid arthritis. For example, the term treatment may include
administration of a TNF.alpha. inhibitor prior to or following the
onset of rheumatoid arthritis thereby preventing or removing signs
of the disease or disorder. As another example, administration of a
TNF.alpha. inhibitor after clinical manifestation of rheumatoid
arthritis to combat the symptoms and/or complications and disorders
associated with rheumatoid arthritis comprises "treatment" of the
disease. Further, administration of the agent after onset and after
clinical symptoms and/or complications have developed where
administration affects clinical parameters of the disease or
disorder and perhaps amelioration of the disease, comprises
"treatment" of rheumatoid arthritis. In one embodiment, treatment
of rheumatoid arthritis in a subject comprises reducing signs and
symptoms. In another embodiment, treatment of rheumatoid arthritis
in a subject comprises inducing major clinical response of
rheumatoid arthritis. In another embodiment, treatment of
rheumatoid arthritis in a subject comprises inhibiting the
progression of structural damage. In one embodiment, treatment of
rheumatoid arthritis comprises improving physical function in adult
patients with moderately to severely active disease.
[0178] Those "in need of treatment" include mammals, such as
humans, already having rheumatoid arthritis, including those in
which the disease or disorder is to be prevented.
[0179] Various aspects of the invention are described in further
detail herein.
[0180] The invention provides improved uses and compositions for
treating rheumatoid arthritis with a TNF.alpha. inhibitor, e.g., a
human TNF.alpha. antibody, or an antigen-binding portion thereof.
Compositions and articles of manufacture, including kits, relating
to the methods and uses for treating rheumatoid arthritis are also
contemplated as part of the invention.
II. TNF Inhibitor
[0181] A TNF.alpha. inhibitor which is used in the methods and
compositions of the invention includes any agent which interferes
with TNF.alpha. activity. In a preferred embodiment, the TNF.alpha.
inhibitor can neutralize TNF.alpha. activity, particularly
detrimental TNF.alpha. activity which is associated with rheumatoid
arthritis, and related complications and symptoms.
[0182] In one embodiment, the TNF.alpha. inhibitor used in the
invention is an TNF.alpha. antibody (also referred to herein as a
TNF.alpha. antibody), or an antigen-binding fragment thereof,
including chimeric, humanized, and human antibodies. Examples of
TNF.alpha. antibodies which may be used in the invention include,
but not limited to, infliximab (Remicade.RTM., Johnson and Johnson;
described in U.S. Pat. No. 5,656,272, incorporated by reference
herein), CDP571 (a humanized monoclonal anti-TNF-alpha IgG4
antibody), CDP 870 (a humanized monoclonal anti-TNF-alpha antibody
fragment), an anti-TNF, dAb (Peptech), CNTO 148 (golimumab; Medarex
and Centocor, see WO 02/12502), and adalimumab (HUMIRA.RTM. Abbott
Laboratories, a human anti-TNF mAb, described in U.S. Pat. No.
6,090,382 as D2E7). Additional TNF antibodies which may be used in
the invention are described in U.S. Pat. Nos. 6,593,458; 6,498,237;
6,451,983; and 6,448,380, each of which is incorporated by
reference herein.
[0183] Other examples of TNF.alpha. inhibitors which may be used in
the methods and compositions of the invention include etanercept
(Enbrel, described in WO 91/03553 and WO 09/406476), soluble TNF
receptor Type I, a pegylated soluble TNF receptor Type I (PEGs
TNF-R1), p55TNFR1gG (Lenercept), and recombinant TNF binding
protein (r-TBP-1) (Serono).
[0184] In one embodiment, the term "TNF.alpha. inhibitor" excludes
infliximab. In one embodiment, the term "TNF.alpha. inhibitor"
excludes adalimumab. In another embodiment, the term "TNF.alpha.
inhibitor" excludes adalimumab and infliximab.
[0185] In one embodiment, the term "TNF.alpha. inhibitor" excludes
etanercept, and, optionally, adalimumab, infliximab, and adalimumab
and infliximab.
[0186] In one embodiment, the term "TNF.alpha. antibody" excludes
infliximab. In one embodiment, the term "TNF.alpha. antibody"
excludes adalimumab. In another embodiment, the term "TNF.alpha.
antibody" excludes adalimumab and infliximab.
[0187] In one embodiment, the invention features uses and
composition for treating or determining the efficacy of a
TNF.alpha. inhibitor for the treatment of rheumatoid arthritis,
wherein the TNF.alpha. antibody is an isolated human antibody, or
antigen-binding portion thereof, that binds to human TNF.alpha.
with high affinity and a low off rate, and also has a high
neutralizing capacity. Preferably, the human antibodies used in the
invention are recombinant, neutralizing human anti-hTNF.alpha.
antibodies. The most preferred recombinant, neutralizing antibody
of the invention is referred to herein as D2E7, also referred to as
HUMIRA.RTM. or adalimumab (the amino acid sequence of the D2E7 VL
region is shown in SEQ ID NO: 1; the amino acid sequence of the
D2E7 VH region is shown in SEQ ID NO: 2). The properties of D2E7
(adalimumab/HUMIRA.RTM.) have been described in Salfeld et al.,
U.S. Pat. Nos. 6,090,382, 6,258,562, and 6,509,015, which are each
incorporated by reference herein. The methods of the invention may
also be performed using chimeric and humanized murine
anti-hTNF.alpha. antibodies which have undergone clinical testing
for treatment of rheumatoid arthritis (see e.g., Elliott, M. J., et
al. (1994) Lancet 344:1125-1127; Elliot, M. J., et al. (1994)
Lancet 344:1105-1110; Rankin, E. C., et al. (1995) Br. J.
Rheumatol. 34:334-342).
[0188] In one embodiment, the method of the invention includes
determining the efficacy of D2E7 antibodies and antibody portions,
D2E7-related antibodies and antibody portions, or other human
antibodies and antibody portions with equivalent properties to
D2E7, such as high affinity binding to hTNF.alpha. with low
dissociation kinetics and high neutralizing capacity, for the
treatment of rheumatoid arthritis. In one embodiment, the invention
provides treatment with an isolated human antibody, or an
antigen-binding portion thereof, that dissociates from human
TNF.alpha. with a K.sub.d of 1.times.10.sup.-8 M or less and a
K.sub.off rate constant of 1.times.10.sup.-3 s.sup.-1 or less, both
determined by surface plasmon resonance, and neutralizes human
TNF.alpha. cytotoxicity in a standard in vitro L929 assay with an
IC.sub.50 of 1.times.10.sup.-7 M or less. More preferably, the
isolated human antibody, or antigen-binding portion thereof,
dissociates from human TNF.alpha. with a K.sub.off of
5.times.10.sup.-4 s.sup.-1 or less, or even more preferably, with a
K.sub.off of 1.times.10.sup.-4 s.sup.-1 or less. More preferably,
the isolated human antibody, or antigen-binding portion thereof,
neutralizes human TNF.alpha. cytotoxicity in a standard in vitro
L929 assay with an IC.sub.50 of 1.times.10.sup.-8 M or less, even
more preferably with an IC.sub.50 of 1.times.10.sup.-9 M or less
and still more preferably with an IC.sub.50 of 1.times.10.sup.-10 M
or less. In a preferred embodiment, the antibody is an isolated
human recombinant antibody, or an antigen-binding portion
thereof.
[0189] It is well known in the art that antibody heavy and light
chain CDR3 domains play an important role in the binding
specificity/affinity of an antibody for an antigen. Accordingly, in
another aspect, the invention pertains to treating Crohn's disease
by administering human antibodies that have slow dissociation
kinetics for association with hTNF.alpha. and that have light and
heavy chain CDR3 domains that structurally are identical to or
related to those of D2E7. Position 9 of the D2E7 VL CDR3 can be
occupied by Ala or Thr without substantially affecting the
K.sub.off. Accordingly, a consensus motif for the D2E7 VL CDR3
comprises the amino acid sequence: Q-R-Y-N-R-A-P-Y-(T/A) (SEQ ID
NO: 3). Additionally, position 12 of the D2E7 VH CDR3 can be
occupied by Tyr or Asn, without substantially affecting the
K.sub.off. Accordingly, a consensus motif for the D2E7 VH CDR3
comprises the amino acid sequence: V-S-Y-L-S-T-A-S-S-L-D-(Y/N) (SEQ
ID NO: 4). Moreover, as demonstrated in Example 2 of U.S. Pat. No.
6,090,382, the CDR3 domain of the D2E7 heavy and light chains is
amenable to substitution with a single alanine residue (at position
1, 4, 5, 7 or 8 within the VL CDR3 or at position 2, 3, 4, 5, 6, 8,
9, 10 or 11 within the VH CDR3) without substantially affecting the
K.sub.off. Still further, the skilled artisan will appreciate that,
given the amenability of the D2E7 VL and VH CDR3 domains to
substitutions by alanine, substitution of other amino acids within
the CDR3 domains may be possible while still retaining the low off
rate constant of the antibody, in particular substitutions with
conservative amino acids. Preferably, no more than one to five
conservative amino acid substitutions are made within the D2E7 VL
and/or VH CDR3 domains. More preferably, no more than one to three
conservative amino acid substitutions are made within the D2E7 VL
and/or VH CDR3 domains. Additionally, conservative amino acid
substitutions should not be made at amino acid positions critical
for binding to hTNF.alpha.. Positions 2 and 5 of the D2E7 VL CDR3
and positions 1 and 7 of the D2E7 VH CDR3 appear to be critical for
interaction with hTNF.alpha. and thus, conservative amino acid
substitutions preferably are not made at these positions (although
an alanine substitution at position 5 of the D2E7 VL CDR3 is
acceptable, as described above) (see U.S. Pat. No. 6,090,382).
[0190] Accordingly, in another embodiment, the antibody or
antigen-binding portion thereof preferably contains the following
characteristics:
[0191] a) dissociates from human TNF.alpha. with a K.sub.off rate
constant of 1.times.10.sup.-3 s.sup.-1 or less, as determined by
surface plasmon resonance;
[0192] b) has a light chain CDR3 domain comprising the amino acid
sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single
alanine substitution at position 1, 4, 5, 7 or 8 or by one to five
conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8
and/or 9;
[0193] c) has a heavy chain CDR3 domain comprising the amino acid
sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single
alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or
by one to five conservative amino acid substitutions at positions
2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12.
[0194] More preferably, the antibody, or antigen-binding portion
thereof, dissociates from human TNF.alpha. with a K.sub.off of
5.times.10.sup.-4 s.sup.-1 or less. Even more preferably, the
antibody, or antigen-binding portion thereof, dissociates from
human TNF.alpha. with a K.sub.off of 1.times.10.sup.-4 s.sup.-1 or
less.
[0195] In yet another embodiment, the antibody or antigen-binding
portion thereof preferably contains a light chain variable region
(LCVR) having a CDR3 domain comprising the amino acid sequence of
SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine
substitution at position 1, 4, 5, 7 or 8, and with a heavy chain
variable region (HCVR) having a CDR3 domain comprising the amino
acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a
single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or
11. Preferably, the LCVR further has a CDR2 domain comprising the
amino acid sequence of SEQ ID NO: 5 (i.e., the D2E7 VL CDR2) and
the HCVR further has a CDR2 domain comprising the amino acid
sequence of SEQ ID NO: 6 (i.e., the D2E7 VH CDR2). Even more
preferably, the LCVR further has CDR1 domain comprising the amino
acid sequence of SEQ ID NO: 7 (i.e., the D2E7 VL CDR1) and the HCVR
has a CDR1 domain comprising the amino acid sequence of SEQ ID NO:
8 (i.e., the D2E7 VH CDR1). The framework regions for VL preferably
are from the V.sub..kappa.I human germline family, more preferably
from the A20 human germline Vk gene and most preferably from the
D2E7 VL framework sequences shown in FIGS. 1A and 1B of U.S. Pat.
No. 6,090,382. The framework regions for VH preferably are from the
V.sub.H3 human germline family, more preferably from the DP-31
human germline VH gene and most preferably from the D2E7 VH
framework sequences shown in FIGS. 2A and 2B of U.S. Pat. No.
6,090,382.
[0196] Accordingly, in another embodiment, the antibody or
antigen-binding portion thereof preferably contains a light chain
variable region (LCVR) comprising the amino acid sequence of SEQ ID
NO: 1 (i.e., the D2E7 VL) and a heavy chain variable region (HCVR)
comprising the amino acid sequence of SEQ ID NO: 2 (i.e., the D2E7
VH). In certain embodiments, the antibody comprises a heavy chain
constant region, such as an IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM
or IgD constant region. Preferably, the heavy chain constant region
is an IgG1 heavy chain constant region or an IgG4 heavy chain
constant region. Furthermore, the antibody can comprise a light
chain constant region, either a kappa light chain constant region
or a lambda light chain constant region. Preferably, the antibody
comprises a kappa light chain constant region. Alternatively, the
antibody portion can be, for example, a Fab fragment or a single
chain Fv fragment.
[0197] In still other embodiments, the invention includes uses of
an isolated human antibody, or an antigen-binding portions thereof,
containing D2E7-related VL and VH CDR3 domains. For example,
antibodies, or antigen-binding portions thereof, with a light chain
variable region (LCVR) having a CDR3 domain comprising an amino
acid sequence selected from the group consisting of SEQ ID NO: 3,
SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID
NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19,
SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID
NO: 24, SEQ ID NO: 25 and SEQ ID NO: 26 or with a heavy chain
variable region (HCVR) having a CDR3 domain comprising an amino
acid sequence selected from the group consisting of SEQ ID NO: 4,
SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID
NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 and SEQ ID NO:
35.
[0198] The TNF.alpha. antibody used in the methods and compositions
of the invention may be modified for improved treatment of
rheumatoid arthritis. In some embodiments, the TNF.alpha. antibody
or antigen binding fragments thereof, is chemically modified to
provide a desired effect. For example, pegylation of antibodies and
antibody fragments of the invention may be carried out by any of
the pegylation reactions known in the art, as described, for
example, in the following references: Focus on Growth Factors
3:4-10 (1992); EP 0 154 316; and EP 0 401 384 (each of which is
incorporated by reference herein in its entirety). Preferably, the
pegylation is carried out via an acylation reaction or an
alkylation reaction with a reactive polyethylene glycol molecule
(or an analogous reactive water-soluble polymer). A preferred
water-soluble polymer for pegylation of the antibodies and antibody
fragments of the invention is polyethylene glycol (PEG). As used
herein, "polyethylene glycol" is meant to encompass any of the
forms of PEG that have been used to derivatize other proteins, such
as mono (Cl--ClO) alkoxy- or aryloxy-polyethylene glycol.
[0199] Methods for preparing pegylated antibodies and antibody
fragments of the invention will generally comprise the steps of (a)
reacting the antibody or antibody fragment with polyethylene
glycol, such as a reactive ester or aldehyde derivative of PEG,
under conditions whereby the antibody or antibody fragment becomes
attached to one or more PEG groups, and (b) obtaining the reaction
products. It will be apparent to one of ordinary skill in the art
to select the optimal reaction conditions or the acylation
reactions based on known parameters and the desired result.
[0200] Pegylated antibodies and antibody fragments may generally be
used to treat rheumatoid arthritis by administration of the
TNF.alpha. antibodies and antibody fragments described herein.
Generally the pegylated antibodies and antibody fragments have
increased half-life, as compared to the nonpegylated antibodies and
antibody fragments. The pegylated antibodies and antibody fragments
may be employed alone, together, or in combination with other
pharmaceutical compositions.
[0201] In yet another embodiment of the invention, TNF.alpha.
antibodies or fragments thereof can be altered wherein the constant
region of the antibody is modified to reduce at least one constant
region-mediated biological effector function relative to an
unmodified antibody. To modify an antibody of the invention such
that it exhibits reduced binding to the Fc receptor, the
immunoglobulin constant region segment of the antibody can be
mutated at particular regions necessary for Fc receptor (FcR)
interactions (see e.g., Canfield, S. M. and S. L. Morrison (1991)
J. Exp. Med. 173:1483-1491; and Lund, J. et al. (1991) J. of
Immunol. 147:2657-2662). Reduction in FcR binding ability of the
antibody may also reduce other effector functions which rely on FcR
interactions, such as opsonization and phagocytosis and
antigen-dependent cellular cytotoxicity.
[0202] An antibody or antibody portion used in the methods of the
invention can be derivatized or linked to another functional
molecule (e.g., another peptide or protein). Accordingly, the
antibodies and antibody portions of the invention are intended to
include derivatized and otherwise modified forms of the human
anti-hTNF.alpha. antibodies described herein, including
immunoadhesion molecules. For example, an antibody or antibody
portion of the invention can be functionally linked (by chemical
coupling, genetic fusion, noncovalent association or otherwise) to
one or more other molecular entities, such as another antibody
(e.g., a bispecific antibody or a diabody), a detectable agent, a
cytotoxic agent, a pharmaceutical agent, and/or a protein or
peptide that can mediate associate of the antibody or antibody
portion with another molecule (such as a streptavidin core region
or a polyhistidine tag).
[0203] One type of derivatized antibody is produced by crosslinking
two or more antibodies (of the same type or of different types,
e.g., to create bispecific antibodies). Suitable crosslinkers
include those that are heterobifunctional, having two distinctly
reactive groups separated by an appropriate spacer (e.g.,
m-maleimidobenzoyl-N-hydroxysuccinimide ester) or homobifunctional
(e.g., disuccinimidyl suberate). Such linkers are available from
Pierce Chemical Company, Rockford, Ill.
[0204] Useful detectable agents with which an antibody or antibody
portion of the invention may be derivatized include fluorescent
compounds. Exemplary fluorescent detectable agents include
fluorescein, fluorescein isothiocyanate, rhodamine,
5-dimethylamine-1-napthalenesulfonyl chloride, phycoerythrin and
the like. An antibody may also be derivatized with detectable
enzymes, such as alkaline phosphatase, horseradish peroxidase,
glucose oxidase and the like. When an antibody is derivatized with
a detectable enzyme, it is detected by adding additional reagents
that the enzyme uses to produce a detectable reaction product. For
example, when the detectable agent horseradish peroxidase is
present, the addition of hydrogen peroxide and diaminobenzidine
leads to a colored reaction product, which is detectable. An
antibody may also be derivatized with biotin, and detected through
indirect measurement of avidin or streptavidin binding.
[0205] An antibody, or antibody portion, used in the methods and
compositions of the invention, can be prepared by recombinant
expression of immunoglobulin light and heavy chain genes in a host
cell. To express an antibody recombinantly, a host cell is
transfected with one or more recombinant expression vectors
carrying DNA fragments encoding the immunoglobulin light and heavy
chains of the antibody such that the light and heavy chains are
expressed in the host cell and, preferably, secreted into the
medium in which the host cells are cultured, from which medium the
antibodies can be recovered. Standard recombinant DNA methodologies
are used to obtain antibody heavy and light chain genes,
incorporate these genes into recombinant expression vectors and
introduce the vectors into host cells, such as those described in
Sambrook, Fritsch and Maniatis (eds), Molecular Cloning; A
Laboratory Manual, Second Edition, Cold Spring Harbor, N.Y.,
(1989), Ausubel, F. M. et al. (eds.) Current Protocols in Molecular
Biology, Greene Publishing Associates, (1989) and in U.S. Pat. No.
4,816,397 by Boss et al.
[0206] To express adalimumab (D2E7) or an adalimumab (D2E7)-related
antibody, DNA fragments encoding the light and heavy chain variable
regions are first obtained. These DNAs can be obtained by
amplification and modification of germline light and heavy chain
variable sequences using the polymerase chain reaction (PCR).
Germline DNA sequences for human heavy and light chain variable
region genes are known in the art (see e.g., the "Vbase" human
germline sequence database; see also Kabat, E. A., et al. (1991)
Sequences of Proteins of Immunological Interest, Fifth Edition,
U.S. Department of Health and Human Services, NIH Publication No.
91-3242; Tomlinson, I. M., et al. (1992) "The Repertoire of Human
Germline V.sub.H Sequences Reveals about Fifty Groups of V.sub.H
Segments with Different Hypervariable Loops" J. Mol. Biol.
227:776-798; and Cox, J. P. L. et al. (1994) "A Directory of Human
Germ-line V.sub.78 Segments Reveals a Strong Bias in their Usage"
Eur. J. Immunol. 24:827-836; the contents of each of which are
expressly incorporated herein by reference). To obtain a DNA
fragment encoding the heavy chain variable region of D2E7, or a
D2E7-related antibody, a member of the V.sub.H3 family of human
germline VH genes is amplified by standard PCR. Most preferably,
the DP-31 VH germline sequence is amplified. To obtain a DNA
fragment encoding the light chain variable region of D2E7, or a
D2E7-related antibody, a member of the V.sub..kappa.I family of
human germline VL genes is amplified by standard PCR. Most
preferably, the A20 VL germline sequence is amplified. PCR primers
suitable for use in amplifying the DP-31 germline VH and A20
germline VL sequences can be designed based on the nucleotide
sequences disclosed in the references cited supra, using standard
methods.
[0207] Once the germline VH and VL fragments are obtained, these
sequences can be mutated to encode the D2E7 or D2E7-related amino
acid sequences disclosed herein. The amino acid sequences encoded
by the germline VH and VL DNA sequences are first compared to the
D2E7 or D2E7-related VH and VL amino acid sequences to identify
amino acid residues in the D2E7 or D2E7-related sequence that
differ from germline. Then, the appropriate nucleotides of the
germline DNA sequences are mutated such that the mutated germline
sequence encodes the D2E7 or D2E7-related amino acid sequence,
using the genetic code to determine which nucleotide changes should
be made. Mutagenesis of the germline sequences is carried out by
standard methods, such as PCR-mediated mutagenesis (in which the
mutated nucleotides are incorporated into the PCR primers such that
the PCR product contains the mutations) or site-directed
mutagenesis.
[0208] Moreover, it should be noted that if the "germline"
sequences obtained by PCR amplification encode amino acid
differences in the framework regions from the true germline
configuration (i.e., differences in the amplified sequence as
compared to the true germline sequence, for example as a result of
somatic mutation), it may be desirable to change these amino acid
differences back to the true germline sequences (i.e.,
"backmutation" of framework residues to the germline
configuration).
[0209] Once DNA fragments encoding D2E7 or D2E7-related VH and VL
segments are obtained (by amplification and mutagenesis of germline
VH and VL genes, as described above), these DNA fragments can be
further manipulated by standard recombinant DNA techniques, for
example to convert the variable region genes to full-length
antibody chain genes, to Fab fragment genes or to a scFv gene. In
these manipulations, a VL- or VH-encoding DNA fragment is
operatively linked to another DNA fragment encoding another
protein, such as an antibody constant region or a flexible linker.
The term "operatively linked", as used in this context, is intended
to mean that the two DNA fragments are joined such that the amino
acid sequences encoded by the two DNA fragments remain
in-frame.
[0210] The isolated DNA encoding the VH region can be converted to
a full-length heavy chain gene by operatively linking the
VH-encoding DNA to another DNA molecule encoding heavy chain
constant regions (CH1, CH2 and CH3). The sequences of human heavy
chain constant region genes are known in the art (see e.g., Kabat,
E. A., et al. (1991) Sequences of Proteins of Immunological
Interest, Fifth Edition, U.S. Department of Health and Human
Services, NIH Publication No. 91-3242) and DNA fragments
encompassing these regions can be obtained by standard PCR
amplification. The heavy chain constant region can be an IgG1,
IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region, but most
preferably is an IgG1 or IgG4 constant region. For a Fab fragment
heavy chain gene, the VH-encoding DNA can be operatively linked to
another DNA molecule encoding only the heavy chain CH1 constant
region.
[0211] The isolated DNA encoding the VL region can be converted to
a full-length light chain gene (as well as a Fab light chain gene)
by operatively linking the VL-encoding DNA to another DNA molecule
encoding the light chain constant region, CL. The sequences of
human light chain constant region genes are known in the art (see
e.g., Kabat, E. A., et al. (1991) Sequences of Proteins of
Immunological Interest, Fifth Edition, U.S. Department of Health
and Human Services, NIH Publication No. 91-3242) and DNA fragments
encompassing these regions can be obtained by standard PCR
amplification. The light chain constant region can be a kappa or
lambda constant region, but most preferably is a kappa constant
region.
[0212] To create a scFv gene, the VH- and VL-encoding DNA fragments
are operatively linked to another fragment encoding a flexible
linker, e.g., encoding the amino acid sequence
(Gly.sub.4-Ser).sub.3, such that the VH and VL sequences can be
expressed as a contiguous single-chain protein, with the VL and VH
regions joined by the flexible linker (see e.g., Bird et al. (1988)
Science 242:423-426; Huston et al. (1988) Proc. Natl. Acad. Sci.
USA 85:5879-5883; McCafferty et al., Nature (1990)
348:552-554).
[0213] To express the antibodies, or antibody portions used in the
invention, DNAs encoding partial or full-length light and heavy
chains, obtained as described above, are inserted into expression
vectors such that the genes are operatively linked to
transcriptional and translational control sequences. In this
context, the term "operatively linked" is intended to mean that an
antibody gene is ligated into a vector such that transcriptional
and translational control sequences within the vector serve their
intended function of regulating the transcription and translation
of the antibody gene. The expression vector and expression control
sequences are chosen to be compatible with the expression host cell
used. The antibody light chain gene and the antibody heavy chain
gene can be inserted into separate vector or, more typically, both
genes are inserted into the same expression vector. The antibody
genes are inserted into the expression vector by standard methods
(e.g., ligation of complementary restriction sites on the antibody
gene fragment and vector, or blunt end ligation if no restriction
sites are present). Prior to insertion of the D2E7 or D2E7-related
light or heavy chain sequences, the expression vector may already
carry antibody constant region sequences. For example, one approach
to converting the D2E7 or D2E7-related VH and VL sequences to
full-length antibody genes is to insert them into expression
vectors already encoding heavy chain constant and light chain
constant regions, respectively, such that the VH segment is
operatively linked to the CH segment(s) within the vector and the
VL segment is operatively linked to the CL segment within the
vector. Additionally or alternatively, the recombinant expression
vector can encode a signal peptide that facilitates secretion of
the antibody chain from a host cell. The antibody chain gene can be
cloned into the vector such that the signal peptide is linked
in-frame to the amino terminus of the antibody chain gene. The
signal peptide can be an immunoglobulin signal peptide or a
heterologous signal peptide (i.e., a signal peptide from a
non-immunoglobulin protein).
[0214] In addition to the antibody chain genes, the recombinant
expression vectors of the invention carry regulatory sequences that
control the expression of the antibody chain genes in a host cell.
The term "regulatory sequence" is intended to include promoters,
enhancers and other expression control elements (e.g.,
polyadenylation signals) that control the transcription or
translation of the antibody chain genes. Such regulatory sequences
are described, for example, in Goeddel; Gene Expression Technology:
Methods in Enzymology 185, Academic Press, San Diego, Calif.
(1990). It will be appreciated by those skilled in the art that the
design of the expression vector, including the selection of
regulatory sequences may depend on such factors as the choice of
the host cell to be transformed, the level of expression of protein
desired, etc. Preferred regulatory sequences for mammalian host
cell expression include viral elements that direct high levels of
protein expression in mammalian cells, such as promoters and/or
enhancers derived from cytomegalovirus (CMV) (such as the CMV
promoter/enhancer), Simian Virus 40 (SV40) (such as the SV40
promoter/enhancer), adenovirus, (e.g., the adenovirus major late
promoter (AdMLP)) and polyoma. For further description of viral
regulatory elements, and sequences thereof, see e.g., U.S. Pat. No.
5,168,062 by Stinski, U.S. Pat. No. 4,510,245 by Bell et al. and
U.S. Pat. No. 4,968,615 by Schaffner et al.
[0215] In addition to the antibody chain genes and regulatory
sequences, the recombinant expression vectors used in the invention
may carry additional sequences, such as sequences that regulate
replication of the vector in host cells (e.g., origins of
replication) and selectable marker genes. The selectable marker
gene facilitates selection of host cells into which the vector has
been introduced (see e.g., U.S. Pat. Nos. 4,399,216, 4,634,665 and
5,179,017, all by Axel et al.). For example, typically the
selectable marker gene confers resistance to drugs, such as G418,
hygromycin or methotrexate, on a host cell into which the vector
has been introduced. Preferred selectable marker genes include the
dihydrofolate reductase (DHFR) gene (for use in dhfr.sup.- host
cells with methotrexate selection/amplification) and the neo gene
(for G418 selection).
[0216] For expression of the light and heavy chains, the expression
vector(s) encoding the heavy and light chains is transfected into a
host cell by standard techniques. The various forms of the term
"transfection" are intended to encompass a wide variety of
techniques commonly used for the introduction of exogenous DNA into
a prokaryotic or eukaryotic host cell, e.g., electroporation,
calcium-phosphate precipitation, DEAE-dextran transfection and the
like. Although it is theoretically possible to express the
antibodies of the invention in either prokaryotic or eukaryotic
host cells, expression of antibodies in eukaryotic cells, and most
preferably mammalian host cells, is the most preferred because such
eukaryotic cells, and in particular mammalian cells, are more
likely than prokaryotic cells to assemble and secrete a properly
folded and immunologically active antibody. Prokaryotic expression
of antibody genes has been reported to be ineffective for
production of high yields of active antibody (Boss, M. A. and Wood,
C. R. (1985) Immunology Today 6:12-13).
[0217] Preferred mammalian host cells for expressing the
recombinant antibodies of the invention include Chinese Hamster
Ovary (CHO cells) (including dhfr-CHO cells, described in Urlaub
and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used
with a DHFR selectable marker, e.g., as described in R. J. Kaufman
and P. A. Sharp (1982) Mol. Biol. 159:601-621), NS0 mycloma cells,
COS cells and SP2 cells. When recombinant expression vectors
encoding antibody genes are introduced into mammalian host cells,
the antibodies are produced by culturing the host cells for a
period of time sufficient to allow for expression of the antibody
in the host cells or, more preferably, secretion of the antibody
into the culture medium in which the host cells are grown.
Antibodies can be recovered from the culture medium using standard
protein purification methods.
[0218] Host cells can also be used to produce portions of intact
antibodies, such as Fab fragments or scFv molecules. It is
understood that variations on the above procedure are within the
scope of the present invention. For example, it may be desirable to
transfect a host cell with DNA encoding either the light chain or
the heavy chain (but not both) of an antibody of this invention.
Recombinant DNA technology may also be used to remove some or all
of the DNA encoding either or both of the light and heavy chains
that is not necessary for binding to hTNF.alpha.. The molecules
expressed from such truncated DNA molecules are also encompassed by
the antibodies of the invention. In addition, bifunctional
antibodies may be produced in which one heavy and one light chain
are an antibody of the invention and the other heavy and light
chain are specific for an antigen other than hTNF.alpha. by
crosslinking an antibody of the invention to a second antibody by
standard chemical crosslinking methods.
[0219] In a preferred system for recombinant expression of an
antibody, or antigen-binding portion thereof, of the invention, a
recombinant expression vector encoding both the antibody heavy
chain and the antibody light chain is introduced into dhfr-CHO
cells by calcium phosphate-mediated transfection. Within the
recombinant expression vector, the antibody heavy and light chain
genes are each operatively linked to CMV enhancer/AdMLP promoter
regulatory elements to drive high levels of transcription of the
genes. The recombinant expression vector also carries a DHFR gene,
which allows for selection of CHO cells that have been transfected
with the vector using methotrexate selection/amplification. The
selected transformant host cells are culture to allow for
expression of the antibody heavy and light chains and intact
antibody is recovered from the culture medium. Standard molecular
biology techniques are used to prepare the recombinant expression
vector, transfect the host cells, select for transformants, culture
the host cells and recover the antibody from the culture
medium.
[0220] In view of the foregoing, nucleic acid, vector and host cell
compositions that can be used for recombinant expression of the
antibodies and antibody portions used in the invention include
nucleic acids, and vectors comprising said nucleic acids,
comprising the human TNF.alpha. antibody adalimumab (D2E7). The
nucleotide sequence encoding the D2E7 light chain variable region
is shown in SEQ ID NO: 36. The CDR1 domain of the LCVR encompasses
nucleotides 70-102, the CDR2 domain encompasses nucleotides 148-168
and the CDR3 domain encompasses nucleotides 265-291. The nucleotide
sequence encoding the D2E7 heavy chain variable region is shown in
SEQ ID NO: 37. The CDR1 domain of the HCVR encompasses nucleotides
91-105, the CDR2 domain encompasses nucleotides 148-198 and the
CDR3 domain encompasses nucleotides 295-330. It will be appreciated
by the skilled artisan that nucleotide sequences encoding
D2E7-related antibodies, or portions thereof (e.g., a CDR domain,
such as a CDR3 domain), can be derived from the nucleotide
sequences encoding the D2E7 LCVR and HCVR using the genetic code
and standard molecular biology techniques.
[0221] Recombinant human antibodies of the invention in addition to
D2E7 or an antigen binding portion thereof, or D2E7-related
antibodies disclosed herein can be isolated by screening of a
recombinant combinatorial antibody library, preferably a scFv phage
display library, prepared using human VL and VH cDNAs prepared from
mRNA derived from human lymphocytes. Methodologies for preparing
and screening such libraries are known in the art. In addition to
commercially available kits for generating phage display libraries
(e.g., the Pharmacia Recombinant Phage Antibody System, catalog no.
27-9400-01; and the Stratagene SurfZAP.TM. phage display kit,
catalog no. 240612), examples of methods and reagents particularly
amenable for use in generating and screening antibody display
libraries can be found in, for example, Ladner et al. U.S. Pat. No.
5,223,409; Kang et al. PCT Publication No. WO 92/18619; Dower et
al. PCT Publication No. WO 91/17271; Winter et al. PCT Publication
No. WO 92/20791; Markland et al. PCT Publication No. WO 92/15679;
Breitling et al. PCT Publication No. WO 93/01288; McCafferty et al.
PCT Publication No. WO 92/01047; Garrard et al. PCT Publication No.
WO 92/09690; Fuchs et al. (1991) Bio/Technology 9:1370-1372; Hay et
al. (1992) Hum Antibod Hybridomas 3:81-65; Huse et al. (1989)
Science 246:1275-1281; McCafferty et al., Nature (1990)
348:552-554; Griffiths et al. (1993) EMBO J 12:725-734; Hawkins et
al. (1992) J Mol Biol 226:889-896; Clackson et al. (1991) Nature
352:624-628; Gram et al. (1992) PNAS 89:3576-3580; Garrard et al.
(1991) Bio/Technology 9:1373-1377; Hoogenboom et al. (1991) Nuc
Acid Res 19:4133-4137; and Barbas et al. (1991) PNAS
88:7978-7982.
[0222] In a preferred embodiment, to isolate human antibodies with
high affinity and a low off rate constant for hTNF.alpha., a murine
anti-hTNF.alpha. antibody having high affinity and a low off rate
constant for hTNF.alpha. (e.g., MAK 195, the hybridoma for which
has deposit number ECACC 87 050801) is first used to select human
heavy and light chain sequences having similar binding activity
toward hTNF.alpha., using the epitope imprinting methods described
in Hoogenboom et al., PCT Publication No. WO 93/06213. The antibody
libraries used in this method are preferably scFv libraries
prepared and screened as described in McCafferty et al., PCT
Publication No. WO 92/01047, McCafferty et al., Nature (1990)
348:552-554; and Griffiths et al, (1993) EMBO J 12:725-734. The
scFv antibody libraries preferably are screened using recombinant
human TNF.alpha. as the antigen.
[0223] Once initial human VL and VH segments are selected, "mix and
match" experiments, in which different pairs of the initially
selected VL and VH segments are screened for hTNF.alpha. binding,
are performed to select preferred VL/VH pair combinations.
Additionally, to further improve the affinity and/or lower the off
rate constant for hTNF.alpha. binding, the VL and VH segments of
the preferred VL/VH pair(s) can be randomly mutated, preferably
within the CDR3 region of VH and/or VL, in a process analogous to
the in vivo somatic mutation process responsible for affinity
maturation of antibodies during a natural immune response. This in
vitro affinity maturation can be accomplished by amplifying VH and
VL regions using PCR primers complimentary to the VH CDR3 or VL
CDR3, respectively, which primers have been "spiked" with a random
mixture of the four nucleotide bases at certain positions such that
the resultant PCR products encode VH and VL segments into which
random mutations have been introduced into the VH and/or VL CDR3
regions. These randomly mutated VH and VL segments can be
rescreened for binding to hTNF.alpha. and sequences that exhibit
high affinity and a low off rate for hTNF.alpha. binding can be
selected.
[0224] Following screening and isolation of an anti-hTNF.alpha.
antibody of the invention from a recombinant immunoglobulin display
library, nucleic acid encoding the selected antibody can be
recovered from the display package (e.g., from the phage genome)
and subcloned into other expression vectors by standard recombinant
DNA techniques. If desired, the nucleic acid can be further
manipulated to create other antibody forms of the invention (e.g.,
linked to nucleic acid encoding additional immunoglobulin domains,
such as additional constant regions). To express a recombinant
human antibody isolated by screening of a combinatorial library,
the DNA encoding the antibody is cloned into a recombinant
expression vector and introduced into a mammalian host cells, as
described in further detail in above.
[0225] Methods of isolating human neutralizing antibodies with high
affinity and a low off rate constant for hTNF.alpha. are described
in U.S. Pat. Nos. 6,090,382, 6,258,562, and 6,509,015, each of
which is incorporated by reference herein.
[0226] Antibodies, antibody-portions, and other TNF.alpha.
inhibitors for use in the methods of the invention, can be
incorporated into pharmaceutical compositions suitable for
administration to a subject. Typically, the pharmaceutical
composition comprises an antibody, antibody portion, or other
TNF.alpha. inhibitor, and a pharmaceutically acceptable carrier. As
used herein, "pharmaceutically acceptable carrier" includes any and
all solvents, dispersion media, coatings, antibacterial and
antifungal agents, isotonic and absorption delaying agents, and the
like that are physiologically compatible. Examples of
pharmaceutically acceptable carriers include one or more of water,
saline, phosphate buffered saline, dextrose, glycerol, ethanol and
the like, as well as combinations thereof. In many cases, it is
preferable to include isotonic agents, for example, sugars,
polyalcohols such as mannitol, sorbitol, or sodium chloride in the
composition. Pharmaceutically acceptable carriers may further
comprise minor amounts of auxiliary substances such as wetting or
emulsifying agents, preservatives or buffers, which enhance the
shelf life or effectiveness of the antibody, antibody portion, or
other TNF.alpha. inhibitor.
[0227] The compositions for use in the methods and compositions of
the invention may be in a variety of forms. These include, for
example, liquid, semi-solid and solid dosage forms, such as liquid
solutions (e.g., injectable and infusible solutions), dispersions
or suspensions, tablets, pills, powders, liposomes and
suppositories. The preferred form depends on the intended mode of
administration and therapeutic application. Typical preferred
compositions are in the form of injectable or infusible solutions,
such as compositions similar to those used for passive immunization
of humans with other antibodies or other TNF.alpha. inhibitors. The
preferred mode of administration is parenteral (e.g., intravenous,
subcutaneous, intraperitoneal, intramuscular). In a preferred
embodiment, the antibody or other TNF.alpha. inhibitor is
administered by intravenous infusion or injection. In another
preferred embodiment, the antibody or other TNF.alpha. inhibitor is
administered by intramuscular or subcutaneous injection.
[0228] Therapeutic compositions typically must be sterile and
stable under the conditions of manufacture and storage. The
composition can be formulated as a solution, microemulsion,
dispersion, liposome, or other ordered structure suitable to high
drug concentration. Sterile injectable solutions can be prepared by
incorporating the active compound (i.e., antibody, antibody
portion, or other TNF.alpha. inhibitor) in the required amount in
an appropriate solvent with one or a combination of ingredients
enumerated above, as required, followed by filtered sterilization.
Generally, dispersions are prepared by incorporating the active
compound into a sterile vehicle that contains a basic dispersion
medium and the required other ingredients from those enumerated
above. In the case of sterile powders for the preparation of
sterile injectable solutions, the preferred methods of preparation
are vacuum drying and freeze-drying that yields a powder of the
active ingredient plus any additional desired ingredient from a
previously sterile-filtered solution thereof. The proper fluidity
of a solution can be maintained, for example, by the use of a
coating such as lecithin, by the maintenance of the required
particle size in the case of dispersion and by the use of
surfactants. Prolonged absorption of injectable compositions can be
brought about by including in the composition an agent that delays
absorption, for example, monostearate salts and gelatin.
[0229] In one embodiment, the invention includes pharmaceutical
compositions comprising an effective TNF.alpha. inhibitor and a
pharmaceutically acceptable carrier, wherein the effective
TNF.alpha. inhibitor may be used to treat rheumatoid arthritis.
[0230] In one embodiment, the antibody or antibody portion for use
in the methods of the invention is incorporated into a
pharmaceutical formulation as described in PCT/1B03/04502 and U.S.
Appln. No. 20040033228, incorporated by reference herein. This
formulation includes a concentration 50 mg/ml of the antibody D2E7
(adalimumab), wherein one pre-filled syringe contains 40 mg of
antibody for subcutaneous injection.
[0231] The antibodies, antibody-portions, and other TNF.alpha.
inhibitors of the present invention can be administered by a
variety of methods known in the art, although for many therapeutic
applications, the preferred route/mode of administration is
parenteral, e.g., subcutaneous injection. In another embodiment,
administration is via intravenous injection or infusion.
[0232] As will be appreciated by the skilled artisan, the route
and/or mode of administration will vary depending upon the desired
results. In certain embodiments, the active compound may be
prepared with a carrier that will protect the compound against
rapid release, such as a controlled release formulation, including
implants, transdermal patches, and microencapsulated delivery
systems. Biodegradable, biocompatible polymers can be used, such as
ethylene vinyl acetate, polyanhydrides, polyglycolic acid,
collagen, polyorthoesters, and polylactic acid. Many methods for
the preparation of such formulations are patented or generally
known to those skilled in the art. See, e.g., Sustained and
Controlled Release Drug Delivery Systems, Robinson, ed., Dekker,
Inc., New York, 1978.
[0233] In one embodiment, the TNF.alpha. antibodies and inhibitors
used in the invention are delivered to a subject subcutaneously. In
one embodiment, the subject administers the TNF.alpha. inhibitor,
including, but not limited to, TNF.alpha. antibody, or
antigen-binding portion thereof, to himself/herself.
[0234] The TNF.alpha. antibodies and inhibitors used in the
invention may also be administered in the form of protein crystal
formulations which include a combination of protein crystals
encapsulated within a polymeric carrier to form coated particles.
The coated particles of the protein crystal formulation may have a
spherical morphology and be microspheres of up to 500 micro meters
in diameter or they may have some other morphology and be
microparticulates. The enhanced concentration of protein crystals
allows the antibody of the invention to be delivered
subcutaneously. In one embodiment, the TNF.alpha. antibodies of the
invention are delivered via a protein delivery system, wherein one
or more of a protein crystal formulation or composition, is
administered to a subject with a TNF.alpha.-related disorder.
Compositions and methods of preparing stabilized formulations of
whole antibody crystals or antibody fragment crystals are also
described in WO 02/072636, which is incorporated by reference
herein. In one embodiment, a formulation comprising the
crystallized antibody fragments described in PCT/IB03/04502 and
U.S. Appln. No. 20040033228, incorporated by reference herein, are
used to treat rheumatoid arthritis using the treatment methods of
the invention.
[0235] In certain embodiments, an antibody, antibody portion, or
other TNF.alpha. inhibitor of the invention may be orally
administered, for example, with an inert diluent or an assimilable
edible carrier. The compound (and other ingredients, if desired)
may also be enclosed in a hard or soft shell gelatin capsule,
compressed into tablets, or incorporated directly into the
subject's diet. For oral therapeutic administration, the compounds
may be incorporated with excipients and used in the form of
ingestible tablets, buccal tablets, troches, capsules, elixirs,
suspensions, syrups, wafers, and the like. To administer a compound
of the invention by other than parenteral administration, it may be
necessary to coat the compound with, or co-administer the compound
with, a material to prevent its inactivation.
[0236] Supplementary active compounds can also be incorporated into
the compositions. In certain embodiments, an antibody or antibody
portion for use in the methods of the invention is coformulated
with and/or coadministered with one or more additional therapeutic
agents, including a rheumatoid arthritis inhibitor or antagonist.
For example, an anti-hTNF.alpha. antibody or antibody portion of
the invention may be coformulated and/or coadministered with one or
more additional antibodies that bind other targets associated with
TNF related disorders (e.g., antibodies that bind other cytokines
or that bind cell surface molecules), one or more cytokines,
soluble TNF.alpha. receptor (see e.g., PCT Publication No. WO
94/06476) and/or one or more chemical agents that inhibit
hTNF.alpha. production or activity (such as cyclohexane-ylidene
derivatives as described in PCT Publication No. WO 93/19751) or any
combination thereof. Furthermore, one or more antibodies of the
invention may be used in combination with two or more of the
foregoing therapeutic agents. Such combination therapies may
advantageously utilize lower dosages of the administered
therapeutic agents, thus avoiding possible side effects,
complications or low level of response by the patient associated
with the various monotherapies.
[0237] The pharmaceutical compositions of the invention may include
a "therapeutically effective amount" or a "prophylactically
effective amount" of an antibody or antibody portion of the
invention. A "therapeutically effective amount" refers to an amount
effective, at dosages and for periods of time necessary, to achieve
the desired therapeutic result. A therapeutically effective amount
of the antibody, antibody portion, or other TNF.alpha. inhibitor
may vary according to factors such as the disease state, age, sex,
and weight of the individual, and the ability of the antibody,
antibody portion, other TNF.alpha. inhibitor to elicit a desired
response in the individual. A therapeutically effective amount is
also one in which any toxic or detrimental effects of the antibody,
antibody portion, or other TNF.alpha. inhibitor are outweighed by
the therapeutically beneficial effects. A "prophylactically
effective amount" refers to an amount effective, at dosages and for
periods of time necessary, to achieve the desired prophylactic
result. Typically, since a prophylactic dose is used in subjects
prior to or at an earlier stage of disease, the prophylactically
effective amount will be less than the therapeutically effective
amount.
[0238] Additional description regarding methods and uses of the
invention comprising administration of a TNF.alpha. inhibitor are
described in Part III of this specification.
[0239] The invention also pertains to packaged pharmaceutical
compositions or kits for administering the anti-TNF antibodies of
the invention for the treatment of rheumatoid arthritis. In one
embodiment of the invention, the kit comprises a TNF.alpha.
inhibitor, such as an antibody and instructions for administration
of the TNF.alpha. inhibitor for treatment of rheumatoid arthritis.
The instructions may describe how, e.g., subcutaneously, and when,
e.g., at week 0, week 2, week 4, etc., the different doses of
TNF.alpha. inhibitor shall be administered to a subject for
treatment.
[0240] Another aspect of the invention pertains to kits containing
a pharmaceutical composition comprising a TNF.alpha. inhibitor,
such as an antibody, and a pharmaceutically acceptable carrier and
one or more pharmaceutical compositions each comprising an
additional therapeutic agent useful for treating rheumatoid
arthritis, and a pharmaceutically acceptable carrier.
Alternatively, the kit comprises a single pharmaceutical
composition comprising an anti-TNF.alpha. antibody, one or more
drugs useful for treating rheumatoid arthritis, and a
pharmaceutically acceptable carrier. The instructions may describe
how, e.g., subcutaneously, and when, e.g., at week 0, week 2, week
4, etc., the different doses of TNF.alpha. inhibitor and/or the
additional therapeutic agent shall be administered to a subject for
treatment.
[0241] The kit may contain instructions for dosing of the
pharmaceutical compositions for the treatment of rheumatoid
arthritis. Additional description regarding articles of manufacture
of the invention are described in subsection III.
[0242] The package or kit alternatively can contain the TNF.alpha.
inhibitor and it can be promoted for use, either within the package
or through accompanying information, for the uses or treatment of
the disorders described herein. The packaged pharmaceuticals or
kits further can include a second agent (as described herein)
packaged with or copromoted with instructions for using the second
agent with a first agent (as described herein).
III. Uses and Compositions for Treating Rheumatoid Arthritis
[0243] Tumor necrosis factor has been implicated in playing a role
in the pathophysiology of a variety of autoimmune diseases,
including rheumatoid arthritis. TNF.alpha. is an important cytokine
in the pathogenesis of rheumatoid arthritis, with elevated
concentrations of TNF.alpha. playing a role in pathologic
inflammation. TNF.alpha. has been implicated in activating tissue
inflammation and causing joint destruction in rheumatoid arthritis
(see e.g., Moeller, A., et al. (1990) Cytokine 2:162-169; U.S. Pat.
No. 5,231,024 to Moeller et al.; European Patent Publication No.
260 610 B1 by Moeller, A.; Tracey and Cerami, supra; Arend, W. P.
and Dayer, J-M. (1995) Arth. Rheum. 38:151-160; Fava, R. A., et al.
(1993) Clin. Exp. Immunol. 94:261-266).
[0244] Tumor necrosis factor (TNF) is a pivotal cytokine in the
pathogenesis of rheumatoid arthritis (RA). In recent years biologic
response modifiers that inhibit TNF activity have become
established therapies for RA. Adalimumab, etanercept, and
infliximab have demonstrated marked improvements in both disease
control and delay and prevention of radiographic damage among RA
patients, particularly when used in combination with methotrexate
(Breedveld et al, Arthritis Rheum 2006; 54:26-37; Genovese et al J
Rheumatol 2005; 32:1232-42; Keystone et al, Arthritis Rheum 2004;
50:1400-11; Navarro-Sarabia et al, Cochrane Database Syst Rev 2005
Jul. 20; (3):CD005113; Smolen et al, Arthritis Rheum 2006;
54:702-10; St. Clair et al Arthritis Rheum 2004; 50:3432-43; van
der Heijde et al, Arthritis Rheum 2006; 54:1063-74).
[0245] In one aspect, the invention discloses that adalimumab is
safe in global clinical trials and has reduced mortality in RA. The
invention further discloses the efficacy and safety of adalimumab
in patients with RA who previously failed etanercept and/or
infliximab in clinical practice and that efficacy and safety is
maintained during long-term treatment of RA within a large cohort
of patients (various age groups, including late-onset RA) in normal
clinical practice across multiple countries. The invention also
discloses that adalimumab is effective and safe with different
traditional concomitant DMARDs in treating RA. Finally, the
invention discloses that disease activity and physical function
improve significantly in most patients with RA receiving
adalimumab.
[0246] Infection with influenza virus and/or Streptococcus
pneumoniae are prominent causes of morbidity and mortality in RA.
Routine influenza and pneumococcal vaccinations are recommended to
prevent these infections. However, treatment with corticosteroids,
immunosuppressants, or TNF antagonists may potentially affect
B-cell function and decrease protective antibody response. The
invention describes combination uses of TNF.alpha. inhibitors
treatments for rheumatoid arthritis and other disorders, including
infectious disorders. In one embodiment, the invention provides a
method of preventing Pneumococcal disease and treating rheumatoid
arthritis (RA) in a subject comprising administering a pneumococcal
vaccine and a human TNF.alpha. antibody, or antigen-binding portion
thereof, to the subject, such that Pneumococcal disease is
prevented and rheumatoid arthritis is treated. The invention also
provides a use of a human TNF.alpha. antibody, or antigen-binding
portion thereof, in the manufacture of a medicament for the
treatment of RA in a subject, wherein the medicament is designed to
be administered in combination with a pneumococcal vaccine for the
prevention of Pneumococcal disease. In one embodiment, the human
TNF.alpha. antibody, or antigen-binding portion thereof, is
administered to the subject in a biweekly dosing regimen In another
embodiment, the human TNF.alpha. antibody, or antigen-binding
portion thereof, is administered to the subject in a dose of 40 mg.
In one embodiment, the human TNF.alpha. antibody, or
antigen-binding portion thereof, is administered to the subject
subcutaneously.
[0247] In one embodiment, the invention provides a method for
treating rheumatoid arthritis in a subject such that signs and
symptoms are reduced. In one embodiment, the methods of the
invention includes inducing a major clinical response of a subject
having RA. The TNF.alpha. antibody, or an antigen-binding portion
thereof, may be administered to the subject on a biweekly dosing
regimen. In one embodiment, biweekly dosing includes a dosing
regimen wherein doses of a TNF.alpha. inhibitor are administered to
a subject every other week beginning at week 0. In one embodiment,
biweekly dosing includes a dosing regimen where doses of a
TNF.alpha. inhibitor are administered to a subject every other week
consecutively for a given time period, e.g., 4 weeks, 8 weeks, 16,
weeks, 24 weeks, 26 weeks, 32 weeks, 36 weeks, 42 weeks, 48 weeks,
52 weeks, 56 weeks, etc.
[0248] In one embodiment, treatment of rheumatoid arthritis is
achieved by administering a TNF.alpha. inhibitor to a subject in
accordance with a biweekly dosing regimen. Biweekly dosing regimens
can be used to treat disorders in which TNF.alpha. activity is
detrimental, and are further described in U.S. application Ser. No.
10/163,657 (US 20030235585), incorporated by reference herein.
[0249] In one embodiment, the invention provides a method of
treating rheumatoid arthritis in a subject comprising administering
a human TNF.alpha. antibody, or antigen-binding portion thereof,
e.g., adalimumab, to the subject at week 0 on a biweekly dosing
regimen. In one embodiment, the human TNF.alpha. antibody, or
antigen-binding portion thereof, is administered subcutaneously. In
one embodiment, rheumatoid arthritis is treated by administering a
human TNF.alpha. antibody, or antigen-binding portion thereof, on
biweekly dosing regimen for at least about 2 weeks, at least about
6 weeks, at least about 12 weeks, at least about 16 weeks, at least
about 33 weeks, at least about 72 weeks, at least about 96 weeks,
at least about 18 months, or at least about 6 years.
[0250] In one embodiment, treatment of rheumatoid arthritis is
achieved by administering a human TNF.alpha. antibody, or an
antigen-binding portion thereof, to a subject having rheumatoid
arthritis, wherein the human TNF.alpha. antibody, or an
antigen-binding portion thereof, is administered on a biweekly
dosing regimen. In one embodiment, the human TNF.alpha. antibody,
or an antigen-binding portion thereof, is administered in a dose of
about 40 mg. In one embodiment, the human TNF.alpha. antibody, or
an antigen-binding portion thereof, is adalimumab.
[0251] Methods of treatment described herein may include
administration of a TNF.alpha. inhibitor to a subject to achieve a
therapeutic goal, e.g., achieving a certain ACR response, e.g.,
ACR20, ACR50, ACR70, improving an SDAI score, improving EULAR
response. Also included in the scope of the invention are uses of a
TNF.alpha. inhibitor in the manufacture of a medicament to achieve
a therapeutic goal, e.g., ACR20, ACR50, ACR70, improving an SDAI
score, improving EULAR response. Thus, where methods are described
herein, it is also intended to be part of this invention that the
use of the TNF.alpha. inhibitor in the manufacture of a medicament
for the purpose of the method is also considered within the scope
of the invention. Likewise, where a use of a TNF.alpha. inhibitor
in the manufacture of a medicament for the purpose of achieving a
therapeutic goal is described, methods of treatment resulting in
the therapeutic goal are also intended to be part of the
invention.
[0252] Dosage unit form as used herein refers to physically
discrete units suited as unitary dosages for the mammalian subjects
to be treated; each unit containing a predetermined quantity of
active compound calculated to produce the desired therapeutic
effect in association with the required pharmaceutical carrier. The
specification for the dosage unit forms of the invention are
dictated by and directly dependent on (a) the unique
characteristics of the active compound and the particular
therapeutic or prophylactic effect to be achieved, and (b) the
limitations inherent in the art of compounding such an active
compound for the treatment of sensitivity in individuals.
[0253] Dosage regimens described herein may be adjusted to provide
the optimum desired response, e.g., treatment of rheumatoid
arthritis, in consideration of the teachings herein. It is to be
noted that dosage values may vary with the type and severity of
rheumatoid arthritis. It is to be further understood that for any
particular subject, specific dosage regimens may be adjusted over
time according to the teachings of the specification and the
individual need and the professional judgment of the person
administering or supervising the administration of the
compositions, and that dosage amounts and ranges set forth herein
are exemplary only and are not intended to limit the scope or
practice of the claimed invention.
[0254] Examples of other methods and uses of TNF.alpha. inhibitors
for the treatment of rheumatoid arthritis are also described in
60/793,737, 60/812705, 60/798149, 60/801584, 60/858328, 60/872753,
60/857352, incorporated herein.
Subpopulations
[0255] The invention provides uses and methods for treating certain
subpopulations of rheumatoid arthritis patients with a TNF.alpha.
inhibitor.
[0256] In one embodiment, the invention provides methods and uses
for treating subjects of a certain age range having rheumatoid
arthritis. In one embodiment, the methods and uses of the invention
are directed to treating subjects having late-onset RA. As such,
the invention provides a method of treating late-onset RA
comprising administering a human TNF.alpha. antibody, or
antigen-binding portion thereof, to a patient having late-onset RA.
The invention also provides a use of a human TNF.alpha. antibody,
or antigen-binding portion thereof, in the manufacture of a
medicament for the treatment of late-onset RA in a subject. In one
embodiment, late-onset RA is defined as RA in a subject who is over
60 years old.
[0257] Although TNF antagonists are highly effective, a subset of
patients with RA may be intolerant to one of these agents or may
experience an inadequate response or a loss of response over time
(Nurmohamed and Dijkmans, 2005). A relevant clinical question,
therefore, is whether switching to a different TNF antagonist would
be effective when the first has failed or resulted in intolerance.
Clinical reports to date in mostly small numbers of patients
suggest that a switch from one TNF antagonist to another is safe
and effective, resulting in few withdrawals due to intolerance or
lack of effectiveness (Brocq et al, Joint Bone Spine 2004;
71:601-3; Gomez-Reino et al, Arthritis Res Ther 2006; 8:R29; Hansen
et al, J Rheumatol 2004; 31:1098-102; Haraoui et a, J Rheumatol
2004; 31:2356-9; Nikas et al, Ann Rheum Dis 2006; 65:257-60; van
Vollenhoven et al, Ann Rheum Dis 2003; 62:1195-8). Most of these
studies addressed switching between infliximab and etanercept. Data
are very limited, however, regarding switching to adalimumab from
one of these other TNF antagonists (Nikas et al, Ann Rheum Dis
2006; 65:257-60).
[0258] In one embodiment, the invention provides a method for
treating a subpopulation of RA patients who are intolerant to or
have lost response to a first TNF.alpha. inhibitor, e.g.,
infliximab, for the treatment of RA.
[0259] In one embodiment, the invention also provides methods and
compositions for use in a subject who has not previously been
administered infliximab. Thus, in one embodiment, the methods and
compositions of the invention are directed to a subpopulation of RA
patients who have not previously received infliximab.
[0260] In one embodiment, the invention provides an article of
manufacture comprising adalimumab and a package insert, wherein the
package insert indicates that adalimumab may be used to treat RA in
patients who have had an inadequate response to conventional
therapy and/or who have lost response to or are intolerant to
infliximab.
Articles of Manufacture
[0261] The invention also provides a packaged pharmaceutical
composition wherein the TNF.alpha. inhibitor, e.g., TNF.alpha.
antibody, is packaged within a kit or an article of manufacture.
The kit or article of manufacture of the invention contains
materials useful for the treatment, including induction and/or
remission, prevention and/or diagnosis of RA. The kit or article of
manufacture comprises a container and a label or package insert or
printed material on or associated with the container which provides
information regarding use of the TNF.alpha. inhibitor, e.g., a
TNF.alpha. antibody, for the treatment of RA.
[0262] A kit or an article of manufacture refers to a packaged
product comprising components with which to administer a TNF.alpha.
inhibitor for treatment of a RA. The kit preferably comprises a box
or container that holds the components of the kit. The box or
container is affixed with a label or a Food and Drug Administration
approved label, including a protocol for administering the
TNF.alpha. inhibitor. The box or container holds components of the
invention which are preferably contained within plastic,
polyethylene, polypropylene, ethylene, or propylene vessels. The
vessels can be capped-tubes or bottles. The kit can also include
instructions for administering the TNF.alpha. antibody of the
invention. In one embodiment the kit of the invention includes the
formulation comprising the human antibody adalimumab (or D2E7), as
described in PCT/IB03/04502 and U.S. application Ser. No.
10/222,140, incorporated by reference herein.
[0263] The term "package insert" is used to refer to instructions
customarily included in commercial packages of therapeutic
products, that contain information about the indications, usage,
dosage, administration, contraindications and/or warnings
concerning the use of such therapeutic products.
[0264] In one embodiment, the article of manufacture of the
invention comprises (a) a first container with a composition
contained therein, wherein the composition comprises a TNF.alpha.
antibody; and (b) a package insert indicating that the TNF.alpha.
antibody may be used for reducing signs and symptoms of RA.
[0265] Suitable containers for the TNF.alpha. inhibitor, e.g., a
TNF.alpha. antibody, include, for example, bottles, vials,
syringes, pens, etc. The containers may be formed from a variety of
materials such as glass or plastic. The container holds a
composition which is by itself or when combined with another
composition effective for treating, preventing and/or diagnosing
the condition and may have a sterile access port.
[0266] In one embodiment, the article of manufacture comprises a
TNF.alpha. inhibitor, e.g., a TNF.alpha. antibody, and a label
which indicates to a subject who will be administering the
TNF.alpha. inhibitor about using the TNF.alpha. inhibitor for the
treatment of RA. The label may be anywhere within or on the article
of manufacture. In one embodiment, the article of manufacture
comprises a container, such as a box, which comprises the
TNF.alpha. inhibitor and a package insert or label providing
information pertaining to use of the TNF.alpha. inhibitor for the
treatment of RA. In another embodiment, the information is printed
on a label which is on the outside of the article of manufacture,
in a position which is visible to prospective purchasers.
[0267] In one embodiment, the package insert of the invention
informs a reader, including a subject, e.g., a purchaser, who will
be administering the TNF.alpha. inhibitor for treatment, that the
TNF.alpha. inhibitor, e.g., a TNF.alpha. antibody such as
adalimumab, is an indicated treatment of RA, including of
moderately to severely active disease in adult patients.
[0268] In one embodiment, the package insert describes certain
patient populations who may respond favorably to the TNF.alpha.
inhibitor within the article of manufacture. For example, the
package insert may indicate that the TNF.alpha. antibody, e.g.,
adalimumab, may be used to treat RA in patients who have had an
inadequate response to conventional therapy and/or who have lost
response to or are intolerant to infliximab.
In another embodiment, the label of the invention indicates that
adalimumab is indicated for treatment of moderately to severely
active RA in adult patients who have had an inadequate response to
conventional therapy. In another embodiment, the label of the
invention indicates that the TNF.alpha. inhibitor, e.g., a
TNF.alpha. antibody such as adalimumab, is also indicated for
treatment in adult patients with moderately to severely active RA
who have lost response to or are intolerant to infliximab.
[0269] In one embodiment, the package insert of the invention
describes certain therapeutic benefits of the TNF.alpha. antibody,
e.g., adalimumab, including specific symptoms of RA which may be
reduced by using the TNF.alpha. antibody, e.g., adalimumab. It
should be noted that the package insert may also contain
information pertaining to other disorders which are treatable using
the TNF.alpha. antibody, e.g., adalimumab. Information described
herein which is provided in a package insert and pertains to other
disorders, i.e., diseases other than RA, is also included within
the scope of the invention. The package insert of the invention may
indicate that extra TNF.alpha. in your body can attack normal
healthy body tissues and cause inflammation especially in the
tissues in your bones, cartilage, joints and digestive tract. The
package insert of the invention may also indicate that adalimumab
helps reduce the signs and symptoms of immune diseases, including
rheumatoid and psoriatic arthritis (pain and swollen joints),
ankylosing spondylitis (morning stiffness and back pain), and
Crohn's disease (abdominal pain and diarrhea).
[0270] The package insert of the invention may also provide
information to subjects who will be receiving adalimumab regarding
combination uses for both safety and efficacy purposes. The package
insert of the invention may contain warnings and precautions
regarding the use of the TNF.alpha. inhibitor, e.g., a TNF.alpha.
antibody such as adalimumab. In one embodiment, the invention
provides an article of manufacture comprising a packaging material;
a TNF.alpha. antibody, or antigen-binding portion thereof; and a
label or package insert contained within the packaging material
indicating that in studies of the TNF.alpha. antibody, or
antigen-binding portion thereof, observed malignancies included
melanoma and/or granulose cell tumor of the ovary.
[0271] In one embodiment, the information provided in the label
describes safety regarding use of the TNF.alpha. inhibitor and
vaccines. In one embodiment, the invention provides an article of
manufacture comprising a packaging material; a TNF.alpha. antibody,
or antigen-binding portion thereof; and a label or package insert
indicating that patients with RA receiving treatment with the
TNF.alpha. antibody, or antigen-binding portion thereof, can be
administered a pneumonococcal vaccine concurrently with the
TNF.alpha. antibody, or antigen-binding portion thereof. The
invention also provides an article of manufacture comprising a
packaging material; pneumonococcal or influenza virus vaccine; and
a label or package insert contained within the packaging material
indicating that patients receiving the pneumonococcal or influenza
virus vaccine can be safely administered a TNF.alpha. inhibitor. In
one embodiment, the pneumonococcal vaccine is a pneumonococcal
polysaccharide vaccine.
[0272] The label of the invention may contain information regarding
the use of the TNF.alpha. a inhibitor, e.g., a TNF.alpha. antibody
such as adalimumab, in clinical studies for RA. In one embodiment,
the label of the invention describes the studies described herein
as the Examples, either as a whole or in portion.
[0273] In one embodiment of the invention, the kit comprises a
TNF.alpha. inhibitor, such as an antibody, an second pharmaceutical
composition comprising an additional therapeutic agent, and
instructions for administration of both agents for the treatment of
RA. The instructions may describe how, e.g., subcutaneously, and
when, e.g., at week 0, week 2, and biweekly thereafter, doses of
TNF.alpha. antibody and/or the additional therapeutic agent shall
be administered to a subject for treatment.
[0274] Another aspect of the invention pertains to kits containing
a pharmaceutical composition comprising an anti-TNF.alpha. antibody
and a pharmaceutically acceptable carrier and one or more
additional pharmaceutical compositions each comprising a drug
useful for treating a TNF.alpha. related disorder and a
pharmaceutically acceptable carrier. Alternatively, the kit
comprises a single pharmaceutical composition comprising an
anti-TNF.alpha. antibody, one or more drugs useful for treating a
TNF.alpha. related disorder and a pharmaceutically acceptable
carrier. The kits further contain instructions for dosing of the
pharmaceutical compositions for the treatment of a TNF.alpha.
related disorder.
[0275] The package or kit alternatively may contain the TNF.alpha.
inhibitor and it may be promoted for use, either within the package
or through accompanying information, for the uses or treatment of
the disorders described herein. The packaged pharmaceuticals or
kits further can include a second agent (as described herein)
packaged with or copromoted with instructions for using the second
agent with a first agent (as described herein).
Additional Therapeutic Agents
[0276] Methods, uses, and compositions of the invention also
include combinations of TNF.alpha. inhibitors, including
antibodies, and other therapeutic agents. It should be understood
that the antibodies of the invention or antigen binding portion
thereof can be used alone or in combination with an additional
agent, e.g., a therapeutic agent, said additional agent being
selected by the skilled artisan for its intended purpose. For
example, the additional agent can be a therapeutic agent
art-recognized as being useful to treat the disease or condition
being treated by the antibody of the present invention. The
additional agent also can be an agent that imparts a beneficial
attribute to the therapeutic composition e.g., an agent which
effects the viscosity of the composition.
[0277] It should further be understood that the combinations which
are to be included within this invention are those combinations
useful for their intended purpose. The agents set forth below are
illustrative for purposes and not intended to be limited. The
combinations, which are part of this invention, can be the
antibodies of the present invention and at least one additional
agent selected from the lists below. The combination can also
include more than one additional agent, e.g., two or three
additional agents if the combination is such that the formed
composition can perform its intended function.
[0278] Binding proteins described herein may be used in combination
with additional therapeutic agents such as a Disease Modifying
Anti-Rheumatic Drug (DMARD) or a Nonsteroidal Antiinflammatory Drug
(NSAID) or a steroid or any combination thereof. Preferred examples
of a DMARD are hydroxychloroquine, leflunomide, methotrexate,
parenteral gold, oral gold and sulfasalazine. Preferred examples of
non-steroidal anti-inflammatory drug(s) also referred to as NSAIDS
include drugs like ibuprofen. Other preferred combinations are
corticosteroids including prednisolone; the well known side effects
of steroid use can be reduced or even eliminated by tapering the
steroid dose required when treating patients in combination with
the anti-TNF.alpha. antibodies of this invention. Non-limiting
examples of therapeutic agents for rheumatoid arthritis with which
an antibody, or antibody portion, of the invention can be combined
include the following: cytokine suppressive anti-inflammatory
drug(s) (CSAIDs); antibodies to or antagonists of other human
cytokines or growth factors, for example, TNF, LT, IL-1, IL-2,
IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-15, IL-16, IL-18, IL-21,
IL-23, interferons, EMAP-II, GM-CSF, FGF, and PDGF. Antibodies of
the invention, or antigen binding portions thereof, can be combined
with antibodies to cell surface molecules such as CD2, CD3, CD4,
CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2),
CD90, CTLA or their ligands including CD154 (gp39 or CD40L).
[0279] Preferred combinations of therapeutic agents may interfere
at different points in the autoimmune and subsequent inflammatory
cascade; preferred examples include TNF antagonists such as soluble
p55 or p75 TNF receptors, derivatives, thereof, (p75TNFR1gG
(Enbrel.TM.) or p55TNFR1gG (Lenercept), chimeric, humanized or
human TNF antibodies, or a fragment thereof, including infliximab
(Remicade.RTM., Johnson and Johnson; described in U.S. Pat. No.
5,656,272, incorporated by reference herein), CDP571 (a humanized
monoclonal anti-TNF-alpha IgG4 antibody), CDP 870 (a humanized
monoclonal anti-TNF-alpha antibody fragment), an anti-TNF dAb
(Peptech), CNTO 148 (golimumab; Medarex and Centocor, see WO
02/12502), and adalimumab (Humira.RTM. Abbott Laboratories, a human
anti-TNF mAb, described in U.S. Pat. No. 6,090,382 as D2E7).
Additional TNF antibodies which can be used in the invention are
described in U.S. Pat. Nos. 6,593,458; 6,498,237; 6,451,983; and
6,448,380, each of which is incorporated by reference herein. Other
combinations including TNF.alpha. converting enzyme (TACE)
inhibitors; IL-1 inhibitors (Interleukin-1-converting enzyme
inhibitors, IL-1RA etc.) may be effective for the same reason.
Other preferred combinations include Interleukin 11. Yet another
preferred combination are other key players of the autoimmune
response which may act parallel to, dependent on or in concert with
TNF.alpha. function; especially preferred are IL-18 antagonists
including IL-18 antibodies or soluble IL-18 receptors, or IL-18
binding proteins. It has been shown that TNF.alpha. and IL-18 have
overlapping but distinct functions and a combination of antagonists
to both may be most effective. Yet another preferred combination
are non-depleting anti-CD4 inhibitors. Yet other preferred
combinations include antagonists of the co-stimulatory pathway CD80
(B7.1) or CD86 (B7.2) including antibodies, soluble receptors or
antagonistic ligands.
[0280] The antibodies of the invention, or antigen binding portions
thereof, may also be combined with agents, such as methotrexate,
6-MP, azathioprine sulphasalazine, mesalazine, olsalazine
chloroquinine/hydroxychloroquine, pencillamine, aurothiomalate
(intramuscular and oral), azathioprine, cochicine, corticosteroids
(oral, inhaled and local injection), beta-2 adrenoreceptor agonists
(salbutamol, terbutaline, salmeteral), xanthines (theophylline,
aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium
and oxitropium, cyclosporin, FK506, rapamycin, mycophenolate
mofetil, leflunomide, NSAIDs, for example, ibuprofen,
corticosteroids such as prednisolone, phosphodiesterase inhibitors,
adensosine agonists, antithrombotic agents, complement inhibitors,
adrenergic agents, agents which interfere with signalling by
proinflammatory cytokines such as TNF.alpha. or IL-1 (e.g. IRAK,
NIK, IKK, p38 or MAP kinase inhibitors), IL-1.beta. converting
enzyme inhibitors, TNF.alpha. converting enzyme (TACE) inhibitors,
T-cell signalling inhibitors such as kinase inhibitors,
metalloproteinase inhibitors, sulfasalazine, azathioprine,
6-mercaptopurines, angiotensin converting enzyme inhibitors,
soluble cytokine receptors and derivatives thereof (e.g. soluble
p55 or p75 TNF receptors and the derivatives p75TNFRIgG (Enbrel.TM.
and p55TNFRIgG (Lenercept)), sIL-1RI, sIL-1RII, sIL-6R),
antiinflammatory cytokines (e.g. IL-4, IL-10, IL-11, IL-13 and
TGF.beta.), celecoxib, folic acid, hydroxychloroquine sulfate,
rofecoxib, etanercept, infliximab, naproxen, valdecoxib,
sulfasalazine, methylprednisolone, meloxicam, methylprednisolone
acetate, gold sodium thiomalate, aspirin, triamcinolone acetonide,
propoxyphene napsylate/apap, folate, nabumetone, diclofenac,
piroxicam, etodolac, diclofenac sodium, oxaprozin, oxycodone hcl,
hydrocodone bitartrate/apap, diclofenac sodium/misoprostol,
fentanyl, anakinra, human recombinant, tramadol hcl, salsalate,
sulindac, cyanocobalamin/fa/pyridoxine, acetaminophen, alendronate
sodium, prednisolone, morphine sulfate, lidocaine hydrochloride,
indomethacin, glucosamine sulf/chondroitin, amitriptyline hcl,
sulfadiazine, oxycodone hcl/acetaminophen, olopatadine hcl,
misoprostol, naproxen sodium, omeprazolec, cyclophosphamide,
rituximab, IL-1 TRAP, MRA, CTLA4-1G, IL-18 BP, anti-IL-18,
Anti-IL15, BIRB-796, SCIO-469, VX-702, AMG-548, VX-740,
Roflumilast, IC-485, CDC-801, and Mesopram. Preferred combinations
include methotrexate or leflunomide and in moderate or severe
rheumatoid arthritis cases, cyclosporine.
[0281] Nonlimiting additional agents which can also be used in
combination with an TNF.alpha. antibody, or antigen-binding portion
thereof, to treat rheumatoid arthritis include, but are not limited
to, the following: non-steroidal anti-inflammatory drug(s)
(NSAIDs); cytokine suppressive anti-inflammatory drug(s) (CSAIDs);
CDP-571/BAY-10-3356 (humanized anti-TNF.alpha. antibody;
Celitech/Bayer); cA2/infliximab (chimeric anti-TNF.alpha. antibody;
Centocor); 75 kdTNFR-IgG/etanercept (75 kD TNF receptor-IgG fusion
protein; Immunex; see e.g., Arthritis & Rheumatism (1994) Vol.
37, S295; J. Invest. Med. (1996) Vol. 44, 235A); 55 kdTNF-IgG (55
kD TNF receptor-IgG fusion protein; Hoffiann-LaRoche);
IDEC-CE9.1/SB 210396 (non-depleting primatized anti-CD4 antibody;
IDEC/SmithKline; see e.g., Arthritis & Rheumatism (1995) Vol.
38, S185); DAB 486-IL-2 and/or DAB 389-IL-2 (IL-2 fusion proteins;
Seragen; see e.g., Arthritis & Rheumatism (1993) Vol. 36,
1223); Anti-Tac (humanized anti-IL-2R.alpha.; Protein Design
Labs/Roche); IL-4 (anti-inflammatory cytokine; DNAX/Schering);
IL-10 (SCH 52000; recombinant IL-10, anti-inflammatory cytokine;
DNAX/Schering); IL-4; IL-10 and/or IL-4 agonists (e.g., agonist
antibodies); IL-1RA (IL-1 receptor antagonist; Synergen/Amgen);
anakinra (Kineret.RTM./Amgen); TNF-bp/s-TNF (soluble TNF binding
protein; see e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9
(supplement), S284; Amer. J. Physiol.--Heart and Circulatory
Physiology (1995) Vol. 268, pp. 37-42); R973401 (phosphodiesterase
Type IV inhibitor; see e.g., Arthritis & Rheumatism (1996) Vol.
39, No. 9 (supplement), S282); MK-966 (COX-2 Inhibitor; see e.g.,
Arthritis & Rheumatism (1996) Vol. 39 No. 9 (supplement), S81);
Iloprost (see e.g., Arthritis & Rheumatism (1996) Vol. 39, No.
9 (supplement), S82); methotrexate; thalidomide (see e.g.,
Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement),
S282) and thalidomide-related drugs (e.g., Celgen); leflunomide
(anti-inflammatory and cytokine inhibitor; see e.g., Arthritis
& Rheumatism (1996) Vol. 39, No. 9 (supplement), S131;
Inflammation Research (1996) Vol. 45, pp. 103-107); tranexamic acid
(inhibitor of plasminogen activation; see e.g., Arthritis &
Rheumatism (1996) Vol. 39, No. 9 (supplement), S284); T-614
(cytokine inhibitor; see e.g., Arthritis & Rheumatism (1996)
Vol. 39, No. 9 (supplement), S282); prostaglandin E1 (see e.g.,
Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement),
S282); Tenidap (non-steroidal anti-inflammatory drug; see e.g.,
Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement),
S280); Naproxen (non-steroidal anti-inflammatory drug; see e.g.,
Neuro Report (1996) Vol. 7, pp. 1209-1213); Meloxicam
(non-steroidal anti-inflammatory drug); Ibuprofen (non-steroidal
anti-inflammatory drug); Piroxicam (non-steroidal anti-inflammatory
drug); Diclofenac (non-steroidal anti-inflammatory drug);
Indomethacin (non-steroidal anti-inflammatory drug); Sulfasalazine
(see e.g., Arthritis & Rheumatism (1996) Vol. 32, No. 9
(supplement), S281); Azathioprine (see e.g., Arthritis &
Rheumatism (1996) Vol. 29, No. 9 (supplement), S281); ICE inhibitor
(inhibitor of the enzyme interleukin-1.beta. converting enzyme);
zap-70 and/or Ick inhibitor (inhibitor of the tyrosine kinase
zap-70 or Ick); VEGF inhibitor and/or VEGF-R inhibitor (inhibitors
of vascular endothelial cell growth factor or vascular endothelial
cell growth factor receptor; inhibitors of angiogenesis);
corticosteroid anti-inflammatory drugs (e.g., SB203580);
TNF-convertase inhibitors; anti-IL-12 antibodies; anti-IL-18
antibodies; interleukin-11 (see e.g., Arthritis & Rheumatism
(1996) Vol. 39, No. 9 (supplement), S296); interleukin-13 (see
e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9
(supplement), S308); interleukin-17 inhibitors (see e.g., Arthritis
& Rheumatism (1996) Vol. 39, No. 9 (supplement), S120); gold;
penicillamine; chloroquine; chlorambucil; hydroxychloroquine;
cyclosporine; cyclophosphamide; total lymphoid irradiation;
anti-thymocyte globulin; anti-CD4 antibodies; CD5-toxins;
orally-administered peptides and collagen; lobenzarit disodium;
Cytokine Regulating Agents (CRAs) HP228 and HP466 (Houghten
Pharmaceuticals, Inc.); ICAM-1 antisense phosphorothioate
oligo-deoxynucleotides (ISIS 2302; Isis Pharmaceuticals, Inc.);
soluble complement receptor 1 (TP 10; T Cell Sciences, Inc.);
prednisone; orgotein; glycosaminoglycan polysulphate; minocycline;
anti-IL2R antibodies; marine and botanical lipids (fish and plant
seed fatty acids; see e.g., DeLuca et al. (1995) Rheum. Dis. Clin.
North Am. 21:759-777); auranofin; phenylbutazone; meclofenamic
acid; flufenamic acid; intravenous immune globulin; zileuton;
azaribine; mycophenolic acid (RS-61443); tacrolimus (FK-506);
sirolimus (rapamycin); amiprilose (therafectin); cladribine
(2-chlorodeoxyadenosine); methotrexate; antivirals; and immune
modulating agents.
[0282] In one embodiment, the TNF.alpha. antibody, or
antigen-binding portion thereof, is administered in combination
with one of the following agents for the treatment of rheumatoid
arthritis: small molecule inhibitor of KDR (ABT-123), small
molecule inhibitor of Tie-2; miethotrexate; prednisone; celecoxib;
folic acid; hydroxychloroquine sulfate; rofecoxib; etanercept;
infliximab; leflunomide; naproxen; valdecoxib; sulfasalazine;
methylprednisolone; ibuprofen; meloxicam; methylprednisolone
acetate; gold sodium thiomalate; aspirin; azathioprine;
triamcinolone acetonide; propxyphene napsylate/apap; folate;
nabumetone; diclofenac; piroxicam; etodolac; diclofenac sodium;
oxaprozin; oxycodone hcl; hydrocodone bitartrate/apap; diclofenac
sodium/misoprostol; fentanyl; anakinra, human recombinant; tramadol
hcl; salsalate; sulindac; cyanocobalamin/fa/pyridoxine;
acetaminophen; alendronate sodium; prednisolone; morphine sulfate;
lidocaine hydrochloride; indomethacin; glucosamine
sulfate/chondroitin; cyclosporine; amitriptyline hcl; sulfadiazine;
oxycodone hcl/acetaminophen; olopatadine hcl; misoprostol; naproxen
sodium; omeprazole; mycophenolate mofetil; cyclophosphamide;
rituximab; IL-1 TRAP; MRA; CTLA4-IG; IL-18 BP; ABT-874; ABT-325
(anti-IL 18); anti-IL 15; BIRB-796; SCIO-469; VX-702; AMG-548;
VX-740; Roflumilast; IC-485; CDC-801; and mesopram. In another
embodiment, a TNF antibody, or antigen-binding portion thereof, is
administered for the treatment of an TNF-related disorder in
combination with one of the above mentioned agents for the
treatment of rheumatoid arthritis.
[0283] The antibodies of the invention, or antigen binding portions
thereof, may also be combined with agents, such as alemtuzumab,
dronabinol, Unimed, daclizumab, mitoxantrone, xaliproden
hydrochloride, fampridine, glatiramer acetate, natalizumab,
sinnabidol, a-immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine
receptor antagonists, BBR-2778, calagualine, CPI-1189, LEM
(liposome encapsulated mitoxantrone), TIHC.CBD (cannabinoid
agonist) MBP-8298, mesopram (PDE4 inhibitor), MNA-715, anti-IL-6
receptor antibody, neurovax, pirfenidone allotrap 1258 (RDP-1258),
sTNF-R1, talampanel, teriflunomide, TGF-beta2, tiplimotide, VLA-4
antagonists (for example, TR-14035, VLA4 Ultrahaler,
Antegran-ELAN/Biogen), interferon gamma antagonists, IL-4
agonists.
IV. Efficacy of TNF.alpha. Inhibitor for Rheumatoid Arthritis
[0284] The invention also provides methods for determining whether
a TNF.alpha. inhibitor is effective at treating rheumatoid
arthritis (RA) in a subject. Such methods may be used to determine
the efficacy of a TNF.alpha. inhibitor, including those which are
unknown or unconfirmed to have such efficacy. Using the methods
described herein, effective TNF.alpha. inhibitors may be determined
or confirmed, and, subsequently, used in the method of treating
RA.
[0285] In one embodiment, the invention provides a method for
determining the efficacy of a TNF.alpha. inhibitor, including a
human TNF.alpha. antibody, for treating RA in a subject, using the
ACR response. The American College of Rheumatology preliminary
criteria for improvement in Rheumatoid Arthritis (ACR20, 50, 70
responses) was developed to provide a efficacy measures for
rheumatoid arthritis (RA) treatments. ACR20, ACR50 and ACR70
requires a greater than 20%, 50% and 70% improvement respectively.
Response criteria are detailed in Felson D T, Anderson J J, Boers
M, Bombardier C, Furst D, Goldsmith C, et al. American College of
Rheumatology preliminary definition of improvement in rheumatoid
arthritis. Arthritis Rheum 1995; 38:727-35, incorporated by
reference herein. Generally, patients are examined clinically at
screening, baseline, and frequently during treatment. The primary
efficacy for signs and symptoms is measured via American College of
Rheumatology preliminary criteria for improvement (ACR20) at 12
weeks. An additional primary endpoint includes evaluation of
radiologic changes over 6 to 12 months to assess changes in
structural damage. The efficacy of a TNF.alpha. inhibitor for
treating RA may be determined by the ACR response of a patient
population who may be evaluated by determining the percentage of
the patient population in whom an ACR response occurs following
administration of the TNF.alpha. inhibitor.
[0286] The ACR response may be used as an index for measuring
efficacy of a TNF.alpha. inhibitor in a patient population having
Crohn's disease, where attaining a certain percentage of patients
within a population who were administered the TNF.alpha. inhibitor
and who achieve an ACR response, i.e. ACR20, ACR50, ACR70,
indicates that the TNF.alpha. inhibitor is effective for treating
RA. In one embodiment, the invention provides a method for
determining whether a human TNF.alpha. antibody is effective for
treating RA.
[0287] In one embodiment, the invention provides a method of
determining the efficacy of a TNF.alpha. inhibitor for treating RA
in a subject comprising determining an ACR20 response of a patient
population having RA and who was administered the TNF.alpha.
inhibitor, wherein an ACR20 response in at least about 80% of the
patient population indicates that the TNF.alpha. inhibitor is an
effective TNF.alpha. inhibitor for the treatment of RA in a
subject. In one embodiment, an ACR20 response in at least about 85%
of the patient population indicates that the TNF.alpha. inhibitor
is an effective TNF.alpha. inhibitor for the treatment of RA in a
subject. In one embodiment, an ACR20 response in at least about
43%, at least about 56%, at least about 60%, at least about 65%, at
least about 66%, at least about 67%, at least about 69%, at least
about 70%, at least about 73%, at least about 75%, at least about
78%, at least about 81%, at least about 82%, or at least about 85%,
of the patient population indicates that the TNF.alpha. inhibitor
is an effective TNF.alpha. inhibitor for the treatment of RA in a
subject. Numbers intermediate to the above recited percentages,
e.g., 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%,
56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%,
69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%,
82%, 83%, 84%, as well as all other numbers recited herein, are
also intended to be part of this invention. Ranges of values using
a combination of any of the above recited values as upper and/or
lower limits are intended to be included in the scope of the
invention.
[0288] In one embodiment, the invention provides a method for
determining the efficacy of a human TNF.alpha. antibody, or
antigen-binding portion thereof, for treating RA in a subject who
has failed prior infliximab treatment comprising determining an
ACR20 response of a patient population having RA who has failed
previous infliximab treatment and who was administered the human
TNF.alpha. antibody, or antigen-binding portion thereof, wherein an
ACR20 response in at least about 50% of the patient population
indicates that the human TNF.alpha. antibody, or antigen-binding
portion thereof, is an effective human TNF.alpha. antibody, or
antigen-binding portion thereof, for the treatment of RA in a
subject who has failed prior infliximab treatment. In one
embodiment, an ACR20 response in at least about 50% of the patient
population indicates that the human TNF antibody, or
antigen-binding portion thereof, is an effective human TNF.alpha.
antibody, or antigen-binding portion thereof, for the treatment of
RA in a subject who has failed prior infliximab treatment. In one
embodiment, an ACR20 response in at least about 55% of the patient
population indicates that the human TNF.alpha. antibody, or
antigen-binding portion thereof, is an effective human TNF.alpha.
antibody, or antigen-binding portion thereof, for the treatment of
RA in a subject who has failed prior infliximab treatment. In one
embodiment, an ACR20 response in at least about 60% of the patient
population indicates that the human TNF.alpha. antibody, or
antigen-binding portion thereof, is an effective human TNF.alpha.
antibody, or antigen-binding portion thereof, for the treatment of
RA in a subject who has failed prior infliximab treatment. In one
embodiment, an ACR20 response in at least about 65% of the patient
population indicates that the human TNF antibody, or
antigen-binding portion thereof, is an effective human TNF.alpha.
antibody, or antigen-binding portion thereof, for the treatment of
RA in a subject who has failed prior infliximab treatment. In one
embodiment, an ACR20 response in at least about 69% of the patient
population indicates that the human TNF.alpha. a antibody, or
antigen-binding portion thereof, is an effective human TNF.alpha.
antibody, or antigen-binding portion thereof, for the treatment of
RA in a subject who has failed prior infliximab treatment.
[0289] Numbers intermediate to the above recited percentages, e.g.,
60%, 63%, 64%, as well as all other numbers recited herein, are
also intended to be part of this invention. Ranges of values using
a combination of any of the above recited values as upper and/or
lower limits are intended to be included in the scope of the
invention.
[0290] In one embodiment, the invention provides a method of
determining the efficacy of a TNF.alpha. inhibitor for treating RA
in a subject comprising determining an ACR50 response of a patient
population having RA and who was administered the TNF.alpha.
inhibitor, wherein an ACR50 response in at least about 62% of the
patient population indicates that the TNF.alpha. inhibitor is an
effective TNF.alpha. inhibitor for the treatment of RA in a
subject. In one embodiment, an ACR50 response in at least about 65%
of the patient population indicates that the TNF.alpha. inhibitor
is an effective TNF.alpha. inhibitor for the treatment of RA in a
subject. In one embodiment, an ACR50 response in at least about
21%, at least about 28%, at least about 35%, at least about 37%, at
least about 40%, at least about 41%, at least about 43%, at least
about 45%, at least about 55%, at least about 57%, at least about
59%, at least about 60%, at least about 62%, at least about 65% of
the patient population indicates that the TNF.alpha. inhibitor is
an effective TNF.alpha. inhibitor for the treatment of RA in a
subject. Numbers intermediate to the above recited percentages,
e.g., 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%,
33%, 34%. 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%,
46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%,
59%, 60%, 61%, 62%, 63%, 64%, 65%, as well as all other numbers
recited herein, are also intended to be part of this invention.
Ranges of values using a combination of any of the above recited
values as upper and/or lower limits are intended to be included in
the scope of the invention.
[0291] In one embodiment, the invention provides a method for
determining the efficacy of a human TNF.alpha. antibody, or
antigen-binding portion thereof, for treating RA in a subject
comprising determining an ACR70 response of a patient population
having RA and who was administered the human TNF.alpha. antibody,
or antigen-binding portion thereof, wherein an ACR70 response in at
least about 20% of the patient population indicates that the human
TNF.alpha. antibody, or antigen-binding portion thereof, is an
effective human TNF.alpha. antibody, or antigen-binding portion
thereof, for the treatment of RA in a subject. In one embodiment,
an ACR70 response in at least about 25% of the patient population
indicates that the human TNF.alpha. antibody, or antigen-binding
portion thereof; is an effective human TNF.alpha. antibody, or
antigen-binding portion thereof, for the treatment of RA in a
subject. In one embodiment, an ACR70 response in at least about 30%
of the patient population indicates that the human TNF.alpha.
antibody, or antigen-binding portion thereof, is an effective human
TNF.alpha. antibody, or antigen-binding portion thereof, for the
treatment of RA in a subject. In one embodiment, an ACR70 response
in at least about 35% of the patient population indicates that the
human TNF.alpha. antibody, or antigen-binding portion thereof, is
an effective human TNF.alpha. antibody, or antigen-binding portion
thereof, for the treatment of RA in a subject. In one embodiment,
an ACR70 response in at least about 40% of the patient population
indicates that the human TNF.alpha. antibody, or antigen-binding
portion thereof, is an effective human TNF.alpha. antibody, or
antigen-binding portion thereof, for the treatment of RA in a
subject. In one embodiment, an ACR70 response in at least about
14%, at least about 16%, at least about 17%, at least about 18%, at
least about 19%, at least about 20%, at least about 21%, at least
about 25%, at least about 26%, at least about 30%, at least about
35%, at least about 36%, at least about 38%, at least about 40% of
the patient population indicates that the human TNF.alpha.
antibody, or antigen-binding portion thereof, is an effective human
TNF.alpha. antibody, or antigen-binding portion thereof, for the
treatment of RA in a subject. Numbers intermediate to the above
recited percentages, e.g., 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%,
23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%. 35%,
36%, 37%, 38%, 39%, 40%, as well as all other numbers recited
herein, are also intended to be part of this invention. Ranges of
values using a combination of any of the above recited values as
upper and/or lower limits are intended to be included in the scope
of the invention.
[0292] In one embodiment, the invention provides a method for
determining the efficacy of a TNF.alpha. inhibitor, including a
human TNF.alpha. antibody, for treating RA in a subject, using the
EULAR response of a subject or patient population. European League
Against Rheumatism (EULAR) Response Criteria is based on the
Disease Activity Score (DAS) index. To be classified as responders,
patients should have a significant change in DAS and also low
current disease activity. Three categories are defined: good,
moderate, and non-responders. For details of EULAR criteria see:
Van Gestel A M, Prevoo M L, van't Hof M A, van Rijswijk M H, van de
Putte L B, van Riel P L. Development and validation of the European
League Against, incorporated by reference herein.
[0293] In one embodiment, the invention provides a method for
determining the efficacy of a human TNF.alpha. antibody, or
antigen-binding portion thereof, for treating RA in a subject
comprising determining a good EULAR response of a patient
population having RA and who was administered the human TNF.alpha.
antibody, or antigen-binding portion thereof, wherein a good EULAR
response in at least about 35% of the patient population indicates
that the human TNF.alpha. antibody, or antigen-binding portion
thereof, is an effective human TNF.alpha. antibody, or
antigen-binding portion thereof, for the treatment of RA in a
subject. In one embodiment, a good EULAR response in at least about
40% of the patient population indicates that the human TNF.alpha.
antibody, or antigen-binding portion thereof, is an effective human
TNF.alpha. antibody, or antigen-binding portion thereof, for the
treatment of RA in a subject. In one embodiment, a good EULAR
response in at least about 13%, at least about 20%, at least about
24%, at least about 25%, at least about 28%, at least about 30%, at
least about 32%, at least about 33%, at least about 35%, at least
about 36%, at least about 38%, or at least about 40% of the patient
population indicates that the human TNF.alpha. antibody, or
antigen-binding portion thereof, is an effective human TNF.alpha.
antibody, or antigen-binding portion thereof, for the treatment of
RA in a subject. Numbers intermediate to the above recited
percentages, e.g., 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%/a, 21%,
22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%.
35%, 36%, 37%, 38%, 39%, 40%, as well as all other numbers recited
herein, are also intended to be part of this invention. Ranges of
values using a combination of any of the above recited values as
upper and/or lower limits are intended to be included in the scope
of the invention.
[0294] In one embodiment, the invention provides a method for
determining the efficacy of a human TNF.alpha. antibody, or
antigen-binding portion thereof, for treating RA in a subject
comprising determining a moderate EULAR response of a patient
population having RA and who was administered the human TNF.alpha.
antibody, or antigen-binding portion thereof, wherein a moderate
EULAR response in at least about 83% of the patient population
indicates that the human TNF.alpha. antibody, or antigen-binding
portion thereof, is an effective human TNF.alpha. antibody, or
antigen-binding portion thereof, for the treatment of RA. In one
embodiment, a moderate EULAR response in at least about 85% of the
patient population indicates that the human TNF.alpha. antibody, or
antigen-binding portion thereof, is an effective human TNF.alpha.
antibody, or antigen-binding portion thereof, for the treatment of
RA. In one embodiment, a moderate EULAR response in at least about
90% of the patient population indicates that the human TNF.alpha.
antibody, or antigen-binding portion thereof, is an effective human
TNF.alpha. antibody, or antigen-binding portion thereof, for the
treatment of RA. In one embodiment, a moderate EULAR response in at
least about 92% of the patient population indicates that the human
TNF.alpha. antibody, or antigen-binding portion thereof, is an
effective human TNF.alpha. antibody, or antigen-binding portion
thereof, for the treatment of RA. In one embodiment, a moderate
EULAR response in at least about 60%, at least about 61%, at least
about 62%, at least about 78%, at least about 80%, at least about
82%, at least about 83%, at least about 85%, at least about 88%, or
at least about 90%, or at least about 92% of the patient population
indicates that the human TNF.alpha. antibody, or antigen-binding
portion thereof, is an effective human TNF.alpha. antibody, or
antigen-binding portion thereof, for the treatment of RA. Numbers
intermediate to the above recited percentages, e.g., 60%, 61%, 62%,
63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%,
76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, as
well as all other numbers recited herein, are also intended to be
part of this invention. Ranges of values using a combination of any
of the above recited values as upper and/or lower limits are
intended to be included in the scope of the invention.
[0295] The invention also provides a method for determining the
efficacy of a TNF.alpha. inhibitor, including a human TNF.alpha.
antibody, for treating RA in a subject, using the Simplified
Disease Activity Score (SDAI). The SDAI is a valid and sensitive
assessment of disease activity and treatment response that is
comparable with the DAS 28 and ACR response criteria; it is easy to
calculate and therefore a viable tool for day-to-day clinical
assessment of RA treatment (see Smolen et al. Rheumatology
(Oxford). 2003 February; 42(2):244-57).
[0296] In one embodiment, the invention provides a method for
determining the efficacy of a TNF.alpha. inhibitor for the
treatment of rheumatoid arthritis (RA) in a subject comprising
determining a Simplified Disease Activity Score (SDAI) of a patient
population having RA and who was administered the TNF.alpha.
inhibitor, wherein a mean SDAI of no greater than about 3.3 in at
least about 11% of the patient population indicates that the
TNF.alpha. inhibitor is an effective TNF.alpha. inhibitor for
treating RA.
[0297] Other indices described in the art, including those
referenced in the Examples, may also be used to determine the
efficacy of a TNF.alpha. inhibitor in accordance with the methods
of the invention. For example, TJC and/or SJC counts may be used,
HAQ scores may be used, and DAS scores may be used to determine
whether a TNF.alpha. inhibitor is efficacious for treating RA in a
subject.
Tender joint count (TJC) is an assessment of 28 or more joints
where several different aspects of tenderness are assessed by
pressure and joint manipulation on physical examination. Swollen
joint count (SJC): an assessment of 28 or more joints where joints
are classified as either swollen or not swollen. For TJC and SJC
scoring see Fuchs and Pincus, Arthritis Rheum 37:470-475, 1994;
American College of Rheumatology Committee on Outcome Measures in
Rheumatoid Arthritis Clinical Trials: Reduced joint counts in
rheumatoid arthritis clinical trials. Arthritis Rheum 37:463-464,
1994).
[0298] Health Assessment Questionnaire (HAQ) is a standardized
disability questionnaire that was initially developed for use in
rheumatoid arthritis (RA). A high HAQ score has been shown to be a
strong predictor of morbidity and mortality in RA, and low HAQ
scores are predictive of better outcomes (see Fries et al.
Arthritis Rheum 1980; 23:137-45.
[0299] DAS28 (disease activity score) is also an accepted measure
of the activity of rheumatoid arthritis in an affected subject. The
following parameters are included in the calculation: Number of
joints tender to the touch (TEN); Number of swollen joints (SW);
Erythrocyte sedimentation rate (ESR); Patient assessment of disease
activity (VAS; mm) (see Van der Heijde et al. Ann Rheum Dis 1990;
49:916-20). In modified DAS (DAS28) 28 joints are assessed (see
Prevoo M L L, et al. Arthritis Rheum 1995; 38:44-8).
[0300] In one embodiment, the invention provides a method for
determining the efficacy of a TNF.alpha. inhibitor, including a
human TNF.alpha. antibody, for treating RA in a subject, using the
CRP level in correlation with a Patient Activity Score (PAS). The
invention. The invention provides a method for predicting the
efficacy of a TNF.alpha. inhibitor for the treatment of rheumatoid
arthritis (RA) in a subject comprising using the combination of a
C-reactive protein (CRP) level of the subject and a Patient
Activity Score (PAS) of the subject, wherein an improvement in the
CRP level and the PAS score early in the treatment of the patient
with the TNF.alpha. inhibitor indicates that the TNF.alpha.
inhibitor is an effective TNF.alpha. inhibitor for the treatment of
RA in the subject. In one embodiment, the improvement in the CRP
level and the PAS score early in the treatment of the subject
occurs at about two weeks following initiation of the treatment in
the subject. In one embodiment, the PAS score is determined using
the Health Assessment Questionnaire (HAQ) of the subject. In one
embodiment, the improvement in the CRP level is at least as
described in the Examples below. In one embodiment, the improvement
in the HAQ score is at least about 0.4.
[0301] Also encompassed in the scope of the invention is
administering the effective TNF inhibitor, e.g., human TNF.alpha.
antibody, or antigen-binding portion thereof, to a subject for the
treatment of RA, wherein the TNF inhibitor is identified as an
effective TNF inhibitor using any of the methods and uses described
herein, as well as those methods described in the Examples.
[0302] The invention further provides a method of treating RA in a
subject comprising administering an effective human TNF.alpha.
antibody, or antigen-binding portion thereof, for the treatment of
RA in a subject, wherein the effective human TNF.alpha. antibody,
or antigen-binding portion thereof, was identified as achieving a
moderate EULAR response in at least about 83% of a patient
population who was administered the human TNF.alpha. antibody, or
antigen-binding portion thereof. In one embodiment, the invention
provides a use of an effective human TNF.alpha. antibody, or
antigen-binding portion thereof, in the manufacture of a medicament
for treating RA in a subject, wherein the effective human
TNF.alpha. antibody, or antigen-binding portion thereof, was
identified as achieving a moderate EULAR response in at least about
83% of a patient population who was administered the human
TNF.alpha. antibody, or antigen-binding portion thereof.
[0303] The invention also provides a method of treating RA based on
the determination of a TNF.alpha. inhibitor as an effective
TNF.alpha. inhibitor for achieving a certain ACR response in a
patient population having taken the TNF.alpha. inhibitor. Thus, in
one embodiment, the invention provides a method of treating in a
subject comprising administering an effective TNF.alpha. inhibitor,
wherein the effective TN Fa inhibitor was identified as providing
an ACR20 response in at least about 80% of a patient population who
received the effective TNF.alpha. inhibitor for the treatment of
RA. The invention also provides, in another embodiment, use of an
effective TNF.alpha. inhibitor in the manufacture of a medicament
for the treatment of RA in a subject, wherein the TNF.alpha.
inhibitor was identified as providing an ACR20 response in at least
about 80% of a patient population who received the effective
TNF.alpha. inhibitor for the treatment of RA.
[0304] In one embodiment, the invention provides a method of
treating RA in a subject comprising administering an effective
human TNF.alpha. antibody, or antigen-binding portion thereof, for
the treatment of RA in a subject, wherein the effective human
TNF.alpha. antibody, or antigen-binding portion thereof, was
identified as achieving an ACR70 response in at least about 20% of
a patient population who was administered the human TNF.alpha.
antibody, or antigen-binding portion thereof. In one embodiment,
the invention provides a use of an effective human TNF.alpha.
antibody, or antigen-binding portion thereof, in the manufacture of
a medicament for treating RA in a subject, wherein the effective
human TNF.alpha. antibody, or antigen-binding portion thereof, was
identified as achieving an ACR70 response in at least about 20% of
a patient population who was administered the human TNF.alpha.
antibody, or antigen-binding portion thereof.
[0305] It should be noted that the Examples provided herein
represent different methods of determining the efficacy of a
TNF.alpha. inhibitor, such as a human TNF.alpha. antibody, or
antigen-binding portion thereof. As such, data and results
described in the Examples section which shows efficacy of a
TNF.alpha. inhibitor, e.g., ability to treat RA, are included in
the methods of determining efficacy of the invention.
[0306] Time points for determining efficacy will be understood by
those of skill in the art to depend on the type of efficacy being
determined. e.g., treatment of RA. In one embodiment, measurements
in scores, e.g., an improvement in the ACR or EULAR response of a
subject, may be measured against a subject's baseline score.
Generally, a baseline refers to a measurement or score of a patient
before treatment, i.e. week 0. Other time points may also be
included as a starting point in determining efficacy, however. For
example, in determining the efficacy of a TNF.alpha. inhibitor for
treating RA in a patient population, a determination of the
percentage of the patient population who is treated, e.g.,
improvement in ACR response, may be determined based on a time
point from when treatment was initiated.
[0307] Patient populations described in the methods of the
invention are generally selected based on common characteristics,
such as, but not limited to, subjects diagnosed with RA who on a
dosing regimen comprising a TNF.alpha. inhibitor. Such a patient
population would be appropriate for determining the efficacy of the
TNF.alpha. inhibitor for treating RA in the given patient
population. In one embodiment, the patient population is an adult
population. In another embodiment, members of a patient population
have all been diagnosed with moderate to severe Ra, including
moderate to severe active RA.
[0308] In one embodiment, the methods of the invention for
determining whether a TNF.alpha. inhibitor is an effective
TNF.alpha. inhibitor, include determining changes, improvements,
measurements, etc., in RA using appropriate indices known in the
art, e.g., ACR, EULAR, DAS, HAQ, from a patient population who has
already been administered the TNF.alpha. inhibitor. Such a patient
population may be pre-selected according to common characteristics,
e.g., RA, loss of response to infliximab, and may have already been
given the TNF.alpha. inhibitor. Administration of the TNF.alpha.
inhibitor may or may not be performed by the same person of
ordinary skill who is determining the efficacy of the TNF.alpha.
inhibitor in accordance with the teachings of the
specification.
[0309] In one embodiment, the methods of the invention comprise
administering the TNF.alpha. inhibitor to the subjects of a patient
population and determining the efficacy of the TNF.alpha. inhibitor
by determining changes, improvements, measurements, etc., using RA
indices known in the art, in the patient population in comparison
to the Examples set forth below. For example, in one embodiment the
invention includes a method for determining efficacy of a
TNF.alpha. inhibitor for the treatment of RA comprising
administering the TNF.alpha. inhibitor to a preselected patient
population having RA; and determining the effectiveness of the
TNF.alpha. inhibitor by using a mean baseline TJC or SJC score of
the patient population and a mean TJC or SJC score following
administration of the TNF.alpha. inhibitor.
[0310] Methods of the invention relating to determining efficacy,
i.e., determining whether a TNF.alpha. inhibitor is an effective
TNF.alpha. inhibitor, may also be applied to specific patient
populations within the overall patient population who together have
specific, common characteristics, i.e., a subpopulation. For
example, the patient population may comprise patients who have
failed prior infliximab treatment.
[0311] In addition, while the above methods are described in terms
of patient populations, methods of efficacy described herein may
also be applied to individual subjects. For example, a method for
determining efficacy may comprise determining whether a subject
having RA and who is on a dosage regimen, e.g., a biweekly dosing
regimen, comprising a human TNF.alpha. antibody, is able to achieve
an ACR50 response, wherein an ACR50 response would indicate that
the human TNF.alpha. antibody is an effective human TNF.alpha.
antibody.
[0312] The Examples and discoveries described herein are
representative of a TNF.alpha. inhibitor, i.e., adalimumab, which
is effective for treating RA, including reducing signs and symptoms
of RA, inducing major clinical response in RA, inhibiting the
radiographic progression of RA, and improving physical function in
patients having RA. As such, the studies and results described in
the Examples section herein may be used as a guideline for
determining the efficacy of a TNF.alpha. inhibitor, i.e., whether a
TNF.alpha. inhibitor is an effective TNF.alpha. inhibitor for the
treatment of RA. In one embodiment, methods of determining efficacy
described herein may be used to determine whether a TNF.alpha.
inhibitor is bioequivalent to another TNF.alpha. inhibitor.
[0313] In one embodiment, the article of manufacture of the
invention comprises instructions regarding how to determine the
efficacy of the TNF.alpha. inhibitor for the treatment of RA.
[0314] The present invention is further illustrated by the
following examples which should not be construed as limiting in any
way.
Example 1
Adalimumab (HUMIRA.RTM.) is Safe in Global Clinical Trials in
Multiple Indications and Reduced Mortality in Rheumatoid
Arthritis
[0315] A study was performed to assess the safety of adalimumab
(ADA) in treating patients (pts) with rheumatoid arthritis (RA),
psoriatic arthritis (PsA), ankylosing spondylitis (AS), psoriasis
(Ps), or juvenile idiopathic arthritis (JIA) in global clinical
trials.
[0316] Patients treated with ADA in global clinical trials were
routinely assessed for safety. Serious adverse events (SAE) of
interest to physicians prescribing anti-tumor necrosis factor (TNF)
therapy were assessed per 100 pt years (E/100PY). SAEs were coded
using the Medical Dictionary for Regulatory Activities
(MedDRA).
[0317] Adverse events (AEs) were routinely collected in global
clinical trials for all indications and labeled as a serious
adverse event (SAE) based on regulatory criteria/definition: 1)
Fatal, 2) Life-threatening, 3) Requires inpatient hospitalization,
4) Prolongs hospitalization, 5) Results in congenital anomaly/birth
defect, 6) Causes persistent or significant disability/incapacity,
7) Important medical event that jeopardizes the patient and
requires medical/surgical intervention to prevent another serious
outcome.
[0318] The Standardized Mortality Ratio (SMR) was calculated using
the expected number of deaths from an age and sex matched general
population as published in the World Health Organization (WHO)
website. The WHO 2000 mortality data for the US was used in
determining the expected number of deaths per age category.
[0319] Randomized clinical trials and open-label studies were
conducted to determine the safety of ADA across several
indications. The patient demographic data is listed in Table 1. The
randomized clinical trials (RCT) and open-label (OL) studies
included as follows, by indication: [0320] RA--All clinical trials
(except for the early RA trial), including Phase II and III RCTs,
OL extensions, and OL Phase IIIb trials. [0321] PsA--A 24-week (wk)
Phase III RCT in NSAID non-responders; a 12-wk Phase III study in
DMARD non-responders; and an ongoing OL extension for completers of
the 2 studies. [0322] AS--Two ongoing Phase III multicenter studies
in US, EU, and Canada, each with a 24-wk RCT phase followed by an
80-wk OL extension. [0323] Ps--A 12-wk Phase II RCT with a 48-wk OL
extension. [0324] JIA--The 16-week OL lead-in and 32-wk RCT phases
of a multicenter Phase III randomized, double-blind stratified
parallel-group study in children with polyarticular JIA.
TABLE-US-00001 [0324] TABLE 1 Baseline Demographics RA PsA AS Ps
JIA N = 10,049+ N = 395 N = 393 N = 142 N = 171 Age, mean (yrs)
53.9 49 42 44.6 11.3 % Female 79.5 44.6 24.2 31 78.9 Disease
duration, 11.0.dagger-dbl. 9.1 11.4 19.2 3.8 mean (yrs) % on
concomitant 85.5 54.2 20.4 .sup. 0* 49.7 immunosuppressive/ DMARD
therapy % on concomitant 64.8 12.4 9.4 .sup. 0* 11.1 corticosteroid
therapy *Per protocol, patients were required to discontinue all
systemic therapies for psoriasis prior to study entry +1 patient
out of the 10,050 had missing demographic information
.dagger-dbl.Based on data from 9,955 patients
[0325] As of Apr. 15, 2005, the ADA RA clinical trial safety
database included data for 10,050 patients, representing 12,506
patient years (PY) of exposure to ADA. The rate of serious
infections, 5.05/100PY, was comparable to that reported on Aug. 31,
2002 (4.9/100PY), and to published reports of RA populations naive
to anti-TNF therapy. (Singh et al. (1999) Arthritis Rheum
42(Suppl):S242 and Doran et al. (2002) Arthritis Rheum 46:2287) The
number of patients, PY of exposure, and rates of SAEs of interest
for ADA-treated patients in multiple indications are given below in
Table 2. In addition, rates of serious infection separated by
indications are given in Table 3 and rates of lymphomas by
indication are given in Table 4.
TABLE-US-00002 TABLE 2 Rates of SAEs of Interest (E/100PY)
Indication RA PsA AS Ps JIA Exposure (PY) 12,506 484 423 135 99
Patients 10,050 395 393 142 171 Serious Infections 5.05 2.07 1.18
0.74 4.04 Tuberculosis 0.27 0 0 0 0 Lymphomas 0.12 0.41 0.24 0 0
Demyelinating Disease 0.08 0 0 0 0 SLE/Lupus-like 0.10 0 0 0 0
Syndrome CHF 0.28 0 0 0 0
TABLE-US-00003 TABLE 3 Rates of Serious Infection by Indication
RA.sup.1 PSA AS Ps JIA N 10,050 395 393 142 171 Exposure (PY)
12,506 484 423 135 99 Events per 100 PY 5.05 2.07 1.18 0.74 4.04
.sup.1Schiff M. H., et al. Ann Rheum Dis 2006; doi:
10.1136/ard.2005.043166.
TABLE-US-00004 TABLE 4 Rates of Lymphomas by Indication RA.sup.1
PSA AS Ps JIA No. of lymphomas 15 2 1 0 0 N 10,050 395 393 142 171
Exposure (PY) 12,506 484 423 135 99 Events per 100 PY 0.12 0.41
0.24 0 0 .sup.1Schiff M. H., et al. Ann Rheum Dis 2006; doi:
10.1136/ard.2005.043166.
[0326] In the RA clinical trials, which have the largest number of
ADA-treated patients, the standardized mortality ratio was
calculated at 0.67 (95% CI 0.53-0.83), a much lower value than
previously reported for the RA population prior to the availability
of anti-TNF agents. (Gabriel et al. Arthritis Rheum 2003; 48(1):54
and Wolfe et al. Arthritis Rheum 1994; 37(4):481). The observed
deaths, and standard mortality ratios, listed by gender and age
matched populations are given below in Table 5.
TABLE-US-00005 TABLE 5 Standardized Mortality Ratios:All
Adalimumab-Treated Patients with RA Compared to a Gender and Age
Matched General Population Expected Observed Gender Age N Deaths
Deaths SMR (95% CI) Female 15-24 137 0.1 0 25-34 534 0.4 0 35-44
1319 2.7 3 45-54 2046 9.2 8 55-64 2147 25.2 19 65-74 1465 35.8 22
>/=75 343 31.6 12 Subtotal 7991 104.9 64 0.61 (0.47-0.78) Male
15-24 19 0 0 25-34 99 0.2 0 35-44 286 1.1 1 45-54 549 5.0 3 55-64
664 12.3 10 65-74 370 15.0 12 >/=75 71 6.3 3 Subtotal 2058 40 29
0.73 (0.49-1.04) Total 10,049 144.9 93 0.64 (0.52-0.79)
[0327] In conclusion, adalimumab treatment demonstrated a
consistent safety profile in global clinical trials for various
TNF-mediated diseases. SAE rates of interest did not differ
significantly across the clinical trials evaluated. In RA clinical
trials, evidence suggests a decrease in mortality in
adalimumab-treated patients compared to a sex and age matched
non-RA population,
Example 2
Adalimumab is Effective in Treating in Patients with Rheumatoid
Arthritis (RA) Who Previously Failed Infliximab Treatment
[0328] A proportion of patients with RA do not respond optimally,
or may be intolerant, to an initial anti-TNF therapy. Limited data
availability prohibited the examination of important questions
about the safety and efficacy of treating such patients with an
alternate TNF antagonist. The objective of this study was to
compare the efficacy and safety of adalimumab (Ada) in a large
cohort of patients with RA who previously failed infliximab (1)
therapy due to lack or loss of response or to intolerance.
[0329] Patients with long-standing, moderate to severe RA were
enrolled in Study A (ReACT) and received adalimumab 40 mg
subcutaneously (sc) every other week (eow). The core study period
was 16 weeks followed by maintenance therapy up to week 56.
[0330] Inclusion criteria included patients over the age of 18,
with RA (American College of Rheumatology criteria) for .gtoreq.6
months. Patients had active RA (DAS28.gtoreq.3.2) and had an
unsatisfactory response, loss of response, or intolerance (e.g.,
infusion reactions) prior to infliximab treatment. Previous use of
infliximab was defined as administration of at least four
infusions. In addition, treatment with another TNF antagonist, if
any, had to have been discontinued .gtoreq.2 months before study
entry.
[0331] Table 6 summarizes the RA disease severity characteristics
and history of prior inflixmab and DMARD administration for the
study population. Of the patients enrolled in the study, 90.2%
completed 16 weeks of treatment, and 30 patients (73.2%) were still
receiving the study drug at the week 56 visit. Of the 11 patients
who withdrew from the study prior to week 56, 6 (14.4%) withdrew
due to the occurrence of one or more adverse effects and 7 (17.1%)
withdrew due to a lack of effectiveness.
TABLE-US-00006 TABLE 6 Disease Severity Characteristics and Prior
Infliximab/DMARD Administration by Reason for Discontinuation of
Prior Infliximab Reason for Discontinuation of Prior Infliximab No
Loss of All Patients Response Response Intolerance Parameter* N =
41 n = 15 n = 21 n = 5 Mean duration of RA (years) 11.6 .+-. 7.4
12.2 .+-. 9.2 11.8 .+-. 7.0 9.2 .+-. 2.5 Number of prior DMARDs 5.3
5.5 5.5 4.2 (includes infliximab) Mean duration of infliximab 17.3
.+-. 15.1 9.3 .+-. 5.3 23.4 .+-. 17.6 15.6 .+-. 14.0 treatment
(months) Mean dose per infliximab 262.4 .+-. 87.6 263.7 .+-. 81.9
267.5 .+-. 100.0 237.2 .+-. 47.8 infusion (mg) DAS28 6.09 .+-. 0.91
5.85 .+-. 0.70 6.18 .+-. 1.03 6.48 .+-. 0.86 Tender joint count (28
joints) 14.81 .+-. 6.57 13.73 .+-. 6.89 14.67 .+-. 6.64 18.60 .+-.
4.72 Swollen joint count (28 joints) 8.22 .+-. 4.75 5.93 .+-. 4.10
8.95 .+-. 4.62 12.00 .+-. 4.42 Physician's global assessment 49.81
.+-. 20.01 41.93 .+-. 17.36 53.00 .+-. 21.28 60.00 .+-. 16.43 of
disease activity (100 mm VAS) Patient's global assessment of 63.02
.+-. 19.76 58.87 .+-. 21.02 68.43 .+-. 16.43 52.80 .+-. 25.67
disease activity (100 mm VAS) Patient's global assessment of 65.78
.+-. 21.00 57.60 .+-. 24.59 73.38 .+-. 14.13 58.40 .+-. 25.97 pain
(100 mm VAS) HAQ DI 1.85 .+-. 0.49 1.92 .+-. 0.52 1.80 .+-. 0.43
1.85 .+-. 0.71 Erythrocyte sedimentation rate 37.34 .+-. 23.24
33.87 .+-. 12.94 39.48 .+-. 27.96 38.80 .+-. 28.86 (mm/h) CRP
(mg/L) 25.13 .+-. 32.00 23.27 .+-. 26.84 26.26 .+-. 38.06 26.00
.+-. 21.43 *Mean .+-. SD except where otherwise specified. CRP =
C-reactive protein; DAS28 = Disease Activity Score 28; DMARD =
disease-modifying antirheumatic drug; HAQ DI = Health Assessment
Questionnaire Disability Index; RA = rheumatoid arthritis; VAS =
visual analog scale.
[0332] A total of 27 patients were receiving DMARDs at baseline,
with methotrexate being the most common (25/27 patients). A total
of 17/41 (41.5%) patients had measurable serum HACA concentrations
at baseline. Nine patients were not assessable for HACA status
owing to remaining infliximab serum concentrations. The mean
interval between the last infliximab infusion and the first
adalimumab injection in HACA-negative and HACA-positive patients
was 12 and 15 weeks, respectively, and in patients without and with
remaining infliximab serum concentrations, the mean interval was 14
and 11 weeks, respectively. HACA status and presence of infliximab
serum concentration at study entry stratified by reason for
discontinuation of infliximab treatment are presented in Table 7. A
total of 6 (14.4%) patients received isoniazid prophylaxis for TB
based on baseline chest radiograph indicative of latent TB,
positive PPD skin test, or other risk factors.
TABLE-US-00007 TABLE 7 Baseline HACA Status and Infliximab Serum
Concentration Status by Reason for Discontinuation of Prior
Infliximab Measurable Infliximab Serum Concentration Reason for
HACA Status* at Study Entry Discontinuation of Positive, Negative,
Yes, No, Prior Infliximab n = 17 n = 15 n = 9 n = 32 No response 4
6 4 10 Loss of response 10 7 5 17 Intolerance 3 2 0 5 *In nine
patients, HACA could not be determined because of measurable
infliximab serum concentrations (see second column from right).
HACA = human anti-chimeric antibody
[0333] Clinically meaningful improvements occurred in all measures
of RA activity in the overall patient population after 16 weeks of
adalimumab treatment, and improvements were maintained through 56
weeks. Patients experienced steady increases in ACR response over
time, with 46.2%, 28.2%, and 12.8% of patients achieving ACR20, 50,
and 70, respectively, at Week 16, and 56.4/o %, 28.2%, and 17.9%
achieving ACR20, 50, and 70, respectively, at Week 56 (Table 9). A
total of 61.0% of patients achieved at least a moderate EULAR
response, and 17.1% of patients achieved a good EULAR response at
Week 16, with clinically important improvements being maintained
through Week 56 (Table 8). Similarly, the DAS28 improved from
baseline, with a mean change of -1.45 at Week 16 (mean-23.0%
change) and of -1.63 at Week 56 (mean-25.8% change) (Table 10).
Patients also experienced decreased TJC and SJC at all measured
time points, with statistically significant (p<0.001)
improvements from baseline of -6.8 (-38.4%) and -7.1 (-41.7%) at
Weeks 16 and 56, respectively, for TJC, and of -4.6 (-52.8%) and
-4.8 (-54.4%) at Weeks 16 and 56, respectively, for SJC.
[0334] Patient assessment of pain and both physician and patient
global assessments of disease activity were similarly clinically
improved (Table 8). HAQ DI scores also improved from baseline at
all measurement time points during adalimumab treatment, with a
mean change from baseline of -0.21 at Week 16 and of -0.19 at Week
56 (>10% decrease from baseline, p<0.037). The mean reduction
in C-reactive protein concentration from baseline was -3.83 mg/L at
Week 16 and -3.46 mg/L (78.5% decrease from baseline, p<0.244)
at Week 56. The erythrocyte sedimentation rate also declined at all
measured time points, with a mean change from baseline of -6.6 mm/h
at Week 16 and of -6.5 mm/h at Week 56 (-6.3% decrease from
baseline, p=0.571).
TABLE-US-00008 TABLE 8 Adalimumab Efficacy at Week 56 (LOCF Data)
Reason for Discontinuation of Prior Infliximab* No Loss of HACA
Status*.sup..dagger-dbl. All Patients* Response Response
Intolerance.sup..dagger. Positive Negative (N = 41) (n = 15) (n =
21) (n = 5) (n = 17) (n = 15) ACR20 response (%) 56 43 65 60 47 64
ACR50 response (%) 28 21 35 20 29 36 ACR70 response (%) 18 14 25 0
18 29 Moderate EULAR response (%) 61 60 62 60 47 67 Good EULAR
response (%) 24 13 33 20 29 27 DAS28, mean change from baseline
Absolute change .+-. SD -1.63 .+-. 1.72 -1.25 .+-. 1.33 -1.97 .+-.
2.08 -1.38 .+-. 0.65 -1.72 .+-. 2.02 -1.79 .+-. 1.70 Percent change
-26 -21 -30 -22 -26 -28 HAQ DI score (0-3), mean change from
baseline Absolute change .+-. SD -0.19 .+-. 0.48 -0.14 .+-. 0.48
-0.25 .+-. 0.54 -0.07 .+-. 0.19 -0.32 .+-. 0.55 -0.03 .+-. 0.43
Percent change -11 -9 -14 -3 -16 -4 Tender joint count (0-28
joints), mean change from baseline Absolute change .+-. SD -7.1
.+-. 8.4 -6.0 .+-. 6.5 -7.4 .+-. 10.2 -9.0 .+-. 5.0 -6.4 .+-. 9.5
-8.4 .+-. 8.7 Percent change -42 -40 -42 -47 -32 -53 Swollen joint
count (0-28 joints), mean change from baseline Absolute change .+-.
SD -4.8 .+-. 6.4 -3.1 .+-. 5.1 -5.2 .+-. 7.3 -7.6 .+-. 4.7 -5.6
.+-. 5.9 -5.3 .+-. 7.2 Percent change -54 -51 -55 -61 -53 -64
Patient's global assessment of disease (0-100 mm VAS), mean change
from baseline Absolute change .+-. SD -22 .+-. 29 -9 .+-. 27 -32
.+-. 25 -14 .+-. 38 -20 .+-. 35 -24 .+-. 27 Percent change -31 -10
-48 -21 -26 -38 Physician's global assessment of disease (0-100 mm
VAS), mean change from baseline Absolute change .+-. SD -21 .+-. 27
-17 .+-. 22 -24 .+-. 32 -22 .+-. 19 -19 .+-. 33 -25 .+-. 25 Percent
change -37 -40 -34 -39 -18 -55 Patient's assessment of pain (0-100
mm VAS), mean change from baseline Absolute change .+-. SD -24 .+-.
32 -9 .+-. 30 -36 .+-. 29 -18 .+-. 31 -24 .+-. 38 -24 .+-. 31
Percent change -27 -7 -49 -37 -30 -25 *Total number of patients
enrolled; last observation carried forward (LOCF).
.sup..dagger.Those patients who had discontinued prior infliximab
treatment for both an efficacy and safety reason were assigned to
the corresponding efficacy subgroup. The intolerance subgroup
consists of patients who had discontinued prior infliximab
treatment strictly because of intolerance. .sup..dagger-dbl.Nine
patients were not assessable for HACA due to measurable infliximab
concentrations. ACR = American College of Rheumatology; DAS28 =
Disease Activity Score 28; EULAR = European League Against
Rheumatism;
[0335] Adalimumab treatment led to clinically relevant improvement
in disease activity irrespective of the reason for stopping prior
infliximab therapy. At Week 16, ACR20 was 28.6% among those
patients who had no response to infliximab, 60.0% among patients
who had experienced a loss of response to infliximab, and 40.0%
among patients who were intolerant to infliximab. By Week 56, 42.9%
(no response subgroup) to 65.0% (loss of response subgroup) of
patients achieved an ACR20 response (Table 9). A similar trend was
observed for ACR50 and ACR70 response rates (Table 9).
TABLE-US-00009 TABLE 9 American College of Rheumatology (ACR) 20,
50, 70 improvement response rates with adalimumab treatment at Week
56 (LOCF) by reason for discontinuation of prior infliximab
PatientType Patients (%) ACR 20 All (N = 41) 56 No response (N =
15) 43 Loss of Response (N = 21) 65 Intolerance (N = 5) 60 ACR 50
All (N = 41) 28 No response (N = 15) 21 Loss of Response (N = 21)
35 Intolerance (N = 5) 20 ACR 70 All (N = 41) 18 No response (N =
15) 14 Loss of Response (N = 21) 25 Intolerance (N = 5) 0
[0336] At Week 16, a moderate EULAR response was achieved by 46.7%
of patients who had no response to infliximab, 66.7% of patients
who had a loss of response to infliximab, and 80% of patients who
were intolerant to infliximab. At Week 56, at least 50% of patients
in each subgroup achieved a moderate EULAR response, with those
patients who had experienced loss of response or no response to
infliximab achieving moderate EULAR response rates of 61.9% and
60.0%, respectively (Table 11). A good EULAR response was achieved
at Week 16 by 6.7%, 23.8%, and 20.0% of patients with no response,
loss of response, and intolerance, respectively. The respective
data among patients with no response, loss of response, and
intolerance at Week 56 were 13.3%, 33.3% and 20.0%/o. The DAS28
improved from baseline in all three subgroups at all time points
evaluated, with the greatest response occurring in those patients
who had stopped infliximab due to loss of response (Table 10).
TABLE-US-00010 TABLE 10 Change in Disease Activity Score 28 (DAS28)
at Week 16 and Week 56 by reason for discontinuation of prior
infliximab (LOCF). Mean Change from Baseline PatientType in DAS28
Week 16 All (N = 41) -1.45* No response (N = 15) -.95* Loss of
Response (N = 21) -1.81* Intolerance (N = 5) -1.44* Week 56 All (N
= 41) -1.63* No response (N = 15) -1.25* Loss of Response (N = 21)
-1.97* Intolerance (N = 5) -1.38* *p < 0.01
TABLE-US-00011 TABLE 11 European League Against Rheumatism (EULAR)
response to adalimumab treatment at Week 56 (LOCF) by reason for
discontinuation of prior infliximab. PatientType Patients (%)
Moderate All (N = 41) 61 EULAR No response (N = 15) 60 Loss of
Response (N = 21) 62 Intolerance (N = 5) 60 GOOD All (N = 41) 24
EULAR No response (N = 15) 13 Loss of Response (N = 21) 33
Intolerance (N = 5) 20
[0337] All three subgroups experienced improvements from baseline
in both TJC and SJC at all time points measured, with those who
reported intolerance to infliximab achieving a slightly greater
benefit compared with those who had an unsatisfactory response or
loss of effectiveness with infliximab (Table 8).
[0338] After 56 weeks of adalimumab treatment, clinically important
mean changes in other measures of disease activity, including
physician's global assessment of disease, patient's global
assessments of disease and pain, and HAQ DI, were achieved in all
three subgroups, including those who had no response to prior
infliximab therapy (Table 8).
[0339] Patients experienced clinically meaningful improvements in
disease activity measures with adalimumab treatment irrespective of
baseline HACA status. At 56 weeks, a total of 47% of HACA-positive
patients and 64% of HACA-negative patients achieved an ACR20
response, while 29% and 36% of these patient subgroups,
respectively, achieved an ACR500 response (Table 8). Similarly, 47%
of HACA-positive patients and 67% of HACA-negative patients
achieved a moderate EULAR response at 56 weeks. Both HACA-positive
and HACA-negative patients achieved clinically important mean
changes in other measures of disease activity, including TJC and
SJC, DAS28, physician's global assessment of disease, patient's
global assessments of disease and pain, and HAQ DI (Table 8).
[0340] From Weeks 17 to 45 of the study, 8 of 41 patients (19.5%)
switched to 40 mg weekly administration of adalimumab based on
disease severity and investigator's request. Twelve of 16 patients
receiving adalimumab 40 mg eow monotherapy without methotrexate and
21 of 25 patients receiving adalimumab 40 mg eow with methotrexate
remained on the original dose regimen for the duration of the
study. The summary statistics of serum adalimumab concentrations
for these patients are provided in Table 12. Mean serum trough
adalimumab concentrations in these patients were within or slightly
above the 4- to 8-.mu.g/mL range, which is the typical trough
concentration for the recommended regimen of 40 mg eow.
TABLE-US-00012 TABLE 12 Summary Statistics of Serum Adalimumab
Concentrations (.mu.g/mL) for Patients Remaining on the Original
Dose Regimen (40 mg every other week) (N = 33) Week Without
Methotrexate With Methotrexate Week Week Baseline* Week 16 56
Baseline* Week 16 56 n 12 10 5 21 19 17 Mean -- 4.4 7.2 -- 6.3 7.1
SD -- 4.0 5.9 -- 3.6 3.9 Min -- 0.0 0.0 -- 0.4 0.0 Median -- 3.1
5.0 -- 5.8 7.6 Max -- 10.6 13.6 -- 14.6 12.6 CV % -- 93.6 81.1 --
56.7 54.4 *For nine patients who had measurable infliximab results
at baseline, baseline adalimumab concentrations were not included
in the summary statistics because there is potential for infliximab
to interfere with the adalimumab assay. CV = coefficient of
variation.
[0341] For patients with measurable HACA at baseline, mean serum
adalimumab trough concentrations ranged from 1 to 4 .mu.g/mL, which
is lower than those achieved in patients without measurable HACA
levels and below the typical trough concentration for 40 mg eow
(data not shown). As noted earlier (see Effectiveness by HACA
status), baseline HACA status did not appear to have a major impact
on effectiveness outcome parameters. Two patients (4.9%, both of
whom had measurable HACA concentrations at baseline) developed AAA,
and both responded well to adalimumab, with a DAS28 change from
baseline to Week 56 of -1.5 in one patient (AAA present at Week 16
only, despite weekly adalimumab injections beyond Week 16) and of
-5.4 in the other patient (AAA present at Week 40 and Week 56, with
no dose increase of adalimumab).
[0342] The mean duration of exposure to adalimumab for all patients
was 46.7 weeks, with total exposure equal to 36.7 patient-years.
Almost all patients (40/41) reported one or more treatment-emergent
adverse events during adalimumab treatment, the most frequent being
RA (14/41, 34.1%; this represents exacerbation of patient's current
condition), nasopharyngitis (13/41, 31.7%), and influenza or
diarrhea (both 6/41, 14.6%). All other adverse events were reported
by .ltoreq.5 patients each.
[0343] Of the 43 events reported by 34 patients that were
considered at least possibly related to study drug administration,
the most common clinical AEs were nasopharyngitis (6/43, 14%),
influenza (4/43, 9.3%), RA (4/43, 9.3%), and pruritus (4/43, 9.3%).
Neither former infliximab intolerance status nor baseline HACA
status appeared to have a clinically meaningful impact on the
frequency or severity of adverse events.
[0344] Five patients experienced six adverse events that led to
withdrawal from the study. Four of these were considered either
possibly or probably related to study drug (common cold, cough with
sputum, adalimumab allergy, and painful injection). Of note, the
medical history of the patient with suspected adalimumab allergy
was significant for drug allergy due to leflunomide and rash. No
demyelinating disorders or other autoimmune disorders, including
lupus-like reactions, were reported. One patient with a history of
hypertension died during the study as a result of intracerebral
bleeding; the death was considered to have been probably unrelated
to study drug administration.
[0345] Two serious infections were reported. One patient developed
pulmonary TB during the study period that was considered probably
related to adalimumab by the investigator. Approximately six months
after study entry, the patient developed dry cough and five
additional months later TB was diagnosed based on a positive
polymerase chain reaction of the sputum. The culture for
mycobacterium TB was negative. At screening, the patient, who had
contact with a person with active TB ten years before, had no
abnormalities in the chest X-ray and a negative PPD test result.
Though night sweats and cough had occurred during the former
infliximab treatment as well, no TB was diagnosed at that time. The
event resolved after nine months of anti-TB therapy. One case of
cellulitis was reported, which the investigator considered probably
related to study drug.
[0346] Two patients reported the development of lymphomas during
the study. Both events were considered either unrelated or probably
unrelated to study drug administration due to the short exposure to
adalimumab and history of previous exposure to other
immunosuppressive agents. A large B-cell lymphoma diagnosed in a
patient two weeks after the initiation of adalimumab treatment was
considered probably not related to study drug due to the short
exposure to adalimumab (three injections), increased risk of
lymphoma in patients with RA, and previous longstanding therapy
with methotrexate (eight years) and infliximab (five years). A
T-cell lymphoma was diagnosed one year after initiation of
adalimumab treatment in a patient with RA and Sjogren's syndrome
who had previously received methotrexate, cyclosporine, and
infliximab. It was considered probably not related to study drug,
given the increased lymphoma risk in patients with RA and Sjogren's
syndrome and the patient's prior immunosuppressive history.
[0347] The results of this study indicate that patients with RA who
had previously discontinued treatment with infliximab, regardless
of the reason for discontinuation, experienced clinically
meaningful improvements in all effectiveness endpoints with
adalimumab treatment. By Week 16 (the primary effectiveness
evaluation period), the mean changes from baseline in TJC and SJC
were -38.4% and -52.8%, respectively, and -23.0%/o (-1.45) for
DAS28. A total of 61.0% of patients achieved a moderate EULAR
response, and 17.1% achieved a good EULAR response by Week 16. ACR
response rates at Week 16 were 46.2% for ACR20, 28.2% for ACR50,
and 12.8% for ACR70. Decreases in the physician's and patient's
global assessment of disease activity, patient's assessment of
pain, and the HAQ DI through Week 16 also were indicative of
clinically significant improvements in disease activity with
adalimumab treatment.
[0348] Of the 41 enrolled patients, 30 continued adalimumab
treatment for 56 weeks. Effectiveness results through 56 weeks of
adalimumab treatment correlated well with improvements observed
through Week 16.
[0349] Subgroup analyses by reason for infliximab discontinuation
indicated that all three subgroups demonstrated clinically relevant
improvements in all disease severity and response measures. The
patients who reported a loss of response under infliximab treatment
appeared to experience the greatest effectiveness with adalimumab
by several disease response measures in this study. At Week 56, 60%
of patients who had no response and 61.9% of patients who had loss
of response to infliximab treatment achieved at least a moderate
EULAR response with adalimumab. In addition, 60% of patients who
were intolerant to infliximab treatment achieved a moderate EULAR
response with adalimumab.
[0350] Results of the pharmacokinetic analysis indicate that, for
the majority of patients, the mean steady-state serum adalimumab
trough concentrations achieved with the recommended regimen of 40
mg eow were near or above 4 to 8 .mu.g/mL, which is consistent with
what has been observed in other pharmacokinetic trials of
adalimumab in patients with RA (Awni et al, 2003; Granneman et al,
2003).
[0351] Adalimumab was generally well-tolerated in this selected
population, and safety results did not suggest any new signals in
regard to the safety of the drug. Five of 41 patients experiencing
six adverse events were withdrawn from the study due to adverse
events, with four of the six events considered possibly or probably
related to study drug administration. The one patient diagnosed
with TB had a history of previous TB contact and had developed
fatigue, night sweats, weight loss, and intermittent cough prior to
study entry.
[0352] In the two patients diagnosed with malignancies (cutaneous
T-cell lymphoma in one and a B-cell lymphoma in the other),
exposure to adalimumab was .ltoreq.1 year, and the patients had
previously undergone extensive immunosuppressive treatment. The
fact that the lymphoma risk is higher in patients with RA also
mitigates any potential relationship to adalimumab administration.
No other significant adverse events of special interest were noted,
such as events associated with congestive heart failure,
demyelinating diseases, or other autoimmune disorders.
Coincidentally, one of the two lymphoma cases occurred in the same
patient that was diagnosed with TB.
[0353] The results of this pilot study indicate that adalimumab is
effective and well-tolerated for the treatment of RA in patients
who have failed infliximab therapy (including those who have
developed HACA for infliximab) and those who are intolerant to
infliximab.
Example 3
Efficacy and Safety of Adalimumab (Humira.RTM.) in Patients with
Rheumatoid Arthritis (RA) Who Previously Failed Etanercept and/or
Infliximab in Clinical Practice
[0354] A proportion of patients with RA do not respond optimally,
or may be intolerant, to an initial anti-TNF therapy. Limited data
availability prohibited the examination of important questions
about the safety and efficacy of treating such patients with an
alternate TNF antagonist. The objective of this study was to
compare the efficacy and safety of adalimumab (Ada) in a large
cohort of patients with RA who previously failed etanercept (E)
and/or infliximab (I) therapies.
[0355] Patients with long-standing, moderate to severe RA were
enrolled in Study A (ReACT) and received adalimumab 40 mg
subcutaneously (sc) every other week (eow). The core study period
was 12 weeks followed by an optional extension phase until
adalimumab was commercially available.
[0356] Inclusion criteria included patients over the age of 18,
with RA (American College of Rheumatology criteria) for .gtoreq.3
months. Patients had active RA (DAS28.gtoreq.3.2) and
unsatisfactory response or intolerance to at least one prior
disease modifying anti-rheumatic drug (DMARD). In addition,
treatment with another TNF antagonist, if any, had to have been
discontinued .gtoreq.2 months before study entry.
[0357] As shown in Table 13, Of the patients enrolled in the study
5711 patients had not experienced anti-TNF treatment before, 899
patients had previously discontinued a treatment with another TNF
antagonist (etanercept and/or infliximab), 591 patients had
received as TNF antagonist infliximab only, 188 patients had
received as TNF antagonist etanercept only, and 120 patients had
been treated with both TNF antagonists
TABLE-US-00013 TABLE 13 Baseline Characteristics by Prior TNF
Antagonist No prior TNF Prior TNF Prior IFX Prior ETN Prior ETN
antagonist antagonist Only Only and IFX (n = 5711) (n = 899) (n =
591) (n = 188) (n = 120) Age (mean, years) 54 53 53 54 52 Female, %
81 81 80 80 86 Rheumatoid factor+, % 73 72 72 71 75 RA Duration
(mean, 11 12 12 13 12 years).dagger. # Prior DMARDs 2.7 5.0 4.6 5.2
7.1 (mean) DAS28 (mean) 6.0 6.3 6.2 6.5 6.6 HAQ DI score (0-3),
1.60 1.85 1.83 1.89 1.93 (mean) DMARD use, % 75 69 75 50 68 Steroid
use, % 70 77 75 78 83 Time from last prior NA 17 17 22 31 TNF
antagonist dose to first dose adalimumab (median, weeks)
[0358] Patients entering Study A received Ada 40 mg sc eow for 12
weeks in addition to their current anti-rheumatic therapy--other
than anti-TNF agents, which had been discontinued--and optionally
continued therapy until Ada was commercially available. Efficacy
and safety were assessed at Wks 2, 6, 12, and every 8 wks
thereafter as shown in FIG. 1. Outcomes were compared by history of
prior anti-TNF therapy, and subgroup analyses were conducted by
reported reason for discontinuation (d/c) of prior anti-TNF therapy
as shown in Table 14.
TABLE-US-00014 TABLE 14 Withdrawal Rates by Prior TNF Antagonist
Therapy and by Reason for lts Discontinuation All withdrawals,
complete Withdrew Withdrew for treatment for adverse lack of N
period, (%) event, (%) efficacy (%) No ETN or IFX 5711 20 10 6 ETN
and/or IFX 899 26 13 11 ETN no response 63 24 10 13 IFX no response
110 30 16 10 ETN loss response 48 31 8 13 IFX loss response 258 19
11 9 ETN intolerance 40 30 13 10 IFX intolerance 139 29 17 9
[0359] As shown in Table 15-Table 21, of 6610 enrolled patients,
899 had received prior E and/or I therapy (median treatment of 9.5
months). Patients with a history of anti-TNF therapy had a higher
baseline disease activity and more prior DMARDs compared to those
without. Mean exposure in the study was 30 weeks for patients with
prior anti-TNF treatment and 34 weeks for those without. Ada
treatment lead to robust responses in both groups, with somewhat
higher responses seen in patients without prior anti-TNF therapy.
Marked responses to Ada therapy were seen in all subgroups, with
responses in patients who had discontinued prior anti-TNF therapy
because of loss of efficacy or intolerance similar to those in
patients naive to anti-TNF. Results were maintained in patients who
continued beyond Wk 12, as demonstrated by last observed values
(Table 13). Up to Week 12, reasons for withdrawal for patients
with/without anti-TNF history included (%): lack of efficacy
2.9/1.2, and adverse events (AE) 5.6/4.1, respectively; for the
entire study duration, reasons included (%): lack of efficacy,
10.6/6.2; and AE, 12.6/10.0, respectively. No new safety signals
were observed. The frequency of patients experiencing serious
infections was 4.3% for those with anti-TNF history and 2.9% for
those without.
TABLE-US-00015 TABLE 15 Ada efficacy overall and by reasons for d/c
prior etanercept and/or infliximab Prior anti- Reason for ACR20
ACR50 ACR70 .DELTA.DAS28* .DELTA.DAS28* TNF d/c N 12 wks 12 wks 12
wks 12 wks last obs. No E or I 5711 70% 41% 19% -2.2 -2.3 E and/or
I 899 60% 33% 13% -1.9 -1.9 Etanercept No 63 41% 26% 11% -2.0 -2.1
response Infliximab No 110 59% 25% 7% -1.8 -2.0 response Etanercept
Lost effic. 48 67% 34% 14% -2.2 -2.0 Infliximab Lost effic. 258 67%
37% 13% -2.0 -1.9 Etanercept Intolerance 40 67% 42% 19% -2.3 -2.2
Infliximab Intolerance 139 67% 37% 16% -2.3 -2.3 Observed values
*Means
TABLE-US-00016 TABLE 16 ACR Response at Week 12 by Prior (p) TNF
Antagonist Therapy % of Patients ACR20 ACR50 ACR70 No pTNF (n =
5711) 70 41 19 pTNF (n = 899) 60 33 13 pETN only (n = 188) 57 34 19
pIFX only (n = 591) 64 34 13 pETN + pIFX (n = 120) 46 29 11
TABLE-US-00017 TABLE 17 ACR Response at Week 12 by Reason for
Discontinuing Prior (p) TNF Antagonist Therapy % of Patients ACR20
ACR50 ACR70 pIFX no response (n = 110) 59 25 7 pETN no response (n
= 63) 41 26 11 pIFX loss of response (n = 258) 67 37 13 pETN loss
of response (n = 48) 67 34 14 pIFX intolerance (n = 139) 67 37 16
pETN intolerance (n = 40) 67 42 19
TABLE-US-00018 TABLE 18 EULAR Response at Week 12 by Prior (p) TNF
Antagonist Therapy % of Patients Moderate EULAR Good EULAR No pTNF
(n = 5711) 84 35 pTNF (n = 899) 76 23 pETN only (n = 188) 79 21
pIFX only (n = 591) 78 26 pETN + pIFX (n = 120) 62 11
TABLE-US-00019 TABLE 19 EULAR Response at Week 12 by Reason for
Discontinuing Prior (p) TNF Antagonist Therapy % of Patients
Moderate EULAR Good EULAR pIFX no response (n = 110) 73 18 pETN no
response (n = 63) 75 20 pIFX loss of response (n = 258) 79 23 pETN
loss of response (n = 48) 81 19 pIFX intolerance (n = 139) 83 31
pETN intolerance (n = 40) 89 20
TABLE-US-00020 TABLE 20 ACR50, ACR70, and Good EULAR Response Rates
(%) at Last Observation* by Reason for Discontinuing Prior (p) TNF
Antagonist Therapy % of Patients ACR50 ACR70 Good EULAR pIFX no
response (n = 110) 30 14 23 pETN no response (n = 63) 27 15 26 pIFX
loss of response 36 16 29 (n = 258) pETN loss of response (n = 48)
38 21 29 pIFX intolerance (n = 139) 38 17 35 pETN intolerance (n =
40) 26 16 18 *Mean/median treatment duration for all patients with
prior TNF-antagonist therapy = 30/28 weeks
TABLE-US-00021 TABLE 21 Mean Change in HAQ from Baseline to Last
Observation* Mean Change from Baseline.sup..dagger. No pETN or pIFX
(n = 5711) -0.58 pETN and/or IFX (n = 899) -0.48 pIFX only (n =
591) -0.52 pETN only (n = 188) -0.45 pETN + IFX (n = 120) -0.31
*Mean/median treatment duration was 30/28 weeks for patients with
prior anti-TNF therapy; and 34/32 weeks for patients naive to TNF
antagonist therapy. .sup..dagger.MCID = Minimum Clinically
Important Difference .gtoreq.-0.22; Goldsmith C, et al. J Rheumatol
1993; 20: 561-5.
[0360] The results shown in Table 16 show that Adalimumab treatment
was effective as assessed by ACR response rates at Week 12 in
patients with a history of treatment with 1 or 2 prior TNF
antagonists. In addition Table 17 shows that Adalimumab treatment
was effective as assessed by ACR response rates at Week 12,
irrespective of mason for discontinuing prior therapy.
[0361] Adalimumab treatment was also effective as assessed by EULAR
response rates at Week 12 in patients with a history of treatment
with 1 or 2 prior TNF antagonists, as shown in Table 18, and
irrespective of reason for discontinuing prior therapy, as shown in
Table 19.
[0362] Additionally, results shown in Table 20 indicate a good
clinical response beyond week 12. The proportion of patients with
good clinical response increased when measured by ACIR50, ACR70,
and good EULAR rates at last observation.
[0363] Treatment with adalimumab also led to clinically important
improvements in physical functioning--including in
difficult-to-treat patients who had previously received 2 TNF
antagonists--as measured by the mean change in HAQ scores from
baseline to the last observation as indicated in Table 21.
[0364] In conclusion, in patients with RA treated in real-life
clinical practice, adalimumab was safe, well-tolerated and
effective in patients with a history of anti-TNF therapy,
irrespective of reason for discontinuation of that therapy.
Example 4
Adalimumab (Humira.RTM.) is Effective and Safe in Treating
Rheumatoid Arthritis (RA) in Real-Life Clinical Practice
[0365] The completed Study A trial (ReAct) offers the largest
database available for a prospective evaluation of the efficacy and
safety of adalimumab (Ada) in patients with active, insufficiently
treated RA, various co-morbidities, a broad range of antirheumatic
co-medications, and varied social care systems. The objective of
this study was to assess and summarize the efficacy and safety of
adalimumab in the final analysis of the Study A trial.
[0366] Patients with active RA and prior DMARD therapy enrolled in
the Study A trial at 448 sites in 11 European countries and
Australia. Selected patients were at least 18 years of age, had RA
(defined by American College of Rheumatology criteria) for at least
3 months, had prior unsatisfactory response or intolerance to at
least one prior DMARD and active RA (DAS28.gtoreq.3.2). Patients
entering Study A received Ada 40 mg sc eow for 12 weeks in addition
to their pre-existing but insufficient antirheumatic standard
therapies, and optionally continued therapy until Ada was
commercially available. Efficacy and safety evaluations were
conducted at Wks 2, 6, 12, and every 8 wks thereafter. Adverse
events (AE) were collected throughout the treatment period.
[0367] In all, 6610 patients enrolled in the Study A trial.
Adalimumab was used alone (26%) or in combination with existing
DMARD(s), leading to 43 Ada-DMARD combinations. After 12 wks, 93%
of patients remained and retention in the study was 79% overall.
The mean exposure to Ada was 33 wks (96 wks, maximum). Mean
baseline characteristics included: age, 54 yrs; female, 71%;
disease duration, 11 yrs; DAS28, 6.0; HAQ, 1.64; TJC28, 14; SJC28,
10; prior DMARDs, 3; RF+, 73%; concomitant DMARD treatment, 74%;
concomitant steroid treatment, 71%; and 13.6% had failed prior
anti-TNF therapy.
[0368] Of those patients on concomitant DMARD treatment, 4004 (61%)
patients received adalimumab in combination with exactly 1 DMARD;
769 (12%) patients, with 2 concomitant DMARDs; and 106 (2%)
patients, with .gtoreq.3 concomitant DMARDs. Of patients on
non-exclusive concomitant DMARD treatment combinations, 3567 (54%)
patients on Methotrexate; 1109 (17%) patients taking Leflunomide;
450 (7%) patients taking Sulfazalazine; 576 (9%) patients taking
Antimalarials; 63 (<1%) patients taking Azathioprine; 52
(<1%) patients taking Parenteral gold; 7 (<1%0) patients
taking Penicillamine; and 3 (<1%) patients taking Oral gold.
[0369] Of those 899 patients whom failed prior anti-TNF therapy
(etanercept and/or infliximab) 591 patients had received as TNF
antagonist infliximab only; 188 patients had received as TNF
antagonist etanercept only; and 120 patients had been treated with
both TNF antagonists.
[0370] The mean treatment duration with adalimumab was 233 days (33
weeks) with a maximum of 669 days (96 weeks) and at Week 12, 93% of
the patients remained in Study A. Overall, of the 6610 patients who
enrolled, 79% completed the trial, which provided data from 4210
patient-years (PY) of adalimumab treatment. Table 22 shows
withdrawal rates because of lack of efficacy or intolerance to
adalimumab (all types side effects), which were low overall.
TABLE-US-00022 TABLE 22 Withdrawals Up to Week 12 and During the
Complete Study Period, by Concomitant Therapy and Reason for
Withdrawal, N (%) No No Prior Concomitant Concomitant TNF Prior TNF
Reason for All DMARDs DMARDs Antagonist Antagonist Withdrawal (N =
6610) (N = 1731) (N = 4879) (N = 5711) (N = 899) All Week 12 470
(7) 174 (10) 296 (6) 381 (7) 89 (10) withdrawals Adverse event 284
(4) 100 (6) 184 (34) 234 (4) 50 (6) Lack of efficacy 94 (1) 39 (2)
55 (1) 68 (1) 26 (3) Total 1377 (21) 468 (27) 909 (19) 1147 (20)
230 (26) withdrawals* Adverse event 682 (10) 226 (13) 456 (9) 569
(10) 113 (13) Lack of efficacy 450 (7) 166 (10) 284 (6) 355 (6) 95
(11) *Withdrawals during complete study period, up to week 96
[0371] Adalimumab was well-tolerated, and no new safety signals
were observed. Overall, reasons for withdrawals included lack of
efficacy in 6.8% and AE in 10.3% of patients. Serious adverse
events of lupus or demyelinating disease were rarely seen, with
only 2 and 4 events reported, respectively. The incidence of
malignancies, including lymphomas, was similar to the general
population. The rate of malignancies (1.1/100PY) gave a Standard
Incidence Ratio (SIR) of 0.71 vs. an age and sex matched
population. Two lymphomas (0.05/100PY; SIR 1.09) were reported. The
rate of serious infections (5.5/100PY) was within the range
previously reported in RA.
[0372] Efficacy was similar across subpopulations using different
Ada-DMARD combinations, and responses were seen irrespective of RF
status or previous failure of anti-TNF therapy. Table 23 presents
key efficacy outcomes to Wk 12 and at last observation.
TABLE-US-00023 TABLE 23 Week 2 Week 6 Week 12 Last visit** ACR20
(%) 42 59 69 67 ACR50 (%) 12 28 40 45 ACR70 (%) 3 10 18 25
.DELTA.DAS28** -1.4 -1.8 -2.1 -2.3 .DELTA.DAS28 <2.6 n.a. n.a 20
26 (%) .DELTA.HAQ* -0.32 -0.45 -0.54 -0.57 Observed values; *Mean
exposure 33 wks; **Means
[0373] Table 24-Table 29 show other key efficacy outcomes. Table 24
shows that adalimumab treatment was efficacious as assessed by ACR
response rates at Week 12 and last observation and Table 25 shows
Moderate and Good EULAR Response (%) at Week 12 (W12) and at Last
Visit (LV) by Concomitant DMARD (cDMARD) and by Prior
TNF-Antagonist (pTNF) Therapy. In addition, Table 26 shows that
Adalimumab significantly decreased the number of tender joints and
Table 27 shows that Adalimumab significantly decreased the number
of swollen joints. Table 28 reports that Adalimumab relevantly
reduced the disease activity measured by mean change from baseline
DAS28 to the last observation (mean of each individual last
observation) and Table 29 demonstrates that treatment with
adalimumab led to clinically important improvement of physical
function, as measured by the mean change from baseline HAQ score to
the last observation (mean of each individual last
observation).
TABLE-US-00024 TABLE 24 ACR Response (%) at Week 12 (W12) and at
Last Visit (LV) by Concomitant DMARD (cDMARD) and by Prior
TNF-Antagonist (pTNF) Therapy % of Patients ACR20 ACR20 ACR50 ACR50
ACR70 ACR70 W12 LV W12 LV W12 LV All 69 67 40 45 18 25 (n = 6110)
No cDMARD 60 60 32 37 15 20 (n = 1731) cDMARD 72 70 43 48 19 26 (n
= 4879) No pTNF 70 69 41 47 19 26 (n = 5711) pTNF 60 56 33 33 13 15
(n = 899)
TABLE-US-00025 TABLE 25 EULAR Response (%) at Week 12 (W12) and at
Last Visit (LV) by Concomitant DMARD (cDMARD) and by Prior
TNF-Antagonist (pTNF) Therapy % of Patients Mod. Good Good Mod.
EULAR EULAR EULAR EULAR W12 LV W12 LV All (n = 6110) 83 82 33 39 No
cDMARD 74 74 23 30 (n = 1731) cDMARD (n = 4879) 86 84 37 42 No pTNF
(n = 5711) 84 83 35 41 pTNF (n = 899) 76 73 23 26
TABLE-US-00026 TABLE 26 Median Tender Joint Count (TJC28) to Week
12 and to Last Visit (Mean of Individual Last Visits) by
Concomitant DMARD (cDMARD) and Prior TNF-Antagonist (pTNF) Therapy
Median Tender Joint Count Last Week 0 Week 2 Week 6 Week 12 Visit
All (n = 6610) 13 6 4 3 2 No cDMARD 14 7 5 4 3 (n = 1731) cDMARD (n
= 4879) 13 6 4 3 2 No pTNF (n = 5711) 12 6 4 3 2 pTNF (n = 899) 15
8 5 4 4
TABLE-US-00027 TABLE 27 Median Swollen Joint Count (SJC28) to Week
12 and to Last Visit (Mean of Individual Last Visits) by
Concomitant DMARD (cDMARD) and Prior TNF-Antagonist (pTNF) Therapy
Median Swollen Joint Count Week 0 Week 2 Week 6 Week 12 Last Visit
All (n = 6610) 10 5 3 2 2 No cDMARD 10 6 4 3 3 (n = 1731) cDMARD 10
5 3 2 2 (n = 4879) No pTNF 10 5 3 2 2 (n = 5711) pTNF (n = 899) 11
6 4 3 3
TABLE-US-00028 TABLE 28 Mean Change in DAS28 from Baseline to Last
Observation Mean Change from Baseline All (n = 6610) -2.3 No cDMARD
(n = 1731) -2.0 cDMARD (n = 4879) -2.4 No pTNF (n = 5711) -2.3 pTNF
(n = 899) -1.9
TABLE-US-00029 TABLE 29 Mean Change in HAQ from Baseline to Last
Observation Mean Change from Baseline* All (n = 6610) -0.57 No
cDMARD (n = 1731) -0.49 cDMARD (n = 4879) -0.59 No pTNF (n = 5711)
-0.58 pTNF (n = 899) -0.48 *MCID = Minimum Clinically Important
Difference .gtoreq.-0.22; Goldsmith C, et al. J Rheumatol 1993; 20:
561-5.
[0374] In addition, the criteria of clinical remission were
fulfilled. Within 2 consecutive visits of at least a 6-week
interval: 21% of patients had DAS<2.6. 16% of patients had no
tender or swollen joints.
[0375] The efficacy of adalimumab was higher when used in
combination with standard DMARDs than with monotherapy. Patients
with a history of treatment with TNF antagonists experienced
relevant reductions in the signs and symptoms of RA during
treatment with adalimumab.
[0376] In conclusion, adalimumab therapy led to clinically
significant and sustained improvements in all key efficacy
parameters. During the entire treatment period with adalimumab, a
DAS28<2.6 was achieved at one or more visits by 38% of all
patients and 30% of all patients were reported to have TJC=0 and
SJC=0 at least at one visit during the study period. Study A data
confirmed observations from adalimumab pivotal trials, and
demonstrated a positive benefit/risk ratio for the treatment of
severe RA when adalimumab is combined with standards of care in
real-life settings. Overall, Adalimumab was well-tolerated and
withdrawal rates because of lack of efficacy or adverse events were
low.
Example 5
Efficacy and Safety of Adalimumab (HUMIRA.RTM.) is Maintained
During Long-Term Treatment of Rheumatoid Arthritis within a Large
Cohort of Patients in Normal Clinical Practice
[0377] Study B (ReAlise) was established to evaluate the long-term
safety and efficacy of adalimumab (Ada) for up to 5 years in
patients with rheumatoid arthritis (RA) who had completed a
previous study, i.e., Study A (ReAct), a Phase IIIb study. In Study
A, Ada 40 mg every other week was added to pre-existing,
inadequate, standard antirheumatic therapies in patients with
long-standing, severely active RA, including patients who had
failed previous biologics. An interim analysis of the efficacy and
safety of Ada therapy in Study B.
[0378] Patients were eligible to enroll in Study B within 12 months
of the conclusion of their participation in Study A (Active RA
defined by Disease Activity Score 28 (DAS28) .gtoreq.3.2 at
baseline and unsatisfactory response or intolerance to at least one
prior DMARD was required for enrollment in Study A). Patients were
treated according to the European Summary of Product
Characteristics (SPC) for HUMIRA.RTM., which recommended Ada 40 mg
every other week given by subcutaneous injections either in
addition to or as replacement of their pre-existing antirheumatic
therapy in the Study A trial. Patients underwent a 12-week study
period that was followed by an optional extension phase with
efficacy assessments performed at Weeks 2, 6, 12, and every eight
weeks thereafter. Patients discontinued the study when they stopped
receiving adalimumab or received commercial HUMIRA.RTM.. During the
study period, parameters of efficacy--including ACR20/50/70
response, moderate and good EULAR response, DAS28 score, tender
joint count (TJC), swollen joint count (SJC), C-reactive protein
(CRP), and health assessment questionnaire-disability index (HAQ),
Physician and patient assessments of disease activity and patient
assessment of pain on a visual analog scale (VAS)--were assessed
every 3 months. Semi-annual assessments were conducted thereafter.
All reports of adverse events (AE) were tabulated per 100 patient
years (E/100PY).
[0379] 3452 patients enrolled in Study B at 432 sites in 11
countries. Data for 3228 patients is presented here for this
analysis (Gender: 79% female, Mean Age: 53 years)(See Table 30).
The mean overall treatment duration for all patients was 502 days,
from the first exposure to Ada in Study A (with a mean treatment
duration of 250 days in Study B). At entry to Study A the mean
disease severity baseline values were; DAS28, 6.0; HAQ, 1.61; SJC,
10.4; and TJC, 13.3. Most patients (72%) received Ada in
combination with DMARDs in Study B, the majority with methotrexate.
Key efficacy parameters were stable over time as compared to
baseline values in Study A (Table 31, N's over time reflect
differing enrolment time points). No new safety signals were
observed in the analysis of AE reported. The rate of serious
infections was low, 3.0/100PY. The rate of malignancies was
1.0/100PY. No serious immunologic reactions were observed.
TABLE-US-00030 TABLE 30 Study B Baseline Clinical Characteristics
Characteristics* N = 3228 Age (years) 55 Duration of RA (years) 12
# previous DMARDs 3.4 DAS28 3.5 HAQ DI 0.89 CRP (mg/L) 9.5 *Mean
values.
TABLE-US-00031 TABLE 31 Efficacy of adalimumab observed over time
in Study B Study B 6 12 18 Parameter baseline months months months
N available 3228 2042 1026 265 ACR20 (%) 79 81 82 85 ACR50 (%) 58
59 62 57 ACR70 (%) 33 36 38 35 Moderate EULAR (%) 91 91 93 94 Good
EULAR (%) 49 53 56 54 .DELTA.DAS28* -2.4 -2.7 -2.8 -2.8 .DELTA.HAQ*
-0.70 -0.69 -0.66 -0.57 *Mean values
[0380] Substantial percentages of patients (78%) had achieved ACR20
responses by the end of Study A, prior to entering Study B. These
high ACR20 response rates were maintained through Month 18 of Study
B as reported in Table 32 and FIG. 2. The same figure also reports
that ACR50 and ACR70 responses observed at the end of 18 months in
Study B were also similar to those observed at the end of Study
A.
[0381] Substantial percentages of patients had also achieved at
least moderate EULAR and good EULAR responses by the end of Study
A, prior to entering Study B. These high EULAR response rates were
maintained through Month 18 of Study B (Table 33, FIG. 3).
[0382] Referring to Table 34, at the start of Study A, patients had
a mean DAS28 of 6.0, and Table 34 indicates DAS28 improvements and
that the DAS28 improvements were sustained through Month 18.
[0383] Similarly in Table 35, at the start of Study A, patients had
a mean HAQ score of 1.61, and Table 35 indicates HAQ improvements
and shows that HAQ improvements were maintained through Month
18.
[0384] In addition, median improvements in TJC and SJC were
sustained through Month 18 as shown in Table 36. Also median CRP
concentrations were low and sustained through Month 18 as shown in
Table 37 and FIG. 4, and significant improvements in disease
activity and pain assessments were maintained through Month 18, as
shown in Table 38 and FIGS. 5-7.
[0385] The safety of adalimumab in Study B was consistent with
reports of the adalimumab safety profile overall. The rate of 3
serious infections per 100-patient-years was lower than rates
previously reported in adalimumab clinical trials and no
demyelinating disease was observed. Data showing the number of
patients recorded with serious averse events is displayed in Table
39.
TABLE-US-00032 TABLE 32 ACR Responses Through 18 Months in Study B
% of Patients ACR20 ACR50 ACR70 Last Obs. Study A 78 55 30 Baseline
Study B 78 60 33 3 Months 78 56 35 6 Months 80 60 35 9 Months 80 62
40 12 Months 80 62 38 18 Months 85 55 35 Observed values. N = 3195
patients achieved at least ACR20 at their last visit in Study A. N
= 2760 patients entered Study B with at least ACR20.
TABLE-US-00033 TABLE 33 EULAR Responses Through 18 Months in Study
B % of Patients Moderate EULAR Good EULAR Last Obs. ReAct 90 48
Baseline ReAlise 90 48 3 Months 85 50 6 Months 90 52 9 Months 90 55
12 Months 90 55 18 Months 92 52 Observed values. N = 3202 patients
achieved at least a Moderate EULAR response at their last visit in
ReAct. N = 2937 patients entered ReAlise with at least a Moderate
EULAR.
TABLE-US-00034 TABLE 34 Mean Change in DAS28 Over Time Mean
.DELTA.DAS28 Last Obs. in ReAct (n = 3203) -2.6 Baseline ReAlise (n
= 2582) -2.7 3 Months (n = 2197) -2.7 6 Months (n = 1842) -2.7 9
Months (n = 1380) -2.8 12 Months (n = 972) -2.8 18 Months (n = 253)
-2.8 P .ltoreq. 0.001 for all time points compared with baseline of
ReAct study. Observed values.
TABLE-US-00035 TABLE 35 Mean Change in HAQ Over Time Mean
.DELTA.HAQ* Last Obs. In ReAct (n = 3206) -0.69 Baseline ReAlise (n
= 2805) -0.70 3 Months (n = 2334) -0.71 6 Months (n = 1949) -0.69 9
Months (n = 1434) -0.68 12 Months (n = 1009) -0.66 18 Months (n =
261) -0.57 P .ltoreq. 0.001 for all time points compared with
baseline of ReAct study. Observed values. *MCID = Minimum
Clinically Important Difference .gtoreq.-0.22.
TABLE-US-00036 TABLE 36 Median TJC and SJC Responses Over Time
Median Median Tender Joint Count Swollen Joint Count Baseline ReAct
13 10 Last Obs. ReAct 2 1 Baseline ReAlise 2 1 3 Months 1 1 6
Months 1 1 9 Months 1 1 12 Months 1 1 18 Months 1 1 Observed
Values
TABLE-US-00037 TABLE 37 Median C-Reactive Protein Concentrations
(mg/L) Over Time Median CRP Concentration (mg/L) Baseline ReAct
14.5 Last Obs. ReAct 3.5 Baseline ReAlise 4.5 3 Months 4 6 Months 4
9 Months 4 12 Months 4 18 Months 5 Observed Values
TABLE-US-00038 TABLE 38 Physician and Patient Assessments of
Disease Activity and Pain Over Time Through 18 Months Mean Score
Physician Assessment Patient of Disease Patient Assessment
Assessment Activity of Disease Activity of Pain Baseline Study A 60
60 65 Last Obs. Study A 20 25 28 Baseline Study B 22 25 28 3 Months
20 25 30 6 Months 20 22 28 9 Months 18 22 28 12 Months 20 22 28 18
Months 20 22 28 P .ltoreq. 0.001 for all time points compared to
mean baseline values of the ReAct study. Observed Values
TABLE-US-00039 TABLE 39 Serious Adverse Events-Interim Analysis of
3228 Patients (N, %) Representing 2195 Patient-Years N (%) All
Serious Adverse Events (SAE) 245 (7.6) Serious infections 61 (1.9)
Congestive heart failure (CHF) 4 (0.1) Gastroinstestinal Disorders
11 (0.3) General Disorders 20 (0.6) Musculoskeletal/Connective
Tissue 50 (1.5) Disorders Systemic lupus erythematosus (SLE) 3
(0.1) Respiratory, Thoracic, Mediastinal Disorders 26 (0.8)
Malignancies 20 (0.6) Lymphoma 3 (0.1)
[0386] In conclusion, in patients with long-standing, severely
active RA who participated in the post-marketing observational
study, Study B, the efficacy of adalimumab was maintained up to 18
months in all key efficacy parameters and no new safety signals
were identified.
Example 6
Clinical Characteristics of Patients Who Continued Long-Term
Treatment in a 6-Year Extension Study of Adalimumab Therapy in
RA
[0387] Open-label extension studies following adalimumab randomized
clinical trials (RCTs) have demonstrated that a majority of
patients receiving continued adalimumab treatment maintain robust
improvements in RA disease activity and physical function. Although
the ACR response rate is a key measure of therapeutic efficacy in
RCTs, its value in therapeutic decision-making has not been
demonstrated in long-term studies of RA.
[0388] The objectives of this study were to determine clinically
relevant characteristics supporting continuation on therapy in an
open-label extension study of adalimumab and methotrexate (MTX); to
determine levels of disease activity and functional measurements in
patients not fulfilling the ACR20 response criteria over time; to
assess sustained efficacy and remission parameters for up to 6
years; and to confirm long-term safety and tolerability over
time.
[0389] Patients enrolled in other studies were eligible to enter an
extension study of adalimumab 40 mg every other week (eow)
subcutaneous (sc) and MTX. Efficacy and safety were evaluated in
all patients' last visits for up to 6 years, including withdrawals
for any reason. The clinical characteristics of patients were
studied in the following 4 categories: (a) ACR20 responders; (b)
ACR20 non-responders who continued on long-term treatment; (c)
ACR20 non-responders who discontinued due to adverse events or
other reasons; and (d) ACR20 non-responders who discontinued due to
lack of efficacy.
[0390] The demographics and baseline disease characteristics of RA
patients were consistent with moderate to severe RA (N=947), as
shown in Table 40.
TABLE-US-00040 TABLE 40 Baseline Demographics and Disease
Characteristics Characteristic Value Age, years* 55 .+-. 12 Gender,
% female 78 Disease duration, years 11 .+-. 9 TJC (0-68)* 28 .+-.
13 SJC (0-66)* 20 .+-. 10 HAQ disability index (0-3)* 1.4 .+-. 0.6
Disease Activity Score 28 (DAS28)* 5.7 .+-. 0.9 CRP, mg/dL* 1.9
.+-. 2.3 Rheumatoid factor, % positive 77 Number of previous
DMARDs* 2.4 .+-. 1.5 *Mean .+-. standard deviation.
[0391] Treatment time was calculated beginning with the first
subcutaneous injection of adalimumab at any dose for: ACR20, ACR50,
ACR70 criteria and indices of remission (DAS28<2.6, TJC68=0,
SJC66=0, HAQ=0). Patients were monitored for adverse events (AEs)
during the entire length of the study. Data collected until Aug.
31, 2005 are reported.
[0392] Of 947 patients entering the 4 RCTs (Mean.+-.SD exposure of
41.+-.22 months), 600 (63%) remained on adalimumab plus MTX for up
to 6 years. FIG. 8 shows reasons for withdrawals included lack of
efficacy (82, 9%), adverse events (140, 15%), and others, such as
protocol violation and loss to follow-up (125, 13%). Table 41 and
Table 42 show that the number of patients withdrawing from the
study decreased over time. Table 41 displays the percentage of
patient withdrawals, which demonstrated a steady decline over time,
especially with patients that withdrew because of lack of efficacy.
Table 42 and FIG. 9 display the results of a Kaplan-Meier curve
providing the probability that patients receiving adalimumab will
remain on therapy at Year 6.
[0393] Table 43 and FIGS. 10-12 show that patients achieving ACR20
response had significant reductions in disease activity (TJC, SJC,
CRP, DAS28) as well as improvements in functional disability (HAQ)
at last visit. While patients who did not achieve ACR20 response,
but who either continued on therapy or discontinued treatment for
adverse events or other reasons, had significant but less
pronounced improvements in TJC, SJC, DAS28, and HAQ. CRP was only
marginally reduced. Those patients who discontinued because of lack
of efficacy had no improvements.
[0394] Referring to Table 44 and FIG. 13, those patients
demonstrating ACR responses showed sustained ACR responses into
Year 6. And over 55% of patients achieved remission (DAS28<2.6)
after 6 years of adalimumab therapy as shown in Table 45. Of all
patients, the proportions achieving clinical response and remission
measures at last visit were ACR20, 50, 70: 66%, 42%, 26%;
DAS28<2.6: 35%; TJC68-0: 24%; SJC66=0: 20%; and HAQ=0: 19%.
Table 46 presents baseline and last visit outcomes of ACR20
responders and 3 categories of ACR20 non-responders: 1) patients
who continued in the study (Mean.+-.SD exposure of 51.+-.18 months)
and demonstrated statistically significant improvements; 2)
patients who discontinued due to AEs or other reasons and who also
showed significant improvement levels; and 3) patients who
discontinued due to lack of efficacy (LOE) and had no improvements.
Rates and types of adverse events (3,203 patient-years) were
consistent with reports from other adalimumab trials. Table 47
shows that rates and types of serious adverse events over the long
term demonstrated a consistent safety profile in relation to the
randomized and controlled pivotal trials.
TABLE-US-00041 TABLE 41 Percentages of Withdrawals by Year and
Reason % of Withdrawals Total % Withdrawals Lack of Efficacy AE
Other* Year 1 (n = 947** 14.7 4.2 4.6 5.9 Year 2 (n = 761) 9.9 2.0
4.0 3.9 Year 3 (n = 679) 9.0 2.0 3.5 3.5 Year 4 (n = 618) 6.8 1.0
3.5 2.3 Year 5 (n = 573) 4.7 0.5 2.2 2 Year 6 (n = 163) 1.8 0 1.8 0
*Includes withdrawals for other reasons: protocol violation, lost
to follow-up, consent withdrawal, administrative reasons. **n =
patients entering the corresponding year.
TABLE-US-00042 TABLE 42 Percent of Patients Continuing on
Adalimumab Treatment from First Dose Time (years) 0 0.5 1.0 1.5 2.0
2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 % of 100 90 85 80 75 72 70 65 60 60
58 57 57 Patients Re- maining on Treat- ment
TABLE-US-00043 TABLE 43 Disease Activity and Functional Disability
Scores by ACR20 Response ACR20 Non- Responders ACR20 ACR20 who Non-
Non- discontinued Responders Responders due to who who adverse
discontinued continued events or due to ACR20 long-term other lack
of Responders treatment reasons efficacy Mean Score TJC68 Baseline
26 28 28 30 Last Visit 5* 18* 22* 28 SJC66 Baseline 22 18 18 22
Last Visit 5* 11* 13* 20 DAS28 Baseline 5.8 5.8 5.8 6 Last Visit
2.8* 4.5* 5* 5.8 HAQ disability index Baseline 1.4 1.4 1.7 1.7 Last
Visit 0.7 1.3 1.5 1.7 CRP CRP Concentration, mg/L Baseline 20 14 18
20 Last Visit 7* .sup. 11.sup..dagger. 20 21 *p < 0.001,
.sup..dagger.p < 0.05, both vs. baseline
TABLE-US-00044 TABLE 44 ACR Response Rates % Responders 6 Month 12
Month 24 Month 36 Month 48 Month 60 Month 72 Month ACR20 70 75 75
70 75 75 70 ACR50 42 50 50 50 50 60 65 ACR70 20 25 30 30 30 35 40
Approximate Observed Values
TABLE-US-00045 TABLE 45 Long-term Indicators of Clinical Remission
% of Patients DAS28 <2.6 TJC = 0 SJC = 0 HAQ = 0 3 Months 18 10
9 12 6 Months 30 16 14 18 12 Months 35 20 22 20 24 Months 40 22 25
20 36 Months 40 27 25 22 48 Months 42 30 22 22 60 Months 52 32 22
27 72 Months 60 37 32 32 Observed Values.
TABLE-US-00046 TABLE 46 Baseline (BL) and Last Visit (LV) Outcomes
of ACR20 Responders and Non-Responders (NR) By Status Of
Continuation and Reasons for Discontinuation ACR20 Patients ACR50,
70 DAS28* HAQ* TJC68* SJC66* CRP* category N = 947 response BL LV
BL LV BL LV BL LV BL LV Responders 621, 66% 64%, 38% 5.7
2.7.sup..dagger. 1.4 0.7.sup..dagger. 27 5.sup..dagger. 21
4.sup..dagger. 20 7.sup..dagger. NR 143, 15% -- 5.6
4.3.sup..dagger. 1.4 1.3.sup..dagger-dbl. 29 17.sup..dagger. 18
11.sup..dagger. 14 11.sup..dagger-dbl. Continued NR Disc. 119, 13%
-- 5.6 4.8.sup..dagger. 1.6 1.5 29 21.sup..dagger. 18
13.sup..dagger. 18 20 AE, Other NR Disc. 64, 7% -- 5.8 5.6 1.6 1.6
30 29 21 19 20 21 LOE *Mean values; .sup..dagger.p < 0.001,
.sup..dagger-dbl.p < 0.05, both last visit vs. baseline
TABLE-US-00047 TABLE 47 Serious Adverse Events (MEDRA Coding)
Extension Study Serious Adverse Event Pivotal Trials 3203 PYs (E)
E/100 PY 793 PYs As of Aug. 31, 2005 Serious Infections 4.16 3.15
Pneumonia 1.13 0.62 Urinary Tract Infections 0.50 0.34 Septic
Arthritis 0.38 0.12 Tuberculosis 0.13 0.06 Histoplasmosis 0.13 0
Demyelinating Diseases 0.13 0.03 Lymphoma 0.25 0.16 SLE/Lupus-like
Syndrome 0.13 0.03 Pancytopenia 0.25 0
[0395] In conclusion, adalimumab plus MTX induced a sustained ACR20
response in 66% and clinical remission in more than 20% of all
patients, including patients who withdrew. Clinical improvements
above 20% in individual ACR components observed in ACR20
non-responders may justify their continuation on therapy. In
addition, patients maintained clinical improvements and significant
reductions in disease activity for up to 6 years of continuous
treatment with adalimumab. Remission (DAS28<2.6) was observed in
over 55% of patients after 6 years on therapy, and adalimumab was
safe and well-tolerated for up to 6 years.
Example 7
Effect of Adalimumab (HUMIRA.RTM.) on Response to Influenza Virus
and Pneumococcal Vaccines in Patients with Rheumatoid Arthritis
(RA)
[0396] The following study evaluated the effects of adalimumab on
antibody response to pneumococcal and influenza virus vaccines in
adult RA patients.
[0397] In this randomized, double-blind, placebo-controlled,
multi-center, 36-day study, patients with active RA were enrolled
during the 2003-04 US influenza season and received adalimumab or
placebo. Patients were considered eligible for the study if they
were 20 years of age or older and had a documented history of RA as
defined by ACR diagnosis criteria. Patients were required to
discontinue administration of any TNF antagonists including ADA, at
least two months prior to Day 1. Exclusion criteria included: a
recent (3-month) history of any influenza or pneumococcal
infection; receipt of any vaccine within 3 months prior to initial
study drug administration; or receipt of an influenza vaccine
within 6 months or a pneumococcal vaccine within 5 years. All
patients underwent purified protein derivative (PPD) testing for
latent tuberculosis infection and chest radiographs at
screening.
[0398] Patients were allowed to continue their pre-study doses of
non-biologic anti-rheumatic therapy, including non-steroidal
anti-inflammatory drugs, corticosteroids (prednisone equivalent of
.ltoreq.10 mg/day), and conventional (non-biologic)
disease-modifying anti-rheumatic drugs (DMARDs); however dosage
changes were not permitted during the blinded phase of the
study.
[0399] Patients were stratified by concomitant MTX use (yes/no).
Patients randomized to adalimumab received 80 mg on Day 1 followed
by 40 mg on Days 15 and 29. Commercially available 2003-2004
trivalent subvirion influenza virus vaccine (0.5 mL) and standard
23-valent pneumococcal vaccine (0.5 mL) were administered
intramuscularly to all patients on Day 8 (vaccination baseline).
Antibody titers for both vaccines were measured on Day 8
(pre-vaccination) and Day 36. For pneumococcal vaccine, antibody
titers for 9V, 14, 18C, 19F, and 23F were measured. Protective
antibody concentration was defined as .gtoreq.1.6 .mu.L in
.gtoreq.3 of 5 antigens and response to vaccination was defined as
.gtoreq.2-fold increase from baseline in antibody titer in
.gtoreq.3 of 5 antigens. For influenza A and B vaccines, antibody
titers for H1N1, H3N2, and Hong Kong were measured. Protective
antibody concentration was defined as .gtoreq.1:40 titer in
.gtoreq.2 of 3 antigens, and response to vaccination was defined as
.gtoreq.4-fold increase from baseline in antibody titer in
.gtoreq.2 of 3 antigens. After Day 36, patients had the option to
continue adalimumab treatment (40 mg every other week) in a 6-month
open-label extension. Safety evaluations, including physical
examinations, laboratory assessments, vital signs, and adverse
event (AE) reports, were assessed throughout the study. FIG. 14
shows the study design.
[0400] Serum pneumococcal antibody titers were determined using the
enzyme-linked immunosorbent assay (ELISA), and serum influenza A
and B antibody titers were determined using the hemagglutination
inhibition antibody assay. All antibody titer analyses were
conducted by ViroMed Laboratories, Minnetonka, Minn.
[0401] The primary measure of response was the percentage of
patients achieving a satisfactory humoral response as defined by a
.gtoreq.2-fold titer increase from vaccination baseline (Day 8) in
.gtoreq.3 of 5 pneumococcal antigens (9V, 14, 18C, 19F, and 23F)
(Go and Ballas, 1996) and a .gtoreq.4-fold titer increase from
vaccination baseline (Day 8) in .gtoreq.2 of 3 influenza antigens
(H1N1, H3N2, and Hong Kong) (Gross et al, 1985; Hermogenes et al,
1992).
[0402] Secondary measures of response included 1) the percentage of
patients with protective antibody titers 4 weeks postvaccination
(defined as antibody titer .gtoreq.1.6 .mu.g/mL for .gtoreq.3 of 5
antigens for the pneumococcal vaccine (Hodges-Savola et al, 2005;
Schmid et al, 1981) and antibody titer .gtoreq.1:40 for .gtoreq.2
of 3 antigens for the influenza vaccine (Gross et al, 1985;
Hermogenes et al, 1992); 2) the percentage of patients achieving a
.gtoreq.2-fold increase in pneumococcal antibody titers and
.gtoreq.4-fold increase in influenza titers from baseline by
antigen; and 3) the mean changes in antibody titers from baseline
by antigen. Results are presented as the means of variables
expressed in a log.sub.2 scale, transformed into GMTs. Differences
between means of variables expressed in a log.sub.2 scale were
transformed into geometric mean ratios (GMRs).
[0403] The primary analysis was performed in a "per-protocol"
population (Hwang and Morikawa, 1999). The Per-protocol Analysis
Set for the pneumococcal/influenza vaccine was defined as all
patients who were randomized; who received the
pneumococcal/influenza vaccine on Day 8 (vaccination baseline); who
received adalimumab or placebo on Day 1 and Day 15; and for whom a
complete set of blood samples for pneumococcal/influenza antibody
assay (from both Day 8 and Day 36) was collected and available for
analysis. Patients who had missing data were classified as
nonresponders. The treatment differences in the percentages were
assessed using chi-square tests.
[0404] Covariates that might influence immunogenicity such as age,
sex, co-morbid conditions (diabetes and pulmonary disease), and
concomitant RA medications (DMARDs, corticosteroids, and MTX) were
examined using logistic regression models.
[0405] 226 patients were randomized. Of the 226 patients randomized
to receive treatment, 115 were assigned to the placebo group and
111 to the adalimumab group. A total of 220 patients completed the
double-blind period of the study and participated in the open label
extension. Of the 226 patients enrolled in the study, 208 met the
per-protocol definition and were included in the efficacy analysis.
Table 48 shows the disposition of all patients.
TABLE-US-00048 TABLE 48 Disposition of Patients Adalimumab Placebo
40 mg Total N = 115 N = 111 N = 226 n (%) Full Analysis Set 115
(100.0) 111 (100.0) 226 (100.0) Completed Day 36 112 (97.4) 108
(97.3) 220 (97.3) visit Death 0 0 0 Early 3 (2.6) 3 (2.7) 6 (2.7)
Discontinuation.sup.a Adverse event 3 (2.6) 1 (0.9) 4 (1.8) Other 0
2 (1.8) 2 (0.9) Withdrew consent 1 (0.9) 0 1 (0.4) Lost to
follow-up 0 0 0
[0406] The 208 patients received at least the first 2 doses of
blinded study drug (on Days 1 and 15) and had both pre- and
post-vaccine blood samples for antibody analysis. There was no
significant difference in baseline demographics or in protective
antibody concentrations between groups. The baseline
characteristics for the 208 patients were comparable between
treatment groups and are presented below in Table 49.
TABLE-US-00049 TABLE 49 Baseline Characteristics Adalimumab Placebo
40 mg eow Total (n = 109) (n = 99) (N = 208) P n (%) n (%) n (%)
value* Age (years), 51.1 .+-. 11.46 52.2 .+-. 11.90 51.7 .+-. 11.66
0.504 mean .+-. SD Age category 0.664 (years), n (%) .ltoreq.40 22
(20.2) 20 (20.2) 42 (20.2) >40-65 78 (71.6) 67 (67.7) 145 (69.7)
>65 9 (8.3) 12 (12.1) 21 (10.1) Sex, n (%) 0.084 Male 27 (24.8)
15 (15.2) 42 (20.2) Female 82 (75.2) 84 (84.8) 166 (79.8) Disease
Diabetes mellitus 4 (3.7) 6 (6.1) 10 (4.9) 0.421 Pulmonary disease
38 (34.9) 30 (30.3) 68 (32.6) 0.484 Concomitant medication MTX, n
(%) 59 (54.1) 55 (55.6) 114 (54.9) 0.836 DMARDs 32 (29.4) 17 (17.2)
49 (46.6) 0.039 (no MTX), n (%) Corticosteroids, 50 (45.9) 45
(45.5) 95 (45.7) 0.952 n (%) CRP status Normal 57 (52.3) 52 (52.5)
109 (52.4) 0.973 Elevated 52 (47.7) 47 (47.5) 99 (47.6) (>0.8
mg/dL) *Continuous comparisons from one-way analysis of variance
model; discrete variables compared using the chi-square test. If
25% of cells had expected count of <5, Fisher's exact test was
used. CRP = C-reactive protein; DMARDs = disease-modifying
anti-rheumatic drugs; eow = every other week; MTX =
methotrexate.
[0407] As can be seen in Table 49, patients had a mean age of 51.7
years. Fifty-two percent (57/109) of placebo-treated patients and
53% (52/99) of adalimumab-treated patients had normal C-reactive
protein (CRP) concentration status (<0.8 mg/dL). No
statistically significant differences were observed between
treatment groups in the percentages of patients using MTX or
corticosteroids; however, there was a significantly higher
percentage of patients in the placebo group using concomitant
DMARDs other than MIX compared with the adalimumab group (29.4% vs.
17.2%, respectively). All patients had negative PPD skin tests.
[0408] There was no significant difference between treatment groups
in baseline antibody titer for the individual pneumococcal and
influenza antigens, with the exception of antibody for pneumococcal
antigen 14 ((1.45 .mu.g/mL in the placebo group; 2.22 .mu.g/mL in
the adalimumab group) (Table 50). Both treatment groups had similar
percentages of patients with baseline protective antibody titers.
Table 51 shows the similarity in immune response to pneumococcal
vaccine between groups.
TABLE-US-00050 TABLE 50 Mean pneumococcal and influenza antibody
titers by antigen at prevaccination and postvaccination and change
in pneumococcal and influenza antibody titers by antigen.
Within-group Between-group comparison comparison Prevaccination
Postvaccination (postvaccination:prevaccination)
(adalimumab:placebo) n GMT GMT GMR (95% CI)* GMR (95% CI)*
Pneumococcal antigen treatment 9V Placebo 109 2.65 6.23 2.34 (1.97,
2.79) 1.00 (0.77, 1.28) Adalimumab 99 2.60 6.10 2.36 (1.96, 2.83)
14 Placebo 109 1.45 4.40 3.03 (2.47, 3.73) 1.32 (0.98, 1.78)
Adalimumab 99 2.22 5.09 2.30 (1.85, 2.86) 18C Placebo 109 2.84 7.49
2.63 (2.18, 3.17) 1.08 (0.82, 1.41) Adalimumab 99 2.90 7.05 2.44
(2.01, 2.97) 19F Placebo 109 2.16 4.16 1.92 (1.61, 2.28) 0.95
(0.74, 1.22) Adalimumab 99 1.96 3.96 2.03 (1.69, 2.43) 23F Placebo
109 2.26 4.22 1.86 (1.57, 2.19) 0.85 (0.67, 1.08) Adalimumab 99
1.84 4.01 2.19 (1.84, 2.60) Influenza antigen treatment H1N1
Placebo 109 51.89 188.68 3.63 (2.92, 4.51) 1.05 (0.77, 1.44)
Adalimumab 99 47.16 162.64 3.46 (2.75, 4.34) H3N2 Placebo 109 89.13
602.81 6.74 (5.04, 9.02) 1.51 (0.99, 2.30) Adalimumab 99 105.86
472.25 4.48 (3.30, 6.08) B (HongKong) Placebo 109 22.71 92.94 4.08
(3.28, 5.08) 1.25 (0.91, 1.71) Adalimumab 99 22.62 73.86 3.27
(2.60, 4.12) *Adjusted GMRs are from analysis of covariance
(ANCOVA) model: model response = therapy methotrexate use, where
response = [log.sub.2 (Day 36 titer) - log.sub.2 (Day 8 titer)]. In
the ANCOVA model, titers are expressed in a log.sub.2 scale.
Log.sub.2 (titer) are analyzed and transformed back to the original
scale (ie, least square means were transformed to GMRs of endpoint
titers and differences of least square means were transformed into
GMRs of titers in adalimumab group to titers in placebo group.
TABLE-US-00051 TABLE 51 Similar Immune Response* to Pneumococcal
Vaccine Between Groups % of Patients Placebo Adalimumab +Protective
Antibody at Baseline 27.4 28.1 -Protective Antibody at Baseline
54.7 50.0 Overall 40.4.sup..dagger. 37.4.sup..dagger. *Response to
vaccination was defined as .gtoreq.2-fold increase from baseline in
antibody titer in .gtoreq.3 of 5 antigens. .sup..dagger.CI 95%
(-16.2, 10.3) for difference between placebo and adalimumab
groups.
TABLE-US-00052 TABLE 52 Similar Percentage of Patients With a
Protective Pneumococcal Antibody Titer* Between Groups at 4 Weeks
Postvaccination % of Patients Placebo Adalimumab +Protective
Antibody at Baseline and 100.0 (n = 62) 100.0 (n = 57) Continued to
have Protective Antibody Post-vaccination -Protective Antibody at
Baseline and 57.4 (n = 27) 66.7 (n = 28) Developed Protective
Antibody Post-vaccination Overall 81.7 (n = 89) 85.9 (n = 85)
*Protective antibody titer was defined as .gtoreq.1.6 .mu.g/mL in
.gtoreq.3 of 5 antigens.
[0409] For pneumococcal vaccine, the percentage of patients with
protective antibody concentrations at Day 36 were similar in both
arms, as were the percentages of patients in both groups who
developed antibody response. Table 52 depicts the similarity in the
percentages of patients with protective pneumococcal antibody titer
between groups at 4 weeks postvaccination. The percentage of
patients who received adalimumab and achieved a .gtoreq.2-fold
increase in .gtoreq.3 of 5 pneumococcal antibody titers was similar
to the placebo group (37.4% vs. 40.4%, respectively; 95% confidence
interval [CI] of difference between treatment groups [-16.2, 10.3])
(Table 53). Across both treatment groups, the percentage of
patients who achieved a .gtoreq.2-fold increase in .gtoreq.3 of 5
pneumococcal antibody titers was higher in the group without
protective antibody titers at baseline (Table 53). Table 53 shows
the primary efficacy results for each co-primary endpoint;
sensitivity analyses of the number (%) of patients with a
.gtoreq.2-fold increase from baseline in .gtoreq.3 of 5
pneumococcal titers and a .gtoreq.4-fold increase from baseline at
Day 36 in .gtoreq.2 of 3 influenza antibody titers.
TABLE-US-00053 TABLE 53 Adalimumab Pneumococcal vaccine Placebo 40
mg eow Per-protocol Analysis Set n = 109 n = 99 Responders, n (%)
44 (40.4) 37 (37.4) Difference between treatment groups, % -3.0
(-16.2, 10.3) (95% CI) Adalimumab Presence of protective antibody
Placebo 40 mg eow concentration at baseline* n = 62 n = 57
Responders, n (%) 17 (27.4) 16 (28.1) Difference between treatment
groups, % 0.7 (-15.5, 16.8) (95% CI) Adalimumab Absence of
protective antibody Placebo 40 mg eow concentration at baseline* n
= 47 n = 42 Responders, n (%) 27 (57.4) 21 (50.0) Difference
between treatment groups, % -7.4 (-28.1, 13.3) (95% CI) Adalimumab
Influenza vaccine Placebo 40 mg eow Per-protocol Analysis Set n =
109 n = 99 Responders, n (%) 69 (63.3) 51 (51.5) Difference between
treatment groups, % -11.8 (-25.2, 1.6) (95% CI) Adalimumab Presence
of protective antibody Placebo 40 mg eow concentration at
baseline.sup..dagger. n = 63 n = 58 Responders, n (%) 35 (55.6) 21
(36.2) Difference between treatment groups, % -19.3 (-36.8, -1.9)
(95% CI) Adalimumab Absence of protective antibody Placebo 40 mg
eow concentration at baseline.sup..dagger. n = 46 n = 41
Responders, n (%) 34 (73.9) 30 (73.2) Difference between treatment
groups, % -0.7 (-19.3, 17.8) (95% CI) *Protective antibody
concentration in .gtoreq.3 of 5 pneumococcal titers at baseline.
Note: Any pneumococcal antibody titer <1.3 .mu.g/mL
(undetectable) was expressed as 0.65 .mu.g/mL; any influenza
antibody titer <1:20 (undetectable) was expressed as 1:10.
.sup..dagger.Protective antibody concentration in .gtoreq.2 of 3
influenza titers at baseline. CI = confidence interval; eow = every
other week.
[0410] Univariate analyses of the primary measure of response
demonstrated that concomitant MTX use (p<0.0001), concomitant
DMARD use (p<0.044), and protective antibody titers at baseline
(p<0.0001) significantly reduced the response rate to
pneumococcal vaccine, whereas elevated baseline CRP concentration
significantly increased the response rate (p<0.035) (Table 54).
Sex, age, race, weight, concomitant corticosteroid use, diabetes,
and pulmonary disease did not affect the response rate.
TABLE-US-00054 TABLE 54 Pneumococcal vaccine Odds Influenza Vaccine
Placebo Adalimumab Ratio* P- Placebo Adalimumab Odds Ratio*
Correlate n/N (%) n/N (%) (95% CI) value* n/N (%) n/N (%) (95% CI)
P-value* Sex 0.820 0.436 Male 9/27 8/15 1.08 15/27 7/15 (46.7) 0.76
(0.39, (33.3) (53.3) (0.54, 2.15) (55.6) 1.51) Female 35/82 29/84
54/82 44/84 (52.4) (42.7) (34.5) (65.9) Age (years) 0.292 0.316
.ltoreq.40 6/22 6/20 1.82 16/22 12/20 (60.0) 0.65 (0.31, (27.3)
(30.0) (0.88, 3.95) (72.7) 1.32) >40-65 35/78 26/67 1.54 35/78
26/67 (38.8) 0.45 (0.15, (44.9) (38.8) (0.50, 4.66) (44.9) 1.32)
>65 3/9 5/12 5/9 5/12 (41.7) (33.3) (41.7) (55.6) MTX
use.sup..dagger. <0.001 0.288 Yes 17/59 10/55 0.23 33/59 29/55
(52.7) 0.74 (0.42, (28.8) (18.2) (0.13, 0.41) (55.9) 1.29) No 27/50
27/44 36/50 22/44 (50.0) (54.0) (61.4) (72.0) MTX 0.321 0.052 dose
(mg/week) >0-10 3/16 3/17 1.12 6/16 6/17 (35.3) 2.92 (1.14,
(18.8) (17.6) (0.35, 3.80) (37.5) 7.78) >10-15 5/21 3/19 2.09
5/21 3/19 (15.8) 2.73 (1.08, (23.8) (15.8) (0.72, 6.68) (23.8)
7.22) >15 9/22 4/19 14/22 11/19 (57.9) (40.9) (21.1) (63.6)
DMARD 0.044 0.810 use (except MTX) Yes 11/32 2/17 0.48 18/32 11/17
(64.7) 1.08 (0.57, (34.4) (11.8) (0.23, 0.96) (56.3) 2.10) No 33/77
35/82 51/77 40/82 (48.8) (42.9) (42.7) (66.2) Corticosteroid 0.776
0.369 use Yes 19/50 17/45 0.92 33/50 25/45 (55.6) 1.29 (0.74,
(38.0) (37.8) (0.53, 1.61) (66.0) 2.25) No 25/59 20/54 36/59 26/54
(48.1) (42.4) (37.0) (61.0) Diabetes 0.944 0.944 Yes 2/4 2/6 1.05
1/4 3/6 (50.0) 0.47 (0.12, (50.0) (33.3) (0.26, 3.79) (25.0) 1.70)
No 42/105 35/93 68/105 48/93 (51.6) (40.0) (37.6) (64.8) Pulmonary
0.645 0.155 disease.sup..dagger-dbl. Yes 17/38 11/30 1.15 27/38
17/30 (56.7) 1.54 (0.85, (44.7) (36.7) (0.63, 2.07) (71.1) 2.84) No
27/71 26/69 42/71 34/69 (49.3) (38.0) (37.7) (59.2) CRP status
0.035 0.596 Normal 18/57 17/52 1.84 35/57 26/52 (50.0) 1.16 (0.67,
(31.6) (32.7) (1.05, 3.24) (61.4) 2.02) Elevated (>0.8 mg/dL)
26/52 20/47 34/52 25/47 (53.2) (50.0) (42.6) (65.4) Protective
<0.001 <0.001 antibody concentration Yes 17/62 16/57 0.33
35/63 21/58 (36.2) 0.31 (0.17, (27.4) (28.1) (0.18, 0.58) (55.6)
0.56) No 27/47 21/42 34/46 30/41 (73.2) (57.4) (50.0) (73.9)
[0411] Similarly high percentages of patients in both the placebo
(81.7%) and adalimumab (85.9%) treatment groups achieved protective
antibody titers (antibody titer .gtoreq.1.6 .mu.g/mL in .gtoreq.3
of 5 antigens) 4 weeks postvaccination (Table 55). Table 55 shows a
shift of protective pneumococcal antibody concentration in
.gtoreq.3 of 5 titers and protective influenza antibody
concentration in .gtoreq.2 of 3 titers from baseline to final value
including by MTX use (Per-protocol Analysis Set). A higher
percentage of adalimumab-treated patients (66.7%) converted from
unprotected to protected status in .gtoreq.3 of 5 antigens versus
placebo-treated patients (57.4%). When shifts from unprotected to
protected status were examined by MTX use, a greater percentage of
patients converted from unprotected status to protected status in
the absence of MTX use (Table 55).
TABLE-US-00055 TABLE 55 Irrespective of MTX use MTX use No MTX use
Therapy Final value Final value Final value Baseline Unprotected
Protected Unprotected Protected Unprotected Protected Value n (%)
Pneumococcal vaccine Placebo Unprotected 20 (42.6) 27 (57.4) 14
(56.0) 11 (44.0) 6 (27.3) 16 (72.7) Protected 0 62 (100.0) 0 34
(100.0) 0 28 (100.0) Total 20 (18.3) 89 (81.7) 14 (23.7) 45 (76.3)
6 (12.0) 44 (88.0) Adalimumab Unprotected 14 (33.3) 28 (66.7) 10
(40.0) 15 (60.0) 4 (23.5) 13 (76.5) Protected 0 57 (100.0) 0 30
(100.0) 0 27 (100.0) Total 14 (14.1) 85 (85.9) 10 (18.2) 45 (81.8)
4 (9.1) 40 (90.9) Influenza vaccine Placebo Unprotected 6 (13.0) 40
(87.0) 4 (20.0) 16 (80.0) 2 (7.7) 24 (92.3) Protected 0 63 (100.0)
0 39 (100.0) 0 24 (100.0) Total 6 (5.5) 103 (94.5) 4 (6.8) 55
(93.2) 2 (4.0) 48 (96.0) Adalimumab Unprotected 1 (2.4) 40 (97.6) 1
(4.2) 23 (95.8) 0 17 (100.0) Protected 1 (1.7) 57 (98.3) 1 (3.2) 30
(96.8) 0 27 (100.0) Total 2 (2.0) 97 (98.0) 2 (3.6) 53 (96.4) 0 44
(100.0) Note: Any pneumococcal antibody titer <1.3 .mu.g/mL
(undetectable) is expressed as 0.65 .mu.g/mL. Any influenza
antibody titer <1:20 (undetectable) was expressed as 1:10. The
protective antibody concentration is defined as an antibody titer
.gtoreq.1:40. MTX = methotrexate.
[0412] Overall, the percentages of patients with a .gtoreq.2-fold
increase in pneumococcal antibody titers from baseline at 4 weeks
postvaccination were similar between treatment groups (Table 56).
Antibody response was fairly uniform among antigens, with a similar
range of response observed between the placebo and adalimumab
treatment groups (36%-50% and 36%-47%, respectively). Table 56
shows the number (%) of patients with a .gtoreq.2-fold increase in
pneumococcal antibody titers or a .gtoreq.4-fold increase in
influenza antibody titers from baseline at Day 36 by antigen
(Per-protocol Analysis Set).
TABLE-US-00056 TABLE 56 Placebo Adalimumab N = 109 N = 99 n (%)
Odds ratio (95% CI)* Pneumococcal antigen 9V 46 (42.2) 45 (45.5)
1.17 (0.66, 2.08) 14 54 (49.5) 41 (41.4) 0.72 (0.41, 1.26) 18C 53
(48.6) 46 (46.5) 0.92 (0.53, 1.61) 19F 39 (35.8) 36 (36.4) 1.04
(0.58, 1.87) 23F 41 (37.6) 44 (44.4) 1.40 (0.78, 2.54) Influenza
antigen H1N1 61 (56.0) 50 (50.5) 0.81 (0.46, 1.40) H3N2 74 (67.9)
58 (58.6) 0.67 (0.38, 1.18) B (Hong Kong) 66 (60.6) 48 (48.5) 0.61
(0.35, 1.07)
Table 57 shows the percentages of patients who overall developed
protective antibody concentrations, or had antibody responses.
TABLE-US-00057 TABLE 57 Adalimumab Placebo Pneumococcal -
Protective antibody concentration 85/99 (85.9%) 89/109 (81.7%)
Pneumococcal - Developed antibody response 37/99 (37.4%) 44/109
(40.4%) Response in patients with protective pneumococcal antibody
16/57 (28.1%) 17/62 (27.4%) concentration at baseline Response in
patients without protective pneumococcal 21/42 (50.0%) 27/47
(54.7%) antibody concentration at baseline Influenza - Protective
antibody concentration 97/99 (98%) 103/109 (94.5%) Influenza
Developed antibody response 51/99 (51.5%) 69/109 (63.3%) Response
in patients with protective influenza antibody 21/58 (36.2%) 35/63
(55.6%) concentration at baseline Response in patients without
protective influenza antibody 30/41 (73.3%) 34/46 (73.9%)
concentration at baseline
[0413] Changes from baseline in antibody titers 4 weeks after
pneumococcal vaccination were statistically significant for all 5
antigens tested and were similar between treatment groups, as
demonstrated by lack of statistical significance between group
comparisons of GMR (Table 50). Similar trends were observed when
the change from baseline at 4 weeks postvaccination was examined by
MTX use; however, markedly larger increases in GMTs were observed
for both treatment groups in the absence of MTX use (data not
shown).
[0414] With respect to the immune response to influenza vaccine, a
smaller, though not statistically significant percentage of
patients who received adalimumab achieved a .gtoreq.4-fold increase
in .gtoreq.2 of 3 influenza antibody titers compared with patients
who received placebo (51.5% vs. 63.3%, 95% CI of difference between
treatment groups [-25.2, 1.6]) (Table 53). Table 58 shows the
similar immune response to influenza vaccine between groups. The
lower percentage of response in the adalimumab group is driven by
the subgroup of patients with pre-existing protective antibody
titers (.gtoreq.1:40 antibody titer to .gtoreq.2 of 3 antigens) at
baseline. In this subgroup, the percentage of patients who achieved
a .gtoreq.4-fold increase in .gtoreq.2 of 3 influenza antibody
titers was 36.2% in the adalimumab group and 55.6% in the placebo
group. In the subgroup of patients without protective antibody
titers at baseline, the percentage of patients who achieved
.gtoreq.4-fold increase in .gtoreq.2 of 3 influenza antibody titers
was similar in the adalimumab and placebo treatment groups (73.3%
and 73.9%, respectively) (Table 53).
[0415] Univariate analyses of the primary measure of response
demonstrated that protective antibody titers at baseline
significantly reduced response rates to influenza vaccine
(p<0.001). Although concomitant MTX use also reduced the
response rate, the reduction was not statistically significant.
Concomitant DMARD use, baseline CRP concentration, sex, age,
concomitant corticosteroid use, diabetes, and pulmonary disease did
not affect the response rate (Table 54).
[0416] Similarly high percentages of patients in the placebo and
adalimumab treatment groups (94.5% and 98.0%, respectively)
achieved protective antibody titers (.gtoreq.1:40 antibody titer in
.gtoreq.2 out of 3 antigens) at 4 weeks postvaccination (Table 55).
Table 59 depicts the similarity in the percentages of patients with
protective influenza antibody titer between groups at 4 weeks
postvaccination. In addition, a greater percentage of
adalimumab-treated vs. placebo-treated patients experienced
conversion to protected status in .gtoreq.2 of 3 antigens (97.6%
vs. 87.0%, respectively). When shifts from unprotected to protected
status were examined by MTX use, a slightly greater percentage of
patients converted from unprotected status to protected status in
the absence of MTX use (Table 55).
TABLE-US-00058 TABLE 58 Similar Immune Response* to Influenza
Vaccine Between Groups % of Patients Placebo Adalimumab +Protective
Antibody at Baseline 55.6 36.2 -Protective Antibody at Baseline
73.9 73.3 Overall 63.3* 51.5* *Response to vaccination was defined
as .gtoreq.4-fold increase from baseline in antibody titer in
.gtoreq.2 of 3 antigens. CI 95% (-25.2, 1.6) for difference between
placebo and adalimumab groups.
TABLE-US-00059 TABLE 59 Similar Percentage of Patients With
Protective Influenza Antibody Titer* Between Groups at 4 Weeks
Post-Vaccination % of Patients Placebo Adalimumab +Protective
Antibody at Baseline and 100.0 (n = 63) 98.3 (n = 57) Continued to
have Protective Antibody Post-vaccination -Protective Antibody at
Baseline and 87 (n = 40) 97.6 (n = 40) Developed Protective
Antibody Post-vaccination Overall 94.5 (n = 103) 98.0 (n = 97)
*Protective antibody concentration was defined as .gtoreq.1:40
titer in .gtoreq.2 of 3 antigens.
[0417] Overall, at Day 36, the percentage of patients with a
.gtoreq.4-fold increase in influenza antibody titers from baseline
by antigen was lower in the adalimumab treatment group versus the
placebo treatment group, although the differences were not
statistically significant (Table 56). Within each treatment group,
the immunogenicity of the 3 antigens was similar (56%-68% in the
placebo group and 49%-59% in the adalimumab group).
[0418] Changes from baseline in antibody titers 4 weeks after
influenza vaccination were statistically significant for all 3
antigens tested in both treatment groups (GMR range from 3.3-6.7).
The increase from baseline was higher in the placebo treatment
group compared with the adalimumab group, though the difference was
not statistically significant (Table 50). Significant increases in
titers 4 weeks post-vaccination were observed in groups with and
without MTX use. However, larger increases in titers, although not
significant, were observed for both treatment groups in the absence
of MTX.
[0419] Adalimumab was generally well-tolerated. During the blinded
period of the study no deaths were reported, and 1 patient
receiving placebo reported a serious AE. A slightly greater
percentage of patients in the placebo group reported an AE than did
patients in the adalimumab group (54.8% [63/115] vs. 45.9%
[51/111], respectively). The most frequently reported
treatment-emergent AEs occurring during the blinded period of the
study were upper respiratory tract infection and injection site
reaction, both were reported more frequently by placebo-treated
patients. There were no serious infectious AEs, malignancies, or
opportunistic infections, including tuberculosis, reported during
the double-blind period. The rate of infectious AEs was
statistically significantly higher in the placebo treatment group
(23.5% [27/115]) vs the adalimumab group (12.6% [14/111])
(p=0.039). The percentages of patients reporting AEs leading to
discontinuation of study drug were similar between the 2
groups.
[0420] In conclusion, in this study, adalimumab does not diminish
humoral response to commercially available 23-valent pneumococcal
polysaccharide and trivalent subvirion influenza virus vaccines in
RA patients, and that 4 weeks after vaccination, the majority of
patients have protective antibody titers. Similarly high percentage
of patients in both the placebo and adalimumab treatment groups
achieved protective pneumococcal antibody titers (81.7% and 85.9%,
respectively) as well as influenza antibody titers (94.5% and
98.0%, respectively) 4 weeks postvaccination, as defined by
antibody tiers .gtoreq.1.6 .mu.g/mL in .gtoreq.3 of 5 antigens and
.gtoreq.1:40 antibody titer in .gtoreq.2 of 3 antigens,
respectively.
[0421] The data described herein shows that RA patients were able
to develop an effective antibody response to pneumococcal vaccine,
and that concomitant adalimumab use did not appear to affect the
response; a .gtoreq.2-fold increase in .gtoreq.3 of 5 pneumococcal
antibody titers was achieved by 37.4% of patients treated with
adalimumab compared with 40.4% of placebo-treated patients.
Patients receiving concomitant MTX, concomitant DMARDs, or with
protective antibody titers at baseline were significantly less
likely to respond to pneumococcal vaccination. It should be noted
that 89 of 208 (43%) subjects entering the study had protective
pneumococcal antibody titer levels at baseline and this led to the
appearance of a lower response rate than other studies. In the
patients without protective antibody titer levels at baseline, the
response rates in the adalimumab and placebo groups were 50.0% and
57.4%, respectively.
[0422] In the subgroup of RA patients without protective antibody
titers at baseline, antibody response to influenza vaccination
(.gtoreq.4-fold increase in .gtoreq.2 of 3 influenza antibody
titers) was similar in the adalimumab and placebo treatment groups
(73.3% and 73.9%, respectively). Protective antibody titers at
baseline (found in 58% of subjects) significantly reduced response
rates to influenza vaccine as did concomitant MTX use; however, the
latter reduction was not statistically significant. Concomitant
DMARD use did not affect the response rate to influenza
vaccination. These findings demonstrate that adalimumab-treated
patients can be safely immunized with these antigens.
Example 8
Adalimumab (HUMIRA.RTM.) is Effective and Safe in the Treatment of
Rheumatoid Arthritis Across all Participating Countries in the
Study a Trial
[0423] The Study A trial (ReAct) was designed to assess the
efficacy and safety of adalimumab (ADA) in real-life clinical
practice in a large cohort of patients across multiple countries
with active, insufficiently treated RA, various co-morbidities, a
broad range of anti-rheumatic co-medications, and varied social
care systems. The objective of this study was to compare the
efficacy and safety results of ADA treatment in different countries
at Week 12 in the Study A trial.
[0424] Patients with active RA despite previous or current DMARD
treatment enrolled at 448 sites in 11 European countries and
Australia in the Study A trial. Patient inclusion criteria required
active RA defined by Disease Activity Score 28 (DAS28) .gtoreq.3.2
at baseline and patients had demonstrated unsatisfactory response
or intolerance to at least 1 prior DMARD. Upon enrollment patients
received ADA 40 mg subcutaneous (sc) every other week (eow) in
addition to their current anti-rheumatic therapy. Routine safety
and efficacy evaluations were conducted at Weeks 2, 6, and 12. Key
baseline (BL) characteristics and Week 12 country-specific efficacy
and safety data were summarised and compared. The efficacy outcomes
measured included: ACR20, ACR50, ACR70, EULAR response, Changes in
DAS28, TJC, SJC, CRP, and HAQ. Adverse events (AE) were also
collected.
[0425] Of 6610 patients enrolled in the Study A trial, nearly 92%
of all patients were enrolled in Italy (I), Spain (E), Germany (D),
France (F), Belgium (B), Greece (GR), and The Netherlands (NL).
Across all countries, patients enrolled had long-standing, severely
active RA with a mean disease duration of 10-11 years, DAS28 scores
ranging from 5.9 to 6.2, and HAQ scores that indicated marked
disability (1.48-2.00). The number of DMARDs used prior to
enrolment (1.6-3.8) and percentage of patients taking concomitant
DMARDs with ADA during the study (66%-84%) varied somewhat between
countries. Only small differences were seen in efficacy outcomes
between countries, and the safety profiles were similar across
countries. Key efficacy and safety results at Week 12 for these
countries are summarised in Table 60, while Table 61 demonstrates
that patient baseline characteristics were similar across
countries. Table 62 shows that the pattern of concomitant DMARDs
used in the participating countries was similar overall;
methotrexate was the most frequently used DMARD, followed (in
varied order) by leflunomide, antimalarials, or sulfazalazine.
TABLE-US-00060 TABLE 60 Efficacy and safety of adalimumab by
country at Week 12 in Study A Country I E D F B GR NL N 1527 1169
1143 1002 455 399 378 Baseline DAS28 6.2 5.9 6.0 5.9 6.1 6.1 6.0
ACR20 (%) 73 70 66 66 70 58 68 ACR50 (%) 43 41 37 37 41 35 37 ACR70
(%) 21 19 16 16 20 18 17 .DELTA.DAS28* -2.2 -2.2 -2.0 -2.0 -2.3
-1.9 -2.0 .DELTA.HAQ* -0.61 -0.52 -0.42 -0.52 -0.69 -0.60 -0.50
Serious infections (%) 0.8 1.5 2.2 1.4 1.5 1.5 0.8 *Mean change
(.DELTA.) from Baseline
TABLE-US-00061 TABLE 61 Patient Baseline Characteristics by Country
Australia Austria Belgium France Germany Greece Italy Nether-lands
Portugal Spain Switzerland UK Patients, n 74 150 455 1002 1143 399
1527 378 125 1169 71 117 Age* (yrs) 55 52 55 54 53 54 54 54 49 54
54 55 Female (%) 74 85 76 78 81 83 84 74 87 82 75 73 Duration RA*
12 10 11 11 11 11 10 10 10 10 10 12 (yrs.) Prior DMARDs* 4.7 1 3
3.4 3.6 1.6 2.4 3.8 1.3 3.2 3.4 3.4 DAS28* 6.9 5.7 6.1 5.9 6.0 6.1
6.2 6.0 6.4 5.9 5.7 6.6 HAQ* 1.83 1.46 2.00 1.65 1.59 1.48 1.61
1.67 1.69 1.61 1.51 1.91 Steroid use (%) 68 81 52 74 78 70 76 64 94
75 56 56 DMARD use (%) 78 69 66 69 72 80 69 78 92 84 66 80
*Means
TABLE-US-00062 TABLE 62 Patient Baseline Concomitant DMARD Use by
Country Australia Austria Belgium France Germany Greece Italy
Netherlands Portugal Spain Switzerland UK Patients, n 74 150 455
1002 1143 399 1527 378 125 1169 71 117 Concomitant 78 69 66 69 72
80 69 78 92 84 66 80 DMARD use, % DMARD (non-exclusive)
Methotrexate, % 74 47 57 49 50 60 55 66 86 61 34 54 Leflunomide, %
38 20 7 18 22 20 10 5 3 28 27 15 Antimalarials, % 26 5 2 4 7 8 13
12 15 9 10 13 Sulfazalazine, % 3 7 6 5 9 2 4 19 16 6 20 19
Azathioprine, % none 3 1 0.2 2 1 1 2 2 1 none 2 Parenteral gold, %
3 none 0.2 0.4 1 1 1 1 1 2 none 3 DMARDs used in less than half of
all countries not shown
[0426] Table 63 and Table 64 demonstrate that the ACR20 and ACR50
(Table 63) and EULAR (Table 64) response rates were similar in all
countries.
[0427] Withdrawal rates were also similar across the studied
countries. Withdrawals due to lack of efficacy or to intolerance to
adalimumab (all types of side-effects) were overall low. Table 65
displays recorded data regarding patients who withdrew from the
study due to an adverse event, broken down by country.
TABLE-US-00063 TABLE 63 ACR20 and ACR50 Response by Country % of
Patients ACR20 ACR50 Australia 82 48 Austria 65 45 Belgium 70 40
France 68 38 Germany 68 38 Greece 60 35 Italy 72 40 Netherlands 70
38 Portugal 72 45 Spain 70 40 Switzerland 68 38 UK 80 55
TABLE-US-00064 TABLE 64 Moderate and Good EULAR Response by Country
% of Patients Moderate EULAR Good EULAR Response Response Australia
92 20 Austria 82 40 Belgium 85 35 France 80 35 Germany 80 35 Greece
78 25 Italy 85 28 Netherlands 82 30 Portugal 88 28 Spain 85 38
Switzerland 80 32 UK 90 30
TABLE-US-00065 TABLE 65 Percentage of Patients Who Withdrew Because
of an Adverse Event (AE) or Lack of Efficacy at Week 12 by Country
Reason for Withdrawal Australia Austria Belgium France Germany
Greece Italy Netherlands Portugal Spain Switzerland UK Total, % 7 7
7 6 10 6 8 6 5 6 13 5 AE, % 7 4 3 3 6 4 5 3 3 4 9 3 Lack of 0 3 1 2
2 1 1 2 0 1 3 0 Efficacy, % Other, % 0 0 3 1 2 1 2 1 2 1 1 2
[0428] In addition to being safe and consistent across all
countries, Adalimumab was effective in decreasing the number of
tender and swollen joints, as shown in Table 66 and Table 67. The
effect of adalimumab measured by the mean change from baseline
DAS28 was comparable across all countries as shown in Table 68.
Adalimumab treatment led to clinically important improvement of
physical function in patients from all countries, as measured by
the mean change from baseline HAQ score at Week 12, shown in Table
69.
[0429] Adalimumab was overall well-tolerated during 12 weeks of
exposure in patients from all participating European countries
(Table 70).
TABLE-US-00066 TABLE 66 Median Tender Joint Count (TJC28) Through
Week 12 by Country Australia Austria Belgium France Germany Greece
Italy Netherlands Portugal Spain Switzerland UK Median Tender Joint
Count Week 0 18 16 14 12 13 12 14 11 15 12 11 15 Week 2 10.5 8 7 7
7 6 7 6 7 5 5 7 Week 6 7 6 4 5 4 5 5 4 4 3 3 4 Week 12 3 5 3 3 3 3
3 3 2 2 2 4
TABLE-US-00067 TABLE 67 Median Swollen Joint Count (SJC28) Through
Week 12 by Country Australia Austria Belgium France Germany Greece
Italy Netherlands Portugal Spain Switzerland UK Median Swollen
Joint Count Week 0 17 8 12 9 10 9 9 12 11 9 11 12 Week 2 10.5 4 6 5
6 4 5 7 5 4 6.5 6 Week 6 8 3 4 4 4 3 3 5 4 3 4.5 5 Week 12 5 2 3 3
3 2 2 4 3 2 3 3
TABLE-US-00068 TABLE 68 Mean Change from Baseline in DAS28 at Week
12 by Country Mean Change from Baseline Australia (n = 74) -2.7
Austria (n = 150) -2.1 Belgium (n = 455) -2.3 France (n = 1002)
-2.0 Germany (n = 1143) -2.0 Greece (n = 399) -1.9 Italy (n = 1527)
-2.2 Netherlands (n = 378) -2.0 Portugal (n = 125) -2.4 Spain (n =
1169) -2.2 Switzerland (n = 71) -1.8 UK (n = 117) -2.7
TABLE-US-00069 TABLE 69 Mean Change from Baseline in HAQ at Week 12
by Country* Mean Change from Baseline Australia (n = 74) -0.63
Austria (n = 150) -0.37 Belgium (n = 455) -0.69 France (n = 1002)
-0.52 Germany (n = 1143) -0.42 Greece (n = 399) -0.47 Italy (n =
1527) -0.61 Netherlands (n = 378) -0.47 Portugal (n = 125) -0.64
Spain (n = 1169) -0.63 Switzerland (n = 71) -0.45 UK (n = 117)
-0.53 *MCID = Minimum Clinically Import Difference .gtoreq.-0.22;
Goldsmith C, et al. J Rheumatol 1993; 20: 561-5
TABLE-US-00070 TABLE 70 Serious Adverse Events (SAE) by Country
Australia Austria Belgium France Germany Greece Italy Netherlands
Portugal Spain Switzerland UK Patients per 74 150 455 1002 1143 399
1527 378 125 1169 71 117 Country, SAE, n (%) 5 9 24 78 115 20 50 19
7 47 6 6 (6.8) (6.0) (5.3) (7.8) (10.1 (5.0) (3.3) (5.0) (5.6)
(4.0) (8.5) (5.1) Serious 3 2 7 14 25 6 12 3 2 18 2 0 Infections, n
(%) (4.1) (1.3) (1.5) (1.4) (2.2) (1.5) (0.8) (0.8) (1.6) (1.5)
(2.8) (0.0) Musculoskeletal/ 1 3 4 26 42 3 4 5 1 10 3 1 connective
tissue (1.4) (2.0) (0.9) (2.6) (3.7) (0.8) (0.3) (1.3) (0.8) (0.9)
(4.2) (0.9) disorders, n (%) indicates data missing or illegible
when filed
[0430] In conclusion, adalimumab therapy led to clinically
important improvements at 12 weeks in all major efficacy parameters
irrespective of the country where patients were treated. In
Australia and the 11 European countries participating in Study A,
patients with long-standing RA and an insufficient response to
previous DMARD therapy achieved substantial improvements with
adalimumab treatment in all key efficacy parameters within 12
weeks. Safety profiles were not markedly different between
countries in real-life clinical practice. In addition, Adalimumab
was well-tolerated. Withdrawal rates because of lack of efficacy or
adverse events within 12 weeks were low and similar across
participating countries. The frequency and pattern of serious
adverse events were similar overall in all countries.
Example 9
Adalimumab (HUMIRA.RTM.) is Effective and Safe with Different
Traditional Concomitant DMARDs in Treating Rheumatoid Arthritis in
Real-Life Clinical Practice
[0431] TNF-antagonist and concomitant methotrexate (MTX) therapy
has been shown to be effective in treating patients with rheumatoid
arthritis (RA). However, some patients are intolerant to MTX
treatment and other factors may limit the use of MTX. Evaluations
of concomitant DMARDs are few and limited. The completed Study A
trial offers the largest database available for the analysis of the
efficacy and safety of TNF-antagonists in combination with other
DMARDs.
[0432] The object of the study is to investigate the efficacy and
the safety of adalimumab when added to various standard DMARDs in a
large patient population with active RA after a 12-week treatment
period in real-life clinical practice. In particular the object of
the study was to assess the efficacy and safety profiles resulting
from adalimumab (ADA) treatment in combination with MIX,
leflunomide (LEF), sulfasalazine (SSZ), or the antimalarials
chloroquine/hydroxychloroquine (AM), in a large cohort of patients
with active RA.
[0433] Patients with active RA enrolled at 448 sites in 11 European
countries and Australia in the Study A trial. All patients had
Active RA as defined by Disease Activity Score 28
(DAS28).gtoreq.3.2 at baseline and demonstrated an unsatisfactory
response or intolerance to at least 1 prior DMARD. All patients
received ADA 40 mg subcutaneously (sc) every other week (eow) in
addition to their existing but insufficient anti-rheumatic
therapies in the Study A trial.
[0434] The efficacy outcomes measured were: ACR20, 50, 70, EULAR
response, change in DAS28, TJC, SJC, HAQ, and CRP. Safety, efficacy
data and adverse events were collected at Weeks 2, 6, and 12.
[0435] In all, 6610 patients enrolled in the Study A trial. Mean
baseline (BL) characteristics included age, 54 yrs; disease
duration, 11 yrs; DAS28, 6.0; and HAQ, 1.64. Of those enrolled, 75%
received ADA-DMARD combination therapy: 61% with 1, 12% with 2, and
2% with 3 or more DMARDs; 43 distinct ADA-DMARD combinations were
reported. See Table 71 for baseline statistics across
subgroups.
TABLE-US-00071 TABLE 71 Baseline Characteristics by Concomitant
DMARD (Exclusively) MTX + Characteristics* MTX LEF AM SSZ MTX + LEF
AM MTX + SSZ N 2794 842 148 133 180 269 182 Duration of RA (yrs) 10
11 8 11 10 8 9 # Prior DMARDs 2.7 3.3 2.8 3.1 3.5 2.9 3.0 % Steroid
use 70 73 78 63 81 74 69 HAQ 1.61 1.58 1.62 1.70 1.55 1.52 1.57
DAS28 6.0 6.0 6.2 6.1 6.1 6.0 5.9 TJC28 13 13 15 14 13 14 13 SJC28
10 11 10 11 11 10 11 *Mean values
[0436] 4,879 (74%) patients received adalimumab with one or more
concomitant DMARDs, accounting for 43 different combinations.
Adalimumab was added to 1 DMARD in 4004 (61%) patients, to 2 DMARDs
in 769 (12%) patients, and to 3 or more DMARDs in 106 (2%)
patients. In patients treated with adalimumab and only 1
concomitant DMARD, 2794 (42% of 6,610) were exclusively treated
with MTX; 842 (13%) with leflunomide (LEF); 148 (0.2%) with
antimalarials (AM); and 133 (0.2%) with sultfasalazine (SSZ)
[0437] Comparisons of BL characteristics for groups receiving ADA
only, ADA+MTX, ADA+LEF, ADA+AM, and ADA+SSZ revealed no marked
differences in BL disease severity--BL DAS28 and HAQ score ranges
measured (6.0-6.2) and (1.58-1.73), respectively. Week 12 ACR
responses and mean changes in DAS28 and HAQ scores in the
combination therapy groups revealed similar responses independent
of the concomitant DMARD used, but superior to responses with
monotherapy. The safety profile was similar across groups. Key
efficacy outcomes and the safety parameter of serious infection
rates are shown in Table 72 for these groups (observed values).
TABLE-US-00072 TABLE 72 Baseline Characteristics and Clinical
Response to ADA Therapy at Week 12 ADA ADA + ADA + ADA + ADA + only
MTX LEF AM SSZ n = 1731 n = 2794 n = 842 n = 148 n = 133 Prior 3.1
2.7 3.3 2.8 3.1 DMARDS* Previous 80 100 76 59 71 MTX (%) ACR20 (%)
60 74 66 72 63 ACR50 (%) 32 45 37 49 37 ACR70 (%) 15 21 14 23 15
.DELTA.DAS28* -1.9 -2.3 -2.0 -2.4 -2.1 .DELTA.HAQ* -0.47 -0.58
-0.49 -0.72 -0.52 Serious 1.5 1.0 1.8 2.0 2.3 infect. (%)
*Means
[0438] The effect of adding adalimumab to LEF, AM, SSZ, or to
combinations of MTX+LEF, MTX+AM, MTX+SSZ, was similar to the effect
of adalimumab and concomitant MTX, as measured by ACR response
(Table 73), EULAR response (Table 74), as measured by the median
change from baseline TJC28 (FIG. 15) and baseline SJC28 (FIG. 16),
and as measured by the mean change from baseline DAS28 (Table 75)
and baseline HAQ score (Table 76).
[0439] Withdrawal rates, as shown in Table 77, because of lack of
efficacy or intolerance to adalimumab (multiple types of side
effects) were low overall. The lowest withdrawal rate through Week
12 was seen for adalimumab and the combination of MTX plus SSZ.
TABLE-US-00073 TABLE 73 ACR Response (%) at Week 12 by DMARD
Combinations with Adalimumab % of Patients ACR20 ACR50 ACR70 MTX (n
= 2794) 74 45 21 LEF (n = 842) 66 37 14 AM (n = 148) 72 49 23 SSZ
(n = 133) 63 37 15 MTX + LEF (n = 180) 67 38 17 MTX + AM (n = 269)
75 45 20 MTX + SSZ (n = 182) 75 46 21
TABLE-US-00074 TABLE 74 EULAR Response (%) at Week 12 by DMARD
Combinations with Adalimumab % of Patients Good EULAR Moderate
EULAR MTX (n = 2794) 39 87 LEF (n = 842) 32 81 AM (n = 148) 34 84
SSZ (n = 133) 35 82 MTX + LEF (n = 180) 31 86 MTX + AM (n = 269) 39
90 MTX + SSZ (n = 182) 38 90
TABLE-US-00075 TABLE 75 Mean Change from Baseline DAS28 Score at
Week 12 by DMARD Combinations with Adalimumab Mean Change from
Baseline MTX (n = 2794) -2.3 LEF (n = 842) -2.0 AM (n = 148) -2.4
SSZ (n = 133) -2.1 MTX + LEF (n = 180) -2.2 MTX + AM (n = 269) -2.4
MTX + SSZ (n = 182) -2.4
TABLE-US-00076 TABLE 76 Mean Change from Baseline HAQ Score* at
Week 12 by DMARD Combinations with Adalimumab Mean Change from
Baseline MTX (n = 2794) -0.58 LEF (n = 842) -0.49 AM (n = 148)
-0.72 SSZ (n = 133) -0.52 MTX + LEF (n = 180) -0.54 MTX + AM (n =
269) -0.63 MTX + SSZ (n = 182) -0.55 *Minimum Clinically Important
Difference .gtoreq.-0.22; Goldsmith C, et al. J Rhuematal 1993; 20:
561-5.
TABLE-US-00077 TABLE 77 Withdrawal Rates Because of Intolerance or
Lack of Efficacy by Concomitant DMARD at Week 12 (%) Reason for MTX
+ MTX + MTX + Withdrawal MTX LEF AM SSZ LEF AM SSZ N 2794 842 148
133 180 269 182 Total* 5.8 8.0 6.1 6.8 3.9 6.7 2.7 Intolerance 3.6
5.0 3.4 3.8 2.8 3.3 0.5 Lack of 1.3 1.0 1.4 0.8 none 1.1 0.5
Efficacy *Not all reasons are shown.
[0440] In conclusion, concomitant adalimumab and DMARD therapies
led to clinically important improvements at Week 12 in all major
efficacy parameters--irrespective of the type of concomitant DMARD
used--and were well-tolerated in the treatment of patients with RA
in real-life clinical practice. Clinical outcomes tended to be
superior to those achieved with monotherapy.
Example 10
Efficacy and Safety of Adalimumab (HUMIRA.RTM.) in Clinical
Practice
[0441] The objective of this study was to evaluate the efficacy and
safety of adalimumab. The Study C (CanAct) was an open-label,
multi-center, Phase IIIb study conducted in Canada. The study
design is shown in FIG. 17. Patients with moderate to severe
rheumatoid arthritis (RA) who had an inadequate response to
standard antirheumatic therapy, including methotrexate (MTX), were
treated with adalimumab 40 mg every other week in addition to their
pre-existing therapies. Criteria Age for inclusion in study C
required the patient be .gtoreq.18 years of age, have RA defined by
ACR criteria for .gtoreq.3 months, with Active RA (>5 swollen
joints and one of positive RF, 1 or more joint erosions, a HAQ
score >1), and an unsatisfactory response or intolerance to
therapy as per provincial guidelines required for biologic therapy.
Finally, concomitant prednisone had to be <10 mg/day.
[0442] Each patient underwent a minimum 12-week treatment period.
Patients who completed the 12-week treatment period before
adalimumab was commercially available could have entered into an
extension phase, which ended when adalimumab became commercially
available. The extension phase, therefore, had variable durations
for different patients. The maximum duration of follow-up for this
analysis was 24 weeks. Efficacy assessments included tender joint
count (TJC, 0-28), swollen joint count (SJC, 0-28), Disease
Activity Score 28 (DAS28), EULAR response, ACR 20/50/70, and the
disability index of the Health Assessment Questionnaire (HAQ).
Safety assessments included collection of adverse events (AEs),
serious AEs, and severe AEs. FIG. 55 shows the study design of
study C.
[0443] A total of 879 patients enrolled in Study C. Baseline
characteristics were: mean age=54.4 years; % female=78.7; mean RA
duration=12.5 years; % with 1, 2, 3 and .gtoreq.3 DMARD failures at
study entry=5.6%, 6.3%, 17.0% and 69.1%, respectively; and the %
with prior exposure to 1 biologic DMARD (BDMARD)=27.5%, all shown
in Table 78. Other baseline characteristics and the data on the
efficacy of adalimumab at 12, and 24 weeks are presented below in
Table 79.
TABLE-US-00078 TABLE 78 Baseline Demographics and Disease Severity
Patients who Patients who All Randomized completed completed
Patients 12 Weeks 24 Weeks Characteristics* N = 879 n = 772 n = 238
Age (years) 54.4 .+-. 11.5 54.1 .+-. 11.4 52.8 .+-. 11.0 Female (%)
79 78 76 Disease duration (years) 12.5 .+-. 9.7 12.3 .+-. 9.5 12.5
.+-. 9.3 TJC (0-28) 14.9 .+-. 7.1 14.9 .+-. 7.l.sup. 16.5 .+-. 7.2
SJC (0-28) 13.2 .+-. 5.2 13.2 .+-. 5.2 14.6 .+-. 5.6 DAS28 6.1 .+-.
1.2 6.1 .+-. 1.2 6.3 .+-. 1.2 HAQ (0-3) 1.5 .+-. 0.6 1.5 .+-. 0.6
1.5 .+-. 0.7 Failed 1 DMARD (%) 6 5 6 Failed 2 DMARDs (%) 6 7 4
Failed 3 DMARDs (%) 17 18 16 Failed >3 DMARDs (%) 69 69 73 Prior
biologics (%) 28 28 27 *Mean values .+-. SD except percentages.
TABLE-US-00079 TABLE 79 Baseline and Efficacy Results from Study C
Baseline 12 week 24 week Efficacy Measures (n = 879) (n = 879) (n =
238) TJC (0-28) (mean) 14.9 6.8 6.0 SJC (0-28) (mean) 13.2 6.4 5.9
DAS28 (mean) 6.1 4.2 3.9 DAS28 (mean) One prior BDMARD 6.3 4.6 4.2
No prior BDMARD 6.1 4.0 3.8 % with DAS28: <3.2 1.3 26.2 31.5
<2.6 0.5 15.3 13.5 <2.4 0.5 11.0 10.9 EULAR % moderate 51.4
51.7 % good 27.0 32.5 % ACR 20/50/70 58/30.6/12.7 71.9/41.2/17.7
HAQ (mean) 1.55 1.04 0.89 % with HAQ <0.5 5.0% 25.5% 33.2% ESR
(mm/hr) 30.3 20.1 16.9 CRP (mm/L) 21.2 11.8 NA NA = not
available.
[0444] The adverse events profile is comparable to that of other
randomized, controlled clinical trials. Only 2 AEs occurred in more
than 5% of patients. These were injection site reaction (10.0%) and
headache (5.5%). In addition, 2.4% of patients experienced an
infection, and 1.1% of patients experienced an infection judged to
be serious. No cases of lymphoma or TB reactivation were reported,
and no new safety signals were observed during this clinical trial.
Table 80 displays the incidents of adverse advents occurring in
greater that 2% of the patients. Table 81 displays the medically
relevant adverse advents.
TABLE-US-00080 TABLE 80 Adverse Events .gtoreq.2% Adverse events
observed in .gtoreq.2% of the patients Events Patients (Probably or
Possibly Related to adalimumab) (n) n (%) Injection site reaction*
NOS.dagger. 268 91 (10.4) Headache 74 56 (6.4) Injection site
erythema 66 35 (4.0) Nausea 42 30 (3.4) Rash NOS.dagger. 37 30
(3.4) Injection site reaction (defined as localized bruising,
burning, dermatitis, erythema, induration, inflammation,
irritation, mass, oedema, pain, pruritus, rash, stinging, swelling
and warmth). .dagger.Not otherwise specified.
TABLE-US-00081 TABLE 81 Medically Relevant Adverse Events Events
Patients Events/100 pt- Medically relevant adverse events (n) (n) %
yrs Serious infections 29 11 (1.3) 7.166 Death* 2 2 (0.2) 0.005
Congestive Heart Failure.dagger. 9 4 (0.5) 0.022
Malignancies.dagger-dbl. 4 3 (0.3) 0.009 *One subject presented
aggravated pneumonia and was diagnosed with metastatic lung cancer
(see below). Both events were classified as probably not related,
and not related to adalimumab, respectively. One subject was
diagnosed has having Staphylococcal sepsis and developed and acute
MI. The sepsis was considered to be possibly related to adalimumab.
The acute MI was considered probably not related to adalimumab.
.dagger.Two subjects had events considered probably or possibly
related to adalimumab. .dagger-dbl.One subject was diagnosed with
basal cell carcinoma. The event was probably not related to
adalimumab. One subject was diagnosed with adenocarcinoma of the
cervix/the event was considered possibly related to adalimumab. One
subject was diagnosed with a metastatic lung cancer. The event was
not related to adalimumab.
[0445] The study revealed a reduction in tender and swollen joints,
a reduction in DAS28 scores, increasing beneficial ACR response
rates over the term of the study, and reduced HAQ scores. At Week
24, mean tender and swollen joint counts reduced by 40% and 45%
from baseline, respectively as shown in Table 82. Table 83
demonstrates that at Weeks 12 and 24, mean DAS28 scores were
reduced by 31% and 36% from baseline, respectively.
[0446] At Week 12, patients with and without previous biologic
experience demonstrated substantial improvement in DAS28 scores
from baseline as shown in Table 84. Table 85 shows that at Week 24,
overall ACR20 and ACR50 response rates were significantly higher
than at Week 12, and ACR70 response rates were maintained from Week
12-59. Additionally, by Week 24, HAQ scores of adalimumab-treated
patients reduced by 42.6% from baseline as shown in Table 86.
TABLE-US-00082 TABLE 82 Mean Tender and Swollen 28 Joint Count
Through Week 24 Mean Joint Count Week 0 Week 12 Week 24 (n = 879)
(n = 767) (n = 236) Tender Joint Count 15 8 6 Swollen Joint Count
13 8 6 Observed data. p < 0.001 vs. baseline at all time
points.
TABLE-US-00083 TABLE 83 DAS28 Scores Through Week 24 Week 0 Week 12
Week 24 (n = 876) (n = 742) (n = 234) Mean DAS28 Scores 6.1 4.2 3.9
95% CI (6.0, 6.2) (4.1, 4.3) (3.7, 4.1) Observed data. p < 0.001
vs. baseline at all time points.
TABLE-US-00084 TABLE 84 DAS28 Scores With or Without Prior Biologic
Use Mean DAS28 Score Baseline Week 12 No Previous Biologics 6.1 (n
= 637) 4.0* (n = 559) 1 Previous Biologic 6.3 (n = 242)
4.6.sup..dagger..dagger-dbl. (n = 213) Mean values. Biologics:
Infliximab, Etanercept, Anakinra, Investigational Drugs. *p <
0.001 vs. baseline (no previous biologics); .sup..dagger.p = 0.0019
vs. baseline (1 previous biologic); .sup..dagger-dbl.p = 0.001 vs.
Week 12 (no previous biologics).
TABLE-US-00085 TABLE 85 ACR Responses at Weeks 12 and 24 % of
Patients ACR20 ACR50 ACR70 Week 12 58.4 (n = 451) .sup. 30.6 (n =
236) .sup. 12.7 (n = 98) Week 24 71.8* (n = 171) 41.2.sup..dagger.
(n = 98) 17.6.sup..dagger-dbl. (n = 42) Mean values. Observed data.
p < 0.001 for all changes from baseline to Week 12. *p = 0.0003,
.sup..dagger.p = 0.003, .sup..dagger-dbl.p = 0.068, Week 24 vs.
Week 12.
TABLE-US-00086 TABLE 86 HAQ Scores Through Week 24 Week 0 Week 12
Week 24 (n = 878) (n = 758) (n = 238) Mean HAQ Score 1.5494 1.0393
0.8889 95% CI (1.5, 1.6) (1.0, 1.1) (0.8, 1.0) Observed data. p
< 0.001 vs. baseline at all time point. MCID = 0.22 - Goldsmith
C, et al. J Rheum 1993; 20: 561-5.
[0447] In conclusion, RA patients in the study who received
adalimumab consistently experienced substantial reductions in the
signs and symptoms of their disease. Efficacy of open-label
adalimumab was demonstrated in Canadian clinical practice setting
and was consistent with findings of other published clinical
studies, such as Study A. Similarly, Adalimumab safety in routine
clinical setting was consistent with other studies and no new
safety concerns were identified. Study C provided confidence in
treatment with adalimumab when used in routine clinical practice
and Adalimumab was generally safe and well-tolerated.
Example 11
Safety of Humira in Patients with Active Rheumatoid Arthritis Who
Participated in Clinical Study D
[0448] Study D was initiated to demonstrate the early efficacy,
safety and tolerability of adalimumab in patients with active
rheumatoid arthritis (RA), with particular emphasis on
patient-reported outcomes and early response.
[0449] The objective of Study D was to determine the rates of
serious adverse events (SAEs) of interest with adalimumab therapy
observed during Study D.
[0450] Study D is an ongoing, randomized, double-blind (first
dose), placebo-controlled, multi-center, Phase IV study in the
United States, designed to demonstrate the efficacy of adalimumab
40 mg subcutaneously (sc) every other week (eow) in patients with
active RA. After a screening period, all eligible patients receive
a single, blinded dose of study medication, followed by 10 weeks of
open-label adalimumab 40 mg sc eow, beginning at week 2.
[0451] Patients were trained to use a Palm OS-based electronic
diary to report on their pain, function, fatigue, morning
stiffness, and disease activity using a visual analog scale. They
completed a report 3 times daily during the screening and baseline
periods up to Week 2, followed by evening-only reports during the
10-week, open-label treatment period. A secondary endpoint of Study
D was the evaluation of serious adverse events (SAEs) and other
safety parameters in RA patients treated with adalimumab. SAEs but
not AEs were collected for each patient from enrollment until 70
days following discontinuation of adalimumab. All SAEs were
followed until resolution or stabilization of the event was
documented. Laboratory assessments were also conducted to monitor
for any abnormalities. In this preliminary safety analysis, we
evaluated the SAEs that have been currently reported, focusing on
those SAEs of interest with anti-TNF therapy.
[0452] At baseline, Week 2, 4 and 12 study visits, the following
measures were evaluated: 1) Physician's global assessment of
disease activity; 2) Swollen and tender joint counts; 3) C-reactive
protein; 4) SF-36 Health Survey; 5) HAQ; 6) FACIT-Fatigue Health
Thermometer; 7) VAS--Functional Limitation; 8) VAS--Morning
Stiffness; 9) Safety Assessments; and 10) Clinical laboratory
assessments were done at screening and Week 12, or if patient
withdrew from the study for any reason.
[0453] An adverse event is labeled as a serious adverse event (SAE)
based on the following regulatory criteria/definition: Fatal;
Life-threatening; Requires inpatient hospitalization; Prolongs
hospitalization; Results in congenital anomaly/birth defect; Causes
persistent or significant disability/incapacity; Important medical
event that jeopardizes the patient and requires medical/surgical
intervention to prevent another serious outcome.
[0454] Only serious adverse events (SAEs) were collected from
enrollment until 70 days following completion or withdrawal from
the study. SAEs were coded using the Medical Dictionary for
Regulatory Activities (MedDRA). Investigators were required to
report SAEs within 24 hours of occurrence or knowledge of the
event. All SAEs were followed until resolution or stablization of
the event was documented.
[0455] Between August 2004 and November 2005, 1938 patients
enrolled in the study and 1807 patients completed the 12-week
trial. FIG. 18 shows the disposition of the study while Table 92
demonstrates baseline demographics for patients who participated in
the Study D. As of Mar. 30, 2006, a total of 69 SAEs were reported
for 61 patients who have received at least one dose of blinded or
open-label study drug (Table 93). There were no cases of lymphoma,
tuberculosis, demyelinating disease, or systemic lupus
erythematosus/lupus-like syndrome observed in either treatment
group
[0456] The numbers and percentages of SAEs of interest are reported
in the Table 94 below. Since the ongoing Study D study has not been
unblinded, neither total patient-years of adalimumab exposure nor
safety data for the placebo cohort were available at the time of
this analysis,
TABLE-US-00087 TABLE 92 Baseline Demographics Placebo Adalimumab
Characteristics n = 962 n = 976 Age, mean (years) 55 54 Sex (%
male) 23 21 Disease Duration, median (years) 3 3 Patients on
concomitant DMARDs (%) 80 84 Education, mean (years) 13 13
TABLE-US-00088 TABLE 93 Serious Adverse Events Observed in Study D
Double-Blind Period Open-Label Period Baseline-Week 2 Weeks 2-12*
No. of Patients (%) All Patients Placebo Adalimumab Adalimumab 40
eow N = 962 N = 976 N = 1905 n (%) n (%) n (%) Any SAE 3 (0.3) 3
(0.3).dagger. 55 (2.9) Any serious infection 0 1 (0.1) 12 (0.6)
Pneumonia 0 0 3 (0.2) Cellulitis 0 1 (0.1) 2 (0.1) Septic Arthritis
0 0 1 (0.1) Malignancies 0 0 5 (0.3).dagger-dbl. Lymphoma 0 0 0
*Includes SAEs reported during the 70-day post-study period.
.dagger.1 case each of acute cholecystitis, rash, and cellulitis.
.dagger-dbl.1 case each of malignant melanoma, colon cancer,
ovarian granulosa-theca cell tumor, prostate cancer, and malignant
neoplasm.
TABLE-US-00089 TABLE 94 Numbers and Percentages of Patients with
SAEs of Interest Adalimumab 40 eow Serious Adverse N = 1920 Events
of Interest Number of Patients (%) Serious Infections 10 (0.5)
Pneumonia 3 (0.2) Cellulitis 3 (0.2)* Urinary Tract Infection 0
Septic Arthritis 1 (0.1) Tuberculosis 0 Malignancies 4 (0.2)
Lymphoma 0 Demyelinating Diseases 0 SLE/lupus-like syndrome 0 *One
case of cellulitis occurred after the single, blinded dose, which
could have been placebo. The 4 malignancies observed were colon
cancer, melanoma. prostate cancer, and granulosa cell tumor of the
ovary.
[0457] In conclusion, in this preliminary analysis of Study D, no
cases of lymphoma, tuberculosis, or demyelinating diseases were
observed with adalimumab treatment. Further, the types and rates of
SAEs observed were similar to what has been observed in other
clinical trials of adalimumab in RA.
Example 12
Cost Effectiveness of the 3 TNF Antagonists Vs. Abatacept in the
Treatment of Moderate to Severe Rheumatoid Arthritis (RA)
[0458] For RA, TNF antagonists have been shown to significantly
reduce the signs and symptoms of the disease, inhibit disease
progression, and improve patients' quality of life (QOL).
Adalimumab (Ada), etanercept (Eta), and infliximab (Inf) in
combination with methotrexate have each demonstrated substantial
advantages in each of these areas compared with traditional DMARDs.
Abatacept (Abat), a selective T-cell co-stimulator, has recently
been added to the RA armamentarium for patients who fail therapy
with traditional DMARDs and TNF antagonists.
[0459] The objective of this analysis was to model, from a US
managed-care perspective, the lifetime cost effectiveness of each
of these 4 therapies as first-line biologic treatment for
long-standing moderate to severe RA.
[0460] The study was performed using a published cost-effectiveness
model developed at the University of Sheffield that simulates
patients' responses to successive traditional DMARD and biologic
therapies to estimate health and economic outcomes following
treatment with each of the TNF antagonists based on efficacy data
from key clinical studies in RA2, 3, 4, 5 (Bansback et al. Ann
Rheum Dis. 2005; 64:995, incorporated by reference herein). The TNF
antagonists were each modeled to yield health outcomes based on
efficacy data from key clinical studies in RA. Adjustments for
control drug response were made following the method proposed by
Choi et al as follows (adjusted response for biologic in trial B
(Bio B) applied to MTX response in trial A [MTX A]):
Marginal response Bio B: (Response Bio B-Response MTX
B)/(1-Response MTX B). Adjusted response: Response MTX A+Marginal
response Bio B.times.[1-Response MTX A].
[0461] Initial response was determined by a Monte-Carlo
patient-level simulation of ACR responses, with a minimum of ACR50,
at 6 months after initiation of each treatment, determining
adequate response. Following response, benefit to patients was
linked to a reduction in patients' health assessment questionnaire
(HAQ) scores (Table 95). HAQ scores were modeled to subsequently
increase (i.e, physical function deteriorates) over variable
durations of continued response compared with non-response.
Eventual withdrawal from biologic therapy (followed by treatment
with traditional DMARDs) and a reversal in original HAQ improvement
were modeled to follow.
[0462] Utility values were assigned to patients in both arms of the
model based on a regression equation associating patients' HAQ
scores with their valuations of QOL measured by the Health Utility
Index Mark 3. Costs included those of all drugs, monitoring and
adverse events, as well as other direct health care costs,
including hospitalizations, which were calculated by applying
published relationships between HAQ scores and US health care
costs. Mortality was based on US life tables and relative risks,
which were also dependent on HAQ. Discounting was performed at 3%
for both costs and outcomes.
TABLE-US-00090 TABLE 95 HAQ Progression and Treatment Withdrawal
Rates HAQ improvement on initial <ACR20 ACR 20-50 ACR 50-70
>ACR70 response 12* 6.4 .+-. 2.4 34.7 .+-. 4.8 57.0 .+-. 4.9
64.6 .+-. 4.8 HAQ progression (per 6 Non response DMARD response
Biologic response months) 13, 14* 0.132 0.044 0.044 Withdrawal from
treatment DMARD Adalimumab/ Infliximab/ (per 6 months) 8*
Etanercept Abatacept 59.7 .+-. 4.8 13.2 .+-. 2.6 15.9 .+-. 3.1
Relative risk for mortality by 2.73 (95% confidence interval: 1.86,
4.02) HAQ point 11.dagger. Utility 7.dagger-dbl. 0.76 .+-. 0.023 -
0.28 .+-. 0.003 .times. HAQ Values are averages .+-. standard
errors unless otherwise stated. *parameter assigned beta
distribution. .dagger.parameter assigned log-normal distribution.
.dagger-dbl.parameter assigned bivariate normal distribution.
[0463] Disease progression is associated with increasing HAQ scores
(ie, deteriorating physical function). During periods of response
disease progression was modeled to be less rapid compared with
non-response as shown in Table 95. Reversals in original HAQ
improvements were modeled to follow eventual withdrawal (determined
at 6-month intervals) from therapy (followed by treatment with
traditional DMARDs).
[0464] Also shown in Table 95, utility values were assigned to
patients, irrespective of treatment, based on a regression equation
associating patients' prevailing HAQ scores with quality of life as
measured by the Health Utility Index Mark 3 in order to generate
quality-adjusted life-years (QALYs) and incremental
cost-effectiveness ratios (ICER).
[0465] Transition-state model: Health economics outcomes were
monitored in 1,000 hypothetical patients. Treatment success or
failure was assessed in 6-month cycles where patients were
transitioned to other DMARDs if they failed to reach a minimum
ACR50 criteria (FIG. 19). All patients modeled had previously been
treated with MTX. Up to 7 further DMARDs were used in sequence
(including MTX in combinations with other DMARDs). In biologic
strategies these DMARD sequences followed failure of, or withdrawal
from biologic therapy (FIG. 62). As infliximab was subject to dose
increases we modeled a second infliximab strategy where loss of
response led to re-treatment with 10 mg/kg.
[0466] When a patient did not show adequate response to therapy
(defined by .gtoreq.ACR 50), or withdrew subsequent to an initial
response, treatment was switched to the next DMARD (or a 10-mg/kg
infliximab dosage in the case of withdrawal from 3-mg/kg infliximab
strategy). The likelihood of response decreased with time (odds
ratio=0.98 per year).
[0467] All patients were monitored throughout their lifetime. Total
costs included those for all drugs, monitoring, adverse events
(Table 96), and other direct health care costs (eg,
hospitalizations), which were calculated by applying published
relationships between HAQ scores and US health care costs.
[0468] Mortality was based on US life tables adjusted for increased
risk associated with higher HAQ scores. Discounting was performed
at 3% for both costs and outcomes.
TABLE-US-00091 TABLE 96 Summary Model Costs (US $) Drug Cost
Monitoring 1st Subsequent 1st Subsequent Adverse 6-month 6-month
6-month 6-month Events period periods period periods All periods
Adalimumab* 7993 7993 411 275 396 Abatacept* 10995 9645 1496 1258
565 Etanercept* 7993 7993 411 275 383 Infliximab (3 mg/kg)* 8478
5579 998 636 565 Infliximab (3/10 mg/kg)* 8478 12758 998 636 565
Leflunomide 2657 2657 395 275 348 Leflunomide* 2852 2852 406 275
348 Sulfasalazine* 280 280 406 275 348 Cyclosporin* 2322 2322 406
275 348 Sulfasalazine + 2407 2407 406 275 348 Cyclosporin
Hydroxychloroquine* 552 552 406 275 348 Gold 1306 1306 416 334 348
*Therapy in combination with methotrexate
[0469] As shown in Table 97 the adalimumab strategy achieved the
greatest Quality-Adjusted Life-Years (QALYs) of any single anti-TNF
sequence (2.73 QALYs after discounting). An additional strategy was
modeled for infliximab in which patients who failed to respond to 3
mg/kg were re-treated with 10 mg/kg. This treatment yielded fewer
QALYs, vs. the single treatment sequence of adalimumab, at an extra
cost of over $2,000. Adalimumab had cost per QALY vs. etanercept,
of approximately $30,000, and had cost-per-QALY ratios vs.
infliximab (3 mg/kg) of $37,500. Abatacept yielded fewer QALYs than
adalimumab, at additional cost, despite patients remaining on
abatacept far less than they did for the other biologics.
TABLE-US-00092 TABLE 97 Health Outcomes Based on Key RA Clinical
Study Results of the TNF Antagonists and Abatacept Traditional
DMARDs Adalimumab Etanercept Infliximab 3 mg/kg Infliximab 3 &
10 mg/kg Abatacept QALYs 1.70 2.73 2.49 2.14 2.23 2.20 Total cost
($) 116,065 157,052 150,096 134,966.dagger. 159,343 159,149 ICER*
for Traditional 39,901 42,820 42,748 80,844 85,607 DMARDs vs. Other
($/QALY) ICER for adalimumab 39,901 29,922 37,749 Dominant Dominant
vs Other ($/QALY) *ICER = Incremental Cost-Effectiveness Ratio.
Table 98 shows a Choi adjustment: the marginal response of each
biologic vs. MTX was applied to the MTX response in Study I. For
example: etanercept:
[0470] Marginal ACR50 response for
etanercept=(39-3)/(100-3)=37%
[0471] Applied to MTX response in Study
I=8+(37.times.[100-8])=42%
TABLE-US-00093 TABLE 98 Efficacy Data With Choi Adjustment
Methotrexate arm Biologic arm Choi Adjusted Biologic ACR 20 (%) 50
(%) 70 (%) 20 (%) 50 (%) 70 (%) 20 (%) 50 (%) 70 (%) Adalimumab 15
8 5 67 55 27 67 55 27 Etanercept 27 3 0 71 39 15 66 42 19
Infliximab 20 5 0 50 29 11 47 31 15 (3 mg/kg) Infliximab 20 5 0 58
26 11 55 28 15 (10 mg/kg) Abatacept 33 11 3 64 32 12 54 30 14 All
therapies were given in combination with methotrexate. Beta
distributions were assigned to all efficacy parameters and derived
based on numbers in each trial (sampling was conditional on
successive ACR categories, e.g. ACR 50 sampled as a proportion of
ACR 20 responders).
[0472] Also shown in Table 97, Etanercept, abatacept, and
infliximab (3 mg/kg) yielded 2.49, 2.20, and 2.14 QALYs,
respectively. Re-treatment strategy of patients who failed
infliximab (3 mg/kg) with 10 mg/kg yielded marginally greater QALYs
than the 3 mg/kg dosage alone, but fewer QALYs than adalimumab.
[0473] As shown in Table 99, Adalimumab was marginally more costly
than etanercept and infliximab (3 mg/kg) because of its better
modeled ACR response and longer time on treatment. Adalimumab
provided 0.24 more QALYs (cost per QALY, $29,922) than etanercept
and 0.59 more QALYs (cost per QALY, $37,749) than infliximab,
respectively. Adalimumab dominated both abatacept and infliximab
strategies while etanercept and infliximab (3 mg/kg) were
extendedly dominated by DMARDs and adalimumab combination.
[0474] An extendedly dominated strategy exists where a linear
combination of two other strategies can produce at least as many
QALYs at lower total cost.
TABLE-US-00094 TABLE 99 Cost Effectiveness Results Infliximab
Infliximab DMARDs (3 mg/kg) Abatacept (3-10 mg/kg) Etanercept
Adalimumab Drug costs ($) 16,517 36,553 52,098 53,314 55,176 63,056
Monitoring ($) 6,418 7,972 10,412 8,805 6,432 6,540 Adverse events
($) 9,368 9,214 10,306 10,372 9,185 9,313 Other Direct Costs ($)
83,762 81,227 86,333 86,852 79,304 78,142 Total Costs ($) 116,065
134,966 159,149 159,343 150,096 157,052 QALYs 1.70 2.14 2.20 2.23
2.49 2.73 ICER vs DMARDs 42,748 85,607 80,844 42,820 39,901
($/QALY) ICER for adalimumab 39,901 37,749 dominant dominant 29,922
-- vs Other ($/QALY)
[0475] Overall, patients were modeled to remain on adalimumab and
methotrexate therapy considerably longer than on other biologic
combinations. The model used a 6-month cycle. In the model, ACR
response is determined 6 months after treatment, and subsequent
withdrawal at 6-month intervals. In addition, following withdrawal,
patients were switched to non-biologic DMARDs or rescue therapy.
The longer acting biologics are associated with far lower total
costs per year. The average time on the first treatment (years, 95%
CI) ranged (in accordance with longevity in years) in relation to
the first treatment in sequence from (low years) DMARDS
(approximately 0.8)/Abatacept (approximately 2)/Infliximab (3
mg/kg) (approximately 2)/etanercept (approximately 3)/adalimumab
(approximately 3.8) (high years). The longer acting biologics were
associated with far lower total costs per year on biologic. The
scatter plot cost-utility plane, shows the distribution of
incremental costs and QALYs for all biologic strategies compared to
traditional DMARDs. Parameter values were randomly sampled from
their assigned distributions over 1,000 probabilistic iterations of
the model. Points with steeper gradients from the origin have
higher cost per QALY ratios vs. DMARDs.
[0476] Adalimumab had a 62% probability of being cost effective at
a minimum willingness to pay (WTP) of $50,000 per QALY in this
analysis, rising to 83% at a WTP of $100,000 per QALY (Table
100).
TABLE-US-00095 TABLE 100 Cost effectiveness Probability for Each
Strategy at Given WTP Infliximab Infliximab WTP/QALY DMARDs
Adalimumab Etanercept (3 mg/kg) (3-10 mg/kg) Abatacept $40,000 40
22 4 34 0 0 $50,000 6 62 14 18 0 0 $60,000 1 75 16 8 0 0
[0477] In conclusion, both Ada and Eta have marked advantages over
Inf and Abat. Adalimumab and etanercept demonstrated better cost
effectiveness profiles than infliximab and abatacept. Adalimumab
was superior to etanercept in terms of QALYs (0.24 more) at
moderate additional cost ($6,956). The cost per QALY of adalimumab
vs. etanercept was approximately $30,000. A combination of DMARDs
and adalimumab could yield equivalent QALYs to etanercept at lower
total cost suggesting that etanercept is extendedly dominated.
Superior TNF-antagonist cost effectiveness to abatacept indicates
that Abat therapy should be considered only after substantial
trials of first-line trad DMARDs and TNF-antagonist therapies have
not yielded satisfactory results.
Example 13
Early Clinical Response in Venezuelan Patients with Rheumatoid
Arthritis (RA) Treated with Adalimumab
[0478] The objective of the study described herein was to assess
early response to adalimumab in key clinical efficacy and
functional measures in a cohort of Venezuelan patients with
moderate to severe rheumatoid arthritis (RA) from a multicenter
trial.
[0479] A group of 77 patients from 9 centers in Venezuela received
adalimumab 40 mg every other week (eow) in addition to concomitant
methotrexate (MTX) therapy in a prospective, open-label, 3-month
trial. Of these, 65 completed the 12-week, open-label study.
Inclusion criteria in this trial included age >18 years, active
RA for .gtoreq.3 months (DAS28.gtoreq.3.2) diagnosed by ACR
criteria, and unsatisfactory response to at least 3 months of MTX
monotherapy. Baseline disease severity indices were consistent with
those of patients with moderate to severe RA (Table 101). The Mean
age was 48 and the mean disease duration was 10 years.
[0480] Patients were screened for latent tuberculosis (PPD and
chest X-ray). Selected efficacy measures, including indicators of
clinical remission, were evaluated after 2 and 12 weeks of therapy.
Regular visits for safety and efficacy monitoring were scheduled
every 2 weeks until Week 12.
[0481] Efficacy (including indicators of clinical remission) and
safety assessments were performed at Weeks 0, 2, 6, and 12.
Outcomes measured included: Disease Activity Score 28 (DAS28);
Tender and Swollen Joint counts (TJC, SJC); Health Assessment
Questionnaire-Disability Index (HAQ-DI); Patients' assessment of
pain using a visual analog scale (VAS); C-reactive protein (CRP);
and Erythrocyte sedimentation rate (ESR). Clinical remission
criteria was: DAS28<2.6; HAQ<0.5; TJC0, SJC=0; and CRP<1
mg/dL. Outcomes of adalimumab therapy at Weeks 0 (baseline), 2, 6,
and 12 were compared. See FIG. 20 for the study design.
[0482] Table 101 below shows that the benefits of adalimumab were
evident as early as 2 weeks following first dose. Patients had
continued to improve further by Week 12 (Table 102). Mean HAQ
improved by -0.5 following a single dose of adalimumab, an
improvement greater than previously reported in clinical trials of
TNF antagonists. In addition, by Weeks 2 and 12, 9.2% and 29.2% of
patients had achieved DAS28<2.6. By Week 12, approximately
one-third of patients had achieved additional criteria for clinical
remission: TJC-0 (32.3%), SJC-0 (46.2%), HAQ<0.5 (43.1%), and
normal CRP concentrations (<1 mg/dL) (40.3%).
TABLE-US-00096 TABLE 101 Clinical Response to Adalimumab Baseline
Week 2 Week 12 Efficacy Criteria (N = 77) (N = 76) (N = 65) DAS28
5.6 4.2 3.1 TJC28 14 7 3 SJC28 13 7 2 HAQ (0-3) 1.7 1.2 0.7 Pain on
VAS (0-100 mm) 64 37 20 ESR (mm/1.sup.st hour) 40 31 28 CRP (mg/dL)
2.4 N/A 1.5* Mean values. p < 0.05 for all Week-2 and Week-12
results vs. baseline. *Data available for 49 patients at Week
12.
TABLE-US-00097 TABLE 102 HAQ Improvement Through Week 12 Week 2
Week 6 Week 12 (n = 76) (n = 71) (n = 65) Mean change from baseline
-0.50.sup..dagger. -0.78.sup..dagger. -0.99.sup..dagger.
.sup..dagger.p < 0.001 vs. baseline, Wilcoxon's test. MCID
(minimum clinically important difference) = -0.22 Observed
data.
TABLE-US-00098 TABLE 103 DAS28 Improvement Through Week 12 Week 0
Week 2 Week 6 Week 12 (n = 77) (n = 76) (n = 72) (n = 65) Mean
DAS28 Scores 5.6 4.2* 3.4*.sup..dagger. 3.1* *p < 0.001 vs.
baseline; .sup..dagger.p < 0.001 vs. Week 2, Wilcoxon's test.
Observed data.
TABLE-US-00099 TABLE 104 Tender and Swollen Joint Counts Through
Week 12 Baseline Week 2 Week 6 Week 12 (n = 77) (n = 76) (n = 72)
(n = 65) Tender Joint Count 14.4 6.9* 3.9*.sup..dagger.
2.7*.sup..dagger-dbl. Swollen Joint Count 13.1 6.9* 3.4*.sup..sctn.
1.9* *p < 0.001 vs. baseline; .sup..dagger.p = 0.002 vs. Week 2;
.sup..dagger-dbl.p = 0.04 vs. Week 6; .sup..sctn.p < 0.001 vs.
Week 2, Wilcoxon's test. Observed data.
TABLE-US-00100 TABLE 105 Reduction of Pain as Assessed by VAS
Through Week 12 Week 2 Week 6 Week 12 (n = 76) (n = 72) (n = 65)
Mean Change from Baseline -2.7 -3.7 -4.4
TABLE-US-00101 TABLE 106 Percentages of Patients with CRP
Normalization Through Week 12 Week 6 Week 12 (n = 80) (n = 49) % of
Patients 49 40 Observed data.
TABLE-US-00102 TABLE 107 Percentages of Patients Who Achieved
Clinical Remission as Assessed by Clinical Remission Indicators %
of Patients HAQ < 0.5 DAS28 < 2.6 TJC = 0 SJC = 0 (n = 76) (n
= 76) (n = 76) (n = 76) Week 2 14 9 9 16 Week 12 43 29 32 46
[0483] Reductions in DAS28 scores were rapid and maintained through
12 weeks of adalimumab treatment (Table 103). Rapid reductions in
TIC and SJC were observed when adalimumab was added to existing MTX
therapy (Table 104). Patients reported a substantial reduction in
pain, 43% and 69% after 2 and 12 weeks of adalimumab therapy,
respectively (Table 105).
[0484] The percentages of patients demonstrating CRP normalization
(<1 mg/dL) (Table 106) as well as decreasing ESR values (data
not shown) after initiation of adalimumab 40 mg eow and after 12
weeks of therapy were maintained through Week 12. By Week 2, 14.5%
and 9.2% of patients had achieved HAQ<0.5 and DAS28<2.6,
respectively. The corresponding percentages for Week 12 were 43.1%
and 29.2% (Table 107). Approximately one-third of patients achieved
criteria for clinical remission: TJCx=(32.3%), SJC=0 (46.2%) (Table
107).
[0485] In conclusion, under clinical trial conditions, Venezuelan
patients with RA showed rapid and significant clinical improvements
after a single dose of 40-mg adalimumab, including a substantial
decrease in HAQ scores. Further, cumulative improvement was
observed at Week 12, including a substantial percentage of patients
achieving clinical remission based on DAS28 and other criteria. In
addition, supplementing adalimumab to insufficient concomitant
methotrexate therapy provides significant improvement in the signs
and symptoms of RA. Thus, adalimumab provides an effective
treatment for Hispanic, e.g., Venezuelan, patients suffering from
RA.
Example 14
Resource Utilization and Costs of Severe Rheumatoid Arthritis (RA)
from Societal and Patient Perspectives
[0486] The following study was performed to investigate resource
utilization and costs for late-stage rheumatoid arthritis (RA)
patients from societal and patient perspectives in several European
countries.
Resource utilization was retrospectively collected from 505
patients with active, severe RA from a period prior to their
enrollment in a multinational, open-label, follow-up clinical trial
of adalimumab, a fully human, anti-tumor necrosis factor (anti-TNF)
monoclonal antibody. At baseline, these patients had severe RA, had
previously failed a mean of 3.7 disease-modifying anti-rheumatic
drugs (DMARDs), and had a mean RA disease duration of 11 years.
Data on 54 resource utilization items were collected, including
direct costs (eg, hospitalizations, procedures, medications);
direct non-medical costs (eg, transportation, devices); and
indirect costs (eg, productivity loss, family support) for 6 months
prior to inclusion in the study using a methodology recently
recommended in a comprehensive review paper on the cost of RA
(Hubertus et al. (2005) Pharmacoeconomics 23:243). In brief, the
hierarchy of resource utilization assessment was as follows: Level
1 was the total, which was divided at level 2 into direct and
indirect. At level 3, direct was subdivided into inpatient and
outpatient. At level 4, outpatient was divided into direct medical
and direct nonmedical. At level 5, inpatient from level 3 was
divided into hospitalizations and rehabilitation. Level 4 direct
medical was divided at level 5 into doctor, medications, and
specific procedure. Level 4 direct nonmedical was divided at level
5 into other treatments, technical work and aids, personal help,
and transportation. At level 5, level 2 indirect was subdivided
into unfit for work. Resources were valuated using German prices
(in 2004 euros). A human-capital approach was employed to estimate
productivity losses.
[0487] Specific sets of health economic questionnaires (HEQs) were
used by investigators (I-HEQ) and patients (P-HEQ) for the
assessment of resource utilization and costs for late-stage
rheumatoid arthritis (RA) patients. The data derived from I-HEQ
included: hospitalization; rehabilitation/recuperation; procedures
performed; specific examinations and lab tests; outpatient
essential RA related examinations; and drug consumption. The data
derived from P-HEQ included: hospitalizations; outpatient visits;
physical/occupational therapy; alternative treatment; medical
devices; transportation; personal support; professional status;
productivity loss; working time; and early
retirement/unemployment.
[0488] A total of 505 patients were included in this analysis.
These patients had severe RA, and had previously failed a mean of
3.7 disease modifying antirheumatic drugs (DMARDs), and also had a
mean RA disease duration of 11 years. Mean societal total cost
during the 6-month period before anti-TNF therapy was initiated was
.epsilon.12 750 per patient per year (annualized) (Table 108), with
54% from direct non-medical cost, 28% from indirect cost (including
reduced functionality at work, 52%; sick leave, 9%; and early
retirement because of RA, 39%), and 19% from direct medical cost.
In addition, 49% of the total direct cost was a result of
hospitalizations. Mean total cost from the patients' perspective
was 2121.epsilon. per year--with 96% from direct non-medical cost,
of which 61% was for home support. More specifically, direct
non-medical costs--societal perspective were 81% personal
assistance, 19% medical device, and 9% transportation. Indirect
costs from a societal perspective included 9% sick leave, 52%
reduced functionality at work, and 39% early retirement. Patients
relied on a number of aids and devices to manage daily life (Direct
nonmedical cost to patient included 61% personal assistance, 18%
medical devices, and 21% transportation).
TABLE-US-00103 TABLE 108AM Total Cost per Patient - Societal
Perspective Costs per patient per year* Category (%) Direct non
medical costs 6,854 (54) Indirect costs 3,529 (28) Direct medical
costs 2,368 (19) Total 12,750 *Unit costs for Germany,
.dagger.Study drug costs not includeds were annualized from a 6-mo
period.
[0489] In conclusion, total cost from a societal perspective in
this study of late-stage RA patients is higher than similar data
reported in the literature for Europe (Hubertus et al.). Total
costs from the patients' perspective were much higher than
previously reported (Huelsemann et al. (2005) Ann Rheum Dis
64:1456), demonstrating the economic burden of the disease on the
patient--an often neglected focus in RA research.
Example 15
Clinical Response by Day 1 with Adalimumab in Patients with Active
Rheumatoid Arthritis: Study D (HERO)
[0490] Adalimumab, a fully human monoclonal antibody targeting TNF,
is approved for the treatment of rheumatoid arthritis, psoriatic
arthritis, and ankylosing spondylitis in the United States, Europe,
and elsewhere. Pivotal trials have proven the efficacy of and rapid
response to adalimumab (as early as one week after study drug
initiation) in patients with RA (Weinblatt M E, et al. Arthritis
Rheum. 2003; 48:35-45; van de Putte L B A, et al. Ann Rheum Dis.
2004; 63:508-16, and van de Putte L B A, et al. Ann Rheum Dis.
2003; 62:1168-77). These trials used a host of clinical, physician,
and patient-reported outcome (PRO) measures at each study visit to
demonstrate responses to therapy. Although these assessments detect
response to therapy at time of first study visit, earlier
improvement cannot be measured reliably without potential for
recall bias.
[0491] Patient-reported outcomes (PRO) can be used to determine
very early responses to therapy. The purpose of this study was to
determine the early time course of response to adalimumab (ADA)
using PRO measures recorded in electronic diaries in Study D
(HERO).
[0492] Study D was a randomized, double-blind (first dose), placebo
(PBO)-controlled, multi-center, Phase IV study of ADA 40 mg sc
every other week in patients with active RA. Its emphasis was on
early response markers and PROs. After screening, all eligible
patients received a blinded dose of study medication, followed by
10 weeks (wks) of open-label (OL) ADA, beginning at week 2. The
study design is depicted in FIG. 21. Patients were trained to use
an electronic diary (e-diary) to report their global assessments of
disease activity (Pt. Global), pain, function, fatigue and morning
stiffness (presence, duration and severity) using a 0-100 visual
analog scale (VAS), with higher values reflecting worse symptoms.
During the screening and blinded first 2 weeks post-baseline,
patients completed three reports per day (morning 5-10 am,
afternoon 2-4 pm, and evening 8-11:45 pm), followed by evening-only
reports during the 10-wk OL period. At baseline, Week 2, Week 4,
and Week 12 study visits, the following assessments were performed
and recorded on paper: Short Form 36 (SF-36) Health Survey, Health
Thermometer, Functional Assessment of Chronic illness
Therapy-Fatigue (FACIT-F) scale, Health Assessment Questionnaire
(HAQ), Physician's global assessment of disease activity, Swollen
and Tender Joint Counts, C-reactive protein, VAS--Functional
Limitation, and VAS--Morning Stiffness. The degree and timing of
improvement in e-diary based PROs between PBO and ADA groups were
determined during the blinded first 2 weeks of the study and after
patients switched to OL therapy. Evening report scores were used
for this analysis. Baseline values are from the last evening report
(Day-1) prior to start of treatment.
[0493] A total of 1,880 patients (953 ADA, 927 PBO) enrolled at 204
study sites had e-diary data available for analysis. The study
disposition is depicted in FIG. 22. In the overall Study D
population, there were no significant differences between the two
treatment arms in terms of baseline demographics. Table 109 lists
the baseline demographics data for the 1880 patients included in
this analysis. There were no significant differences between the
two treatment groups in terms of baseline e-diary evening
assessments, except for duration of morning stiffness (p=0.012), as
shown in Table 110. Compliance with the e-diary was greater than
90% from screening to the end of the study.
TABLE-US-00104 TABLE 109 Baseline Demographics Placebo Adalimumab
Characteristics n = 927 n = 953 Age (mean, years) 54.5 54.0 Sex (%
male) 23.0 21.3 Disease duration (mean, years) 6.9 7.0 Patients on
concomitant DMARDs (%) 78.9 82.5 Education categories (%) 0-8 yrs
3.5 3.6 9-11 yrs 9.3 9.1 12 yrs 36.9 39.7 13-15 yrs 30.8 26.0
.gtoreq.16 yrs 19.5 21.6
TABLE-US-00105 TABLE 110 Baseline e-Diary Assessments VAS scores
(0-100) Placebo Adalimumab e-PaGA 50.6 49.8 Pain 50.9 50.9 Function
51.1 50.6 Fatigue 56.4 55.2 Presence of AM stiffness (%) 93.5 91.7
Duration of AM stiffness (minutes) 140.7 161.7 Severity of AM
stiffness 53.3 51.3
[0494] Statistically significant separation from the PBO patients
occurred after 1 day of treatment for all variables (P<0.001)
(Table 111), with mean 14-day improvement differences ranging from
4.7 units (fatigue) to 7.6 units (stiffness) (P<0.001) (see
Table 112). Adalimumab patients experienced significantly shorter
periods of morning stiffness compared with placebo patients by Day
1 (mean decrease of 32.8 minutes for adalimumab patients vs. 0.3
minutes for placebo patients). Improvement in e-diary assessments
at Weeks 2 and 12 are depicted in Table 113. Based on the e-diary
assessments, the improvements in symptom severity PROs of the
adalimumab group were significantly better than the placebo group
for every day of the entire 2-week double-blind period. Placebo
patients who switched to open-label adalimumab had similar symptom
improvements as the adalimumab group. FIG. 23 depicts the time
course of mean change in e-diary assessments to Week 12. The effect
of adalimumab treatment on patient pain, functional disability,
fatigue and AM morning stiffness severity during the double-blind
period of 14 days followed by open-label adalimumab are shown in
FIG. 24, FIG. 25, FIG. 26 and FIG. 27 respectively.
[0495] Baseline morning scores were approximately 3 units greater
than evening scores, but response to treatment was similar.
Improvement in Pt. Global continued throughout the OL period (see
FIG. 28). Improvement in evening PROs are shown in Table 111
below.
TABLE-US-00106 TABLE 111 Improvement in Evening PROs in Study D
Adalimumab Arm All Patients Improvement Improvement Mean Change
difference difference Base- from from placebo from placebo line
Baseline at at Day 1 over 14 days PRO* (S.D.) Week 12 (95% CI) (95%
CI) (95% CI) Pt. 50.1 -19.3 (-20.5 to -18.2) 5.0 (2.4-7.7) 6.1
(4.9-7.3) Global (22.9) Pain 50.8 -20.2 (-21.4 to -19.1) 5.7
(2.8-8.6) 7.1 (5.9-8.4) (23.8) Function 50.8 -19.5 (-20.6 to -18.3)
5.5 (2.7-8.2) 6.5 (5.3-7.7) (23.7) Fatigue 55.8 -19.7 (-20.9 to
-18.5) 3.7 (0.8-6.5) 4.7 (3.5-5.9) (25.4) Stiffness 52.3 -25.6
(-27.0 to -24.3) 4.3 (1.2-7.5) 7.6 (6.3-9.0) (25.9) *Mean
values
TABLE-US-00107 TABLE 112 Improvements in e-Diary Assessments at Day
1 Mean Improvement from Baseline AM Stiffness e-PaGA Pain Function
Fatigue Severity Placebo 0.9 1.1 1.4 2.0 3.5 Adalimumab 5.7* 6.7*
6.7* 5.3* 7.3* *p < 0.001 vs. placebo
TABLE-US-00108 TABLE 113 Improvement in e-Diary Assessments at
Weeks 2 and 12 % Improvement AM Stiffness e-PaGA Pain Function
Fatigue (Severity) Week 2 Double-blind period Placebo Arm -1.9 -5.4
-5.0 -2.0 9.5 Adalimumab Arm 16.9* 16.9* 17.7* 10.3* 24.8* Week 12
Open-label period Placebo Arm 30.3 20.6 18.7 23.6 49.3 Adalimumab
Arm 33.2 33.3 32.5 23.7 47.7 *p < 0.001 vs. placebo
[0496] In conclusion, statistically significant responses to ADA in
patients with RA occurred very quickly after the first dose.
Recognition of this rapid response was made possible by the use of
an e-diary which allowed real-time data capture of PROs on a daily
basis. Almost half of the overall benefit from ADA was observed
during the first 14 days.
Example 16
A Comparison of Patient and Physician Measures in Assessing
Treatment Response in Rheumatoid Arthritis: Results from Study
D
[0497] In clinical trials and in clinical practice, many variables
are used to capture treatment effect. Assessments used to detect
the existence of treatment effect must have a strong effect size
(ES). For assessments used to determine the magnitude of
improvement, the "truth" of the measure is more important than the
effect size. Truth is compromised when non-treatment effects
contribute to the total treatment effect (Table 114). The true
component is the effect attributable to treatment. The false
components are placebo effect and the effects attributed to
regression to the mean and to the natural course of illness; the
latter effects are time dependent.
TABLE-US-00109 TABLE 114 Truth: Non-Treatment Effects Contribute to
the Total Treatment Effect Effect Received Treatment Received
Placebo True Effect Yes No Placebo Effect Yes Yes Regression to the
mean effect Depends on duration Depends on duration Course of
illness effect Depends on duration Depends on duration
[0498] Long term observations in clinical trials typically do not
allow for the regression to the mean and course of illness effects
to be factored out, and these time-dependent effects cannot be
separated from true placebo effect. Early assessments allow for
only treatment and placebo effects to influence results.
[0499] The purpose of this study was to determine which variables
best measure treatment effect. In Study D, the rapid improvement
that occurs with anti-TNF therapy was used to evaluate response
variables two weeks after starting adalimumab (ADA). Early
assessments do not include improvement that may occur with time as
a function of regression to the mean, leaving only treatment and
placebo (PBO) effects to influence results.
[0500] Study D was a randomized, double-blind, PBO-controlled,
multi-center, Phase IV study of ADA 40 mg every other week (wk) in
patients (pts) with active RA, with emphasis on patient-reported
outcomes (PROs) and early response. The study design is depicted in
FIG. 21.
[0501] Patients were trained to use a Palm.COPYRGT. OS-based
e-diary to report on the following using a 0-100 visual analog
scale (VAS): Patient's Global Assessment of disease activity
(e-PaGA), pain, function, fatigue, morning stiffness (AM
Stiffness), presence of AM stiffness, duration of AM stiffness
(minutes), and severity of AM stiffness. During screening and the
blinded first 2 weeks of the study, patients were prompted to
complete 3 sets of reports per day (morning 5-10 AM, afternoon 2-4
PM, and evening 8-11:45 PM). Once patients were switched to
open-label adalimumab at Week 2, they were prompted to complete
only daily evening reports until the end of the study.
[0502] Patients received a blinded dose of study drug, followed by
10 weeks of open-label (OL) ADA at Week 2. Physician measures,
C-reactive protein (CRP) and PROs were collected at baseline, Weeks
2, 4, and 12. Patient Activity Score (PAS) was based on Health
Assessment Questionnaire (HAQ) disability score, pain on a visual
analog scale (VAS) and patient global VAS. Week 2 blinded data was
evaluated to determine how well each variable captured ADA or PBO
effect.
[0503] This analysis evaluated early assessments from the Week 2
blinded data in order to determine how well selected variables
could capture treatment (adalimumab) and placebo effects. Effect
sizes (ES), for both placebo group and the adalimumab group, were
determined by the following function: (Baseline score-Week 2
score)/pooled standard deviation. To assess magnitude of treatment
effect, effect sizes (ES) (standardized responses) was calculated
at Week 2 for PBO (ES[P]) and for ADA, labelled ES[T+P] was
calculated as there is a true (T) treatment effect and a PBO
component (P) in each observed response. Kendall's Tau-a was
calculated between type of treatment (ADA or PBO) and change in
study variables. Variables with higher Tau-a scores have greater
ability to detect treatment effect. The area under the Receiver
Operating Curve (AUC), a standardized multivariable measure of
treatment effect, was used to compare groups of variables.
[0504] In the ADA arm, ACR 20/50/70 response rates were 24/13/9 at
Week 2 and 58/47/40 at Week 12. Greatest PBO effect (ES[P]) was
found for DAS-28, physician global (MD global), VAS stiffness and
tender joint count (TJC). Only CRP was without PBO effect. ADA
treatment ES (ES [T+P]) was greatest for MD global, DAS-28 and VAS
stiffness. The results are shown in Table 115.
TABLE-US-00110 TABLE 115 Magnitude of Treatment Effect Mean Mean
All pts ES ES (P) All pts. (Week (T + P) (Week Tau-a Variable
(Baseline) 12) (Week 2) 2) (Week 2) CRP (mg/dL) 1.40 0.70 0.47
-0.01 0.213 PAS (0-10) 5.07 2.99 0.54 0.16 0.142 VAS Pain (0-10)
5.79 3.22 0.60 0.17 0.139 DAS-28 3.89 2.55 0.63 0.29 0.135 VAS
Stiffness 5.59 2.75 0.62 0.24 0.123 (0-10) Pt. Global (0-10) 5.28
3.00 0.50 0.14 0.118 MD Global (0-10) 5.65 2.43 0.72 0.29 0.116
HAQ-II (0-3) 1.19 0.83 0.32 0.09 0.100 MD HAQ (0-3) 0.94 0.61 0.34
0.11 0.099 HAQ (0-3) 1.24 0.82 0.31 0.11 0.094 VAS Fatigue 5.78
3.54 0.35 0.15 0.087 (0-10) SJC (0-28) 9.70 4.46 0.41 0.21 0.085
TJC (0-28) 12.28 5.22 0.40 0.23 0.068 VAS QOL (0-10) 0.76 0.82
-0.30 -0.04 -0.075 FACIT Fatigue 28.07 34.82 -0.35 -0.14 -0.078
(0-52)
[0505] A total of 1938 patients enrolled in Study D. This analysis
evaluated data from 1891 patients who completed at least the
baseline and Week 2 assessments. No significant differences existed
between groups at baseline (see Table 116).
TABLE-US-00111 TABLE 116 Study D Baseline Demographics and Disease
Characteristics Mean SD Mean SD Variable Adalimumab Placebo N 958
933 Age (years) 54.0 12.5 54.5 12.9 Sex (% male) 21.23 23.0
Physician & Laboratory Measures Physician global (0-10) 5.6 2.0
5.7 2.1 Swollen joint count (0-28) 9.7 6.4 9.7 6.4 Tender joint
count (0-28) 12.2 8.2 12.4 7.9 CRP (mg/100 ml) 1.4 2.3 1.4 2.1
DAS28 3.9 1.0 3.9 1.0 Patient Self-report Measures PaGA (0-10) 5.3
2.3 5.3 2.3 Pain (0-10) 5.7 2.4 5.9 2.4 PAS (0-10) 5.0 2.0 5.1 2.0
VAS functional (0-10) 5.2 2.3 5.3 2.3 disability Fatigue (0-10) 5.7
2.7 5.9 2.7 Stiffness (0-10) 5.6 2.6 5.7 2.6 HAQ (0-3) 1.2 0.6 1.3
0.6 HAQ2 (0-3) 1.2 0.6 1.2 0.6 MDHAQ (0-3) 0.9 0.5 1.0 0.5 FACIT
fatigue (0-52) 28.4 10.0 28.0 9.7
[0506] The superior efficacy of adalimumab vs. placebo through Week
12 is evident in ACR 20/50/70 responses and improvements in e-diary
patient assessments (see FIGS. 21 and 25). Effect size should be
approximately 0 for placebo-treated patients if there is no placebo
effect. CRP was the only variable without placebo effect (see Table
117). Adalimumab treatment ES were greatest for MD global, VAS
stiffness and DAS28.
TABLE-US-00112 TABLE 117 Effect Sizes and Kendall's Tau-a at the
End of the Double Blind Period (Week 2) Mean Adalimumab Placebo All
patients Effect Size Effect Size Tau-a Variable (baseline) (Week 2)
(Week 2) (Week 2) CRP (mg/dL) 1.40 0.47 -0.01 0.21 (0.19-0.24) PAS
(0-10) 5.07 0.54 0.16 0.14 (0.12-0.17) VAS Pain (0-10) 5.79 0.60
0.17 0.14 (0.11-0.16) DAS-28 3.89 0.63 0.28 0.14 (0.11-0.16) VAS
Stiffness (0-10) 5.59 0.62 0.24 0.12 (0.10-0.15) Patient Global
(0-10) 5.28 0.50 0.14 0.12 (0.09-0.14) MD Global (0-10) 5.65 0.72
0.29 0.12 (0.09-0.14) HAQ-II (0-3) 1.19 0.32 0.09 0.10 (0.07-0.13)
MD HAQ (0-3) 0.94 0.34 0.11 0.10 (0.07-0.13) HAQ (0-3) 1.24 0.31
0.11 0.09 (0.07-0.12) VAS Fatigue (0-10) 5.78 0.35 0.15 0.09
(0.06-0.11) SJC (0-28) 9.70 0.41 0.21 0.08 (0.06-0.11) TJC (0-28)
12.28 0.40 0.23 0.07 (0.04-0.9) VAS QOL (0-10) 0.76 -0.30 -0.04
-0.08 (-0.05-(-)0.10) FACIT Fatigue (0-52) 28.07 -0.35 -0.14 -0.08
(-0.05-(-)0.10) CRP is the best at distinguishing treatment effect.
Measures in bold are statistically indistinguishable. Measures that
are italicized are the poorest at distinguishing treatment
effect.
[0507] Looking at the ratio of placebo ES to treatment ES, the
variables with the greatest placebo ES were TJC, SJC, DAS28, VAS
fatigue, and MD global (see Table 118). As assessed by Tau-a, the
metrics that best distinguished treatment effects were CRP, PAS,
VAS Pain, and DAS28 (Table 117). The addition of CRP to PAS
(PAS+CRP) substantially improves the ability to detect treatment
effect compared to DAS28 or PAS alone. The area under the curve
(AUC) was 0.64 for either PAS or DAS-28. However, combining PAS+CRP
increased the AUC to 0.71. However, when considering the confidence
intervals, three groups were seen with respect to Kendall's Tau-a:
1) CRP was the best identifier of treatment effect; 2) variables
that were statistically indistinguishable from each other (in
bold); and 3) variables that were poorest in distinguishing
treatment effect (italicized). CRP best distinguishes treatment
effect, while physician-based variables perform worst at the end of
a 2-week double blind period. However, at the end of the 12-week
open-label period, overall effect sizes are greatest for MD Global
(1.57), DAS-28 (1.28), VAS Stiffness (1.10), VAS Pain (1.04) and
PAS (1.00) as the increasing effect of adalimumab treatment becomes
recognized.
TABLE-US-00113 TABLE 118 Ratio of Placebo ES to Treatment ES
Percent CRP -2.1 VAS QOL 13.3 Patient Global 28.0 HAQ-II 28.1 Pain
28.3 PAS 29.6 MD HAQ 32.4 HAQ 35.5 VAS Stiffness 38.7 FACIT Fatigue
40.0 *MD Global 40.3 *VAS Fatigue 42.9 *DAS28 44.4 *Swollen Joint
Count 51.2 *Tender Joint Count 57.5 *Variables with greatest
placebo effect size
[0508] In conclusion, physician and patient-based measures have PBO
components that can limit their usefulness. At Week 2 of this
study, certain pt-based measures were equal or superior to
individual physician variables and DAS-28 in determining efficacy,
due to increased PBO effect in physician measures. The PAS+CRP
combination is an effective and less biased way to evaluate early
improvement and appears to be suitable for clinical practice
use.
Example 17
HAQ and FACIT-F are Better Predictors of Societal Costs of
Rheumatoid Arthritis than DAS28
[0509] Health economists and outcomes researchers are currently
debating which patient-reported measures best predict clinical and
health economic outcomes. Changes in HAQ scores for patients with
RA have been shown to predict future disability, health-related
quality of life (HRQoL), and long-term costs (Kobelt G, et al.
Rheumatology. 2005; 44: 1169-75). This analysis investigated the
differences between several patient-reported outcomes (PROs) in
predicting future costs and/or changes in HRQoL in RA. Adalimumab,
a fully human monoclonal antibody targeting TNF, is approved for
the treatment of rheumatoid arthritis, psoriatic arthritis, and
ankylosing spondylitis in the United States, Europe, and
elsewhere.
[0510] The objective of this analysis was to investigate the
differences between several patient-reported outcomes (PROs) in
predicting future costs and/or QOL in rheumatoid arthritis
(RA).
[0511] This study analyzed data on 505 patients who had received
adalimumab therapy during one of six Phase II/III studies (most
patients under double-blind, randomized conditions for at least 26
weeks of treatment). These patients were enrolled in a long-term,
open-label health economic extension study (40 mg adalimumab every
other week) and followed for up to 144 weeks (FIG. 29). Patients
and/or investigators were asked to fill out several HRQoL-related
instruments at baseline and multiple time points during the study:
Health Assessment Questionnaire (HAQ); Functional Assessment of
Chronic Illness Therapy--Fatigue Scale (FACIT-F); Health Utilities
Index (HUI3); and Short form--36 questionnaire (SF-36). Among other
clinical outcomes, investigators assessed DAS28 at baseline and at
multiple times during the study. In addition, patients and
investigators were asked to document resource utilization during
the study.
[0512] Two linear regression models were constructed: one to
determine prognostic factors for health-related QOL and one to
determine progressive factors for costs from a societal
perspective, which included direct medical costs, indirect costs
(lost productivity) and costs to the patient.
[0513] A correlation analysis using Spearman correlation
coefficients was conducted for the following data at baseline:
TJC68 (tender joint count based on 68 joints); SJC66 (swollen joint
count based on 66 joints); DAS28 (modified disease activity score)
Disease activity by patient on a visual analog scale (VAS); Pain
VAS by patient Disease activity by physician; Morning stiffness;
ACR-rank (ie, no response=0, ACR20=1, ACR50=2, ACR70=3). Using
correlation analyses, the factors influencing HRQoL outcome and
costs per patient were pre-examined. The analyses were performed on
all major covariates to check for possible associations between the
covariates. Any correlations between explanatory variables which
achieved correlation coefficients of r=0.5 or higher were to be
removed from the selected statistical model for the analysis of
influences of medical parameters and effectiveness factors on HRQoL
and costs.
[0514] The following HRQoL outcome variables were modeled
separately for DAS28: Quality adjusted life year calculated for HUI
values over time (QALY HUI), Area under the curve for HUI over time
(AUC HUI), Area under the curve for FACIT-F (AUC FACIT), Area under
the curve for SF-36 mental component score over time (AUC SF-36
MCS). Area under the curve for SF-36 physical component score over
time (AUC SF-36 PCS), and Area under the curve for HAQ over time
(AUC HAQ). The explanatory variable DAS28 or the clinical
parameters (TJC, SJC, disease activity, pain, morning stiffness)
were removed from the model if they did not show an influence on
HRQoL outcome (p>0.1). Those variables with a p-value.ltoreq.0.1
were considered as prognostic or progressive in the final model.
Models were calculated using SAS Software (SAS 8.2).
[0515] Number of previously failed DMARDs, mean age, RA duration,
TJC and SJC clearly indicate the severity of RA in these patients
(Table 119). Baseline patient characteristics were: female, 77%;
age, 55 years; % working, 30.1%; working time in employed patients,
30.89 hours per week; duration of disease, 12.36 years; TJC (0-68),
14.58; SJC (0-66), 8.23; HAQ score, 1.15; DAS28 (0-10), 4.58;
DMARDs failed, 3.7; and body mass index, 25.06 (all mean values
except % gender, working). The correlation analysis of baseline
data using Spearman correlation coefficients showed that all input
parameters analyzed were statistically significantly correlated
with each other (p<0.0001).
TABLE-US-00114 TABLE 119 Baseline Demographics and Disease Activity
Study 8 population Variable (n = 505) Female n (%) 390 (77.2) Age
(years) median (range) 55.0 (22-82) Weight (kg) Mean .+-. SD 69.12
.+-. 12.90 Height (cm) Mean .+-. SD 166.06 .+-. 8.90 Caucasian n
(%) 498 (98.6) BMI (kg/m.sup.2) Mean .+-. SD 25.06 .+-. 4.34
Employed n (%) 152 (30.1) Retired n (%) 220 (43.6) RA duration Mean
.+-. SD 12.36 .+-. 7.69 No. of previous DMARDs Mean .+-. SD 3.7
.+-. 1.82 failed TJC (0-68) Mean .+-. SD 14.58 .+-. 14.89 SJC
(0-68) Mean .+-. SD 8.23 .+-. 8.18 DAS28 Mean .+-. SD 4.58 .+-.
1.58
[0516] The correlation analysis of baseline data using Spearman
correlation coefficients showed that all input parameters analyzed
were statistically significantly correlated with each other
(p<0.0001). For each of the HRQoL variables, the DAS28 at
baseline had an influence on the outcome of the respective HRQoL
variable. In addition, RA duration, age, and professional status at
baseline were determined as explanatory factors for HRQoL outcome.
As for the progressive factors model, DAS28, RA duration, age, and
professional status were determined as explanatory factors for the
outcome of HRQoL variables in the analysis with DAS28 response
(Table 120). For all HRQoL variables analyzed, DAS28 was the factor
with the strongest influence on HRQoL outcome.
TABLE-US-00115 TABLE 120 Progressive HRQoL analysis with DAS28
Response - Generalized Linear Model (N = 505) Progressive factors
determined n by stepwise regression Pr > F QALY HUI 415 DAS28
mean <0.0001 RA duration 0.0012 age 0.0160 AUC HUI 344 DAS28
mean <0.0001 RA duration 0.0797 professional status 0.0140 AUC
FACIT 422 DAS28 mean <0.0001 AUC SF-36 physical 443 DAS28 mean
<0.0001 component score RA duration 0.0235 age 0.0830
professional status 0.0065 AUC SF-36 mental 456 DAS28 mean 0.0006
component score AUC HAQ 456 DAS28 mean <0.0001 RA duration
<0.0001 professional status <0.0001 sex <0.0001 AUC = area
under the curve, DAS28 = Modified Disease Activity Score 28, DMARD
= Disease Modifying Anti-Rheumatic Drug, n = observations used for
the analysis, SF 36 = Short form-36 questionnaire, SS = sum of
squares. Pr > F represents the p-value, i.e. the probability
(Pr) that SS is greater than the quantil of an F-distribution
(F).
[0517] The results for the progressive cost analyses are summarized
in Table 121. Since the explanatory variables that were used in the
model (AUC HAQ, AUC FACIT, and DAS28) were all strongly correlated
with each other, it was decided to analyze separate models, based
on just one independent variable each. The analysis shows that the
costs for RA from the societal perspective are strongly influenced
by the outcome variables. AUC HAQ and AUC FACIT (p<0.01)
however, are not strongly influenced by the clinical variable DAS28
over time (p>0.1).
TABLE-US-00116 TABLE 121 Progressive cost analysis Progressive
factors determined n by stepwise regression Pr > F Costs from
societal 505 AUC HAQ 0.0007 perspective Costs from societal 463 AUC
FACIT <0.0001 persective Costs from societal 461 DAS28 0.1493
perspective Pr > F represents the p-value, i.e. the probability
(Pr) that SS is greater than the quantil of an F-distribution
(F).
[0518] Based on the correlation analysis, the DAS 28 at baseline
was chosen as the most representative factor for the correlated
parameters. The first model showed that, for each of the QOL
variables, the DAS28 at baseline had an influence on the outcome of
the respective variable. The second model on costs showed that the
costs for RA from the societal perspective were strongly influenced
by HAQ and FACIT-F values (p<0.001). However, they were not
strongly influenced by the DAS28 score (p>0.1).
[0519] In this observational study over 3 years, the DAS28 has
proven to be an important tool in predicting QOL in patients with
severe RA. However, HAQ and FACIT-F are better predictors of
long-term societal costs, and RA patients with unmitigated fatigue
are costly to treat in the long term.
Example 18
Treatment with Adalimumab (HUMIRA.RTM.) is Well-Tolerated and
Efficacious in Patients with Active RA in Various Age Groups
Including Patients with Late-Onset RA--Subanalysis of 6610 Patients
in Study A
[0520] Limited data exist about the impact of age on safety and
efficacy of anti-TNF therapy in patients with active RA. The
recently completed Study A provides a large database to examine
this question.
[0521] Adults aged .gtoreq.18 with active RA and prior insufficient
response to disease-modifying antirheumatic drugs (DMARDs) received
adalimumab (ADA) 40 mg sc every other week for 12 weeks in Study A,
with an optional extension phase until ADA was commercially
available. Efficacy and routine safety evaluations were conducted
at Weeks 2, 6, and 12, and every 8 weeks thereafter. Efficacy
outcomes were analyzed by 4 age groups and by late-onset RA [RA
beginning at age >60 yrs (LORA)] at Week 12. Adverse events (AE)
were collected throughout the entire treatment period (up to a
maximum of 96 weeks).
[0522] Baseline characteristics in patients of age (n)<40 yrs
(1.002), 40-<65 yrs (4,125), 65-<75 yrs (1,245), and
.gtoreq.75 yrs (238) varied with increasing values from young to
elderly in means of disease duration (7-14 yrs), disability index
of the Health Assessment Questionnaire (HAQ) (1.45-2.00 units),
Disease Activity Score 28 (DAS28) (5.8-6.3), percentage of patients
receiving steroids (68-77%), and percentage receiving adalimumab
monotherapy (24-35%). Co-morbidities were more frequent with
increasing age and contributed to occurrences of AEs. With respect
to the LORA-group the mean baseline HAQ was 1.64 in 266 pts with
disease duration .ltoreq.3 yrs and 1.76 in 492 pts with disease
duration >3 yrs. Respective DAS28 values were 6.3 and 6.2.
Overall, the mean exposure to ADA was 233 days, up to a maximum of
96 weeks. Key efficacy outcomes at Week 12, withdrawal rates, and
safety results for the complete treatment period are presented
(Table 122). Except for ACR20, all efficacy values continued to
improve beyond Week 12 in all age groups. Patients with LORA of
short duration achieved better results than patients with LORA>3
yrs.
TABLE-US-00117 TABLE 122 Adalimumab Efficacy and Safety by Age
Group and Disease Duration for Late-Onset RA LORA LORA Age<40
yrs Age 40-<65 yrs Age 65-<75 yrs Age .gtoreq.75 yrs
.ltoreq.3 yrs >3 yrs Efficacy at Week 12 n = 1002 n = 4125 n =
1245 n = 238 n = 266 n = 492 ACR20 (%) 74 68 68 61 75 63 ACR50 (%)
49 40 35 35 44 34 ACR70 (%( ) 26 18 15 12 21 12 Mean Change in
DAS28* -2.3 -2.1 -2.1 -1.9 -2.3 -2.0 Mean Change in HAQ* -0.61
-0.54 -0.48 -0.37 -0.59 -0.43 Total withdrawals.sup..dagger. Due to
loss of efficacy (%) 7 7 6 6 5 6 Due to AE (%) 8 10 13 19 9 17
Safety, complete period.sup..dagger. Pts with Severe AE (%) 5.9 8.4
12.1 16.0 9.8 12.6 Pts with Serious 2.2 2.6 4.8 5.9 3.4 4.5
Infection (% pts) Observed values *p < 0.001. .sup..dagger.Up to
a maximum of 96 weeks.
[0523] Adalimumab led to clinically significant improvement in
disease activity and physical function in all age groups and
patients with LORA. Adalimumab was generally well-tolerated with an
expected increase of severe AEs in pts of higher age. The
benefit-risk ratio in elderly patients was generally positive.
Example 19
Disease Activity and Physical Function Improve Significantly in
Most Patients with RA Receiving Adalimumab for up to 6 Years
Irrespective of ACR20 Response
[0524] Significant improvements in disease activity and physical
function have been demonstrated in a majority of patients with RA
treated with adalimumab plus methotrexate (MTX) in randomized
clinical trials (RCTs) and open-label extension studies. Although
the ACR response rate is a key measure of therapeutic efficacy in
RCTs, it is unclear what clinical benefits are achieved by patients
on long-term therapy who do not reach ACR20 responses.
[0525] The objective of this study was to determine, in an
open-label extension study of adalimumab and MTX, the extent to
which there were significant improvements in various aspects of
disease activity in patients who did not fulfill ACR20 response
criteria.
[0526] Patients enrolled in Study 1, Study 1, Study K, Study 6, and
Study 7 RCTs were eligible to enter an extension study of
adalimumab 40 mg eow sc and MTX. Efficacy and safety were evaluated
in all patients' last visits for up to 6 years, including those who
withdrew for any reason. The clinical characteristics of patients
who did or did not achieve an ACR20 response and who continued or
did not continue on long-term treatment were evaluated.
[0527] Of 1465 patients treated with adalimumab plus MTX for up to
6 years (mean.+-.SD exposure of 45.+-.24 months), 64%, 43% and 25%
achieved ACR20, 50 and 70 responses, respectively, at their last
visits. The remission parameters at last visit were DAS28<2.6:
34%; TJC68=0: 24%; SJC66=0: 23%; and HAQ=0: 20%. Rates and types of
adverse events of all patients (5501 patient-years) were consistent
with previous reports. The ACR20 non-responders were categorized as
follows: 1) patients who continued in the study; 2) patients who
discontinued (d/c) because of AEs or other reasons; and 3) patients
who d/c because of lack of efficacy (LOE). Despite the lack of
ACR20 response, the first two categories showed significant
improvements in DAS28 and most of the core components of the ACR
index (Table 123). Baseline characteristics were similar between
all groups.
TABLE-US-00118 TABLE 123 Last Visit Outcomes in ACR20 Responders
and Non-Responders (NR) to Adalimumab Plus MTX Patients Patient
Physician % (n) TJC68* SJC66* Global* Global* HAQ* CRP* DAS28
Baseline 100 (1465) 28 20 53 59 1.4 18 5.7 Responders 64 (937)
5.sup..dagger. 4.sup..dagger. 20.sup..dagger. 14.sup..dagger.
0.7.sup..dagger. 8.sup..dagger. 2.8.sup..dagger. NR Continued 15
(226) 16.sup..dagger. 11.sup..dagger. 41.sup..dagger.
29.sup..dagger. 1.1.sup..dagger. 10.sup..dagger-dbl.
4.1.sup..dagger. NR d/c, AE, 15 (213) 20.sup..dagger.
13.sup..dagger. 51 40.sup..dagger. 1.4.sup..dagger. 15
4.6.sup..dagger. Other NR d/c, LOE 6 (89) 28 19 64
56.sup..dagger-dbl. 1.6 22 5.6 *Mean values. .sup..dagger.P <
0.001, .sup..dagger-dbl.P < 0.01, vs. baseline in same
category.
[0528] In conclusion, Adalimumab plus MTX induced sustained ACR20
response in 64% and remission in >20% of patients treated for up
to 6 years. Patients not meeting the ACR20 response criteria who
either continued on long-term adalimumab therapy or withdrew for
reasons other than inefficacy showed significant improvements in
individual facets of disease activity, including functional
status.
Example 20
Remission and Major Clinical Response in Patients with Active
Rheumatoid Arthritis (RA) after Treatment with Adalimumab
(HUMIRA.RTM.)
[0529] Concepts of improvement and current disease state are
important to consider. While it is important to show how much RA
patients have improved with therapy, it is even more important to
demonstrate that they have achieved very low degrees of disease
activity, including remission (Dougados M. J Rheumatol 2006;
32:1-2). Since the advent of tumor necrosis factor (TNF)
antagonists, clinical remission has become a reachable treatment
goal for patients with RA.
[0530] The objective of this study was to investigate the
effectiveness of adalimumab treatment measured by five selected
clinical remission criteria or MCR in relation to baseline and
treatment characteristics, respectively, in a large RA
population.
[0531] Since the introduction of TNF antagonists, clinical
remission activity and a major clinical response (MCR) have become
attainable therapeutic goals for patients with active RA. Different
definitions of clinical remission have been provided by EULAR, ACR,
and the FDA. We determined the proportions (%) of patients who
participated in the recently completed Study A and who achieved
remission or MCR using several criteria.
Methods
[0532] Patients with active RA and prior disease modifying
anti-rheumatic drug (DMARD) therapy enrolled in the Study A trial
(see FIG. 1 for study design) [0533] Adalimumab was administered
(40 mg every other week [eow] sc) for 12 weeks in addition to
current antirheumatic therapy [0534] Patients optionally continued
therapy until adalimumab was commercially available [0535]
Effectiveness and safety evaluations were conducted at Weeks 2, 6,
12, and every 8 weeks thereafter [0536] Inclusion criteria included
[0537] Age.gtoreq.18 years [0538] RA (defined by American College
of Rheumatology criteria) for .gtoreq.3 months [0539]
Unsatisfactory response or intolerance to at least one prior DMARD
[0540] Active RA defined as Disease Activity Score 28
(DAS28).gtoreq.3.2 [0541] Five different criteria defining clinical
remission in RA were used. The percentage of patients was
calculated who achieved: [0542] DAS28<2.6 based on ESR (Fransen
J, et al. Rheum 2004; 43:1252) [0543] Simplified Disease Activity
Index (SDAI)<5 or SDAI.ltoreq.3.3 (Aletaha D and Smolen J. Clin
Exp Rheumatol 2005; 23(suppl 39):S100) [0544] Clinical Disease
Activity Index (CDAI).ltoreq.2.8 (Aletaha D and Smolen J. Clin Exp
Rheumatol 2005; 23(suppl 39):S100) [0545] Tender+Swollen Joint
Count (TJC+SJC)=0 [0546] TJC+SJC+normal ESR first hour (defined as
<20 mm in men and <30 in women) (Makinen H, et al. Ann Rheum
Dis 2005, 64:1410) [0547] Major Clinical Response [0548] ACR70
response for .gtoreq.6 continuous months (www.fda.gov) in patients
who continued up to Week 52 [0549] Time points for calculation of
clinical remission (DAS28<2.6, SDAI.ltoreq.3.3, CDAI.ltoreq.2.8,
TJC+SJC=0, TJC+SJC+normal ESR) at: [0550] Week 12 [0551] Individual
last observed value (mean treatment duration, 7 months) [0552]
Any-time during the entire treatment phase [0553] Two subsequent
time-points at least 6 weeks apart. [0554] The number of patients
with available values at different time-points was used to
calculate percentages [0555] Further subanalysis for DAS28<2.6
remission criteria by baseline categories: [0556] DAS28
(categories: .ltoreq.5.1, >5.1) [0557] Health assessment
questionnaire disability index (HAQ DI) (categories: <1.0,
1.0-<5, 1.5-<2.0, .gtoreq.2.0) [0558] Concomitant DMARD
therapy (yes, no)
[0559] Generally, adults with active RA despite therapy with
disease-modifying antirheumatic drugs (DMARDs) received adalimumab
(ADA) 40 mg sc every other week for 12 weeks in the ReAct trial,
with an optional extension phase until ADA was commercially
available. Efficacy and routine safety evaluations were conducted
at Weeks 2, 6, and 12, and every 8 weeks thereafter. Criteria for
remission were Disease Activity Score (DAS28)<2.6; tender and
swollen joint counts (TJC, SJC)=0, alone or in addition to a normal
ESR (ESR<20 (male) or <30 (female) mm/1.sup.st hour; ACR70
and SDAI (Simplified Disease Activity Index)<5 measured at Week
12, at last observation, and at any time during the treatment
period. Maintenance of remission was evaluated by two subsequent
time points with an interval of at least 6 weeks. For pts who
received ADA therapy for at least 52 weeks, the proportion who
fulfilled ACR70 for 6 months was calculated (MCR). Data were
stratified by baseline (BL) DAS28 and by concomitant DMARDs.
Results
[0560] Clinical study Results: [0561] 6,147 (93%) of 6,610 patients
remained in ReAct through Week 12 [0562] A great percentage of
patients (79%) remained in treatment up to a maximum of 96 weeks
[0563] Mean treatment duration was 7 months
TABLE-US-00119 [0563] TABLE 124 Baseline characteristics Total
patients enrolled in Study A 6,610 Age (years) 54 Female (%) 71
Rheumatoid factor + (%) 73 Disease duration (years) 11 # of prior
DMARDs 3 DAS28 6.0 HAQ DI 1.64 TJC28 14 SJC28 10 *Mean values of
continuous data.
[0564] Of 6,610 patients enrolled, 81% were female, 73% were RF+,
74% were receiving concomitant (concom) DMARDs; and 71% were
receiving steroids. Mean baseline characteristics included age, 54
yrs; disease duration, 11 yrs; DAS28, 6.0; and HAQ, 1.64 (Table
124). The mean exposure to ADA was 233 days, up to a maximum of 96
weeks. The number of participants decreased over time because of
regular termination or withdrawals. Based on available joint count
data, there were 6,235 pts at Week 12; 4,119 at Week 28, and 3,021
at Week 36. Of 1,251 pts at Week 52, 164 (13%) had sustained ACR70
without interruption for at least 6 months (MCR).
TABLE-US-00120 TABLE 125 Proportion (%) of Patients in Remission or
with Continuous Good Clinical Response (Observed Values) Week Last
Any 2 Consecutive All patients (6,610).sup..dagger. 12 Observation
Time Visits* DAS28 <2.6 20 25 38 21 TJV + SJC = 0 12 19 30 16
TJC + SJC = 0, 10 15 25 12 normal ESR ACR70 (%) 18 25 38 21 SDAI
<5 18 24 35 19 DAS28 <2.6 by BL subgroups (n.sup..dagger.)
DAS28 .ltoreq.5.1 (1,282.sup..dagger.) 40 44 63 40 DAS28 >5.1
(5,328.sup..dagger.) 15 21 32 16 No concom DMARDs 13 18 28 14
(1,731.sup..dagger.) .gtoreq.1 concom DMARDs 22 28 42 24
(4879.sup..dagger.) *At least 6 weeks apart .sup..dagger.Baseline n
only; denominators by time point are not shown.
[0565] As shown in Tables 125-127, the percentages of patients (%)
who achieved clinical remission increased beyond Week 12,
irrespective of the assessment method. Nearly one-third of the
patients achieved remission using various definitions during the
adalimumab treatment phase (Table 127). Greater percentages of
patients with low HAQ DI scores at baseline achieved and maintained
a DAS28<2.6 compared to patients who were more disabled at study
entry (Table 128). About half of the patients with a baseline HAQ
DI of 1.0-.ltoreq.1.5 experienced clinical remission during the
Study A study (Table 128). A greater percentage of patients with
lower DAS28 at baseline (DAS28 .ltoreq.5.1) achieved and maintained
remission status compared to patients who had high disease activity
(DAS28>5.1) at all time-points (Table 129). A greater percentage
of patients with concomitant DMARD(s) achieved and maintained
remission status compared to patients treated with adalimumab
monotherapy at all time-points (Table 130).
TABLE-US-00121 TABLE 126 Percentages of Patients Achieving Clinical
Remission at Week 12 and at Last Observed Time Point % of Patients
Week 12 LV DAS28 <2.6 20 25 SDAI .ltoreq.3.3 11 16 CDAI
.ltoreq.2.8 11 17 TJC + SJC = 0 12 19 TJC + SJC = 0; ESR normal 10
15 LV = last observed value
TABLE-US-00122 TABLE 127 Percentages of Patients Achieving Clinical
Remission During Adalimumab Treatment % of Patients Remission at
Continuous Remission .gtoreq.6 Any Time Weeks Apart DAS28 <2.6
38 21 SDAI .ltoreq.3.3 24 12 CDAI .ltoreq.2.8 27 14 TJC + SJC = 0
30 16 TJC + SJC = 0; ESR normal 25 12
TABLE-US-00123 TABLE 128 Percentages of Patients with DAS28 <2.6
During Adalimumab Treatment in Relation to Baseline HAQ DI % of
Patients HAQ HAQ HAQ HAQ DI <1.0 DI 1.0-<1.5 DI 1.5-<2.0
DI .gtoreq.2.0 (n = 1034) (n = 1275) (n = 1603) (n = 2,118) Week 12
33 26 17 12 Any time 58 47 37 25 Twice 37 27 19 11 subsequently
Anytime = remission measured any time during the treatment period.
Twice subsequently = maintenance of remission was evaluated by two
subsequent time points with an interval of at least 6 weeks.
TABLE-US-00124 TABLE 129 Percentages of Patients with DAS28 <2.6
During Adalimumab Treatment in Relation to DAS28 at Entry % of
Patients DAS28 .ltoreq.5.1 DAS28 .gtoreq.5.1 (n = 1266) (n = 5207)
Week 12 40 15 Any time 63 32 Twice 40 16 subsequently Anytime =
remission measured any time during the treatment period. Twice
subsequently = maintenance of remission was evaluated by two
subsequent time points with an interval of at least 6 weeks.
TABLE-US-00125 TABLE 130 Percentages of Patients with DAS28 <2.6
During Adalimumab Treatment in Relation to Concomitant DMARD Use %
of patients 0 Concomitant DMARD .gtoreq.1 Concomitant DMARD(s) (n =
1672) (n = 4801) Week 12 13 22 Any time 28 42 Twice 14 24
subsequently Anytime = remission measured any time during the
treatment period. Twice subsequently = maintenance of remission was
evaluated by two subsequent time points with an interval of at
least 6 weeks.
[0566] More than 1/3 of the patients achieved a DAS28<2.6 at any
time during therapy, and more than 1/5 had sustained remission
based on DAS28 or ACR70 in 2 consecutive to visits. Nearly 2/3 of
patients with a DAS28.ltoreq.55.1 at study entry experienced
clinical remission.
[0567] Of 1,251 patients treated with adalimumab for 52 weeks
during the Study A trial, 164 (13%) patients achieved a major
clinical response, which is an ACR70 response for .gtoreq.6
continuous months.
[0568] In conclusion, in a large cohort of patients with
long-standing, active RA in real-life clinical practice, adalimumab
provided clinical remission in a substantial percentage of
patients, irrespective of the assessment method. To similar
degrees, remission was observed across different definitions of
clinical remission and maintained up to Week 12 and at last
observed time point. The percentages of patients who experienced
clinical remission were greater with adalimumab/DMARD combination
therapy vs. adalimumab monotherapy. Less-disabled RA patients with
moderate disease activity had a better chance of achieving clinical
remission. Despite established and long standing RA, adalimumab
therapy led to clinical remission or continuous good clinical
response in a considerable proportion of patients even in a real
life setting.
Example 21
Adalimumab Clinical Trial Safety in Multiple Indications and
Reduction in Mortality in Rheumatoid Arthritis
[0569] The objective of this study was to evaluate the safety of
adalimumab (ADA) in global clinical trials for multiple
indications.
[0570] Safety data were routinely collected in all ADA clinical
trials for various diseases (Table 131). Rates of serious adverse
events (SAE) of interest to physicians prescribing anti-TNF therapy
were assessed per 100 patient-years (E/100PY). These rates were
compared to previously reported rates in ADA RA clinical
trials.
TABLE-US-00126 TABLE 131 Adalimumab Clinical Trials and Studies
Indication Clinical Trials Included RA Rheumatoid arthritis
clinical trials: All Phase I-III randomized controlled trials
(RCTs), open-label extensions (OLE), and OL Phase IIIb clinical
trials, except the early RA trial PsA Psoriatic arthritis clinical
trials: a 24-wk Phase III RCT in NSAID non-responders, a 12-wk
Phase III study in DMARD non-responders, an OLE for completers of
the 2 studies AS Ankylosing spondylitis clinical trials: 2 ongoing
Phase III multicenter studies in US, EU, and Canada, each composed
of a 24-wk RCT phase and an 80-wk OLE Ps Psoriasis clinical trials:
a 12-wk Phase II RCT and 48-wk OLE JIA Juvenile idiopathic
arthritis clinical trials: the 16-wk OL lead-in and 32-wk RCT
phases of a multicenter Phase III randomized, double-blind
stratified parallel-group study in children with polyarticular JIA
CD Crohn's disease clinical trials: 4 Phase II/III multicenter RCT
trials and an OLE
[0571] As of Apr. 15, 2005, the ADA RA clinical trial safety
database included data for 10,050 patients (12,506 PY) of ADA
exposure (Schiff M H, et al. Ann Rheum Dis 2006;
doi:10.1136/ard.2005.043166). Serious infection rate (5.05/100PY)
was comparable to that reported on Aug. 31, 2002 (4.9/100PY) and to
published reports of anti-TNF naive RA populations (Singh G, et al.
Arthritis Rheum 1999; 42(Suppl):S242 and Doran M F, et al.
Arthritis Rheum 2002; 46:2287-9). Table 132 summarizes the number
of patients, PY of exposure and rates of SAE of interest for
ADA-treated patients in multiple indications. In RA clinical
trials, the calculated standardized mortality ratio of 0.67 (95%
CI, 0.53-0.83) was much lower than previously reported for the RA
population prior to the advent of anti-TNF therapy (Gabriel S E, et
al. Arthritis Rheum 2003; 48(1):54-58 and Wolfe F, et al. Arthritis
Rheum 1994; 37(4):481-94),
TABLE-US-00127 TABLE 132 Serious Adverse Events of Interest
(E/100PY) Indication RA.sup.1 PsA AS Ps JIA CD Exposure 12,506 484
423 135 99 1506 (PY) Patients (N) 10,050 395 393 142 171 1459
Serious 5.05 2.07 1.18 0.74 4.04 5.98 Infections Tuberculosis 0.27
0.00 0.00 0.00 0.00 0.20 Lymphomas 0.12 0.41 0.24 0.00 0.00 0.07
Demy- 0.08 0.00 0.00 0.00 0.00 0.13 elinating Disease SLE/ 0.10
0.00 0.00 0.00 0.00 0.07 Lupus-like Syndrome CHF 0.28 0.00 0.00
0.00 0.00 0.00
[0572] In conclusion, adalimumab therapy showed consistent safety
profiles in global clinical trials for TNF-mediated diseases. SAE
rates of interest did not differ significantly across these
clinical trials in multiple indications. In RA clinical trials,
evidence suggests a decrease in mortality in adalimumab-treated
patients compared to a sex and age matched non-RA population.
Example 22
Screening Outcomes for Latent TB in Worldwide Adalimumab Clinical
Trials
[0573] TNF is important in granuloma formation and homeostasis
during Mycobacterium tuberculosis (TB) infection..sup.1
TNF-deficient animals produced by TNF gene knockout.sup.2 or by
administration of TNF antagonists.sup.3,4 cannot develop or
maintain granulomas, and mycobacterial infections result. TB cases
have been reported following treatment with each of the three TNF
antagonists..sup.5-8 Screening for TB infection is recommended for
patients who receive anti-TNF therapy.sup.9. Isoniazid (INH) is
used for treatment and prophylaxis of active TB.
[0574] The objective of the following study was to assess the
incidence of TB cases in adalimumab clinical trials and the
effectiveness of isoniazid (INH) and other prophylaxis in
preventing reactivation in high-risk patients, and to evaluate the
effect of screening on the incidence of TB in adalimumab clinical
trials and the effectiveness of INH in preventing reactivation of
latent TB in high-risk patients
[0575] Patients with RA, AS, CD, PsA, and Ps participated in many
Phase II, III, IIIb, and open-label extension adalimumab clinical
trials. Data were collected from these previous trials, and
reviewed for the incidence of TB and effectiveness of isoniazid
(INH) prophylaxis in preventing TB reactivation in high-risk
patients. TB rates for rheumatoid arthritis (RA), ankylosing
spondylitis (AS), Crohn's disease, psoriatic arthritis (PsA), and
psoriasis (Ps) were calculated for the periods before screening
(primarily Phase 1) and after screening. Screening included
clinical interviews, PPD tests (PPD+ defined by
local/country-specific guidelines), and chest X-rays (most
patients). Overall TB rates were calculated prior to implementation
of TB screening (pre-screening), and after implementation of TB
screening (post-screening). INH or other prophylaxis was given for
PPD+ and LTB-reactivation high-risk patients (investigator
identified).
[0576] TB screening methods varied by location and generally
followed local/country-specific guidelines at the discretion of
individual investigators. These included one or more of the
following: clinical interviews/patient histories; tuberculin skin
test with purified protein derivative (PPD); and chest X-ray.
[0577] Incidence of TB in the Research in one of the large,
open-label, Phase IIIb adalimumab trials for RA was evaluated
(Study A). Study A provided a unique perspective on the
effectiveness of TB screening, as the trial was one of the largest
clinical trials using a TNF antagonist and was designed to follow
real-life clinical practice. In Study A, patients with active RA
received adalimumab 40 mg subcutaneous every other week (eow) for
12 weeks. Patients could elect to enter an extension phase and
receive adalimumab until it was commercially available to them.
Upon enrollment, all patients were screened by various methods for
TB. Study A patients at high-risk for latent TB reactivation
(identified by investigators) were administered INH (5
mg/kg/d.times.9 months, max. 300 mg/d). A total of 6,610 patients
were enrolled in Europe and Australia, where the incidence of TB is
more prevalent than other countries. Differences in adalimumab
clinical trials before and after TB screening was implemented are
shown in Table 133.
TABLE-US-00128 TABLE 133 Characteristics of Adalimumab Clinical
Trials Pre- and Post-Implementation of TB Screening Pre-Screening*
Post-Screening* Phase I and early Phase II studies Phase II-IIIb
studies Dose finding studies; many patients Most received 40 mg eow
received >40 mg eow sc dosing Patients from Europe
Geographically diverse: patients From North America, Europe and
Australia *Pre-screening- prior to implementation of TB screening;
Post-screening-after implementation of TB screening
[0578] The number of patients and total years of exposure to
adalimumab were greater in Europe and Australia than North America.
Adalimumab exposure in clinical trials by region included the
following (Table 134):
TABLE-US-00129 TABLE 134 Patients n (%) Exposure PYs (%)* North
America 5,501 (39%) 8,397 (48%) Europe and Australia 8,451 (61%)
9,161 (52%)
[0579] Across all indications from worldwide adalimumab clinical
trials, implementation of screening procedures resulted in an
approximately 82% reduction in the incidence of TB cases. The
impact of screening on TB rates (based on 17,870 PYs from worldwide
adalimumab clinical trials) saw an 82% decrease in the number of
1.5 events per 100-PY. Pre-screening showed 8 cases in 534
exposures (PYS), resulting in 1.5 events per 100-PY (events per
100-PY included cases for which screening was not performed because
of enrollment in early Phase I/II clinical trials before
implementation of TB screening). Post-screening identified 46 cases
in 17,336 exposures (PYs), resulting in 0.27 events per 100-PY.
[0580] Differences in TB rates between North American and
Europe/Australia after screening was implemented: there were 0.04
events per 100-PY in North America (6 cases in 8,397 exposures
(PYs), while there were 0.32 events per 100-PY in Europe and North
America (29 cases in 9,161 exposures (PYs). This data was based on
17,558 exposure PYs in North America, Europe, and Australia
(excluding PYs from patients in Asia). For the TB cases that
occurred after screening procedures were implemented, the incidence
was approximately 8-fold higher in Europe and Australia compared
with North America.
[0581] Of the 54 total TB cases observed in adalimumab clinical
trials examined in the study, 30 (56%) were culture positive and 33
(61%) were extrapulmonary disease cases. All cases resolved, as
described below in Table 135.
TABLE-US-00130 TABLE 135 Summary of Cases Observed Total cases 54
Culture positive 30 (56%) Mean age 59 years Extrapulmonary 33 (61%)
Median days from treatment to diagnosis (range) 232 days (29-1,636)
Outcome resolved 54* Data through November 2005. Based on 17,558
PYs from adalimumab clinical trials in North America, Europe, and
Australia. *Three patients died; two of unrelated causes and the
third refused treatment for TB.
Study A was an open-label adalimumab trial with 6,610 RA patients,
and provided insight into the effective management for reactivation
of latent TB in patients receiving anti-TNF therapy. At enrollment,
all patients were screened for latent TB using various methods.
Screening identified high-risk patients for which INH prophylaxis
was required. 16.4% of ReAct patients had positive PPD skin tests
(.gtoreq.5 mm), whereas only 3% exhibited abnormal chest X-rays.
Results of TB screening in Study A (based on 6,610 patients from
Europe and Australia) included the following: PPD (.gtoreq.10 mm),
11.6% positive and 88.4% negative; PPD (.gtoreq.5 mm), 16.4%
positive and 83.6% negative; and chest x-ray, 3% abnormal and 97%
normal.
[0582] Only 5 out of 835 (0.60%) RA patients from Study A who
received INH prophylaxis developed TB* (Table 136) (*The number of
patients who developed TB is lower than a previously reported study
(Ferebee S H. Bibl Tuberc 1970; 26:28-106). Reasons for INH
prophylaxis are also presented in Table 136. The range of time
between initiation of INH prophylaxis and adalimumab treatment
varied greatly from 0 days to >43 days (Table 136).
TABLE-US-00131 TABLE 136 INH Prophylaxis in ReAct Time Between
Initiation of INH 835 RA Patients Received INH and Adalimumab PPD
positive: 621 (74.4%) 0-14 days 4.5% With chest X-ray indicative of
15-28 days 22.3% past TB: 121 (14.5%) With both abnormal: 76 (9.1%)
29-42 days 50.2% Other reasons: 17 (2.0%) >43 days 23.0% Based
on 6,610 patients from Europe and Australia. Compliance was not
measured.
[0583] Three cases of TB were reported in CD patients. No cases of
TB were reported among adalimumab-treated patients with AS, PsA, or
Ps.
[0584] To summarize the results, 14,563 patients (17,870
patient-years [PYs] of exposure) were treated with adalimumab in
clinical trials (8,397 PYs [NA] and 9,161 PYs [Europe]). Before
screening, there were 8 TB cases in 534 PYs (0.015/PY). None of
these patients received prophylaxis. After screening there were 46
TB cases in 17,336 PYs (0.0027/PY). Six were in NA (0.00047/PY),
and 29 were in Europe (0.0032/PY). No patients who received
adalimumab for Ps, PsA, or AS developed TB at this cutoff. Median
time to TB development (in days) was 232 (range: 29-1,636). There
were 30/54 (56%) culture-confirmed cases, and 33/54 (61%)
extrapulmonary disease cases. The ratio of TB prior to screening to
after screening represents an 82% reduction in TB development rate.
In a subanalysis of 6,610 European patients screened uniformly, 12%
and 16% were classified as PPD+ by .gtoreq.10-mm and 5-mm
induration cutoffs. A total of 835 high-risk patients were
identified (most were PPD+) and received INH prior to the study
drug. Five patients (1%) developed TB despite INH prophylaxis.
[0585] In conclusion, TB screening resulted in substantial
reduction in a LTB reactivation rate. TB rates were approximately
seven-fold lower in NA than in Europe. Patients identified as
high-risk for TB, and given prophylaxis prior to adalimumab
treatment, rarely had LTB reactivation. Prior to initiation of any
TNF antagonist, all patients should be screened for LTB. Incidence
of TB reactivation decreased by approximately 82% in adalimumab
clinical trials when TB screening was implemented. PPD status was
positive in 16.4% of the ReAct patient population, whereas chest
X-rays were abnormal in only 3% of patients. No cases of TB were
reported in patients with AS, PsA, or Ps. INH prophylaxis was
effective in preventing reactivation of latent TB in 99.4% of ReAct
patients who received anti-TNF therapy. [0586] 1. Flynn J L, et al.
Annu Rev Immunol 2001; 19:93-129. [0587] 2. Smith S, et al. Infect
Immun 2002; 70:2082-2089. [0588] 3. Flynn J L, et al. Immunity
1995; 2:561-572. [0589] 4. Garcia I, et al. Eur J Immtmol 1997;
27:3182-3190. [0590] 5. Keane, et al. New Engl J Med 2001;
345:1098-1104. [0591] 6. Mohan, et al. Clin Infect Dis 2004;
39:295-299. [0592] 7. Gomez-Reino, et al. Arthritis Rheum 2003;
48:2122-2127. [0593] 8. Schiff et al. Ann Rheum Dis 2006;
65(7):889-894. [0594] 9. Furst D E, et al. Ann Rheum Dis 2005;
64:iv2-iv14.
Example 23
Efficacy of Adalimumab (Humira.RTM.) in Clinical Practice: Patients
with Moderate Disease Activity were Compared to Those with Severe
Disease Activity
[0595] The objective of this study was to compare the efficacy of
adalimumab in patients with moderate and severe disease
activity.
[0596] The following study was an open-label, multi-center, Phase
IIIb study. Patients with moderate to severe rheumatoid arthritis
who had an inadequate response to standard antirheumatic therapy
were treated with adalimumab 40 mg every other week in addition to
their pre-existing therapies. Patients with moderately to severely
active RA who had an inadequate response to standard therapy,
including methotrexate (MTX), were enrolled in this study. Patients
were treated for 12 weeks with subcutaneous adalimumab 40 mg every
other week (eow) in addition to their pre-existing but inadequate
therapies. Inclusion criteria included: .gtoreq.18 years old; RA
defined by ACR criteria for >3 months; active RA (>5 swollen
joints and one of: RF+, 1 or more joint erosions, HAQ score >1);
unsatisfactory response or intolerance to therapy as per provincial
guidelines required for biologic therapy; and concomitant
prednisone had to be <10 mg/day.
[0597] Effectiveness assessments included Disease Activity Score 28
(DAS28), ACR20/50/70 (including 0-28 SIC and TJC scores), and the
Health Assessment Questionnaire (HAQ). Efficacy was assessed at
baseline, 12 weeks, and 24 weeks of the study. Results for patients
with moderate RA vs. patients with severe RA as defined by baseline
DAS28 scores (moderate RA=3.2<DAS28.ltoreq.5.1) and severe
RA=DAS28>5.1) were compared.
[0598] A total of 879 patients enrolled in the study. Totals of 772
and 238 patients were followed for 12 and 24 weeks, respectively.
The study design included 879 patients during the open label
treatment period, which was 12 weeks. During the open label period,
patients received 40 mg of adalimumab every other week (eow),
subcutaneously. The 12-week continuation period of the study
included 772 patients, and occurred following the 12 week open
label treatment period.
[0599] Baseline characteristics were: mean age=54.4 years; %
female=78.7; mean RA duration=12.5 years; % with moderate
(3.2<DAS28.ltoreq.5.1) and severe (DAS28 >5.1) disease
activity=8 and 80, respectively; mean DAS28 scores for patients
with moderate and severe disease activity=4.5.+-.0.5 and
6.6.+-.0.8, respectively; mean HAQ score for patients with moderate
and severe disease activity=1.2.+-.0.6 and 1.7.+-.0.6,
respectively. The baseline characteristics of the subgroup of
patients who completed Week 24 were comparable to those of the
overall study population. Baseline demographics are provided in
Table 137 and 138:
TABLE-US-00132 TABLE 137 Baseline Demographics and Disease Severity
Moderate Moderate Severe and Severe Characteristics* n = 162 n =
700 N = 862 Age (years) 52.8 .+-. 11.8 54.8 .+-. 11.4 54.4 .+-.
11.5 Female (%) 123 (75.9) 556 (79.4) 679 (78.8) Disease duration
(years) 12.9 .+-. 9.8 12.2 .+-. 9.5 12.3 .+-. 9.6 CRP
(mg/L).dagger-dbl. 8.5 .+-. 12.1 24.6 .+-. 32.0 21.6 .+-. 30.0 ESR
(mm/hr).sctn. 12.5 .+-. 10.5 35.0 .+-. 24.0 30.7 .+-. 23.8 HAQ
(0-3) 1.2 .+-. 0.6 1.7 .+-. 0.6 1.6 .+-. 0.6 DAS28 4.5 .+-. 0.5 6.6
.+-. 0.8 6.2 .+-. 1.1 SJC (0-28) 10.5 .+-. 4.0 13.9 .+-. 5.3 13.3
.+-. 5.2 TJC (0-28) 8.0 .+-. 5.5 16.7 .+-. 6.2 15.1 .+-. 7.0 RF
>20 IU/ml, n (%) 110 (67.9) 544 (77.7) 654 (75.9) *Mean values
.+-. SD, except percentages. .sctn.Normal values for men and women
are <20 mm/hr and <30 mm/hr, respectively. .dagger-dbl.Normal
values is <10 mg/L.
TABLE-US-00133 TABLE 138 Baseline Demographics: Prior Antirheumatic
Therapies Moderate Severe Characteristics* n = 162 n = 700 P-value
% Failed 0 DMARD 0.6 2.4 0.222 % Failed 1 DMARDs 3.1 6.1 0.181 %
Failed 2 DMARDs 3.7 6.9 0.153 % Failed >3 DMARDs 92.6 84.6 0.008
% Failed prior BDMARD 19.8 29.3 0.015 % Failed prior TNF inhibitor
13.6 24.9 0.041 % Failed infliximab 6.2 8.9 >0.999 % Failed
etanercept 7.4 16.7 0.055
[0600] Both groups achieved statistically significant improvement
in DAS28 scores at 12 weeks. Patients with severe disease activity
demonstrated even greater decreases in DAS28 scores. DAS28 results
are described below in Table 139.
TABLE-US-00134 TABLE 139 Course of DAS28 Scores for Patients with
Moderate vs. Severe Disease Activity at Baseline Time course
Baseline Week 4 Week 8 Week 12 Moderate disease activity 6.6 5.1
4.7 4.5.dagger-dbl. Mean score Severe disease activity 4.5 3.5 3.3
3.1.dagger-dbl..sctn. Mean score .dagger-dbl.p < 0.001 for
within-group comparison (follow-up visit vs. baseline). .sctn.p
< 0.005 for change between groups from Week 12 to baseline.
[0601] At 12 weeks, significantly more patients with moderate
disease activity at baseline achieved clinical remission
(DAS28<2.6) and other scores indicating remission and low
disease activity (described in more detail below). Patients with
severe disease activity demonstrated greater reductions in DAS28
scores than patients with moderate disease.
[0602] At Week 12, more patients with severe disease activity at
baseline achieved an ACR20. At Week 12, ACR50 and ACR70 response
rates were comparable between groups.
[0603] Both groups achieved statistically significant improvement
in HAQ scores at 12 weeks. Patients with severe disease activity
demonstrated greater reductions in DAS28 scores than patients with
moderate disease. At 12 weeks, significantly more patients with
moderate disease activity at baseline achieved HAQ scores
indicating no physical limitations and other predefined target
scores of the HAQ. HAQ score results are also presented below in
Tables 140 and 141.
TABLE-US-00135 TABLE 140 Course of Mean HAQ Scores for Patients
with Moderate vs. Severe Disease Activity at Baseline Time course
Baseline Week 4 Week 8 Week 12 Mean Moderate disease 1.7.sctn. 1.3
1.2 1.1.dagger-dbl..sctn. HAQ activity score Severe disease 1.2 0.9
0.9 0.8.dagger-dbl. activity .dagger-dbl.p < 0.001 for
within-group comparison (Week 12 vs. baseline). .sctn.p < 0.005
for between-group comparison (Week 12 vs. baseline).
TABLE-US-00136 TABLE 141 Percentages of Patients with Moderate vs.
Severe Disease Activity by Categories of HAQ Score HAQ <1.0 HAQ
<0.5 HAQ = 0 % Moderate disease 60.0* 40** 18.6*** patients
activity Severe disease 43.6 22.3 10.6 activity *p < 0.005, **p
< 0.005, ***p < 0.014 for between-group comparisons.
[0604] Overall, the results show that patients that had a moderate
or a severe disease activity at baseline showed improvements of
1.5.+-.1.1 and 2.1.+-.1.4 in the DAS28 at 12 weeks (p<0.001 each
group vs. baseline), respectively. Improvements in the HAQ scores
for the same groups at 12 weeks were 0.4.+-.0.4 and 0.5.+-.0.6
(p<0.001 each groups vs. baseline). Significantly more patients
that had a moderate than a severe disease activity at baseline
achieved low disease activity and clinical remission at week 12,
DAS28<3.2=55.4% vs. 19.5% p<0.001 and DAS28<2.6=31.7% vs.
11.0% p<0.001, respectively. In addition, DAS28<2.4=23.7% for
moderate disease activity and 7.6% for severe disease activity
(p<0.005). As well, significantly more patients with moderate
than with severe disease activity at baseline achieved a
HAQ<1.0, (60.0% vs. 43.6% p=0.001). Importantly, those effects
were observed despite comparable improvements between the groups.
Indeed, 51.0%, 25.2% and 12.6% of the patients that had a moderate
disease activity at baseline achieved ACR20/50/70 responses at week
12. 61.1%, 32.4% and 13.0% of the patients that had a severe
disease activity at baseline achieved ACR20/50/70 responses.
Between groups analyses showed a differences in ACR20 response
rates (p=0.03).
[0605] In conclusion, significantly more patients with moderate
than with severe disease activity at baseline achieved clinical
remission, as defined by DAS28<2.6, and HAQ<0.1. During the
first 12 weeks, patients with severe disease activity at baseline
experienced greater reductions in the signs and symptoms of the
disease. More patients with moderate disease activity at baseline
achieved clinical remission (DAS28<2.6) and a level of no
functional limitations (HAQ=0). The treatment effects of adalimumab
were comparable between both sub-groups of patients. These
observations support the utility of adalimumab therapy in RA
patients early in the disease course. Adalimumab therapy led to
good outcomes in both subgroups, with patients with moderate RA
achieving even better results. Adalimumab should be used in both
patient populations. Its use in patients with moderate disease,
before they reach more severe disease states, may increase the
likelihood of achieving clinical remission.
Example 24
Real Life Evaluation of Rheumatoid Arthritis in Patients Taking
HUMIRA: Analysis at 6 Months of Adalimumab Therapy
[0606] The following study addresses the long-term effectiveness of
adalimumab in the clinical care setting. Thus, the objective of the
study was to describe the clinical effectiveness, functional status
and disease activity of rheumatoid arthritis patients receiving
adalimumab therapy (HUMIRA.TM.) over a two year period.
[0607] The study was a multi-center, open-label observational study
of adalimumab used in routine practice. A total of 1000 patients
will be enrolled from approximately 150 sites.
[0608] Eligible participants are .gtoreq.18 years of age, either
naive to adalimumab therapy are receiving adalimumab therapy for
less than 4 months and have moderate to severe active disease.
Physicians collected baseline demographics and medical history
including previous and concomitant anti-rheumatic medication and
comorbidities. Physicians also completed a DAS28 while patients
completed a HAQ-DI, RADAI and global assessment at every 6 months.
Eligibility criteria included: [0609] .gtoreq.18 years of age
[0610] Moderately to severely active RA [0611] Naive to adalimumab
therapy OR receiving adalimumab therapy .ltoreq.4 months [0612]
Inadequate response to one or more DMARDs [0613] Written and
informed consent Preliminary analysis included 127 patients who
received adalimumab therapy for .gtoreq.6 months. Data collected by
the patients and physician included the following: Physician:
comorbidities; previous antirheumatic therapies; concomitant
antirhemautic therapies; previous DAS28 or HAQ; and DAS28 score.
Patient: HAQ; RADAI; and global.
[0614] This initial analysis reports on the 127 patients who had
received .gtoreq.6 months of adalimumab therapy at the time of the
analysis. 78.4% were female and 89.8% were Caucasian, with a mean
age of 57.0 and a mean disease duration of 10.5 years. Baseline
disease measures were DAS28-5.41, HAQ=1.54, and RADAI=5.33.
Baseline demographics are shown in Table 142.
TABLE-US-00137 TABLE 142 Baseline Patient Demographics and Clinical
Characteristics (N = 127) Age (mean .+-. SD) 57.0 .+-. 12.1 Disease
duration (mean .+-. SD) 10.5 .+-. 10.0 Characteristics N (%) Female
100 (78.7) Caucasian 114 (89.8) Disease Status Mean .+-. SD DAS28
5.41 .+-. 1.41 HAQ pain (0-3) 1.74 .+-. 0.75 HAQ DI (0-3) 1.54 .+-.
0.71 RADAI (0-10) 5.33 .+-. 1.84 Patient Global 3.20 .+-. 0.82
Previous biologics 0.50 .+-. 0.77 Previous DMARDS 3.28 .+-. 1.19
Current antirheumatic therapies 2.09 .+-. 1.11
[0615] The results show that mean decrease (improvement) from
baseline to 6 months in DAS28 was 1.35 (p<0.001, n=101), with
66% of patients reaching a EULAR response of good or moderate, 16%
achieving low disease activity (2.6.ltoreq.DAS28.ltoreq.3.2), and
18% reaching clinical remission (DAS28<2.6). HAQ improved by
0.36 (p<0.001, n=124). A minimum clinically important
improvement of at least 0.22 in the HAQ was observed for 55% of
patients (n=124). Mean HAQ DI and HAQ pain scores are shown in
Table 143.
TABLE-US-00138 TABLE 143 Mean HAQ DI and HAQ Pain Scores at
Baseline and 6 Months of Adalimumab Therapy HAQ DI (0-3) HAQ Pain
(0-3) Baseline 1.54 1.74 6 Months 1.18* 1.29* *p < 0.001
DAS improvements are shown in Tables 144 and 145.
TABLE-US-00139 TABLE 144 Mean DAS28 scores, TJC, and SJC at
Baseline and 6 Months of Adalimumab Therapy DAS score Total Joint
Count Swollen Joint Count (0-9.4) (0-28) (0-28) Baseline 5.41 11.01
9.33 6 Months 4.06* 6.27* 4.28* *p < 0.001
TABLE-US-00140 TABLE 145 Mean DAS28 scores and Changes in DAS28
Scores by Disease Activity at Baseline and 6 Months of Adalimumab
Therapy Disease activity Low DAS28 Moderate DAS28 High DAS28
(<3.2) (>3.2 and <5.1) (>5.1) Baseline 2.49 4.48 6.26 6
Month 2.2 3.5** 4.67** .DELTA. Change -0.29 -0.99* -1.6* *p <
0.001, **p < 0.05
[0616] The RADAI score decreased (improved) by 1.43 (p<0.0001,
n=125), and the patient global decreased (improved) by 0.55
(p<0.0001, n=125). The improvement in the mean RADAI score is
shown below in Table 146. Correlation of RADAI and DAS28 scores
after 6 months of adalimumab therapy (n=100) is shown in FIG.
30.
TABLE-US-00141 TABLE 146 Mean RADAI, Total Joint Count, Total Joint
Score, and Stiffness Score at Baseline and 6 Months of Adalimumab
Therapy RADAI Total Joint Total Joint Stiffness score (0-10) Count
(0-16) Score (0-3) (0-6) Baseline 5.33 9.64 1.71 2.43 6 Months 3.9*
7.87* 1.46* 1.96** p < 0.001, **p < 0.05
Improvements in global scores over 6 months are shown in Table
147.
TABLE-US-00142 TABLE 147 Percentages of Patients with Various
Global Scale Scores at Baseline and 6 Months of Adalimumab Therapy
Very poor Poor Fair Good Very good % pts baseline 5% 27% 56% 9% 4%
% pts 6 Months 5% 9% 42% 35% 10%
[0617] Moreover, 54% of patients indicated that their symptoms had
improved. In addition, 35% of patients had previous experience with
an RA biologic (TNF antagonist, to 95%; IL-1 receptor antagonist,
20%; both, 14%), and 94% had received .gtoreq.2 DMARDs before
initiating adalimumab (mean=3.28). The most common previous DMARDs
were methotrexate (48%), leflunomide (40%), and hydroxychloroquine
(24%). Currently, 67% of patients are receiving .gtoreq.2 or more
DMARDs concomitantly, with methotrexate and prednisone accounting
for 70% and 33%, respectively. Correlation between EULAR responses
and DAS28 scores are shown below in Table 148. Biologic and DMARD
use prior to and during adalimumab therapy is shown in Tables
149-151.
TABLE-US-00143 TABLE 148 Patients with Good, Moderate, or No EULAR
Response of DAS28 Following 6 Months of Adalimumab Therapy
Improvement in DAS28 from Baseline N = 101 >1.2 >0.6 and
<1.2 <0.6 .ltoreq.3.2 26% good 38% moderate 37% none >3.2
and .ltoreq.5.1 38% moderate 38% moderate 37% none >5.1 38%
moderate 37% none 37% none
TABLE-US-00144 TABLE 149 Biologic Use Prior to Adalimumab Therapy
Previous Biologic Use (N = 127) N (%) No Previous Biologic Use 83
(65.4) Previous Biologic Use 44 (34.6) TNF Antagonist 42 (95.5)
IL-1 Receptor Antagonist 9 (20.5) Both 6 (13.6)
TABLE-US-00145 TABLE 150 DMARD Use Prior to Adalimumab Therapy
Previous DMARD Use N (%) Methotrexate 43 (47.8) Leflunomide 36
(40.0) Hydroxychloroquine 22 (24.4) Plaquenil 18 (20.0)
Sulfasalazine 17 (18.9) Prednisone 13 (14.4)
TABLE-US-00146 TABLE 151 Concomitant DMARD Use During Adalimumab
Therapy Current DMARD Use N (%) Methotrexate 85 (69.7) Prednisone
40 (32.8) Plaquenil 29 (23.8) Leflunomide 22 (18.0) Celebrex 15
(12.3) Sulfasalazine 12 (9.8)
[0618] In conclusion, the patients in the above study are
representative of a moderate to severe RA population. At baseline,
they had moderate to severe disease activity (DAS28), and
established, long-standing disease. The majority had previously
received .gtoreq.2 DMARDs, and even a previous RA biologic before
initiating adalimumab. After 6 months of adalimumab therapy, most
patients had achieved clinically important improvements in disease
activity and physical function. 66% of patients obtained a EULAR
response of good or moderate, with 18% achieving clinical remission
(DAS28<2.6) and 16% reaching a low disease activity
(2.6.ltoreq.DAS28.gtoreq.3.2). After 6 months of treatment, most
patients had achieved clinically important improvements in both
disease activity and physical function.
Example 25
Improvement and Long-Term Maintenance of Quality of Life During
Treatment with Adalimumab in Severe Rheumatoid Arthritis
[0619] Measurement of patient reported outcomes (PRO) are relevant
to an overall health care quality assessment (FDA et al, 2006).
Although improvements in clinical parameters with novel biologic
therapies have been established in RA, the impact of biologics on
certain PROs in this disease requires further research. There are
data to support the impact of biologics on HAQ and the SF-36;
however, little or no information on other aspects of HRQL, such as
special facets of quality of life (e.g., fatigue) or health-related
utility, are available. Evaluation of fatigue in RA patients is
especially important because clinically significant oppressive
fatigue is present in 40% to 80% of RA patients and research
supports an association between disability and fatigue (Rupp et al
2004). Also, from the perspective of the patient, a reduction of
fatigue constitutes an important component of disease remission. It
is not surprising that the Outcome Measures in Rheumatoid Arthritis
Clinical Trials (OMERACT) group devoted discussion during a recent
patient-perspective workshop to the relative impact of fatigue on
patients.
[0620] In the current study, a number of PRO were applied measures
simultaneously in a 3-year single-study setting. The aim is to
analyze these results from patients with long-standing severe RA,
focusing on measurement of fatigue and health utility.
[0621] This long-term, open-label health outcomes extension study
(Study 8) included 505 patients with long-standing RA who had
received adalimumab therapy during one of six Phase II/III studies,
of which most were double-blind, randomized, placebo-controlled
studies of at least 26 weeks in duration (FIG. 31). Patients
received adalimumab 40 mg every other week and were followed for up
to 144 weeks. The study was performed at 47 investigational sites
in three countries, and conducted in conjunction with another
clinical study, which was a multicenter, open-label study
evaluating the clinical effectiveness of adalimumab in patients
with RA.
[0622] The following example provides the largest of the preceding
randomized dose-finding studies, and was a pivotal 6-month, Phase
III, placebo-controlled study. Because data in the below study were
collected in a manner similar to this study, data from patients in
the placebo and adalimumab treatment arms were analyzed as a
subgroup in this study. The subgroups described below refer to the
current study, unless otherwise indicated.
[0623] Sociodemographic and medical history data were assessed at
the baseline visit. Clinical examination findings (e.g., joint
examination, morning stiffness), disease assessments (patients' and
physicians' global assessment of disease activity and patients'
assessment of pain), and HRQL data were recorded every 8 weeks.
[0624] Patients with RA, as defined by the 1987-revised American
College of Rheumatology (ACR) criteria (Arnett et al 1988), were
included in the study. Exclusion criteria included the following:
1) pregnant or breastfeeding females; 2) known human
immunodeficiency virus (HIV)-positive status; 3) a history of
alcohol or drug abuse within 6 months prior to study entry; 4)
ongoing or active clinically relevant infection or any major
episode of infection requiring hospitalization or treatment with
intravenous antibiotics (within 30 days) or oral antibiotics
(within 15 days); and 5) underlying cardiac, pulmonary, metabolic,
renal, or gastrointestinal conditions; chronic or latent infectious
diseases; immune deficiency; or abnormal laboratory values that, in
the opinion of the investigator or the medical monitor, placed the
patient at an unacceptable risk.
[0625] The SF-36 is the most widely used generic measure of HRQL.
It covers eight areas of health status, including physical
functioning, role-physical, bodily pain, general health, vitality,
social functioning, role-emotional, and mental health. The SF-36
scores range between 0 (worst) and 100 (best). In addition,
physical component summary (PCS) and mental component summary (MCS)
scores can be derived. In RA, minimum clinically important
differences (MCIDs) were defined as a 5- to 10-point change from
baseline for the SF-36 subdomains and a 2.5- to 5-point change from
baseline for the PCS and MCS (Kosinski et al, 2000).
[0626] Studies showed that patients regard oppressive fatigue as a
major determinant of their overall HRQL (Kirwan et al 2005). The
FACIT-Fatigue was used to assess fatigue in patients enrolled in
this study. The FACIT-Fatigue scale includes 13 specific items
linked with fatigue: fatigue, weakness, listlessness, tiredness,
trouble with starting things, trouble with finishing things,
energy, activity, sleep, eating, help doing activities,
frustration, and social activities. FACIT-Fatigue scores range from
0 to 52, with higher scores representing less fatigue. The
instrument has been validated for the general population and for
patients with RA. The MCID for FACIT-Fatigue in RA was determined
to be at least a 4-point change from baseline (Celia et al,
2005).
[0627] The health-related utility of patients suffering from RA was
evaluated using the HUI3. The first component of the HUI3 is a
multi-attribute health status classification system that is used to
describe the health status of the patient (e.g., emotion or pain).
The second component is a multi-attribute utility function that is
used to value the health status as measured within the
corresponding multi-attribute health status classification system.
These scores can be directly converted into quality-adjusted life
years (QALYs). Health utility scores range from 0 to 1, with 1
denoting perfect health and 0 denoting death. The construction of
the scale is one of preference or desirability. The more preferable
or desirable a health state, the higher its utility. In addition,
negative scores are possible and represent health states considered
worse than death. Score changes of 0.03 are considered clinically
important (Horsman et al, 2003).
[0628] All patients enrolled in the study were included in the full
analysis set. For dichotomous and categorical variables, absolute
and relative frequencies were calculated. Metric parameters are
described by mean, standard deviation, and/or standard error of the
mean. HRQL data are presented as observed cases. A
last-observation-carried-forward approach was used in some analyses
for the subgroup of patients from study DE026 who participated in
the placebo-controlled study with 40 mg adalimumab every other week
for 26 weeks (n=99). All statistical analyses were performed using
SAS.RTM. Version 8.2 (SAS Institute Inc., Cary, N.C., USA).
Patients
[0629] A total of 505 patients were enrolled in the study, with the
greatest percentage of patients enrolled in Germany (n=153).
Patients were recruited from several preceding dose-finding
studies; the majority of patients originated from (FIG. 31).
[0630] On average, patients participated in the health outcomes
study for 1.6 years (mean: 1.57.+-.0.63 years, median: 1.8 years).
Baseline patient characteristics are provided for two patient
populations (Table 152): the current subgroup and the overall Study
8 population. Baseline data for the subgroup (n=99) capture data
from patients who were naive to biologic treatment and who received
the same adalimumab dosage regimen (adalimumab 40 mg every other
week) as the overall population for 26 weeks. Data from the cohort
are included in the entire study population (N=505). There were no
statistically significant differences between placebo and
adalimumab groups at baseline from the study for all measures.
TABLE-US-00147 TABLE 152 Baseline demographic data from subgroup
and overall Study 8 population Subgroup receiving 40 mg adalimumab
for Overall Study 26 weeks prior to 8 population Variable DE033 (n
= 99) (N = 505) Female n (%) 79 (79.8) 390 (77.2) Age (y) Median 54
(19-80) 55.sup.a (22-82) (range) Weight (kg) Mean .+-. SD 69.7 .+-.
13.92 69.12 .+-. 12.90 Height (cm) Mean .+-. SD 165.9 .+-. 8.47
166.06 .+-. 8.90 Caucasian n (%) 95 (96.0) 498 (98.6) BMI
(kg/m.sup.2) Mean .+-. SD 25.4 .+-. 4.96 25.06.sup.b .+-. 4.34
.sup. Employed.sup.c n (%) NA 152 (30.1) Retired n (%) NA 220
(43.6) RA Mean .+-. SD 10.3 .+-. 7.05 12.36 .+-. 7.69 duration
Number of Mean .+-. SD 3.8 .+-. 1.77 3.7 .+-. 1.82 previous DMARDS
failed TJC (0-68).sup.d Mean .+-. SD 33.81 .+-. 15.97 14.58 .+-.
14.89 SJC (0-66).sup.d Mean .+-. SD 21.02 .+-. 10.97 8.23 .+-. 8.18
DAS28 Mean .+-. SD 5.39 .+-. 1.62 4.58 .+-. 1.58 .sup.aEight
patients missing. .sup.bTwo patients missing. .sup.cIncluding
self-employed. .sup.dBaseline data for both cohorts differ, because
patients in the overall population had already been treated with
adalimumab. BMI = body mass index. DAS28 = Disease Activity Score
28; DMARDs = disease-modifying antirheumatic drugs; RA = rheumatoid
arthritis; SJC = swollen joint count; TJC = total joint count.
[0631] Overall, most of the patients in the entire study group had
long-standing severe to RA, with a mean duration of 12.4 years and
an average of up to four failed previous disease-modifying
antirheumatic drugs. Approximately three quarters of patients were
female, confirming a similar gender distribution of RA patients
among industrialized countries.
[0632] Among the subgroup, there were no significant differences in
baseline SF-36 scores between the placebo and adalimumab treatment
groups. At Week 26, patients receiving adalimumab achieved
significant improvement in all SF-36 subdomains; changes were
statistically significant compared with placebo and compared with
baseline (Table 153). Increases in all SF-36 subdomains in the
subgroup were maintained over 3 years (Table 154). Table 155
provides a comparison of the baseline SF-36 scores for patients in
the study (reflecting scores prior to adalimumab treatment),
baseline SF-36 score of the entire study population, and SF-36
scores after 144 weeks of adalimumab treatment. SF-36 scores from
the subgroup (Table 154) were consistent with SF-36 scores from the
entire study population (Table 155). All increases in the SF-36
subdomains of the SF-36 were clinically relevant.
TABLE-US-00148 TABLE 153 Short Form 36 (SF-36) health profile
scores at baseline and after 26 weeks of treatment with adalimumab
or placebo in the subgroup (n = 99) PatientType SF-36 Domain Scores
Physical Placebo (Baseline) 28 Functioning Placebo (week 26) 30
Adalimumab 40 mg eow (Baseline) 26 Adalimumab (week 26) 39 Bodily
Pain Placebo (Baseline) 26 Placebo (week 26) 33 Adalimumab 40 mg
eow (Baseline) 24 Adalimumab (week 26) 43 Role - Placebo (Baseline)
15 Physical Placebo (week 26) 23 Adalimumab 40 mg eow (Baseline) 11
Adalimumab (week 26) 34 Role - Placebo (Baseline) 45 Emotional
Placebo (week 26) 45 Adalimumab 40 mg eow (Baseline) 40 Adalimumab
(week 26) 57 General Placebo (Baseline) 40 Health Placebo (week 26)
41 Adalimumab 40 mg eow (Baseline) 41 Adalimumab (week 26) 49
Mental Placebo (Baseline) 58 Health Placebo (week 26) 60 Adalimumab
40 mg eow (Baseline) 57 Adalimumab (week 26) 66 Vitality Placebo
(Baseline) 33 Placebo (week 26) 36 Adalimumab 40 mg eow (Baseline)
32 Adalimumab (week 26) 47 Social Placebo (Baseline) 53 Functioning
Placebo (week 26) 56 Adalimumab 40 mg eow (Baseline) 48 Adalimumab
(week 26) 61 Adalimumab P < 0.01 vs. baseline and vs. placebo
for all subdomains except role-physical, which was P < 0.05. The
placebo-treated patients did not achieve statistical significance
vs. baseline. Last observation carried forward. eow = every other
week. *United States population norms from Ware et al. 1997.
TABLE-US-00149 TABLE 154 Short Form 36 (SF-36) health profile
scores in the subgroup over 3 years (n = 99) Weeks SF-36 Domain
Scores Physicial 0 25 Functioning 26 35 50 35 98 35 170 35 Bodily 0
24 Pain 26 45 50 40 98 40 170 40 Role - 0 11 Physical 26 35 50 28
98 30 170 30 Role - 0 40 Emotional 26 58 50 56 98 54 170 55 General
0 41 Health 26 49 50 48 98 47 170 48 Mental 0 56 Health 26 66 50 65
98 66 170 67 Vitality 0 32 26 47 50 44 98 45 170 47 Social 0 48
Functioning 26 60 50 59 98 58 170 57 Adalimumab P < 0.02 vs.
baseline for all domains except role-physical, which was P <
0.05, on and after week 26. Last observation carried forward.
TABLE-US-00150 TABLE 155 Change in SF-36 values over 3 years
Baseline of subgroup Baseline of overall AUC for 144 weeks of
(current study) Study 8 population treatment.sup.a,b SF-36 domain n
SD Mean .+-. Median n SD Mean .+-. Median Mean .+-. SD Median
Physical 97 25.81 .+-. 19.49 20.0 501 44.06 .+-. 25.34 45.0 44.93
.+-. 23.25 44.58 functioning Role 95 11.05 .+-. 21.49 0.0 501 40.81
.+-. 41.34 25.0 39.74 .+-. 31.56 35.42 physical Bodily pain 98
24.03 .+-. 16.56 22.0 501 49.54 .+-. 21.73 51.0 50.16 .+-. 17.32
48.56 General 95 41.23 .+-. 18.31 40.0 501 50.32 .+-. 20.10 47.0
50.03 .+-. 17.87 48.92 health Vitality 98 31.85 .+-. 17.76 30.0 501
49.17 .+-. 20.94 50.0 49.50 .+-. 17.75 49.58 Social 98 47.58 .+-.
22.82 50.0 501 68.65 .+-. 25.63 75.0 68.53 .+-. 20.77 68.75
functioning Role 95 40.35 .+-. 44.80 33.3 500 62.06 .+-. 43.77
100.0 59.91 .+-. 34.50 64.73 emotional Mental 98 56.95 .+-. 21.86
60.0 501 67.58 .+-. 19.76 72.0 66.68 .+-. 17.31 68.67 health
Physical NA 500 33.95 .+-. 9.72 33.3 33.47 .+-. 8.87 33.32
component score (PCS) Mental NA 500 49.36 .+-. 11.37 51.9 47.33
.+-. 10.60 48.60 component score (MCS) .sup.aArea under the curve
(AUC) values are based on the average value per visit throughout
the whole study. .sup.bResults demonstrate no significant changes
from baseline of overall DE033 population and maintenance of
effects of initial treatment.
[0633] In the subgroup, rapid and statistically significant
improvements from baseline in FACIT-Fatigue scores were observed
after 12 weeks of adalimumab treatment and were maintained for more
than 3 years (FIG. 32). The FACIT-Fatigue score for adalimumab
patients at baseline was 26.08 (.+-.10.41) and increased to 34.63
(.+-.11.67) at Week 26. From Week 26 to Week 170, FACIT-Fatigue
scores remained stable (33.28.+-.11.42 at Week 170). The difference
between adalimumab and placebo and the differences in change from
baseline between placebo and adalimumab treatments were both
statistically significant and clinically meaningful at each time
point assessed. For adalimumab-treated patients, mean improvements
in FACIT-Fatigue scores were more than 4, indicating clinically
meaningful improvements. The changes from baseline in fatigue
scores for the placebo group were not statistically significant or
clinically important. Results were robust to various methods of
imputation for missing values.
[0634] In the subgroup, adalimumab-treated patients had a
significant increase from baseline in the overall utility score at
26 weeks, which was maintained over 3 years (FIG. 33). HUI3 scores
were 0.27 and 0.29 at baseline and 0.45 and 0.35 at Week 26 for
adalimumab and placebo, respectively. The differences between
adalimumab and placebo were statistically significant at 26 weeks.
At Week 170, the utility score was 0.45 for adalimumab treatment.
After adjusting for placebo, the adalimumab group experienced an
increase of 0.11 in HUI3 scores, reflecting a clinically meaningful
difference between treatment groups. Results were consistent
regardless of whether or not imputation for missing values was
conducted.
[0635] This health outcomes trial was conducted as a companion
study to the adalimumab clinical trials in patients with
long-standing RA. HRQL was assessed using specific quality-of-life
questionnaires (SF-36, FACIT-Fatigue, HUI3). All HRQL measures
reflected a rapid and statistically significant improvement from
baseline in HRQL after initiation of adalimumab therapy.
[0636] Improvements in HRQL measures were considered clinically
meaningful and were maintained for up to 3 years. Mean SF-36,
FACIT-Fatigue, and HUI3 scores rapidly improved and remained stable
during the entire treatment period. SF-36 scores indicated that
patients with late-stage RA are especially impaired in their
physical functioning, physical role, bodily pain, general health,
and vitality. The maintenance of the utility values over time is
important to clinical practice as disability and clinical
parameters, such as joint and bone destruction, progress over time,
especially among patients with long-standing RA, such as those
enrolled in this study (Pollard et al, 2005).
[0637] This study provided the only information to date on the
positive and clinically meaningful effects of long-term treatment
with adalimumab or any other TNF antagonist on certain facets of
HRQL. This was the first trial to measure long-term effects of a
TNF antagonist on fatigue. Measuring fatigue as a marker of
impairment proved to be valid; FACIT-Fatigue results significantly
correlated with other more well-established HRQL measures. To date,
the HUI3 previously has been used only once in a clinical trial of
RA patients receiving TNF-antagonist treatment. Consistent with the
results of this study, adalimumab provided significant improvement
in HUI3 in patients with long-standing RA during the 12-month
duration of the study (Torrance et al, 2004).
[0638] This study clearly demonstrated that, with the evaluated
instrument, even relatively small improvements can be observed. The
strengths of this study are the long study duration, the size of
the cohort, the parallel assessment of multiple PRO outcomes
measures in identical time frames, the multinational approach in
industrialized countries (all with existing high treatment standard
for RA patients), and the combination of PRO results within a
clinical trial.
[0639] In addition to the HAQ, a measure routinely incorporated in
clinical trials, this study supports the use of at least two
additional measures to further characterize the burden of disease
imposed on patients. These are the SF-36 and the FACIT-Fatigue. The
SF-36 can be used to gain utilities and reflects eight different
facets of HRQL. Each of these facets describes an area in which
patients with RA exhibit significant impairment as compared with
the general population. The FACIT-Fatigue also provides researchers
insight into one of the issues of particular concern to patients:
oppressive fatigue.
EQUIVALENTS
[0640] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
herein. Such equivalents are intended to be encompassed by the
following claims. The contents of all references, patents and
published patent applications cited throughout this application are
incorporated herein by reference.
Sequence CWU 1
1
371107PRTArtificial Sequenceadalimumab light chain variable region
1Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5
10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn
Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr
Cys Gln Arg Tyr Asn Arg Ala Pro Tyr 85 90 95 Thr Phe Gly Gln Gly
Thr Lys Val Glu Ile Lys 100 105 2121PRTArtificial
Sequenceadalimumab heavy chain variable region 2Glu Val Gln Leu Val
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15 Ser Leu Arg
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala
Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val
50 55 60 Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser
Leu Tyr65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser
Ser Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser 115 120 39PRTArtificial Sequenceadalimumab light chain variable
region CDR3 3Gln Arg Tyr Asn Arg Ala Pro Tyr Xaa1 5
412PRTArtificial Sequenceadalimumab heavy chain variable region
CDR3 4Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Xaa1 5 10
57PRTArtificial Sequenceadalimumab light chain variable region CDR2
5Ala Ala Ser Thr Leu Gln Ser1 5 617PRTArtificial Sequenceadalimumab
heavy chain variable region CDR2 6Ala Ile Thr Trp Asn Ser Gly His
Ile Asp Tyr Ala Asp Ser Val Glu1 5 10 15 Gly711PRTArtificial
Sequenceadalimumab light chain variable region CDR1 7Arg Ala Ser
Gln Gly Ile Arg Asn Tyr Leu Ala1 5 10 85PRTArtificial
Sequenceadalimumab heavy chain variable region CDR1 8Asp Tyr Ala
Met His1 5 9107PRTArtificial Sequence2SD4 light chain variable
region 9Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Ile
Gly1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile
Arg Asn Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Gln Ser Gly
Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe
Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80 Glu Asp Val Ala Thr
Tyr Tyr Cys Gln Lys Tyr Asn Ser Ala Pro Tyr 85 90 95 Ala Phe Gly
Gln Gly Thr Lys Val Glu Ile Lys 100 105 10121PRTArtificial
Sequence2SD4 heavy chain variable region 10Gln Val Gln Leu Val Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met
His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Asp Trp Val 35 40 45
Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val 50
55 60 Glu Gly Arg Phe Ala Val Ser Arg Asp Asn Ala Lys Asn Ala Leu
Tyr65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val
Tyr Tyr Cys 85 90 95 Thr Lys Ala Ser Tyr Leu Ser Thr Ser Ser Ser
Leu Asp Asn Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 119PRTArtificial Sequence2SD4 light chain variable region
CDR3 11Gln Lys Tyr Asn Ser Ala Pro Tyr Ala1 5 129PRTArtificial
SequenceEP B12 light chain variable region CDR3 12Gln Lys Tyr Asn
Arg Ala Pro Tyr Ala1 5 139PRTArtificial SequenceVL10E4 light chain
variable region CDR3 13Gln Lys Tyr Gln Arg Ala Pro Tyr Thr1 5
149PRTArtificial SequenceVL100A9 light chain variable region CDR3
14Gln Lys Tyr Ser Ser Ala Pro Tyr Thr1 5 159PRTArtificial
SequenceVLL100D2 light chain variable region CDR3 15Gln Lys Tyr Asn
Ser Ala Pro Tyr Thr1 5 169PRTArtificial SequenceVLL0F4 light chain
variable region CDR3 16Gln Lys Tyr Asn Arg Ala Pro Tyr Thr1 5
179PRTArtificial SequenceLOE5 light chain variable region CDR3
17Gln Lys Tyr Asn Ser Ala Pro Tyr Tyr1 5 189PRTArtificial
SequenceVLLOG7 light chain variable region CDR3 18Gln Lys Tyr Asn
Ser Ala Pro Tyr Asn1 5 199PRTArtificial SequenceVLLOG9 light chain
variable region CDR3 19Gln Lys Tyr Thr Ser Ala Pro Tyr Thr1 5
209PRTArtificial SequenceVLLOH1 light chain variable region CDR3
20Gln Lys Tyr Asn Arg Ala Pro Tyr Asn1 5 219PRTArtificial
SequenceVLLOH10 light chain variable region CDR3 21Gln Lys Tyr Asn
Ser Ala Ala Tyr Ser1 5 229PRTArtificial SequenceVL1B7 light chain
variable region CDR3 22Gln Gln Tyr Asn Ser Ala Pro Asp Thr1 5
239PRTArtificial SequenceVL1C1 light chain variable region CDR3
23Gln Lys Tyr Asn Ser Asp Pro Tyr Thr1 5 249PRTArtificial
SequenceVL0.1F4 light chain variable region CDR3 24Gln Lys Tyr Ile
Ser Ala Pro Tyr Thr1 5 259PRTArtificial SequenceVL0.1H8 light chain
variable region CDR3 25Gln Lys Tyr Asn Arg Pro Pro Tyr Thr1 5
269PRTArtificial SequenceLOE7.A light chain variable region CDR3
26Gln Arg Tyr Asn Arg Ala Pro Tyr Ala1 5 2712PRTArtificial
Sequence2SD4 heavy chain variable region CDR3 27Ala Ser Tyr Leu Ser
Thr Ser Ser Ser Leu Asp Asn1 5 10 2812PRTArtificial SequenceVH1B11
heavy chain variable region CDR3 28Ala Ser Tyr Leu Ser Thr Ser Ser
Ser Leu Asp Lys1 5 10 2912PRTArtificial SequenceVH1D8 heavy chain
variable region CDR3 29Ala Ser Tyr Leu Ser Thr Ser Ser Ser Leu Asp
Tyr1 5 10 3012PRTArtificial SequenceVH1A11 heavy chain variable
region CDR3 30Ala Ser Tyr Leu Ser Thr Ser Ser Ser Leu Asp Asp1 5 10
3112PRTArtificial SequenceVH1B12 heavy chain variable region CDR3
31Ala Ser Tyr Leu Ser Thr Ser Phe Ser Leu Asp Tyr1 5 10
3212PRTArtificial SequenceVH1E4 heavy chain variable region CDR3
32Ala Ser Tyr Leu Ser Thr Ser Ser Ser Leu His Tyr1 5 10
3312PRTArtificial SequenceVH1F6 heavy chain variable region CDR3
33Ala Ser Phe Leu Ser Thr Ser Ser Ser Leu Glu Tyr1 5 10
3412PRTArtificial Sequence3C-H2 heavy chain variable region CDR3
34Ala Ser Tyr Leu Ser Thr Ala Ser Ser Leu Glu Tyr1 5 10
3512PRTArtificial SequenceVH1-D2.N heavy chain variable region CDR3
35Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Asn1 5 10
36321DNAArtificial Sequenceadalimumab light chain variable region
36gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtagggga cagagtcacc
60atcacttgtc gggcaagtca gggcatcaga aattacttag cctggtatca gcaaaaacca
120gggaaagccc ctaagctcct gatctatgct gcatccactt tgcaatcagg
ggtcccatct 180cggttcagtg gcagtggatc tgggacagat ttcactctca
ccatcagcag cctacagcct 240gaagatgttg caacttatta ctgtcaaagg
tataaccgtg caccgtatac ttttggccag 300gggaccaagg tggaaatcaa a
32137363DNAArtificial Sequenceadalimumab heavy chain variable
region 37gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ccggcaggtc
cctgagactc 60tcctgtgcgg cctctggatt cacctttgat gattatgcca tgcactgggt
ccggcaagct 120ccagggaagg gcctggaatg ggtctcagct atcacttgga
atagtggtca catagactat 180gcggactctg tggagggccg attcaccatc
tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga acagtctgag
agctgaggat acggccgtat attactgtgc gaaagtctcg 300taccttagca
ccgcgtcctc ccttgactat tggggccaag gtaccctggt caccgtctcg 360agt
363
* * * * *