U.S. patent application number 15/642201 was filed with the patent office on 2017-10-19 for low frequency glatiramer acetate therapy.
The applicant listed for this patent is Yeda Research & Development Co., Ltd.. Invention is credited to Ety Klinger.
Application Number | 20170296464 15/642201 |
Document ID | / |
Family ID | 43605835 |
Filed Date | 2017-10-19 |
United States Patent
Application |
20170296464 |
Kind Code |
A1 |
Klinger; Ety |
October 19, 2017 |
LOW FREQUENCY GLATIRAMER ACETATE THERAPY
Abstract
A method of alleviating a symptom of relapsing-remitting
multiple sclerosis in a human patient suffering from
relapsing-remitting multiple sclerosis or a patient who has
experienced a first clinical episode and is determined to be at
high risk of developing clinically definite multiple sclerosis
comprising administering to the human patient three subcutaneous
injections of a therapeutically effective dose of glatiramer
acetate over a period of seven days with at least one day between
every subcutaneous injection so as to thereby alleviate the symptom
of the patient.
Inventors: |
Klinger; Ety; (Tel Aviv,
IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Yeda Research & Development Co., Ltd. |
Rehovot |
|
IL |
|
|
Family ID: |
43605835 |
Appl. No.: |
15/642201 |
Filed: |
July 5, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15469758 |
Mar 27, 2017 |
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15642201 |
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15380579 |
Dec 15, 2016 |
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15469758 |
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15148215 |
May 6, 2016 |
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15380579 |
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14630326 |
Feb 24, 2015 |
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15148215 |
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13770677 |
Feb 19, 2013 |
8969302 |
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14630326 |
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12806684 |
Aug 19, 2010 |
8399413 |
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13770677 |
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61274687 |
Aug 20, 2009 |
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61337612 |
Feb 11, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 3/10 20180101; A61K
9/0019 20130101; A61K 31/19 20130101; A61K 38/16 20130101; A61K
38/07 20130101; A61K 31/785 20130101; A61K 38/02 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 38/02 20060101 A61K038/02; A61K 31/19 20060101
A61K031/19 |
Claims
1. A method of alleviating a symptom of relapsing-remitting
multiple sclerosis in a human patient suffering from
relapsing-remitting multiple sclerosis or a patient who has
experienced a first clinical episode and is determined to be at
high risk of developing clinically definite multiple sclerosis
comprising administering to the human patient three subcutaneous
injections of a therapeutically effective dose of glatiramer
acetate over a period of seven days with at least one day between
every subcutaneous injection so as to thereby alleviate the symptom
of the patient.
2. The method of claim 1, wherein alleviating a symptom comprises
reducing the frequency of relapses.
3. The method of claim 1 or 2, wherein alleviating a symptom
comprises reducing the mean cumulative number of Gd-enhancing
lesions in the brain of the patient.
4. The method of any one of claims 1-3, wherein alleviating a
symptom comprises reducing the mean number of new T.sub.2 lesions
in the brain of the patient.
5. The method of any one of claims 1-4, wherein alleviating a
symptom comprises reducing the cumulative number of enhancing
lesions on T.sub.1-weighted images.
6. The method of any one of claims 1-5, wherein alleviating a
symptom comprises reducing brain atrophy in the patient.
7. The method of any one of claims 1-6, wherein alleviating a
symptom comprises increasing the time to a confirmed relapse in the
patient.
8. The method of any one of claims 1-7, wherein alleviating a
symptom comprises reducing the total number of confirmed relapses
in the patient.
9. The method of any one of claims 1-8, wherein alleviating a
symptom comprises reducing the progression of MRI-monitored disease
activity in the patient.
10. The method of any one of claims 1-9, wherein alleviating a
symptom comprises reducing total volume of T.sub.2 lesions in the
patient.
11. The method of any one of claims 1-10, wherein alleviating a
symptom comprises reducing the number of new hypointense lesions on
enhanced T.sub.1 scans in the patient.
12. The method of any one of claims 1-11, wherein alleviating a
symptom comprises reducing the total volume of hypointense lesions
on enhanced T.sub.1 scans.
13. The method of any one of claims 1-12, wherein alleviating a
symptom comprises reducing the level of disability as measured by
EDSS Score in the patient.
14. The method of any one of claims 1-13, wherein alleviating a
symptom comprises reducing the change in EDSS Score in the
patient.
15. The method of any one of claims 1-14, wherein alleviating a
symptom comprises reducing the change in Ambulation Index in the
patient.
16. The method of any one of claims 1-15, wherein alleviating a
symptom comprises reducing the level of disability as measured by
EuroQoL (EQ5D) questionnaire in the patient.
17. The method of any one of claims 1-16, wherein alleviating a
symptom comprises reducing the level of disability as measured by
the work productivity and activities impairment-General Health
(WPAI-GH) questionnaire in the patient.
18. The method of any one of claims 1-17, wherein the
pharmaceutical composition is in a prefilled syringe for self
administration by the patient.
19. The method of any one of claims 1-17, wherein the
therapeutically effective dose of glatiramer acetate is 40 mg.
20. The method of any one of claims 1-19, wherein the patient has
not received glatiramer acetate therapy prior to initiation of the
subcutaneous injections.
21. The method of any one of claims 1-20, wherein the frequency of
an immediate post injection reaction or the frequency of an
injection site reaction is reduced relative to daily subcutaneous
administration of 20 mg glatiramer acetate.
22. A method of increasing the tolerability of GA treatment in a
human patient suffering from relapsing-remitting multiple sclerosis
or a patient who has experienced a first clinical episode and is
determined to be at high risk of developing clinically definite
multiple sclerosis which comprises reducing the frequency of
subcutaneous injections of a pharmaceutical composition comprising
a therapeutically effective dose of glatiramer acetate to three
times over a period of seven days with at least one day between
every injection.
23. The method of claim 22, wherein increasing the tolerability of
glatiramer acetate treatment in the human patient suffering from a
relapsing form of multiple sclerosis comprises reducing the
frequency of an immediate post injection reaction.
24. The method of claim 22 or 23, wherein the immediate post
injection reaction is palpitations, feeling hot, flushing, hot
flushes, tachycardia, dyspnoea, chest discomfort, chest pain,
non-cardiac chest, asthenia, back pain, bacterial infection,
chills, cyst, face edema, fever, flu syndrome, infection, injection
site erythema, injection site hemorrhage, injection site
induration, injection site inflammation, injection site mass,
injection site pain, injection site pruritus, injection site
urticaria, injection site welt, neck pain, pain, migrane, syncope,
tachycardia, vasodilatation, anorexia, diarrhea, gastroenteritis,
gastrointestinal disorder, nausea, vomiting, ecchymosis, peripheral
edema, arthralgia, agitation, anxiety, confusion, foot drop,
hypertonia, nervousness, nystagmus, speech disorder, tremor,
vertigo, bronchitis, dyspnea, laryngismus, rhinitis, erythema,
herpes simplex, pruritus, rash, skin nodule, sweating, urticaria,
ear pain, eye disorder, dysmenorrheal, urinary urgency, or vaginal
moniliasis.
25. The method of claim 22, wherein increasing the tolerability of
glatiramer acetate treatment in the human patient suffering from a
relapsing form of multiple sclerosis comprises reducing the
frequency of an injection site reaction.
26. The method of claim 22 or 24, wherein the injection site
reaction is erythema, hemorrhage, induration, inflammation, mass,
pain, pruritus, urticaria, or welt that occurs immediately around
the site of injection.
27. Use of glatiramer acetate in the preparation of a medicament
for treating relapsing-remitting multiple sclerosis in a human
patient suffering from relapsing-remitting multiple sclerosis or a
patient who has experienced a first clinical episode and is
determined to be at high risk of developing clinically definite
multiple sclerosis wherein the administration pattern of the
medicament is three subcutaneous injections of a therapeutically
effective dose of glatiramer acetate over a period of seven days
with at least one day between every subcutaneous injection.
28. Use of glatiramer acetate in the preparation of a medicament
for treating relapsing-remitting multiple sclerosis in a human
patient suffering from relapsing-remitting multiple sclerosis or a
patient who has experienced a first clinical episode and is
determined to be at high risk of developing clinically definite
multiple sclerosis wherein the medicament is prepared for an
administration pattern of three subcutaneous injections of a
therapeutically effective dose of glatiramer acetate over a period
of seven days with at least one day between every subcutaneous
injection.
29. Use of glatiramer acetate in the preparation of a medicament
for increasing the tolerability of GA treatment in a human patient
suffering from relapsing-remitting multiple sclerosis or a patient
who has experienced a first clinical episode and is determined to
be at high risk of developing clinically definite multiple
sclerosis wherein the administration pattern of the medicament is
three subcutaneous injections of a therapeutically effective dose
of glatiramer acetate over a period of seven days with at least one
day between every subcutaneous injection.
30. Use of glatiramer acetate in the preparation of a medicament
for increasing the tolerability of GA treatment in a human patient
suffering from relapsing-remitting multiple sclerosis or a patient
who has experienced a first clinical episode and is determined to
be at high risk of developing clinically definite multiple
sclerosis wherein the medicament is prepared for an administration
pattern of three subcutaneous injections of a therapeutically
effective dose of glatiramer acetate over a period of seven days
with at least one day between every subcutaneous injection.
31. Glatiramer acetate for use in treating relapsing-remitting
multiple sclerosis in a human patient suffering from
relapsing-remitting multiple sclerosis or a patient who has
experienced a first clinical episode and is determined to be at
high risk of developing clinically definite multiple sclerosis by
three subcutaneous injections over a period of seven days with at
least one day between every subcutaneous injection.
32. Glatiramer acetate for use in increasing the tolerability of GA
treatment in a human patient suffering from relapsing-remitting
multiple sclerosis or a patient who has experienced a first
clinical episode and is determined to be at high risk of developing
clinically definite multiple sclerosis by three subcutaneous
injections over a period of seven days with at least one day
between every subcutaneous injection.
Description
[0001] This application claims the benefit of U.S. Provisional
Application Nos. 61/274,687, filed Aug. 20, 2009 and 61/337,612,
filed Feb. 11, 2010. The contents of which are hereby incorporated
by reference in their entirety.
[0002] Throughout this application various publications are
referenced by their full citations. The disclosures of these
publications in their entireties are hereby incorporated by
reference into this application in order to more fully describe the
state of the art to which this invention pertains.
BACKGROUND OF THE INVENTION
[0003] Multiple Sclerosis (MS) is a chronic, debilitating disease
of the central nervous system (CNS). MS has also been classified as
an autoimmune disease. MS disease activity can be monitored by
magnetic resonance imaging (MRI) of the brain, accumulation of
disability, as well as rate and severity of relapses.
[0004] There are five main forms of multiple sclerosis:
1) Benign Multiple Sclerosis:
[0005] Benign multiple sclerosis is a retrospective diagnosis which
is characterized by 1-2 exacerbations with complete recovery, no
lasting disability and no disease progression for 10-15 years after
the initial onset. Benign multiple sclerosis may, however, progress
into other forms of multiple sclerosis.
2) Relapsing-Remitting Multiple Sclerosis (RRMS):
[0006] Patients suffering from RRMS experience sporadic
exacerbations or relapses, as well as periods of remission. Lesions
and evidence of axonal loss may or may not be visible on MRI for
patients with RRMS.
3) Secondary Progressive Multiple Sclerosis (SPMS):
[0007] SPMS may evolve from RRMS. Patients afflicted with SPMS have
relapses, a diminishing degree of recovery during remissions, less
frequent remissions and more pronounced neurological deficits than
RRMS patients. Enlarged ventricles, which are markers for atrophy
of the corpus callosum, midline center and spinal cord, are visible
on MRI of patients with SPMS.
4) Primary Progressive Multiple Sclerosis (PPMS);
[0008] PPMS is characterized by a steady progression of increasing
neurological deficits without distinct attacks or remissions.
Cerebral lesions, diffuse spinal cord damage and evidence of axonal
loss are evident on the MRI of patients with PPMS.
5) Progressive-Relapsing Multiple Sclerosis (PRMS):
[0009] PRMS has periods of acute exacerbations while proceeding
along a course of increasing neurological deficits without
remissions. Lesions are evident on MRI of patients suffering from
PRMS (Multiple sclerosis: its diagnosis, symptoms, types and
stages, 2003, albany.net/.about.tjc/multiple-sclerosis.html; What
are the Types of Multiple Sclerosis?, 2005,
<imaginis.com/multiple-sclerosis/types-of-ms.asp?mode=1>).
[0010] Chronic progressive multiple sclerosis is a term used to
collectively refer to SPMS, PPMS, and PRMS (Types of Multiple
Sclerosis (MS), 2005,
<themcfox.com/multiple-sclerosis/types-of-ms/types-of-multiple-scleros-
is.htm>). The relapsing forms of multiple sclerosis are SPMS
with superimposed relapses, RRMS and PRMS.
[0011] Glatiramer acetate (GA), a mixture of polypeptides which do
not all have the same amino acid sequence, is marketed under the
tradename Copaxone.RTM.. GA comprises the acetate salts of
polypeptides containing L-glutamic acid, L-alanine, L-tyrosine and
L-lysine at average molar fractions of 0.141, 0.427, 0.095 and
0.338, respectively. The average molecular weight of Copaxone.RTM.
is between 5,000 and 9,000 daltons. ("Copaxone", Physician's Desk
Reference, (2005), Medical Economics Co., Inc., (Montvale, N.J.),
3115.) Chemically, glatiramer acetate is designated L-glutamic acid
polymer with L-alanine, L-lysine, L-tyrosine, acetate (salt).
[0012] Its structural formula is:
(Glu,Ala,Lys,Tyr) x.X CH.sub.3COOH
(C.sub.5H.sub.9NO.sub.4.C.sub.3H.sub.7NO.sub.2.C.sub.6H.sub.14N.sub.2O.s-
ub.2.C.sub.9H.sub.11NO.sub.3) x.x CHO
CAS-147245-92-9
[0013] Copaxone.RTM. ("Copaxone", Full Prescribing Information,
(February, 2009), FDA Marketing Label) (20 mg glatiramer acetate
daily injection) is an approved therapy for patients with relapsing
remitting multiple sclerosis (RRMS), including patients who have
experienced a first clinical episode and have MRI features
consistent with multiple sclerosis.
[0014] GA has also been disclosed for use in the treatment of other
autoimmune diseases (U.S. Patent Publication No. 2002/0055466 A1
(R. Aharoni et al.), inflammatory non-autoimmune diseases (U.S.
Patent Publication No. 2005/0014694 A1 (V. Wee Yong et al.); and
U.S. Patent Application No. 2002/0077278 A1, published Jun. 20,
2002 (Young et al.)) and other diseases (U.S. Patent Publication
Nos. 2003/0004099 A1 and 2002/0037848 A1 (Eisenbach-Schwartz, et
al.); U.S. Pat. No. 6,514,938 B1, issued Feb. 4, 2003 (Gad et al.);
PCT International Publication No. WO 01/60392, published Aug. 23,
2001 (Gilbert et al.); PCT International Publication No. WO
00/27417, published May 19, 2000 (Aharoni et al.); and PCT
International Publication No. WO 01/97846, published Dec. 27, 2001
(Moses et al.).
[0015] The 20 mg/day subcutaneous (s.c.) dose has been shown to
reduce the total number of enhancing lesions in MS patients as
measured by MRI (G. Comi et al., European/Canadian Multicenter,
Double-Blind, Randomized, Placebo-Controlled Study of the Effects
of Glatiramer Acetere on Magnetic Resonance Imaging-Measured
Disease Activity and Burden in Patients with Relapsing Multiple
Sclerosis, Ann. Neurol. 49:290-297 (2001)).
[0016] Safety data accumulated for GA in clinical trials shows that
the drug product is safe and well tolerated.
[0017] Disclosed is an effective low frequency dosage regimen of GA
administration to patients suffering from a relapsing form of
multiple sclerosis, including patients who have experienced a first
clinical episode and have MRI features consistent with multiple
sclerosis.
SUMMARY OF THE INVENTION
[0018] This invention provides a method of alleviating a symptom of
relapsing-remitting multiple sclerosis in a human patient suffering
from relapsing-remitting multiple sclerosis or a patient who has
experienced a first clinical episode and is determined to be at
high risk of developing clinically definite multiple sclerosis
comprising administering to the human patient three subcutaneous
injections of a therapeutically effective dose of glatiramer
acetate over a period of seven days with at least one day between
every subcutaneous injection so as to thereby alleviate the symptom
of the patient.
[0019] This invention also provides a method of increasing the
tolerability of GA treatment in a human patient suffering from
relapsing-remitting multiple sclerosis or a patient who has
experienced a first clinical episode and is determined to be at
high risk of developing clinically definite multiple sclerosis
which comprises reducing the frequency of subcutaneous injections
of a pharmaceutical composition comprising a therapeutically
effective dose of glatiramer acetate to three times over a period
of seven days with at least one day between every injection.
[0020] In another embodiment, the therapeutically effective dose of
glatiramer acetate is 40 mg/ml.
[0021] This invention also provides a use of glatiramer acetate in
the preparation of a medicament for treating relapsing-remitting
multiple sclerosis in a human patient suffering from
relapsing-remitting multiple sclerosis or a patient who has
experienced a first clinical episode and is determined to be at
high risk of developing clinically definite multiple sclerosis
wherein the administration pattern of the medicament is three
subcutaneous injections of a therapeutically effective dose of
glatiramer acetate over a period of seven days with at least one
day between every subcutaneous injection.
[0022] This invention additionally provides a use of glatiramer
acetate in the preparation of a medicament for treating
relapsing-remitting multiple sclerosis in a human patient suffering
from relapsing-remitting multiple sclerosis or a patient who has
experienced a first clinical episode and is determined to be at
high risk of developing clinically definite multiple sclerosis
wherein the medicament is prepared for an administration pattern of
three subcutaneous injections of a therapeutically effective dose
of glatiramer acetate over a period of seven days with at least one
day between every subcutaneous injection.
[0023] This invention yet also provides a use of glatiramer acetate
in the preparation of a medicament for increasing the tolerability
of GA treatment in a human patient suffering from
relapsing-remitting multiple sclerosis or a patient who has
experienced a first clinical episode and is determined to be at
high risk of developing clinically definite multiple sclerosis
wherein the administration pattern of the medicament is three
subcutaneous injections of a therapeutically effective dose of
glatiramer acetate over a period of seven days with at least one
day between every subcutaneous injection.
[0024] This invention further provides a use of glatiramer acetate
in the preparation of a medicament for increasing the tolerability
of GA treatment in a human patient suffering from
relapsing-remitting multiple sclerosis or a patient who has
experienced a first clinical episode and is determined to be at
high risk of developing clinically definite multiple sclerosis
wherein the medicament is prepared for an administration pattern of
three subcutaneous injections of a therapeutically effective dose
of glatiramer acetate over a period of seven days with at least one
day between every subcutaneous injection.
[0025] This invention provides glatiramer acetate for use in
treating relapsing-remitting multiple sclerosis in a human patient
suffering from relapsing-remitting multiple sclerosis or a patient
who has experienced a first clinical episode and is determined to
be at high risk of developing clinically definite multiple
sclerosis by three subcutaneous injections over a period of seven
days with at least one day between every subcutaneous
injection.
[0026] This invention also provides glatiramer acetate for use in
increasing the tolerability of GA treatment in a human patient
suffering from relapsing-remitting multiple sclerosis or a patient
who has experienced a first clinical episode and is determined to
be at high risk of developing clinically definite multiple
sclerosis by three subcutaneous injections over a period of seven
days with at least one day between every subcutaneous
injection.
DETAILED DESCRIPTION OF THE INVENTION
[0027] This invention provides a method of alleviating a symptom of
relapsing-remitting multiple sclerosis in a human patient suffering
from relapsing-remitting multiple sclerosis or a patient who has
experienced a first clinical episode and is determined to be at
high risk of developing clinically definite multiple sclerosis
comprising administering to the human patient three subcutaneous
injections of a therapeutically effective dose of glatiramer
acetate over a period of seven days with at least one day between
every subcutaneous injection so as to thereby alleviate the symptom
of the patient.
[0028] In another embodiment, there are three injections for every
seven days and there must be at least one day between each
injection. In a further embodiment, possible injection schedules
include Day 1, Day 3, Day 5; Day 1, Day 3, Day 6; Day 1, Day 3, Day
7; Day 1, Day 4, Day 6; Day 1, Day 4, Day 7; Day 1, Day 5, Day 7;
Day 2, Day 4, Day 6; Day 2, Day 4, Day 7; Day 2, Day 5, Day 7; or
Day 3, Day 5, Day 7.
[0029] In an embodiment, alleviating a symptom comprises reducing
the frequency of relapses.
[0030] In yet another embodiment, alleviating a symptom comprises
reducing the mean cumulative number of Gd-enhancing lesions in the
brain of the patient.
[0031] In another embodiment, alleviating a symptom comprises
reducing the mean number of new T.sub.2 lesions in the brain of the
patient.
[0032] In a further embodiment, alleviating a symptom comprises
reducing the cumulative number of enhancing lesions on
T.sub.1-weighted images in the patient.
[0033] In another embodiment, alleviating a symptom comprises
reducing brain atrophy in the patient.
[0034] In another embodiment, alleviating a symptom comprises
increasing the time to a confirmed relapse in the patient.
[0035] In another embodiment, alleviating a symptom comprises
reducing the total number of confirmed relapses in the patient.
[0036] In another embodiment, alleviating a symptom comprises
reducing the progression of MRI-monitored disease activity in the
patient.
[0037] In another embodiment, alleviating a symptom comprises
reducing total volume of T.sub.2 lesions in the patient.
[0038] In another embodiment, alleviating a symptom comprises
reducing the number of new hypointense lesions on enhanced T.sub.1
scans in the patient.
[0039] In another embodiment, alleviating a symptom comprises
reducing the total volume of hypointense lesions on enhanced
T.sub.1 scans in the patient.
[0040] In another embodiment, alleviating a symptom comprises
reducing the level of disability as measured by EDSS Score in the
patient.
[0041] In another embodiment, alleviating a symptom comprises
reducing the change in EDSS Score in the patient.
[0042] In another embodiment, alleviating a symptom comprises
reducing the change in Ambulation Index in the patient.
[0043] In another embodiment, alleviating a symptom comprises
reducing the level of disability as measured by EuroQoL (EQ5D)
questionnaire in the patient.
[0044] In another embodiment, alleviating a symptom comprises
reducing the level of disability as measured by the work
productivity and activities impairment-General Health (WPAI-GH)
questionnaire in the patient.
[0045] In an additional embodiment, the pharmaceutical composition
is in a prefilled syringe for self administration by the
patient.
[0046] In yet another embodiment, the therapeutically effective
dose of glatiramer acetate is 40 mg/ml. In a further embodiment,
the therapeutically effective dose of glatiramer acetate is 40
mg/0.75 ml.
[0047] In a further embodiment, the patient has not received
glatiramer acetate therapy prior to initiation of the subcutaneous
injections.
[0048] In an embodiment, the pharmaceutical composition is in the
form of a sterile solution.
[0049] In another embodiment, the pharmaceutical composition
further comprises mannitol.
[0050] In yet another embodiment, the pharmaceutical composition
has a pH in the range of 5.5 to 8.5.
[0051] In an embodiment, the pharmaceutical composition has a pH in
the range of 5.5 to 7.0.
[0052] In an embodiment the frequency of an immediate post
injection reaction or the frequency of an injection site reaction
is reduced relative to daily subcutaneous administration of 20 mg
glatiramer acetate.
[0053] This invention also provides a method of increasing the
tolerability of GA treatment in a human patient suffering from
relapsing-remitting multiple sclerosis or a patient who has
experienced a first clinical episode and is determined to be at
high risk of developing clinically definite multiple sclerosis
which comprises reducing the frequency of subcutaneous injections
of a pharmaceutical composition comprising a therapeutically
effective dose of glatiramer acetate to three times over a period
of seven days with at least one day between every injection.
[0054] In another embodiment, increasing the tolerability of GA
treatment in the human patient suffering from a relapsing form of
multiple sclerosis comprises reducing the frequency of an immediate
post injection reaction.
[0055] In yet another embodiment, the immediate post injection
reaction is palpitations, feeling hot, flushing, hot flushes,
tachycardia, dyspnoea, chest discomfort, chest pain, non-cardiac
chest, asthenia, back pain, bacterial infection, chills, cyst, face
edema, fever, flu syndrome, infection, injection site erythema,
injection site hemorrhage, injection site induration, injection
site inflammation, injection site mass, injection site pain,
injection site pruritus, injection site urticaria, injection site
welt, neck pain, pain, migrane, syncope, tachycardia,
vasodilatation, anorexia, diarrhea, gastroenteritis,
gastrointestinal disorder, nausea, vomiting, ecchymosis, peripheral
edema, arthralgia, agitation, anxiety, confusion, foot drop,
hypertonia, nervousness, nystagmus, speech disorder, tremor,
vertigo, bronchitis, dyspnea, laryngismus, rhinitis, erythema,
herpes simplex, pruritus, rash, skin nodule, sweating, urticaria,
ear pain, eye disorder, dysmenorrheal, urinary urgency, or vaginal
moniliasis.
[0056] In an additional embodiment, increasing the tolerability of
GA treatment in the human patient suffering from a relapsing form
of multiple sclerosis comprises reducing the frequency of an
injection site reaction.
[0057] In a further embodiment, the injection site reaction is
erythema, hemorrhage, induration, inflammation, mass, pain,
pruritus, urticaria, or welt that occurs immediately around the
site of injection.
[0058] In an embodiment, a single clinical attack includes a
clinical episode of optic neuritis, blurring of vision, diplopia,
involuntary rapid eye movement, blindness, loss of balance,
tremors, ataxia, vertigo, clumsiness of a limb, lack of
coordination, weakness of one or more extremity, altered muscle
tone, muscle stiffness, spasms, tingling, paraesthesia, burning
sensations, muscle pains, facial pain, trigeminal neuralgia,
stabbing sharp pains, burning tingling pain, slowing of speech,
slurring of words, changes in rhythm of speech, dysphagia, fatigue,
bladder problems (including urgency, frequency, incomplete emptying
and incontinence), bowel problems (including constipation and loss
of bowel control), impotence, diminished sexual arousal, loss of
sensation, sensitivity to heat, loss of short term memory, loss of
concentration, or loss of judgment or reasoning.
[0059] In another embodiment, prior to administration the patient
has at least 1 cerebral lesion detectable by an MRI scan and
suggestive of multiple sclerosis.
[0060] In yet another embodiment, the lesion is associated with
brain tissue inflammation, myelin sheath damage or axonal
damage.
[0061] In an additional embodiment, the lesion is a demyelinating
white matter lesion visible on brain MRI.
[0062] In a further embodiment, the white matter lesions are at
least 3 mm in diameter.
[0063] This invention also provides a use of glatiramer acetate in
the preparation of a medicament for treating relapsing-remitting
multiple sclerosis in a human patient suffering from
relapsing-remitting multiple sclerosis or a patient who has
experienced a first clinical episode and is determined to be at
high risk of developing clinically definite multiple sclerosis
wherein the administration pattern of the medicament is three
subcutaneous injections of a therapeutically effective dose of
glatiramer acetate over a period of seven days with at least one
day between every subcutaneous injection.
[0064] This invention additionally provides a use of glatiramer
acetate in the preparation of a medicament for treating
relapsing-remitting multiple sclerosis in a human patient suffering
from relapsing-remitting multiple sclerosis or a patient who has
experienced a first clinical episode and is determined to be at
high risk of developing clinically definite multiple sclerosis
wherein the medicament is prepared for an administration pattern of
three subcutaneous injections of a therapeutically effective dose
of glatiramer acetate over a period of seven days with at least one
day between every subcutaneous injection.
[0065] This invention yet also provides a use of glatiramer acetate
in the preparation of a medicament for increasing the tolerability
of GA treatment in a human patient suffering from
relapsing-remitting multiple sclerosis or a patient who has
experienced a first clinical episode and is determined to be at
high risk of developing clinically definite multiple sclerosis
wherein the administration pattern of the medicament is three
subcutaneous injections of a therapeutically effective dose of
glatiramer acetate over a period of seven days with at least one
day between every subcutaneous injection.
[0066] This invention further provides a use of glatiramer acetate
in the preparation of a medicament for increasing the tolerability
of GA treatment in a human patient suffering from
relapsing-remitting multiple sclerosis or a patient who has
experienced a first clinical episode and is determined to be at
high risk of developing clinically definite multiple sclerosis
wherein the medicament is prepared for an administration pattern of
three subcutaneous injections of a therapeutically effective dose
of glatiramer acetate over a period of seven days with at least one
day between every subcutaneous injection.
[0067] This invention provides glatiramer acetate for use in
treating relapsing-remitting multiple sclerosis in a human patient
suffering from relapsing-remitting multiple sclerosis or a patient
who has experienced a first clinical episode and is determined to
be at high risk of developing clinically definite multiple
sclerosis by three subcutaneous injections over a period of seven
days with at least one day between every subcutaneous
injection.
[0068] This invention also provides glatiramer acetate for use in
increasing the tolerability of GA treatment in a human patient
suffering from relapsing-remitting multiple sclerosis or a patient
who has experienced a first clinical episode and is determined to
be at high risk of developing clinically definite multiple
sclerosis by three subcutaneous injections over a period of seven
days with at least one day between every subcutaneous
injection.
DEFINITIONS
[0069] As used herein, immediate post injection reaction (IRPR)
refers to a reaction such as, palpitations, feeling hot, flushing,
hot flushes, tachycardia, dyspnoea, chest discomfort, chest pain,
and non-cardiac chest pain that occurs immediately following
injection. Reactions may also include asthenia, back pain,
bacterial infection, chills, cyst, face edema, fever, flu syndrome,
infection, injection site erythema, injection site hemorrhage,
injection site induration, injection site inflammation, injection
site mass, injection site pain, injection site pruritus, injection
site urticaria, injection site welt, neck pain, pain, migrane,
syncope, tachycardia, vasodilatation, anorexia, diarrhea,
gastroenteritis, gastrointestinal disorder, nausea, vomiting,
ecchymosis, peripheral edema, arthralgia, agitation, anxiety,
confusion, foot drop, hypertonia, nervousness, nystagmus, speech
disorder, tremor, vertigo, bronchitis, dyspnea, laryngismus,
rhinitis, erythema, herpes simplex, pruritus, rash, skin nodule,
sweating, urticaria, ear pain, eye disorder, dysmenorrheal, urinary
urgency, and vaginal moniliasis.
[0070] As used herein, injection site reaction (ISR) refers to a
reaction such as erythema, hemorrhage, induration, inflammation,
mass, pain, pruritus, urticaria, and welt that occurs immediately
around the site of injection.
[0071] As used herein, "tolerability" relates to the level of
discomfort associated with GA treatment. Tolerability is associated
with the frequency and severity of post injection reactions and
injection site reactions. Tolerability influences the period that a
patient can follow GA treatment.
[0072] As used herein, the term Gd-enhancing lesions, refers to
lesions that result from a breakdown of the blood-brain barrier,
which appear in contrast studies using gandolinium contrast agents.
Gandolinium enhancement provides information as to the age of a
lesion, as Gd-enhancing lesions typically occur within a six week
period of lesion formation.
[0073] As used herein, the term T.sub.1-weighted MRI images refers
to an MR-image that emphasizes T.sub.1 contrast by which lesions
may be visualized. Abnormal areas in a T.sub.1-weighted MRI image
are "hypointense" and appear as dark spots. These spots are
generally older lesions.
[0074] As used herein, the term T.sub.2-weighted MRI image, refers
to an MR-image that emphasizes T.sub.2 contrast by which lesions
may be visualized. T.sub.2 lesions represent new inflammatory
activity.
[0075] As used herein, the term "unit dosage" refers to physically
discrete units suited as single administration dose for a subject
to be treated, containing a therapeutically effective quantity of
active compound in association with the required pharmaceutical
carrier, e.g., a syringe.
[0076] As used herein, clinically isolated syndrome (CIS) refers to
1) a single clinical attack suggestive of MS and 2) at least one
lesion suggestive of MS. As an example, the patient has at least 1
cerebral lesion detectable by an MRI scan and suggestive of
multiple sclerosis. As an additional example the lesion is
associated with brain tissue inflammation, myelin sheath damage or
axonal damage. As another example the lesion is a demyelinating
white matter lesion visible on brain MRI. In a further example, the
white matter lesions are at least 3 mm in diameter.
[0077] The term "single clinical attack" is used synonymously with
"first clinical episode", "first clinical attack", and "first
clinical event" which, for example, presents as a clinical episode
of optic neuritis, blurring of vision, diplopia, involuntary rapid
eye movement, blindness, loss of balance, tremors, ataxia, vertigo,
clumsiness of a limb, lack of coordination, weakness of one or more
extremity, altered muscle tone, muscle stiffness, spasms, tingling,
paraesthesia, burning sensations, muscle pains, facial pain,
trigeminal neuralgia, stabbing sharp pains, burning tingling pain,
slowing of speech, slurring of words, changes in rhythm of speech,
dysphagia, fatigue, bladder problems (including urgency, frequency,
incomplete emptying and incontinence), bowel problems (including
constipation and loss of bowel control), impotence, diminished
sexual arousal, loss of sensation, sensitivity to heat, loss of
short term memory, loss of concentration, or loss of judgment or
reasoning.
[0078] As used herein, the criteria, as defined by Poser et al.
Neurology, March 1983, 13 (3): 227-230, used to determine if a
subject meets the condition consistent with clinically definite
multiple sclerosis (CAMS) are: [0079] Two attacks and clinical
evidence of two separate lesions or [0080] Two attacks; clinical
evidence of one lesion and paraclinical evidence of another
separate lesion.
[0081] An attack (also referred to as an exacerbation, flare, or
relapse,) is defined clinically as the sudden appearance or
worsening of a symptom or symptoms of neurological dysfunction,
with or without objective confirmation.
[0082] Clinical evidence of a lesion is defined as signs of
neurological dysfunction demonstrable by neurological examination.
An abnormal sign constitutes clinical evidence even if no longer
present, but was recorded in the past by a competent examiner.
[0083] Paraclinical evidence of a lesion is defined as the
demonstration by means of various tests and procedures of the
existence of a lesion of the CNS that has not produced clinical
signs but that may or may not have caused symptoms in the past.
Such evidence may be derived from the hot-bath test, evoked
response studies, neuroimaging, and expert neurological assessment.
These tests are considered to be extensions of the neurological
examination and not laboratory procedures.
[0084] As used herein, the term "glatiramoid" refers a complex
mixture of the acetate salts of synthetic polypeptides, non-uniform
with respect to molecular weight and sequence.
[0085] This invention is illustrated in the Examples section which
follows. This section is set forth to aid in an understanding of
the invention but is not intended to, and should not be construed
to, limit in any way the invention as set forth in the claims which
follow thereafter.
EXPERIMENTAL DETAILS
Example 1
[0086] A multinational, multicenter, randomized, phase III
parallel-group study performed in subjects with Relapsing-Remitting
Multiple Sclerosis (RRMS) to assess the efficacy, safety and
tolerability of Glatiramer Acetate (GA) injection 40 mg/ml
administered three times weekly by subcutaneous injection over
placebo in a double-blind design.
Methods:
[0087] The study is designed to select three days a week for
injection. Three injections are administered for every seven days
and there must be at least one day between each injection.
Study Duration:
[0088] Screening phase: 1 month [0089] Placebo Controlled (PC)
Phase: 12 months of 40 mg/ml or matching placebo administered three
times weekly by subcutaneous injection. [0090] Open Label (OL)
Extension: All subjects will continue treatment with the GA 40
mg/ml administered three times a week, until this dose is
commercially available for the treatment of relapsing remitting
multiple sclerosis (RRMS) patients or until the development of this
dose for MS is stopped by the Sponsor.
Study Population:
[0091] Subjects with RRMS
Number of Subjects:
[0092] 1350 subjects
Study Objective(s):
[0093] To assess the efficacy, safety and tolerability of
Glatiramer Acetate (GA) injection 40 mg/ml administered three times
weekly compared to placebo in a double-blind study design.
Study Design:
[0094] Eligible subjects are randomized in a 2:1 ratio (40
mg:placebo) and assigned to one of the following three treatment
arms: [0095] 1. 40 mg s.c. GA three times weekly (900 subjects)
[0096] 2. Matching placebo three times weekly (450 subjects)
[0097] During the PC phase, subjects are evaluated at study sites
for a total of 7 scheduled visits at months: -1 (screening), 0
(baseline), 1, 3, 6, 9, and 12 (End of PC phase).
[0098] Subjects successfully completing the study are offered the
opportunity to enter into an open label extension in which all
subjects will continue treatment with 40 mg/ml GA dose. This is
done until the 40 mg/ml GA dose is commercially available for the
treatment of relapsing remitting multiple sclerosis (RRMS) patients
or until the development of this dose regimen is stopped by the
Sponsor.
[0099] The termination visit of the PC phase will serve as the
baseline visit of the OL phase. This phase will include scheduled
visits every 3 months for the first 12 months, then scheduled
visits every 6 months and will be completed with a termination
visit.
[0100] During the study, the following assessments are performed
(regardless of the treatment assignment) at the specified time
points: [0101] Vital signs are measured at each study visit. [0102]
A physical examination is performed at months -1 (screening), 0
(baseline) 6, 12 (end of PC phase) and every 6 months thereafter.
In addition, a physical examination will be performed at the
termination visit of the OL phase. [0103] The following safety
clinical laboratory tests are performed: [0104] Complete blood
count (CBC) with differential--at all scheduled visits in the PC
phase, and every 12 months thereafter. In addition this test will
be performed at the termination visit of the OL phase. [0105] Serum
chemistry (including electrolytes, creatinine, urea and liver
enzymes) and urinalysis--at all scheduled visits in the PC phase,
and every 12 months thereafter. In addition this test will be
performed at the termination visit of the OL phase. [0106] Serum
.beta.-hCG in women of child-bearing potential is performed at
months -1 (screening), 0 (baseline), 12 (end of PC phase), and
every 12 months thereafter. In addition this test will be performed
at the termination visit of the OL phase. [0107] ECG is performed
at months -1 (screening), 0 (baseline), 12 (end of PC phase), and
every 12 months thereafter. In addition an ECG will be performed at
the termination visit of the OL phase. [0108] Chest X-ray is
performed at month -1 (screening) if not performed within 6 months
prior to screening visit. [0109] Adverse Events (AEs) are monitored
throughout the study. [0110] Concomitant Medications are monitored
throughout the study. [0111] Neurological evaluations, including
Neurostatus [Functional Systems (FS), Expanded Disability Status
Scale (EDSS), Ambulation Index (AI)] are performed at months -1
(screening), 0 (baseline), 3, 6, 9, 12 (end of PC phase) and every
6 months thereafter. In addition, a neurological examination are
performed at the termination visit of the OL phase. [0112] The
general health status is assessed by the EuroQoL (EQ5D)
questionnaire at months 0 (baseline) and 12 (end of PC phase).
[0113] Additional quality of life parameters are assessed by the
WPAI (Work Productivity and Activities Impairment) Questionnaire at
month 0 (baseline), 3, 6, 9 and 12 (end of PC phase). [0114] All
subjects undergo MRI scans at months 0 (13-7 days prior to baseline
visit), 6 and 12 (end of PC phase). Following the results of the PC
phase, the Sponsor may decide to perform an MRI scan at the
termination visit of the OL phase. [0115] Relapses are
confirmed/monitored throughout the study.
Ancillary Studies:
[0115] [0116] Blood samples for determination of anti-GA antibodies
are collected for all subjects at months 0 (baseline), 1, 3, 6, 9,
12 (end of PC phase), 18 and 24. [0117] Blood samples for
evaluation of PBL proliferation in response to GA, as well as other
immunological parameters, are collected in a subset of subjects at
months 0 (baseline), 1, 3, 6, and 12 (end of PC phase). [0118]
Blood samples for Pharmacogenetic (PGx) analysis are collected for
all subjects twice during the study, preferably at month 0
(baseline) and month 1.
[0119] The allowed treatment for a multiple sclerosis relapse will
be intravenous methylprednisolone 1 gr/day for up to 5 consecutive
days.
Re-Consent Criteria
[0120] In case of a confirmed diagnosis of MS relapse (as defined
in the protocol), or in case of an increase in EDSS of 1.5 points
or more, sustained for at least 3 months, during the
placebo-controlled phase, the following actions are taken: [0121]
The subject is reminded of the current available MS
medications/treatments and the opportunity to terminate the study.
[0122] The subject is requested to re-sign an informed consent form
if he/she chooses to continue to participate in the study, in the
same treatment assignment.
[0123] The study is closely monitored through the study course by
the sponsor's personnel as well as by an external independent data
monitoring committee (DMC) in order to ensure subjects'
welfare.
Inclusion/Exclusion:
Inclusion Criteria:
[0124] Subjects must have a confirmed and documented MS diagnosis
as defined by the Revised McDonald criteria (Ann Neurol 2005:
58:840-846), with a relapsing-remitting disease course. [0125]
Subjects must be ambulatory with an EDSS score of 0-5.5 in both
screening and baseline visits. [0126] Subjects must be in a
relapse-free, stable neurological condition and free of
corticosteroid treatment [intravenous (IV), intramuscular (IM)
and/or per os (PO)] or ACTH 30 days prior to screening (month -1)
and between screening (month -1) and baseline (month 0) visits.
[0127] Subjects must have had experienced one of the following:
[0128] At least one documented relapse in the 12 months prior to
screening, or [0129] At least two documented relapses in the 24
months prior to screening, or [0130] One documented relapse between
12 and 24 months prior to screening with at least one documented
T.sub.1-Gd enhancing lesion in an MRI performed within 12 months
prior to screening. [0131] Subjects must be between 18 and 55 years
of age, inclusive. [0132] Women of child-bearing potential must
practice an acceptable method of birth control [acceptable methods
of birth control in this study include: surgical sterilization,
intrauterine devices, oral contraceptive, contraceptive patch,
long-acting injectable contraceptive, partner's vasectomy or a
double-barrier method (condom or diaphragm with spermicide)].
[0133] Subjects must be able to sign and date a written informed
consent prior to entering the study. [0134] Subjects must be
willing and able to comply with the protocol requirements for the
duration of the study.
Exclusion Criteria:
[0134] [0135] Subjects with progressive forms of MS. [0136] Use of
experimental or investigational drugs, and/or participation in drug
clinical studies within the 6 months prior to screening. [0137] Use
of immunosuppressive (including Mitoxantrone (Novantrone.RTM.) or
cytotoxic agents within 6 months prior to the screening visit.
[0138] Previous use of either natalizumab (Tysabri.RTM.) or any
other monoclonal antibodies within 2 years prior to screening.
[0139] Use of cladribine within 2 years prior to screening. [0140]
Previous treatment with immunomodulators (including IFN.beta. 1a
and 1b, and IV Immunoglobulin (IVIg) within 2 months prior to
screening. [0141] Previous use of GA or any other glatiramoid.
[0142] Chronic (more than 30 consecutive days) systemic (IV, PO or
IM) corticosteroid treatment within 6 months prior to screening
visit. [0143] Previous total body irradiation or total lymphoid
irradiation. [0144] Previous stem-cell treatment, autologous bone
marrow transplantation or allogenic bone marrow transplantation.
[0145] Known human immunodeficiency virus (HIV) positive status.
[0146] Pregnancy or breastfeeding. [0147] Subjects with a
clinically significant or unstable medical or surgical condition
that would preclude safe and complete study participation, as
determined by medical history, physical exams, ECG, abnormal
laboratory tests and chest X-ray. Such conditions may include
hepatic, renal or metabolic diseases, systemic disease, acute
infection, current malignancy or recent history (5 years) of
malignancy, major psychiatric disorder, history of drug and/or
alcohol abuse and allergies that could be detrimental according to
the investigator's judgment. [0148] A known history of sensitivity
to Gadolinium. [0149] Inability to successfully undergo MRI
scanning. [0150] A known drug hypersensitivity to mannitol.
Route and Dosage Form:
[0150] [0151] Glatiramer Acetate 40 mg in 1 ml for subcutaneous
injection in a pre-filled syringe (PFS), administered three times a
week. [0152] Matching placebo injection (mannitol in 1 ml WFI) for
subcutaneous injection in a pre-filled syringe (PFS).
Outcome Measures:
Primary Outcome Measure:
[0152] [0153] The total number of confirmed relapses during the 12
month PC phase.
Secondary Outcome Measure:
[0153] [0154] The number of new T.sub.2 lesions at month 12 (end of
PC phase) as compared to baseline scan. [0155] The cumulative
number of enhancing lesions on T.sub.1-weighted images taken at
months 6 and 12 (end of PC phase). [0156] Brain atrophy as defined
by the percent brain volume change from baseline to month 12 (end
of PC phase).
Exploratory Endpoints:
[0157] The following assessments are presented in an exploratory
manner. [0158] The time to the first confirmed relapse during the
placebo-controlled phase. [0159] The proportion of relapse-free
subjects during the placebo-controlled phase. [0160] The total
number of confirmed relapses during the placebo-controlled phase
requiring hospitalization and/or IV steroids. [0161] The proportion
(%) of subjects with confirmed EDSS progression during the
placebo-controlled phase (progression of at least 1 EDSS point
sustained for at least 3 months). [0162] Change from baseline to
month 12 (end of placebo-controlled phase) in EDSS Score. [0163]
Change from baseline to month 12 (end of placebo-controlled phase)
in Ambulation Index. [0164] The total volume of T.sub.2 lesions at
month 12 (end of placebo-controlled phase) [0165] The number of new
hypointense lesions on enhanced T.sub.1 scans at month 12 (end of
placebo-controlled phase) as compared to the baseline scan. [0166]
The total volume of hypointense lesions on enhanced T.sub.1 scans
at month 12 (end of placebo-controlled phase). [0167] Brain atrophy
as defined by the percentage change from baseline to month 12 (end
of placebo-controlled phase) in normalized gray matter volume and
in normalized white matter volume. [0168] The general health
status, as assessed by the EuroQoL (EQ5D) questionnaire. [0169]
Assessment of the effect of general health and symptom severity on
work, using the work productivity and activities impairment-General
Health (WPAI-GH) questionnaire.
Safety and Tolerability Outcome Measures:
Safety:
[0169] [0170] Adverse events [0171] Vital signs [0172] ECG findings
[0173] Clinical laboratory parameters
Tolerability:
[0173] [0174] Proportion of subjects (%) who prematurely
discontinued from the study, reason of discontinuation and the time
to withdrawal. [0175] Proportion of subjects (%) who prematurely
discontinued from the study, due to AEs and the time to
withdrawal.
Statistical Considerations:
[0176] The sample size considerations for the study are based on
the following assumptions: [0177] An individual subject's number of
confirmed relapses during a one year period reflects a Poisson
process with an individual rate of .lamda.i, and this individual
subject rates .lamda.i are exponentially distributed with mean
1/.theta., where .theta. is the population's annualized relapse
rate. This approach models the total number of confirmed relapses
as an Over Dispersed Poisson distribution. [0178] The expected
annualized relapse rate in an untreated subject population is
.theta.=0.35 relapses per year. [0179] Treatment with 40 mg s.c. GA
three times weekly reduces the subject population annualized
relapse rate by 30% or more when compared to the placebo group.
That is, the expected annualized relapse rate of the GA treated
populations is .theta.=0.245 relapses per year or less.
[0180] In addition, the following are also incorporated in the
sample size calculation: [0181] 15% of the subjects drop out during
the treatment duration. This drop out rate is taken into account in
the calculations, as on the average, a subject who drops out of the
study contributes 6 months of exposure to the treatment
[0182] Hochberg's step-up modification to Bonferroni's method is
used to maintain the experiment-wise type-I error when comparing
multiple treatment arms to placebo, and the p-values for the IAs
are calculated using the O'brien-Fleming alpha spending
functions.
[0183] A simulation study accounting for the above underlying
assumptions used the Quasi-Likelihood (over-dispersed) Poisson
Regression (SAS.RTM. PROC GENMOD), revealed that a total of 1350
subjects (900 subjects in the 40 mg GA arm, and 450 subjects to the
placebo arm) provide approximately 90% power to detect a
significant difference in the total number of confirmed relapses as
described above.
[0184] The analysis of the total numbers of confirmed relapses
during the study period is based on baseline adjusted
Quasi-Likelihood (over-dispersed) Poisson Regression.
[0185] The analysis of the number of new T.sub.2 lesions at month
12 and of the cumulative number of enhancing lesions on
T.sub.1-weighted images taken at months 6 and 12 is based on
baseline-adjusted Negative Binomial Regression.
[0186] The analysis of Brain Atrophy will be based on Analysis of
Covariance (ANCOVA).
Results
Primary Outcome Measure:
[0187] Treatment with 40 mg s.c. GA three times weekly reduces the
subject population annualized relapse rate by 30% or more when
compared to the placebo group. Treatment with 40 mg s.c. GA three
times weekly is at least as effective as 20 mg s.c. GA daily
administration at reducing the subject population annualized
relapse rate.
Secondary Outcome Measures:
[0188] Treatment with 40 mg s.c. GA three times weekly
significantly reduces the number of new T.sub.2 lesions at month
12. Treatment with 40 mg s.c. GA three times weekly is at least as
effective as 20 mg s.c. GA daily administration at reducing the
number of new T.sub.2 lesions at month 12. [0189] Treatment with 40
mg s.c. GA three times weekly significantly reduces the cumulative
number of enhancing lesions on T.sub.1-weighted images taken at
months 6 and 12. Treatment with 40 mg s.c. GA three times weekly is
at least as effective as 20 mg s.c. GA daily administration at
reducing the cumulative number of enhancing lesions on
T.sub.1-weighted images taken at months 6 and 12. [0190] Treatment
with 40 mg s.c. GA three times weekly significantly reduces brain
atrophy as defined by the percent brain volume change from baseline
to month 12. Treatment with 40 mg s.c. GA three times weekly is at
least as effective as 20 mg s.c. GA daily administration at
reducing brain atrophy as defined by the percent brain volume
change from baseline to month 12.
Exploratory Endpoints:
[0190] [0191] Treatment with 40 mg s.c. GA three times weekly
significantly increases the time to the first confirmed relapse
during the placebo-controlled phase. Treatment with 40 mg s.c. GA
three times weekly is at least as effective as 20 mg s.c. GA daily
administration at increasing the time to the first confirmed
relapse during the placebo-controlled phase. [0192] Treatment with
40 mg s.c. GA three times weekly significantly increases the
proportion of relapse-free subjects during the placebo-controlled
phase. Treatment with 40 mg s.c. GA three times weekly is at least
as effective as 20 mg s.c. GA daily administration at increasing
the proportion of relapse-free subjects during the
placebo-controlled phase. [0193] Treatment with 40 mg s.c. GA three
times weekly significantly increases the proportion of relapse-free
subjects during the placebo-controlled phase. Treatment with 40 mg
s.c. GA three times weekly is at least as effective as 20 mg s.c.
GA daily administration at increasing the proportion of
relapse-free subjects during the placebo-controlled phase. [0194]
Treatment with 40 mg s.c. GA three times weekly significantly
reduces the total number of confirmed relapses during the
placebo-controlled phase requiring hospitalization and/or IV
steroids. Treatment with 40 mg s.c. GA three times weekly is at
least as effective as 20 mg s.c. GA daily administration at
reducing the total number of confirmed relapses during the
placebo-controlled phase requiring hospitalization and/or IV
steroids. [0195] Treatment with 40 mg s.c. GA three times weekly
significantly reduces the progression of MRI-monitored disease
activity in the patient. Treatment with 40 mg s.c. GA three times
weekly is at least as effective as 20 mg s.c. GA daily
administration at reducing the progression of MRI-monitored disease
activity in the patient. [0196] Treatment with 40 mg s.c. GA three
times weekly significantly reduces the total volume of T.sub.2
lesions at month 12. Treatment with 40 mg s.c. GA three times
weekly is at least as effective as 20 mg s.c. GA daily
administration at reducing total volume of T.sub.2 lesions at month
12. [0197] Treatment with 40 mg s.c. GA three times weekly
significantly reduces the number of new hypointense lesions on
enhanced T.sub.1 scans at month 12 as compared to the baseline
scan. Treatment with 40 mg s.c. GA three times weekly is at least
as effective as 20 mg s.c. GA daily administration at reducing the
number of new hypointense lesions on enhanced T.sub.1 scans at
month 12 as compared to the baseline scan. [0198] Treatment with 40
mg s.c. GA three times weekly significantly reduces the total
volume of hypointense lesions on enhanced T.sub.1 scans at month
12. Treatment with 40 mg s.c. GA three times weekly is at least as
effective as 20 mg s.c. GA daily administration at reducing the
total volume of hypointense lesions on enhanced T.sub.1 scans at
month 12. [0199] Treatment with 40 mg s.c. GA three times weekly
significantly reduces brain atrophy as defined by the percentage
change from baseline to month 12 in normalized gray matter volume
and in normalized white matter volume. Treatment with 40 mg s.c. GA
three times weekly is at least as effective as 20 mg s.c. GA daily
administration at reducing brain atrophy as defined by the
percentage change from baseline to month 12 in normalized gray
matter volume and in normalized white matter volume. [0200]
Treatment with 40 mg s.c. GA three times weekly significantly
reduces the level of disability as measured by EDSS Score.
Treatment with 40 mg s.c. GA three times weekly is at least as
effective as 20 mg s.c. GA daily administration at reducing the
level of disability as measured by EDSS Score. [0201] Treatment
with 40 mg s.c. GA three times weekly significantly reduces the
proportion (%) of subjects with confirmed EDSS progression during
the placebo-controlled phase (progression of at least 1 EDSS point
sustained for at least 3 months). Treatment with 40 mg s.c. GA
three times weekly is at least as effective as 20 mg s.c. GA daily
administration at reducing proportion (%) of subjects with
confirmed EDSS progression during the placebo-controlled phase
(progression of at least 1 EDSS point sustained for at least 3
months). [0202] Treatment with 40 mg s.c. GA three times weekly
significantly reduces the change from baseline to month 12 (end of
placebo-controlled phase) in EDSS Score. Treatment with 40 mg s.c.
GA three times weekly is at least as effective as 20 mg s.c. GA
daily administration at reducing the change from baseline to month
12 (end of placebo-controlled phase) in EDSS Score. [0203]
Treatment with 40 mg s.c. GA three times weekly significantly
reduces the change from baseline to month 12 (end of
placebo-controlled phase) in Ambulation Index. Treatment with 40 mg
s.c. GA three times weekly is at least as effective as 20 mg s.c.
GA daily administration at reducing the change from baseline to
month 12 (end of placebo-controlled phase) in Ambulation Index.
[0204] Treatment with 40 mg. s.c. GA three times weekly
significantly reduces the level of disability as measured by
EuroQoL (EQ5D) questionnaire. Treatment with 40 mg s.c. GA three
times weekly is at least as effective as 20 mg s.c. GA daily
administration at reducing the level of disability as measured by
EuroQoL (EQ5D) questionnaire. [0205] Treatment with 40 mg s.c. GA
three times weekly significantly reduces the level of disability as
measured by the work productivity and activities impairment-General
Health (WPAI-GH) questionnaire. Treatment with 40 mg s.c. GA three
times weekly is at least as effective as 20 mg s.c. GA daily
administration at reducing the level of disability as measured by
the work productivity and activities impairment-General Health
(WPAI-GH) questionnaire.
Discussion
[0206] A significant drawback to GA therapy is the requirement of
daily injections, which can be inconvenient. Moreover, in all
clinical trials, injection-site reactions were seen to be the most
frequent adverse reactions and were reported by the majority of
patients receiving GA. In controlled studies, the proportion of
patients reporting these reactions, at least once, was higher
following treatment with GA (70%) than placebo injections (37%).
The most commonly reported injection-site reactions, which were
more frequently reported in GA vs. placebo-treated patients, were
erythema, pain, mass, puritus, edema, inflammation and
hypersensitivity.
[0207] However, several obstacles and limitations with potential
approaches for addressing the drawbacks exist to current GA
therapy. Subcutaneous drug delivery is limited, firstly, by the
acceptable injection volume. Typically no more than 1 to 2 ml of
solution is permitted (Kansara V, Mitra A, Wu Y, Subcutaneous
Delivery. Drug Deliv Technol, June 2009; 9(6):38-42). Secondly, the
potential exists for drug degradation at the site of injection
resulting in reduced bioavailability. Thirdly, based on the
physiochemical properties of the drug, potent compounds may become
locally trapped in the interstitial space which can lead to further
localized irritation, precipitation of the drug and
concentration-dependent adverse effects (Kansara V, Mitra A, Wu Y,
Subcutaneous Delivery. Drug Deliv Technol, June 2009; 9(6):38-42).
Finally, due to the complex pharmacokinetic behavior of a drug,
variation in the frequency of administration is unpredictable and
requires empirical testing. For example, although controlled
clinical trials have demonstrated the efficacy of IFN.beta.-1b in
the treatment of MS, patient compliance, efficacy and tolerability
are affected by the dosage regimen used. Merely increasing the dose
of IFN.beta.-1b is insufficient to increase efficacy, the frequency
of administration must also be increased (Luca Durelli, J Neurol
(2003) 250 [Suppl 4]).
[0208] Accordingly, the subject application discloses an effective
low frequency dosage regimen of GA administration to patients
suffering from a relapsing form of multiple sclerosis, including
patients who have experienced a first clinical episode and have MRI
features consistent with multiple sclerosis. Based on the
performance of the dosage regimen in these studies, the
administration of three s.c. injections over a period of seven days
with at least one day between every injection is also expected to
work in the treatment of patients who have experienced a clinically
isolated syndrome (CIS). This is based on the fact that the 20 mg
daily s.c. injection has been shown to work in PCT International
Application No. PCT/US2008/013146 (see International Publication
No. WO 2009/070298 and also U.S. Patent Application Publication No.
US 2009-0149541 A1).
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