U.S. patent application number 14/224766 was filed with the patent office on 2014-07-31 for soluble tumor necrosis factor receptor treatment of medical disorders.
This patent application is currently assigned to Immunex Corporation. The applicant listed for this patent is Immunex Corporation. Invention is credited to Barbara K. FINCK.
Application Number | 20140212420 14/224766 |
Document ID | / |
Family ID | 46301347 |
Filed Date | 2014-07-31 |
United States Patent
Application |
20140212420 |
Kind Code |
A1 |
FINCK; Barbara K. |
July 31, 2014 |
SOLUBLE TUMOR NECROSIS FACTOR RECEPTOR TREATMENT OF MEDICAL
DISORDERS
Abstract
The invention pertains to methods and compositions for treating
medical disorders characterized by elevated levels or abnormal
expression of TNF.alpha. by administering a TNF.alpha. antagonist,
such as recombinant TNFR:Fc.
Inventors: |
FINCK; Barbara K.; (San
Francisco, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Immunex Corporation |
Thousand Oaks |
CA |
US |
|
|
Assignee: |
Immunex Corporation
Thousand Oaks
CA
|
Family ID: |
46301347 |
Appl. No.: |
14/224766 |
Filed: |
March 25, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13773319 |
Feb 21, 2013 |
8722631 |
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14224766 |
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13367071 |
Feb 6, 2012 |
8410060 |
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13773319 |
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13021545 |
Feb 4, 2011 |
8119605 |
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13367071 |
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12394962 |
Feb 27, 2009 |
7915225 |
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13021545 |
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10853479 |
May 25, 2004 |
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12394962 |
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09602351 |
Jun 23, 2000 |
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10853479 |
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09373828 |
Aug 13, 1999 |
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09602351 |
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60164676 |
Nov 10, 1999 |
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60184864 |
Feb 25, 2000 |
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60130074 |
Apr 19, 1999 |
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60134320 |
May 14, 1999 |
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60143959 |
Jul 15, 1999 |
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60148234 |
Aug 11, 1999 |
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Current U.S.
Class: |
424/134.1 |
Current CPC
Class: |
Y10S 530/866 20130101;
Y10S 514/863 20130101; A61K 38/1793 20130101; C07K 2319/30
20130101; A61P 17/06 20180101; A61K 38/1793 20130101; C07K 14/70578
20130101; A61K 39/39533 20130101; A61K 31/519 20130101; A61K
2300/00 20130101; A61K 38/00 20130101; A61K 31/519 20130101; A61K
2300/00 20130101; A61P 19/02 20180101 |
Class at
Publication: |
424/134.1 |
International
Class: |
A61K 38/17 20060101
A61K038/17; A61K 39/395 20060101 A61K039/395 |
Claims
1. A method for treating a patient having psoriasis comprising
administering to the patient a therapeutically effective dose of
TNFR:Fc.
2. The method of claim 1, wherein the patient has psoriatic
arthritis.
3. The method of claim 2, wherein a dose of 50-100 mg is
administered once per week.
4. The method of claim 2, wherein a dose of 25-50 mg is
administered twice per week.
5. The method of claim 2, wherein the TNFR:Fc is administered by
subcutaneous injection.
6. The method of claim 1, wherein the patient does not have
psoriatic arthritis.
7. The method of claim 6, wherein a dose of 50-100 mg is
administered once per week.
8. The method of claim 6, wherein a dose of 25-50 mg is
administered twice per week.
9. The method of claim 6, wherein the TNFR:Fc is administered by
subcutaneous injection.
10. The method of claim 1, wherein the patient has plaque
psoriasis.
11. The method of claim 10, wherein the patient has psoriatic
arthritis.
12. The method of claim 11, wherein a dose of 50-100 mg is
administered once per week.
13. The method of claim 11, wherein a dose of 25-50 mg is
administered twice per week.
14. The method of claim 11, wherein the TNFR:Fc is administered by
subcutaneous injection.
15. The method of claim 10, wherein the patient does not have
psoriatic arthritis.
16. The method of claim 15, wherein a dose of 50-100 mg is
administered once per week.
17. The method of claim 15, wherein a dose of 25-50 mg is
administered twice per week.
18. The method of claim 15, wherein the TNFR:Fc is administered by
subcutaneous injection.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 13/773,319, filed Feb. 21, 2013, now allowed, which is a
divisional of U.S. application Ser. No. 13/367,071, filed Feb. 6,
2012, now U.S. Pat. No. 8,410,060; which is a divisional of U.S.
application Ser. No. 13/021,545, filed Feb. 4, 2011, now U.S. Pat.
No. 8,119,605; which is a continuation of U.S. application Ser. No.
12/394,962, filed Feb. 27, 2009, now U.S. Pat. No. 7,915,225; which
is a divisional of U.S. application Ser. No. 10/853,479, filed May
25, 2004, now abandoned; which is a divisional of U.S. application
Ser. No. 09/602,351, filed Jun. 23, 2000, now abandoned, which
claims benefit of U.S. Provisional Application Nos. 60/164,676,
filed Nov. 10, 1999, now abandoned, and 60/184,864, filed Feb. 25,
2000, now abandoned; and which is a continuation-in-part of U.S.
application Ser. No. 09/373,828, filed Aug. 13, 1999, now
abandoned, which claims the benefit of U.S. Provisional Application
Nos. 60/130,074, filed Apr. 19, 1999, now abandoned, 60/134,320,
filed May 14, 1999, now abandoned, 60/143,959, filed Jul. 15, 1999,
now abandoned, and 60/148,234, filed Aug. 11, 1999, now abandoned;
all of which are incorporated herein by reference in their
entirety.
FIELD OF THE INVENTION
[0002] The invention pertains to methods for treating various
medical disorders that are characterized by abnormal or excessive
TNF.alpha. levels by administering a TNF.alpha. antagonist,
preferably a soluble TNF.alpha.. The TNF.alpha. inhibitor may be
administered in combination with other biologically active
molecules.
BACKGROUND OF THE INVENTION
[0003] The pleiotropic cytokine tumor necrosis factor alpha
(TNF.alpha.) is associated with inflammation and binds to cells
through membrane receptor molecules, including two molecules having
molecular weights of approximately 55 kDa and 75 kDa (p55 and p75).
In addition to binding TNF.alpha., the p55 and p75 TNF receptors
mediate the binding to cells of homotrimers of TNF.beta., which is
another cytokine associated with inflammation and which shares
structural similarities with TNF.alpha. (e.g., see Cosman, Blood
Cell Biochem 7:51-77, 1996). TNF.beta. is also known as
lymphotoxin-.alpha. (LT.alpha.).
[0004] It has been proposed that a systemic or localized excess of
TNF.alpha. contributes to the progression of numerous medical
disorders. For example, patients with chronic heart failure have
elevated levels of serum TNF.alpha., which have been shown to
increase with disease progression (see, for example, Levine et al.,
N Eng J Med 323:236-241, 1990). A variety of other diseases are
associated with elevated levels of TNF.alpha. (see, for example,
Feldman et al., Transplantation Proceedings 30:4126-4127,
1998).
[0005] Psoriatic arthritis (PsA) is a chronic autoimmune condition
that shares some features with both rheumatoid arthritis (RA) and
the inflammatory skin disease psoriasis (for review, see
Breathnach, In Klippel and Dieppe eds. Rheumatology, 2.sup.nd Ed.,
Mosby, 1998, 22.1-22.4). Psoriasis is characterized by epidermal
keratinocyte hyperproliferation, accompanied by neutrophil and T
cell infiltration, and is associated with elevated levels of
inflammatory cytokines, including TNF.alpha., IL-6 and TGF.beta.
(see, for example, Bonifati et al., Clin Exp Dermatol 19:383-387,
1994). Psoriasis and PsA are different clinical entities, and are
associated with somewhat different MHC haplotypes (Gladman, Rheum
Dis Clin NA. 18:247-256, 1992; Breathnach, 1998). The overall
prognosis for PsA is far worse than for ordinary psoriasis.
Nonetheless, treatments used for the psoriatic lesions of PsA
generally are similar to those used to treat psoriasis.
[0006] Psoriatic skin lesions are present in patients with PsA,
although only a minority of psoriasis sufferers actually have PsA.
Ordinary psoriasis occasionally is accompanied by joint pain, but
does not involve the extreme pain and often deforming degeneration
of joints and bone that occurs in PsA patients.
[0007] Treatments that sometimes are effective in treating ordinary
psoriasis include topical medications (e.g., steroids, coal tar,
anthralin, Dead Sea salts, various natural oils, vitamin D3 and its
analogs, sunshine, topical retinoids), phototherapy (e.g.,
ultraviolet light, photochemotherapy (PUVA)), and internal
medications (e.g., methotrexate, systemic steroids, oral retinoids,
cyclosporine, or a rotating regimen of these three). In addition,
it has been proposed that psoriasis could be treated with
TNF-derived peptides, quinolinesulfonamides, pyrrolidinone
derivatives, catechol diether compounds, isoxazoline compounds,
matrix metalloproteinase inhibitors or mercapto alkyl peptidyl
compounds, all of which inhibit either TNF.alpha. production or its
release from cultured cells (see, for example, U.S. Pat. No.
5,691,382, U.S. Pat. No. 5,834,485, U.S. Pat. No. 5,420,154, U.S.
Pat. No. 5,563,143, U.S. Pat. No. 5,869,511 and U.S. Pat. No.
5,872,146), as well as with various combination therapies involving
TNF.alpha. antagonists (for example, see U.S. Pat. No. 5,888,511 or
U.S. Pat. No. 5,958,413).
[0008] Conflicting results have been reported regarding the role of
TNF.alpha. in psoriasis. Some investigators have proposed that
overproduction of TNF.alpha. contributes to the pathology of
psoriasis (e.g., Pigatto et al., J Invest Dermatol 94:372-376,
1990; Sagawa et al., Dermatol 187:81-83, 1993; Ameglio et al.,
Dermatol 189:359-363, 1994). One group reported some improvement
after treatment with pentoxifylline, a drug that can inhibit the
release of TNF.alpha., but which exerts many of its physiological
effects by inhibiting cyclic AMP phosphodiesterase (Omulecki et
al., J Am Acad Dermatol 34:714-715, 1996; Centola et al., J Androl
16:136-142, 1995; Elferinck et al., Biochem Pharmacol 54:475-480,
1997). However, other reports have cast doubt on the hypothesis
that overproduction of TNF.alpha. exacerbates psoriasis. For
example, some investigators have reported that treatment with
TNF.alpha. itself actually can mitigate psoriasis (see, e.g.,
Takematsu et al., Br J Dermatol 124:209-210, 1991; Creaven et al.,
J Am Acad Dermatol 24:735-737, 1991).
[0009] In addition to psoriatic lesions, PsA is characterized by
distal interphalangeal joint (DIP) involvement, enthesopathy, nail
lesions, spondylitis and dactylitis. The histopathogenesis of PsA
and the more well-studied rheumatoid arthritis share certain
features. In both RA and in active PsA, patients exhibit increased
levels of HLA-DR.sup.+ T cells and MHC class II antigens in their
synovial membranes and synovial fluid, as well as increased
expression of the cytokine TNF.alpha.. In addition, both diseases
are associated with prominent synovial vascular changes.
[0010] The discovery of rheumatoid factor in the serum of RA
patients provided an important tool for differentiating PsA from
RA, but the realization that RA and PsA are distinct diseases was
based primarily on their many clinical differences (e.g., Helliwell
and Wright, In Klippel and Dieppe eds. Rheumatology, 2.sup.nd Ed.,
Mosby, 1998, 21.1-21.8). Studies have shown that levels of
TNF.alpha., I1-1.beta., I1-8 as well as TNF.alpha. receptors in
synovial fluids were higher in PsA patients than in osteoarthritis
patients, though they were lower than in RA patients (Partsch et
al., J Rheumatol 24:518-523, 1997; Partsch et al., J Rheumatol
25:105-110, 1998; Partsch et al., Ann Rheum Dis 57:691-693, 1998).
PsA is distinguished from RA also by radiographic appearance, a
notably higher degree of synovial membrane vascularity as well as
differences in the levels of various cytokines in the synovial
fluids (Ritchlin et al., J Rheumatol 25:1544-52, 1998; Veale et
al., Arth Rheum 36:893-900, 1993). Veale et al. noted differences
in synovial membrane adhesion molecules and numbers of macrophages
when they compared RA and PsA patients, as well as observing a
minimal degree of hyperplasia and hypertrophy of synoviocytes in
PsA as compared with RA patients. Because of such differences,
coupled with the association of PsA but not RA with class I MHC
antigens, Ritchlin et al. have suggested that PsA must be triggered
by different mechanisms than those underlying RA. Veale et al.
suggested for similar reasons that different cytokines were likely
to be interacting in the synovium of PsA and RA patients.
[0011] Most of the drugs used for treating the arthritic aspects of
PsA are similar to those used in RA (Salvarini et al., Curr Opin
Rheumatol 10:229-305, 1998), for example the non-steroidal
antiinflammatories (NSAIDs), which may be used alone or in
combination with the disease-modifying anti-rheumatic drugs, or
"DMARDs." However, one group found that long-term administration of
the DMARD methotrexate failed to slow the progression of joint
damage in PsA patients (Abu-Shakra et al., J Rheumatol 22:241-45,
1995), and another group reported very little improvement in PsA
patients who had received methotrexate (Willkens et al., Arthr
Rheum 27:376-381, 1984). Similarly, Clegg et al. found only a
slight improvement over placebo in PsA patients treated with
sulfasalazine, another drug classified as a DMARD (Clegg et al.,
Arthritis Rheum 39: 2013-20, 1996). Some studies have indicated
that the immunosuppressor cyclosporine is effective in treating PsA
(reviewed in Salvarini et al., 1998), though this drug has severe
side effects. In addition, others have proposed that PsA could be
treated with truncated TNF.alpha. receptors or with a combination
of methotrexate and antibodies against TNF.alpha. (WO 98/01555; WO
98/0537).
[0012] A recent meta-analysis of a number of PsA treatment studies
concluded that PsA and RA differed not only in their response to
treatment with specific drugs, but in the relative magnitudes of
improvement in the placebo arms of the studies (Jones et al., Br J
Rheumatol 36:95-99, 1997). As an example, PsA patients responded
better to gold salt therapy than did RA patients, though the gold
did not affect the psoriatic skin lesions (Dorwart et al.,
Arthritis Rheum 21:515-513, 1978).
[0013] It has been suggested that the suppression of TNF.alpha.
might be beneficial in patients suffering from various disorders
characterized by abnormal or excessive TNF.alpha. expression.
However, although progress has been made in devising effective
treatment for such diseases, improved medicaments and methods of
treatment are needed.
SUMMARY OF THE INVENTION
[0014] Provided herein are methods for treating a number of medical
disorders characterized by abnormal TNF.alpha. expression by
repeatedly administering an antagonist of TNF.alpha., such as a
soluble TNF.alpha. receptor, for a period of time sufficient to
induce a sustained improvement in the patient's condition.
DETAILED DESCRIPTION OF THE INVENTION
[0015] This invention provides compounds, compositions and methods
for treating a mammalian patient, including a human patient, who is
suffering from a medical disorder that is characterized by abnormal
or elevated expression of TNF.alpha.. For purposes of this
disclosure, the terms "illness," "disease," "medical condition,"
"abnormal condition" and the like are used interchangeably with the
term "medical disorder."
[0016] The subject methods involve administering to the patient a
soluble TNF.alpha. antagonist that is capable of reducing the
effective amount of endogenous biologically active TNF.alpha., such
as by reducing the amount of TNF.alpha. produced, or by preventing
the binding of TNF.alpha. to its cell surface receptor (TNFR).
Antagonists capable of inhibiting this binding include
receptor-binding peptide fragments of TNF.alpha., antibodies
directed against TNF.alpha., and recombinant proteins comprising
all or portions of receptors for TNF.alpha. or modified variants
thereof, including genetically-modified muteins, multimeric forms
and sustained-release formulations. Other compounds suitable for
treating the diseases described herein include thalidomide and
pentoxifylline.
[0017] Preferred embodiments of the invention utilize soluble TNFRs
as the TNF.alpha. antagonist. Soluble forms of TNFRs may include
monomers, fusion proteins (also called "chimeric proteins), dimers,
trimers or higher order multimers. In certain embodiments of the
invention, the soluble TNFR derivative is one that mimics the 75
kDa TNFR or the 55 kDa TNFR and that binds to TNF.alpha. in the
patient's body. The soluble TNFR mimics of the present invention
may be derived from TNFRs p55 or p75 or fragments thereof. TNFRs
other than p55 and p75 also are useful for deriving soluble
compounds for treating the various medical disorders described
herein, such for example the TNFR described in WO 99/04001. Soluble
TNFR molecules used to construct TNFR mimics include, for example,
analogs or fragments of native TNFRs having at least 20 amino
acids, that lack the transmembrane region of the native TNFR, and
that are capable of binding TNF.alpha.. Antagonists derived from
TNFRs compete for TNF.alpha. with the receptors on the cell
surface, thus inhibiting TNF.alpha. from binding to cells, thereby
preventing it from manifesting its biological activities. Binding
of soluble TNFRs to TNF.alpha. or LT.alpha. can be assayed using
ELISA or any other convenient assay. This invention provides for
the use of soluble TNF.alpha. receptors in the manufacture of
medicaments for the treatment of numerous diseases.
[0018] The soluble TNFR polypeptides or fragments of the invention
may be fused with a second polypeptide to form a chimeric protein.
The second polypeptide may promote the spontaneous formation by the
chimeric protein of a dimer, trimer or higher order muimer that is
capable of binding a TNF.alpha. and/or LT.alpha. molecule and
preventing it from binding to cell-bound receptors. Chimeric
proteins used as antagonists include, for example, molecules
derived from an antibody molecule and a TNFR. Such molecules are
referred to herein as TNFR-Ig fusion proteins. A preferred TNFR-Ig
fusion protein suitable for treating diseases in humans and other
mammals is recombinant TNFR:Fc, a term which as used herein refers
to "etanercept," which is a dimer of two molecules of the
extracellular portion of the p75 TNF.alpha. receptor, each molecule
consisting of a 235 amino acid TNFR-derived polypeptide that is
fused to a 232 amino acid Fc portion of human IgG.sub.1. Etanercept
is currently sold by Immunex Corporation under the trade name
ENBREL..RTM. Because the p75 receptor protein that it incorporates
binds not only to TNF.alpha., but also to the inflammatory cytokine
LT.alpha., etanercept can act as a competitive inhibitor not only
of TNF.alpha., but also of LT.alpha.. This is in contrast to
antibodies directed against TNF.alpha., which cannot inhibit
LT.alpha.. Also encompassed by the invention are treatments using a
compound that comprises the extracellular portion of the 55 kDa
TNFR fused to the Fc portion of IgG, as well as compositions and
combinations containing such a molecule. Encompassed also are
therapeutic methods involving the administration of TNFR-Ig
proteins derived the extracellular regions of TNF.alpha. receptor
molecules other than the p55 and p75 TNFRs, such as for example the
TNFR described in WO 99/04001.
[0019] In one preferred embodiment of the invention,
sustained-release forms of soluble TNFRs are used, including
sustained-release forms of TNFR:Fc. Sustained-release forms
suitable for use in the disclosed methods include, but are not
limited to, TNFRs that are encapsulated in a slowly-dissolving
biocompatible polymer (such as the alginate microparticles
described in U.S. Pat. No. 6,036,978), admixed with such a polymer
(including topically applied hydrogels), and or encased in a
biocompatible semi-permeable implant. In addition, the soluble TNFR
may be conjugated with polyethylene glycol (pegylated) to prolong
its serum half-life or to enhance protein delivery.
[0020] In accord with this invention, medical disorders
characterized by abnormal or excess expression of TNF.alpha. are
administered a therapeutically effective amount of a TNF.alpha.
inhibitor. The TNF.alpha. inhibitor may be a TNF.alpha.-binding
soluble TNF.alpha. receptor, preferably TNFR:Fc. As used herein,
the phrase "administering a therapeutically effective amount" of a
therapeutic agent means that the patient is treated with the agent
in an amount and for a time sufficient to induce a sustained
improvement in at least one indicator that reflects the severity of
the disorder. An improvement is considered "sustained" if the
patient exhibits the improvement on at least two occasions
separated by one or more weeks. The degree of improvement is
determined based on signs or symptoms, and determinations may also
employ questionnaires that are administered to the patient, such as
quality-of-life questionnaires.
[0021] Various indicators that reflect the extent of the patient's
illness may be assessed for determining whether the amount and time
of the treatment is sufficient. The baseline value for the chosen
indicator or indicators is established by examination of the
patient prior to administration of the first dose of the etanercept
or other TNF.alpha. inhibitor. Preferably, the baseline examination
is done within about 60 days of administering the first dose. If
the TNF.alpha. antagonist is being administered to treat acute
symptoms, such as for example to treat a traumatic knee injury, the
first dose is administered as soon as practically possible after
the injury has occurred.
[0022] Improvement is induced by administering TNFR:Fc or other
TNF.alpha. antagonist until the patient manifests an improvement
over baseline for the chosen indicator or indicators. In treating
chronic conditions, this degree of improvement is obtained by
repeatedly administering this medicament over a period of at least
a month or more, e.g., for one, two, or three months or longer, or
indefinitely. A period of one to six weeks, or even a single dose,
often is sufficient for treating acute conditions. For injuries or
acute conditions, a single dose may be sufficient.
[0023] Although the extent of the patient's illness after treatment
may appear improved according to one or more indicators, treatment
may be continued indefinitely at the same level or at a reduced
dose or frequency. Once treatment has been reduced or discontinued,
it later may be resumed at the original level if symptoms should
reappear.
[0024] Any efficacious route of administration may be used to
therapeutically administer TNFR:Fc or other TNF.alpha. antagonists.
If injected, TNFR:Fc can be administered, for example, via
intra-articular, intravenous, intramuscular, intralesional,
intraperitoneal or subcutaneous routes by bolus injection or by
continuous infusion. Other suitable means of administration include
sustained release from implants, aerosol inhalation, eyedrops, oral
preparations, including pills, syrups, lozenges or chewing gum, and
topical preparations such as lotions, gels, sprays, ointments or
other suitable techniques. Alternatively, proteinaceous TNF.alpha.
inhibitors, such as a soluble TNFR, may be administered by
implanting cultured cells that express the protein, for example, by
implanting cells that express TNFR:Fc. In one embodiment, the
patient's own cells are induced to produce TNFR:Fc by transfection
in vivo or ex vivo with a DNA that encodes TNFR:Fc. This DNA can be
introduced into the patient's cells, for example, by injecting
naked DNA or liposome-encapsulated DNA that encodes TNFR:Fc, or by
other means of transfection. When TNFR:Fc is administered in
combination with one or more other biologically active compounds,
these may be administered by the same or by different routes, and
may be administered simultaneously, separately or sequentially.
[0025] TNFR:Fc or other soluble TNFRs preferably are administered
in the form of a physiologically acceptable composition comprising
purified recombinant protein in conjunction with physiologically
acceptable carriers, excipients or diluents. Such carriers are
nontoxic to recipients at the dosages and concentrations employed.
Ordinarily, the preparation of such compositions entails combining
the TNF.alpha. antagonist with buffers, antioxidants such as
ascorbic acid, low molecular weight polypeptides (such as those
having fewer than 10 amino acids), proteins, amino acids,
carbohydrates such as glucose, sucrose or dextrins, chelating
agents such as EDTA, glutathione and other stabilizers and
excipients. Neutral buffered saline or saline mixed with
conspecific serum albumin are exemplary appropriate diluents. In
accordance with appropriate industry standards, preservatives may
also be added, such as benzyl alcohol. TNFR:Fc preferably is
formulated as a lyophilizate using appropriate excipient solutions
(e.g., sucrose) as diluents. Appropriate dosages can be determined
in standard dosing trials, and may vary according to the chosen
route of administration. The amount and frequency of administration
will depend, of course, on such factors as the nature and severity
of the indication being treated, the desired response, the age and
condition of the patient, and so forth.
[0026] In one embodiment of the invention, TNFR:Fc is administered
one time per week to treat the various medical disorders disclosed
herein, in another embodiment is administered at least two times
per week, and in another embodiment is administered at least three
times per week. An adult patient is a person who is 18 years of age
or older. If injected, the effective amount of TNFR:Fc per adult
dose ranges from 1-20 mg/m.sup.2, and preferably is about 5-12
mg/m.sup.2. Alternatively, a flat dose may be administered, whose
amount may range from 5-100 mg/dose. Exemplary dose ranges for a
flat dose to be administered by subcutaneous injection are 5-25
mg/dose, 25-50 mg/dose and 50-100 mg/dose. In one embodiment of the
invention, the various indications described below are treated by
administering a preparation acceptable for injection containing
TNFR:Fc at 25 mg/dose, or alternatively, containing 50 mg per dose.
The 25 mg or 50 mg dose may be administered repeatedly,
particularly for chronic conditions. If a route of administration
other than injection is used, the dose is appropriately adjusted in
accord with standard medical practices. In many instances, an
improvement in a patient's condition will be obtained by injecting
a dose of about 25 mg of TNFR:Fc one to three times per week over a
period of at least three weeks, or a dose of 50 mg of TNFR:Fc one
or two times per week for at least three weeks, though treatment
for longer periods may be necessary to induce the desired degree of
improvement. For incurable chronic conditions, the regimen may be
continued indefinitely, with adjustments being made to dose and
frequency if such are deemed necessary by the patient's
physician.
[0027] For pediatric patients (age 4-17), a suitable regimen
involves the subcutaneous injection of 0.4 mg/kg, up to a maximum
dose of 25 mg of TNFR:Fc, administered by subcutaneous injection
one or more times per week.
[0028] The invention further includes the administration of TNFR:Fc
concurrently with one or more other drugs that are administered to
the same patient in combination with the TNFR:Fc, each drug being
administered according to a regimen suitable for that medicament.
"Concurrent administration" encompasses simultaneous or sequential
treatment with the components of the combination, as well as
regimens in which the drugs are alternated, or wherein one
component is administered long-term and the other(s) are
administered intermittently. Components may be administered in the
same or in separate compositions, and by the same or different
routes of administration. Examples of drugs to be administered
concurrently include but are not limited to antivirals,
antibiotics, analgesics, corticosteroids, antagonists of
inflammatory cytokines, DMARDs and non-steroidal
anti-inflammatories. DMARDs that can be administered in combination
with the subject TNF.alpha. inhibitors such as TNFR:Fc include
azathioprine, cyclophosphamide, cyclosporine, hydroxychloroquine
sulfate, methotrexate, leflunomide, minocycline, penicillamine,
sulfasalazine and gold compounds such as oral gold, gold sodium
thiomalate and aurothioglucose. Additionally, TNFR:Fc may be
combined with a second TNF.alpha. antagonist, including an antibody
against TNF.alpha. or TNFR, a TNF.alpha.-derived peptide that acts
as a competitive inhibitor of TNF.alpha. (such as those described
in U.S. Pat. No. 5,795,859), a TNFR-IgG fusion protein other than
etanercept, such as one containing the extracellular portion of the
p55 TNF.alpha. receptor, a soluble TNFR other than an IgG fusion
protein, or other molecules that reduce endogenous TNF.alpha.
levels, such as inhibitors of the TNF.alpha. converting enzyme (see
e.g., U.S. Pat. No. 5,594,106). In further embodiments of this
invention, TNFR:Fc is administered in combination with
pentoxifylline or thalidomide.
[0029] If an antibody against TNF.alpha. is used as the TNF.alpha.
inhibitor, a preferred dose range is 0.1 to 20 mg/kg, and more
preferably is 1-10 mg/kg. Another preferred dose range for
anti-TNF.alpha. antibody is 0.75 to 7.5 mg/kg of body weight.
Humanized antibodies are preferred, that is, antibodies in which
only the antigen-binding portion of the antibody molecule is
derived from a non-human source. such antibodies may be injected or
administered intravenously.
[0030] In one preferred embodiment of the invention, the various
medical disorders disclosed herein as being treatable with
inhibitors such as TNFR:Fc are treated in combination with another
cytokine or cytokine inhibitor. For example, TNFR:Fc may be
administered in a composition that also contains a compound that
inhibits the interaction of other inflammatory cytokines with their
receptors. Examples of cytokine inhibitors used in combination with
TNFR:Fc include, for example, antagonists of TGF.beta., I1-6 or
I1-8. TNF.alpha. inhibitors such as TNFR:Fc also may be
administered in combination with the cytokines GM-CSF, IL-2 and
inhibitors of protein kinase A type 1 to enhance T cell
proliferation in HIV-infected patients who are receiving
anti-retroviral therapy. Other combinations for treating the
hereindescribed diseases include TNFR:Fc administered concurrently
with compounds that block the binding of RANK and RANK-ligand, such
as antagonistic antibodies against RANK or RANK-ligand, soluble
forms of RANK-ligand that do not trigger RANK, osteoprotegerin or
soluble forms of RANK, including RANK:Fc. Soluble forms of RANK
suitable for these combinations are described, for example, in U.S.
Pat. No. 6,017,729. The concurrent administration of TNFR:Fc and
RANK:Fc or TNFR:Fc and osteoprotegerin is useful for preventing
bone destruction in various settings including but not limited to
various rheumatic disorders, osteoporosis, multiple myeloma or
other malignancies that cause bone degeneration, or anti-tumor
therapy aimed at preventing metastasis to bone, or bone destruction
associated with prosthesis wear debris or with periodontitis.
[0031] The present invention also relates to the use of the
disclosed TNF.alpha. inhibitors, such as TNFR:Fc, in the
manufacture of a medicament for the prevention or therapeutic
treatment of each medical disorder disclosed herein.
[0032] The disclosed TNF.alpha. inhibitors, compositions and
combination therapies described herein are useful in medicines for
treating bacterial, viral or protozoal infections, and
complications resulting therefrom. One such disease is Mycoplasma
pneumonia. In addition, provided herein is the use of TNFR:Fc to
treat AIDS and related conditions, such as AIDS dementia complex,
AIDS associated wasting, lipidistrophy due to antiretroviral
therapy; and Kaposi's sarcoma. Provided herein is the use of
TNFR:Fc for treating protozoal diseases, including malaria and
schistosomiasis. Additionally provided is the use of TNFR:Fc to
treat erythema nodosum leprosum; bacterial or viral meningitis;
tuberculosis, including pulmonary tuberculosis; and pneumonitis
secondary to a bacterial or viral infection. Provided also herein
is the use of TNFR:Fc to prepare medicaments for treating
louse-borne relapsing fevers, such as that caused by Borrelia
recurrentis. TNFR:Fc can also be used to prepare a medicament for
treating conditions caused by Herpes viruses, such as herpetic
stromal keratitis, corneal lesions, and virus-induced corneal
disorders. In addition, TNFR:Fc can be used in treating human
papillomavirus infections. TNFR:Fc is used also to prepare
medicaments to treat influenza.
[0033] Cardiovascular disorders are treatable with the disclosed
TNF.alpha. inhibitors, pharmaceutical compositions or combination
therapies, including aortic aneurisms; arteritis; vascular
occlusion, including cerebral artery occlusion; complications of
coronary by-pass surgery; ischemia/reperfusion injury; heart
disease, including atherosclerotic heart disease, myocarditis,
including chronic autoimmune myocarditis and viral myocarditis;
heart failure, including chronic heart failure (CHF), cachexia of
heart failure; myocardial infarction; restenosis after heart
surgery; silent myocardial ischemia; post-implantation
complications of left ventricular assist devices; Raynaud's
phenomena; thrombophlebitis; vasculitis, including Kawasaki's
vasculitis; giant cell arteritis, Wegener's granulomatosis; and
Schoenlein-Henoch purpura.
[0034] TNF.alpha. and IL-8 have been implicated as chemotactic
factors in athersclerotic abdominal aortic aneurism (Szekanecz et
al., Pathobiol 62:134-139 (1994)). Abdominal aortic aneurism may be
treated in human patients by administering a soluble TNFR, such as
TNFR:Fc, which may be administered in combination with an inhibitor
of IL-8, such treatment having the effect of reducing the
pathological neovascularization associated with this condition.
[0035] A combination of a TNF.alpha. inhibitor and one or more
other anti-angiogenesis factors may be used to treat solid tumors,
thereby reducing the vascularization that nourishes the tumor
tissue. Suitable anti-angiogenic factors for such combination
therapies include IL-8 inhibitors, angiostatin, endostatin, kringle
5, inhibitors of vascular endothelial growth factor (such as
antibodies against vascular endothelial growth factor),
angiopoietin-2 or other antagonists of angiopoietin-1, antagonists
of platelet-activating factor and antagonists of basic fibroblast
growth factor
[0036] In addition, the subject TNF.alpha. inhibitors, compositions
and combination therapies are used to treat chronic pain
conditions, such as chronic pelvic pain, including chronic
prostatitis/pelvic pain syndrome. As a further example, TNFR:Fc and
the compositions and combination therapies of the invention are
used to treat post-herpetic pain.
[0037] Provided also are methods for using TNF.alpha. inhibitors,
compositions or combination therapies to treat various disorders of
the endocrine system. For example, the TNF.alpha. inhibitors are
used to treat juvenile onset diabetes (includes autoimmune and
insulin-dependent types of diabetes) and also to treat maturity
onset diabetes (includes non-insulin dependent and obesity-mediated
diabetes). In addition, the subject compounds, compositions and
combination therapies are used to treat secondary conditions
associated with diabetes, such as diabetic retinopathy, kidney
transplant rejection in diabetic patients, obesity-mediated insulin
resistance, and renal failure, which itself may be associated with
proteinurea and hypertension. Other endocrine disorders also are
treatable with these compounds, compositions or combination
therapies, including polycystic ovarian disease, X-linked
adrenoleukodystrophy, hypothyroidism and thyroiditis, including
Hashimoto's thyroiditis (i.e., autoimmune thyroiditis).
[0038] Conditions of the gastrointestinal system also are treatable
with TNF.alpha. inhibitors, compositions or combination therapies,
including coeliac disease. In addition, the compounds, compositions
and combination therapies of the invention are used to treat
Crohn's disease; ulcerative colitis; idiopathic gastroparesis;
pancreatitis, including chronic pancreatitis and lung injury
associated with acute pancreatitis; and ulcers, including gastric
and duodenal ulcers.
[0039] Included also are methods for using the subject TNF.alpha.
inhibitors, compositions or combination therapies for treating
disorders of the genitourinary system, such as glomerulonephritis,
including autoimmune glomerulonephritis, glomerulonephritis due to
exposure to toxins or glomerulonephritis secondary to infections
with haemolytic streptococci or other infectious agents. Also
treatable with the compounds, compositions and combination
therapies of the invention are uremic syndrome and its clinical
complications (for example, renal failure, anemia, and hypertrophic
cardiomyopathy), including uremic syndrome associated with exposure
to environmental toxins, drugs or other causes. Further conditions
treatable with the compounds, compositions and combination
therapies of the invention are complications of hemodialysis;
prostate conditions, including benign prostatic hypertrophy,
nonbacterial prostatitis and chronic prostatitis; and complications
of hemodialysis.
[0040] Also provided herein are methods for using TNF.alpha.
inhibitors, compositions or combination therapies to treat various
hematologic and oncologic disorders. For example, TNFR:Fc is used
to treat various forms of cancer, including acute myelogenous
leukemia, Epstein-Barr virus-positive nasopharyngeal carcinoma,
glioma, colon, stomach, prostate, renal cell, cervical and ovarian
cancers, lung cancer (SCLC and NSCLC), including cancer-associated
cachexia, fatigue, asthenia, paraneoplastic syndrome of cachexia
and hypercalcemia. Additional diseases treatable with the subject
TNF.alpha. inhibitors, compositions or combination therapies are
solid tumors, including sarcoma, osteosarcoma, and carcinoma, such
as adenocarcinoma (for example, breast cancer) and squamous cell
carcinoma. In addition, the subject compounds, compositions or
combination therapies are useful for treating leukemia, including
acute myelogenous leukemia, chronic or acute lymphoblastic leukemia
and hairy cell leukemia. Other malignancies with invasive
metastatic potential can be treated with the subject compounds,
compositions and combination therapies, including multiple myeloma.
In addition, the disclosed TNF.alpha. inhibitors, compositions and
combination therapies can be used to treat anemias and hematologic
disorders, including anemia of chronic disease, aplastic anemia,
including Fanconi's aplastic anemia; idiopathic thrombocytopenic
purpura (ITP); myelodysplastic syndromes (including refractory
anemia, refractory anemia with ringed sideroblasts, refractory
anemia with excess blasts, refractory anemia with excess blasts in
transformation); myelofibrosis/myeloid metaplasia; and sickle cell
vasocclusive crisis.
[0041] Various lymphoproliferative disorders also are treatable
with the disclosed TNF.alpha. inhibitors, compositions or
combination therapies. These include, but are not limited to
autoimmune lymphoproliferative syndrome (ALPS), chronic
lymphoblastic leukemia, hairy cell leukemia, chronic lymphatic
leukemia, peripheral T-cell lymphoma, small lymphocytic lymphoma,
mantle cell lymphoma, follicular lymphoma, Burkitt's lymphoma,
Epstein-Barr virus-positive T cell lymphoma, histiocytic lymphoma,
Hodgkin's disease, diffuse aggressive lymphoma, acute lymphatic
leukemias, T gamma lymphoproliferative disease, cutaneous B cell
lymphoma, cutaneous T cell lymphoma (i.e., mycosis fungoides) and
Sezary syndrome.
[0042] In addition, the subject TNF.alpha. inhibitors, compositions
and combination therapies are used to treat hereditary conditions
such as Gaucher's disease, Huntington's disease, linear IgA
disease, and muscular dystrophy.
[0043] Other conditions treatable by the disclosed TNF.alpha.
inhibitors, compositions and combination therapies include those
resulting from injuries to the head or spinal cord, and including
subdural hematoma due to trauma to the head.
[0044] The disclosed TNF.alpha. inhibitors, compositions and
combination therapies are further used to treat conditions of the
liver such as hepatitis, including acute alcoholic hepatitis, acute
drug-induced or viral hepatitis, hepatitis A, B and C, sclerosing
cholangitis and inflammation of the liver due to unknown
causes.
[0045] In addition, the disclosed TNF.alpha. inhibitors,
compositions and combination therapies are used to treat various
disorders that involve hearing loss and that are associated with
abnormal TNF.alpha. expression. One of these is inner ear or
cochlear nerve-associated hearing loss that is thought to result
from an autoimmune process, i.e., autoimmune hearing loss. This
condition currently is treated with steroids, methotrexate and/or
cyclophosphamide, which may be administered concurrently with the
TNFR:Fc or other TNF.alpha. inhibitor. Also treatable with the
disclosed TNF.alpha. inhibitors, compositions and combination
therapies is cholesteatoma, a middle ear disorder often associated
with hearing loss.
[0046] In addition, the subject invention provides TNF.alpha.
inhibitors, compositions and combination therapies for the
treatment of non-arthritic medical conditions of the bones and
joints. This encompasses osteoclast disorders that lead to bone
loss, such as but not limited to osteoporosis, including
post-menopausal osteoporosis, periodontitis resulting in tooth
loosening or loss, and prosthesis loosening after joint replacement
(generally associated with an inflammatory response to wear
debris). This latter condition also is called "orthopedic implant
osteolysis." Another condition treatable by administering
TNFR.alpha. inhibitors, such as TNFR:Fc, is temporal mandibular
joint dysfunction (TMJ).
[0047] A number of pulmonary disorders also can be treated with the
disclosed TNF.alpha. inhibitors, compositions and combination
therapies. One such condition is adult respiratory distress
syndrome (ARDS), which is associated with elevated TNF.alpha., and
may be triggered by a variety of causes, including exposure to
toxic chemicals, pancreatitis, trauma or other causes. The
disclosed compounds, compositions and combination therapies of the
invention also are useful for treating broncho-pulmonary dysplasia
(BPD); lymphangioleiomyomatosis; and chronic fibrotic lung disease
of preterm infants. In addition, the compounds, compositions and
combination therapies of the invention are used to treat
occupational lung diseases, including asbestosis, coal worker's
pneumoconiosis, silicosis or similar conditions associated with
long-term exposure to fine particles. In other aspects of the
invention, the disclosed compounds, compositions and combination
therapies are used to treat pulmonary disorders, including chronic
obstructive pulmonary disease (COPD) associated with chronic
bronchitis or emphysema; fibrotic lung diseases, such as cystic
fibrosis, idiopathic pulmonary fibrosis and radiation-induced
pulmonary fibrosis; pulmonary sarcoidosis; and allergies, including
allergic rhinitis, contact dermatitis, atopic dermatitis and
asthma.
[0048] Cystic fibrosis is an inherited condition characterized
primarily by the accumulation of thick mucus, predisposing the
patient to chronic lung infections and obstruction of the pancreas,
which results in malabsorption of nutrients and malnutrition.
TNFR:Fc may be administered to treat cystic fibrosis. If desired,
treatment with TNFR:Fc may be administered concurrently with
corticosteroids, mucus-thinning agents such as inhaled recombinant
deoxyribonuclease I (such as PULMOZYME.RTM.; Genentech, Inc.) or
inhaled tobramycin (TOBI.RTM.; Pathogenesis, Inc.). TNFR:Fc also
may be administered concurrently with corrective gene therapy,
drugs that stimulate cystic fibrosis cells to secrete chloride or
other yet-to-be-discovered treatments. Sufficiency of treatment may
be assessed, for example, by observing a decrease in the number of
pathogenic organisms in sputum or lung lavage (such as Haemophilus
influenzae, Stapholococcus aureus, and Pseudomonas aeruginosa), by
monitoring the patient for weight gain, by detecting an increase in
lung capacity or by any other convenient means.
[0049] TNFR:Fc or TNFR:Fc combined with the cytokine IFN.gamma.-1b
(such as ACTIMMUNE.RTM.; InterMune Pharmaceuticals) may be used for
treating cystic fibrosis or fibrotic lung diseases, such as
idiopathic pulmonary fibrosis, radiation-induced pulmonary fibrosis
and bleomycin-induced pulmonary fibrosis. In addition, this
combination is useful for treating other diseases characterized by
organ fibrosis, including systemic sclerosis (also called
"scleroderma"), which often involves fibrosis of the liver. For
treating cystic fibrosis, TNFR:Fc and IFN.gamma.-1b may be combined
with PULMOZYME.RTM. or TOBI.RTM. or other treatments for cystic
fibrosis.
[0050] TNFR:Fc alone or in combination with IFN.gamma.-1b may be
administered together with other treatments presently used for
treating fibrotic lung disease. Such additional treatments include
glucocorticoids, azathioprine, cyclophosphamide, penicillamine,
colchisicine, supplemental oxygen and so forth. Patients with
fibrotic lung disease, such as IPF, often present with
nonproductive cough, progressive dyspnea, and show a restrictive
ventilatory pattern in pulmonary function tests. Chest radiographs
reveal fibrotic accumulations in the patient's lungs. When treating
fibrotic lung disease in accord with the disclosed methods,
sufficiency of treatment may be detected by observing a decrease in
the patient's coughing (when cough is present), or by using
standard lung function tests to detect improvements in total lung
capacity, vital capacity, residual lung volume or by administering
a arterial blood gas determination measuring desaturation under
exercising conditions, and showing that the patient's lung function
has improved according to one or more of these measures. In
addition, patient improvement may be determined through chest
radiography results showing that the progression of fibrosis in the
patient's lungs has become arrested or reduced.
[0051] In addition, TNF inhibitors (including soluble TNFRs or
antibodies against TNF.alpha. or TNFR) are useful for treating
organ fibrosis when administered in combination with relaxin, a
hormone that down-regulates collagen production thus inhibiting
fibrosis, or when given in combination with agents that block the
fibrogenic activity of TGF-.beta.. Combination therapies using
TNFR:Fc and recombinant human relaxin are useful, for example, for
treating systemic sclerosis or fibrotic lung diseases, including
cystic fibrosis, idiopathic pulmonary fibrosis, radiation-induced
pulmonary fibrosis and bleomycin-induced pulmonary fibrosis.
[0052] Other embodiments provide methods for using the disclosed
TNF.alpha. inhibitors, compositions or combination therapies to
treat a variety of rheumatic disorders. These include: adult and
juvenile rheumatoid arthritis; systemic lupus erythematosus; gout;
osteoarthritis; polymyalgia rheumatica; seronegative
spondylarthropathies, including ankylosing spondylitis; and
Reiter's disease. The subject TNF.alpha. inhibitors, compositions
and combination therapies are used also to treat psoriatic
arthritis and chronic Lyme arthritis. Also treatable with these
compounds, compositions and combination therapies are Still's
disease and uveitis associated with rheumatoid arthritis. In
addition, the compounds, compositions and combination therapies of
the invention are used in treating disorders resulting in
inflammation of the voluntary muscle, including dermatomyositis and
polymyositis. Moreover, the compounds, compositions ant
combinations disclosed herein are useful for treating sporadic
inclusion body myositis, as TNF.alpha. may play a significant role
in the progression of this muscle disease. In addition, the
compounds, compositions and combinations disclosed herein are used
to treat multicentric reticulohistiocytosis, a disease in which
joint destruction and papular nodules of the face and hands are
associated with excess production of proinflammatory cytokines by
multinucleated giant cells.
[0053] For purposes of this invention, patients are defined as
having psoriatic arthrisis (PsA) if they have one or more swollen
joints or one or more painful or tender joints, and also manifest
at least one psoriatic lesion of the skin or nails. The psoriatic
lesions may appear before or after the onset of swollen or tender
joints. It is understood that prior to treatment, manifestations of
PsA may have persisted over time, e.g., for several months or
years, and may involve several joints. According to one
classification system (reviewed in Alonso et al., 1991), PsA
patients can be categorized based on their arthritic symptoms into
five clinical subgroups: 1) DIP; 2) mutilans arthritis; 3)
symmetrical polyarthritis; 4) oligoarticular arthritis; and 5)
ankylosing spondylitis-like. The disclosed therapies, compounds and
compositions are suitable for treating all five forms of PsA.
[0054] The TNF.alpha. inhibitors, compositions and combination
therapies of the invention may be used to inhibit hypertrophic
scarring, a phenomenon believed to result in part from excessive
TNF.alpha. secretion. TNF inhibitors may be administered alone or
concurrently with other agents that inhibit hypertrophic scarring,
such as inhibitors of TGF-.alpha..
[0055] Cervicogenic headache is a common form of headache arising
from dysfunction in the neck area, and which is associated with
elevated levels of TNF.alpha., which are believed to mediate an
inflammatory condition that contributes to the patient's discomfort
(Martelletti, Clin Exp Rheumatol 18(2 Suppl 19):S33-8 (March-April,
2000)). Cervicogenic headache may be treated by administering an
inhibitor of TNF.alpha. as disclosed herein, thereby reducing the
inflammatory response and associated headache pain.
[0056] The TNF.alpha. inhibitors, compositions and combination
therapies of the invention are useful for treating primary
amyloidosis. In addition, the secondary amyloidosis that is
characteristic of various conditions also are treatable with
TNF.alpha. inhibitors such as TNFR:Fc, and the compositions and
combination therapies described herein. Such conditions include:
Alzheimer's disease, secondary reactive amyloidosis; Down's
syndrome; and dialysis-associated amyloidosis. Also treatable with
the compounds, compositions and combination therapies of the
invention are inherited periodic fever syndromes, including
familial Mediterranean fever, hyperimmunoglobulin D and periodic
fever syndrome and TNF-receptor associated periodic syndromes
(TRAPS).
[0057] Disorders associated with transplantation also are treatable
with the disclosed TNF.alpha. inhibitors, compositions or
combination therapies, such as graft-versus-host disease, and
complications resulting from solid organ transplantation, including
transplantion of heart, liver, lung, skin, kidney or other organs.
TNFR:Fc may be administered, for example, to prevent or inhibit the
development of bronchiolitis obliterans after lung transplantation.
Patients undergoing autologous hematopoietic stem cell
transplantation in the form of peripheral blood stem cell
transplantation may develop "engraftment syndrome," or "ES," which
is an adverse and generally self-limited response that occurs about
the time of hematopoietic engraftment and which can result in
pulmonary deterioration. ES may be treated with inhibitors of
either IL-8 or TNF.alpha. (such as TNFR:Fc), or with a combination
of inhibitors against both of these cytokines.
[0058] Ocular disorders also are treatable with the disclosed
TNF.alpha. inhibitors, compositions or combination therapies,
including rhegmatogenous retinal detachment, and inflammatory eye
disease, and inflammatory eye disease associated with smoking and
macular degeneration.
[0059] TNF.alpha. inhibitors such as TNFR:Fc and the disclosed
compositions and combination therapies also are useful for treating
disorders that affect the female reproductive system. Examples
include, but are not limited to, multiple implant
failure/infertility; fetal loss syndrome or IV embryo loss
(spontaneous abortion); preeclamptic pregnancies or eclampsia; and
endometriosis.
[0060] In addition, the disclosed TNF.alpha. inhibitors,
compositions and combination therapies are useful for treating
obesity, including treatment to bring about a decrease in leptin
formation. Also, the compounds, compositions and combination
therapies of the invention are used to treat sciatica, symptoms of
aging, severe drug reactions (for example, 11-2 toxicity or
bleomycin-induced pneumopathy and fibrosis), or to suppress the
inflammatory response prior, during or after the transfusion of
allogeneic red blood cells in cardiac or other surgery, or in
treating a traumatic injury to a limb or joint, such as traumatic
knee injury. Various other medical disorders treatable with the
disclosed TNF.alpha. inhibitors, compositions and combination
therapies include; multiple sclerosis; Behcet's syndrome; Sjogren's
syndrome; autoimmune hemolytic anemia; beta thalassemia;
amyotrophic lateral sclerosis (Lou Gehrig's Disease); Parkinson's
disease; and tenosynovitis of unknown cause, as well as various
autoimmune disorders or diseases associated with hereditary
deficiencies.
[0061] The disclosed TNF.alpha. inhibitors, compositions and
combination therapies furthermore are useful for treating acute
polyneuropathy; anorexia nervosa; Bell's palsy; chronic fatigue
syndrome; transmissible dementia, including Creutzfeld-Jacob
disease; demyelinating neuropathy; Guillain-Barre syndrome;
vertebral disc disease; Gulf war syndrome; myasthenia gravis;
silent cerebral ischemia; sleep disorders, including narcolepsy and
sleep apnea; chronic neuronal degeneration; and stroke, including
cerebral ischemic diseases.
[0062] Disorders involving the skin or mucous membranes also are
treatable using the disclosed TNF.alpha. inhibitors, compositions
or combination therapies. Such disorders include acantholytic
diseases, including Darier's disease, keratosis follicularis and
pemphigus vulgaris. Also treatable with the subject TNF.alpha.
inhibitors, compositions and combination therapies are acne; acne
rosacea; alopecia greata; aphthous stomatitis; bullous pemphigoid;
burns; eczema; erythema, including erythema multiforme and erythema
multiforme bullosum (Stevens-Johnson syndrome); inflammatory skin
disease; lichen planus; linear IgA bullous disease (chronic bullous
dermatosis of childhood); loss of skin elasticity; mucosal surface
ulcers; neutrophilic dermatitis (Sweet's syndrome); pityriasis
rubra pilaris; psoriasis; pyoderma gangrenosum; and toxic epidermal
necrolysis.
[0063] Patients are defined as having ordinary psoriasis if they
lack the more serious symptoms of PsA (e.g., distal interphalangeal
joint DIP involvement, enthesopathy, spondylitis and dactylitis)
but have one of the following: 1) inflamed swollen skin lesions
covered with silvery white scale (plaque psoriasis or psoriasis
vulgaris); 2) small red dots appearing on the trunk, arms or legs
(guttate psoriasis); 3) smooth inflamed lesions without scaling in
the flexural surfaces of the skin (inverse psoriasis); 4)
widespread reddening and exfoliation of fine scales, with or
without itching and swelling (erythrodermic psoriasis); 5)
blister-like lesions (pustular psoriasis); 6) elevated inflamed
scalp lesions covered by silvery white scales (scalp psoriasis); 7)
pitted fingernails, with or without yellowish discoloration,
crumbling nails, or inflammation and detachment of the nail from
the nail bed (nail psoriasis).
[0064] Ordinary psoriasis may be treated by administering to a
human patient compositions containing a therapeutically effective
amount of a TNF.alpha. inhibitor such as a soluble TNF receptor or
an antibody against TNF.alpha..
[0065] In one preferred embodiment, the therapeutic agent is a
soluble TNF receptor, and preferably is a TNFR-Ig. In a preferred
embodiment, the TNFR-Ig is TNFR:Fc, which may be administered in
the form of a pharmaceutically acceptable composition as described
herein. Psoriasis may be treated by administering TNFR:Fc one or
more times per week by subcutaneous injection, although other
routes of administration may be used if desired. In one exemplary
regimen for treating adult human patients, 25 mg of TNFR:Fc is
administered by subcutaneous injection two times per week or three
times per week for one or more weeks, and preferably for four or
more weeks. Alternatively, a dose of 5-12 mg/m.sup.2 or a flat dose
of 50 mg is injected subcutaneously one time or two times per week
for one or more weeks. In other embodiments, psoriasis is treated
with TNFR:Fc in a sustained-release form, such as TNFR:Fc that is
encapsulated in a biocompatible polymer, TNFR:Fc that is admixed
with a biocompatible polymer (such as topically applied hydrogels),
and TNFR:Fc that is encased in a semi-permeable implant.
[0066] Various other medicaments used to treat ordinary psoriasis
may also be administered concurrently with compositions comprising
TNF.alpha. inhibitors, such as TNFR:Fc. Such medicaments include:
NSAIDs; DMARDs; analgesics; topical steroids; systemic steroids
(e.g., prednisone); cytokines; antagonists of inflammatory
cytokines; antibodies against T cell surface proteins; anthralin;
coal tar; vitamin D3 and its analogs; topical retinoids; oral
retinoids; salicylic acid; and hydroxyurea. Suitable analgesics for
such combinations include: acetaminophen, codeine, propoxyphene
napsylate, oxycodone hydrochloride, hydrocodone bitartrate and
tramadol. DMARDs suitable for such combinations include:
azathioprine, cyclophosphamide, cyclosporine, hydroxychloroquine
sulfate, methotrexate, leflunomide, minocycline, penicillamine,
sulfasalazine, oral gold, gold sodium thiomalate and
aurothioglucose. In addition, the TNFR:Fc or other TNFR mimic may
be administered in combination with antimalarials or colchicine.
NSAIDs suitable for the subject combination treatments of psoriasis
include: salicylic acid (aspirin) and salicylate derivatives;
ibuprofen; indomethacin; celecoxib; rofecoxib; ketorolac;
nambumetone; piroxicam; naproxen; oxaprozin; sulindac; ketoprofen;
diclofenac; and other COX-1 and COX-2 inhibitors, propionic acid
derivatives, acetic acid derivatives, fumaric acid derivatives,
carboxylic acid derivatives, butyric acid derivatives, oxicams,
pyrazoles and pyrazolones, including newly developed
anti-inflammatories.
[0067] If an antagonist against an inflammatory cytokine is
administered concurrently with TNFR:Fc to treat psoriasis, suitable
targets for such antagonists include TGF.beta., I1-6 and I1-8.
[0068] In addition, TNFR:Fc may be used to treat psoriasis in
combination with topical steroids, systemic steroids, antagonists
of inflammatory cytokines, antibodies against T cell surface
proteins, anthralin, coal tar, vitamin D3 and its analogs
(including 1,25-dihydroxy vitamin D3 and calcipotriene), topical
retinoids, oral retinoids (including but not limited to etretinate,
acitretin and isotretinoin), topical salicylic acid, methotrexate,
cyclosporine, hydroxyurea and sulfasalazine. In addition, TNFR:Fc
may be administered to treat psoriasis in combination with one or
more of the following compounds; minocycline; misoprostol; oral
collagen; 6-mercaptopurine; nitrogen mustard; gabapentin;
bromocriptine; somatostatin; peptide T; anti-CD4 monoclonal
antibody; fumaric acid; polyunsaturated ethyl ester lipids; zinc;
and other drugs that may be used to treat psoriasis. TNFR:Fc may
also be used to treat psoriasis in combination with the use of
various oils, including fish oils, nut oils and vegetable oils;
aloe vera; jojoba; Dead Sea salts; capsaicin; milk thistle; witch
hazel; moisturizers; and Epsom salts. In addition, psoriasis may be
treated with compositions containing TNFR:Fc in combination with
the following therapies: plasmapheresis; phototherapy with
ultraviolet light B; psoralen combined with ultraviolet light A
(PUVA); and sunbathing.
[0069] For determining the sufficiency of treatment when treating
ordinary psoriasis in accord with the invention, the TNFR:Fc (or
other TNF.alpha. inhibitor) is administered in an amount and for a
time sufficient to induce an improvement in an indicator such as
psoriasis area and severity index (PASI) or an improvement in
Target Lesion Assessment score, which is an index for assessing the
severity of individual skin lesions. In one embodiment, the
treatment is regarded as sufficient when the patient exhibits an at
least 50% improvement in his or her PASI score, and in another
embodiment, when the patient exhibits an at least 75% improvement
in PASI score. The sufficiency of treatment for psoriasis may also
be determined by evaluating individual psoriatic lesions for
improvement in severity (Psoriasis Target Lesion Assessment Score),
and continuing treatment until an improvement is noted according to
this scoring system. This scoring system involves determining for
an individual lesion whether improvement has occurred in plaque
elevation, amount and degree of scaling or degree of erythema, and
target lesion response to treatment, each of which is separately
scored. Psoriasis Target Lesion Assessment Score is determined by
adding together the separate scores for all four of the
aforementioned indicia.
[0070] In addition to human patients, inhibitors of TNF.alpha. are
useful in the treatment of autoimmune and inflammatory conditions
in non-human animals, such as pets (dogs, cats, birds, primates,
etc.), domestic farm animals (horses cattle, sheep, pigs, birds,
etc.), or any animal that suffers from a TNF.alpha.-mediated
inflammatory or arthritic condition. In such instances, an
appropriate dose may be determined according to the animal's body
weight. For example, a dose of 0.2-1 mg/kg may be used.
Alternatively, the dose is determined according to the animal's
surface area, an exemplary dose ranging from 0.1-20 mg/m.sup.2, or
more preferably, from 5-12 mg/m.sup.2. For small animals, such as
dogs or cats, a suitable dose is 0.4 mg/kg. In a preferred
embodiment, TNFR:Fc (preferably constructed from genes derived from
the same species as the patient), or another soluble TNFR mimic, is
administered by injection or other suitable route one or more times
per week until the animal's condition is improved, or it may be
administered indefinitely.
Example
Evaluation of TNFR:Fc in Patients with Psoriatic Arthritis
[0071] Sixty patients with active psoriatic arthritis (PsA) were
enrolled in a Phase II double-blind, randomized, placebo controlled
study to determine whether the subcutaneous biweekly administration
of etanercept (recombinant TNFR:Fc) was safe in this patient
population and whether efficacy could be documented for both the
arthritic and psoriatic aspects of this disease.
[0072] In this study, a flat dose of 25 mg of TNFR:Fc was injected
subcutaneously two times a week. After 12 weeks, patients who
completed the study were eligible for continuation into a 24 week
open-label extension of the study, with assessments made at weeks
16, 36 and 30 days post-study. All patients participating in the
study extension received etanercept, including those patients who
had received placebo during the blinded portion of the study.
[0073] In order to qualify for enrollment, subjects had to have at
least one of the following forms of PsA: 1) DIP involvement; 2)
polyarticular arthritis, absence of rheumatoid nodules and presence
of psoriasis; 3) arthritis mutilans; 4) asymmetric peripheral
arthritis; or 5) ankylosing spondylitis-like PsA. Subjects
furthermore had to exhibit three or more swollen joints and three
or more tender or painful joints at the time of enrollment, and to
have exhibited an inadequate response to NSAID therapy. Subjects
who were on other medications, including methotrexate, NSAIDs or
oral corticosteroids were permitted to continue these other
treatments at the same dose so long as the investigator considered
these other treatments to inadequately control the patient's
disease. Methotrexate was concurrently taken by 47% of the
etanercept group, and 47% of the placebo group, NSAIDs were
concurrently taken by by 67% of the etanercept and 77% of the
placebos and oral corticosteroids by 40% of the etanercept and 20%
of the placebo patients. Pain medications, including acetaminophen,
codeine, propoxyphene napsylate, oxycodone hydrochloride,
hydrocodone bitartrate and tramadol, also were permitted during the
study, as well as the use of topical tar compounds.
[0074] To qualify as having PsA, patients had to have experienced
at least one psoriatic lesion of the skin or nails. Patients were
evaluated at baseline (day 1 of treatment) as follows: 1) complete
joint assessment; 2) psoriasis assessment; 3) duration of morning
stiffness; 4) health assessment (quality of life) questionnaire,
visual analog scale (HAQ/VAS); 5) patient global assessment; 6)
erythrocyte sedimentation rate (ESR, Westergren); 7) C-reactive
protein (CRP); and 8) urinalysis. At weeks 4 and 8, patients were
evaluated as follows: 1) complete joint assessment; 2) psoriasis
assessment; 3) duration of morning stiffness; 4) HAQ/VAS; 5)
patient global assessment. At the end of 12 weeks, subjects were
evaluated as follows: 1) complete joint assessment; 2) psoriasis
assessment; 3) focused physical exam; 4) duration of morning
stiffness; 5) HAQ/VAS; 6) patient global assessment; 6) hematology
profile; 7) chemistry profile; 8) ESR; 9) CRP; 10) urinalysis; 11)
serum tested for antibody to TNFR:Fc. Only those patients whose
psoriasis was stable and covered .gtoreq.3% of body area were
evaluated for psoriasis response during this trial, although
patients whose psoriasis was inactive or covered less area were
permitted to enroll.
[0075] A primary endpoint for clinical improvement or worsening of
PsA was the Psoriatic Arthritis Response score, which is a
composite score based on the following four measures: 1) patient
self-assessment; 2) physician assessment; 3) joint pain or
tenderness; 4) joint swelling. Both self- and physician
assessments, i.e., overall assessment of disease status, were
measured according to a five point Likert scale, in which a patient
was considered as "improved" if his or her score decreased by one
category, or as "worse" if his or her score increased by one
category. Joint pain or tenderness was measured on a 5-point scale,
wherein 1=none and 5=severe (withdrawal on examination). Joint
swelling was evaluated on a 4-point scale in which 1=none; 2=mild
(detectable synovial thickening without loss of bony contour);
3=moderate (loss of distinctness of bony contours); and 4=severe
(bulging synovial proliferation with cystic characteristics). For
this last measure, a decrease in swelling of .gtoreq.30% was scored
as an "improvement," and an increase in swelling of .gtoreq.30% was
scored as a "worsening." Patients were classified as "improved"
under the Psoriatic Arthritis Response scoring system if they
exhibited an improvement in at least two of the four measures
described above, provided that one of the improved areas was joint
pain or joint tenderness, and where there was no worsening in any
of the four measures.
[0076] In addition, a secondary endpoint used for assessing
psoriatic arthritis was a modified version of the American College
of Rheumatology Preliminary Definition of Improvement in Rheumatoid
Arthritis (modified ACR 20 response) (Felson et al., 1995). To
qualify as "improved" according to this measure, a patient must
have exhibited .gtoreq.20% improvement in both tender joint count
(78 joints assessed) and swollen joint count (76 joints assessed),
and also must have shown an improvement in three of the following
five: 1) subject pain assessment; 2) subject global assessment; 3)
physician global assessment; 4) subject self-assessed disability;
5) acute-phase reactant (Westergreen erythrocyte sedimentation rate
or C-reactive protein level). The joint count was done by scoring
several different aspects of tenderness, such as pressure and joint
manipulation on physical examination, wherein each joint was scored
as "tender" or "nontender." Similarly, each joint is scored after
physical examination as "swollen" or "not swollen." The subject's
pain assessment was based on a horizontal visual analog scale
(usually 10 cm) or Likert scale. The subject's and physician's
global assessments of the subject's current disease status was
based on an anchored horizontal visual analog scale (usually 10
cm), or Likert scale response. The subject's self-assessment of
disability was based on any of the following measures, all of which
have been validated in RA trials: Arthritis Impact Measurement
Scale (AIMS); Health Assessment Questionnaire; the Quality (or
Index) of Well Being Scale; the McMaster Health Inventory
Questionnaire (MHIQ); and the McMaster-Toronto Arthritis patient
preference questionnaire (MACTAR).
[0077] A primary endpoint used to assess the psoriatic aspects of
PsA was the standard psoriasis area and severity index (PASI)
(Fredriksson and Petersson, Dermatologica 157:238-244, 1978). For
this study, a positive treatment response was defined as an at
least 50% or an at least 75% improvement in a patient's PASI score.
For assessing area and severity, the body is divided into four
regions: head (10%); trunk (30%); upper extremities (20%); and
lower extremities (40%). Each quadrant also was scored for the
severity of erythema (E), infiltration (I) and desquamation (D),
using a four point scale, in which 0=no symptoms present; 1=slight
symptoms; 2=moderate symptoms; 3=striking symptoms; 4=exceptionally
striking symptoms. Using a 6-point scale, each region was scored
also for the percent of total area that was involved in the
psoriatic manifestations of the disease, wherein 0=no involvement;
1=<10% involvement; 2=10-<30% involvement; 3=30-<50%
involvement; 4=50-<70% involvement; 5=70-<90% involvement;
6=90-100% involvement. PASI scores were calculated according to the
formula given below, in which E=severity score for erythrema,
I=severity score for infiltration, D=severity score for
desquamation and A=total area involved. In this formula, the
letters "h," "t," "u" and "1" represent, respectively, the scores
in each of the four body regions, i.e., head, trunk, upper
extremities and lower extremities. The PASI score varies in steps
of 0.1 units from 0.0 (no psoriatic lesions at all) to 72.0
(complete erythroderma of the severest possible degree).
PASI=0.1(Eh+Ih+Dh)Ah+0.3(Et+It+Dt)At
+0.2(Eu+Iu+Du)Au+0.4(El+Il+Dl)Al
[0078] A secondary endpoint used for the psoriatic aspect of
psoriatic arthritis was the Target Lesion Assessment Score. This
score was determined for a single target lesion that was selected
to be monitored throughout the trial. This measurement is a
composite of four different evaluations: 1) plaque evaluation; 2)
scaling; 3) erythrema; and 4) target lesion response to treatment.
The following scale was used for the plaque elevation: 0=none (no
evidence of plaque above normal skin level); 1=mild (slight but
definite elevation above normal skin level); 2=moderate (moderate
elevation with rounded or sloped edges to plaque); 3=severe (hard,
marked elevation with sharp edges to plaque); 4=very severe (very
marked elevation with very hard sharp edges to plaque). For the
scaling assessment: 0=none (no scaling on the lesion); 1=mild
(mainly fine scales, with some of the lesion at least partially
covered); 2=moderate (somewhat coarser scales, most of the lesion
at least partially covered); 3=severe (coarse, thick scales,
virtually all the lesion covered, rough surface); 4=very severe
(very coarse thick scales, all the lesions covered, very rough
surface). For the erythema evaluation: 0=none (no erythema); 1=mild
(light red coloration); 2=moderate (red coloration); 3=severe (very
red coloration); 4=very severe (extreme red coloration). For target
lesion response to treatment score: 0=completely cleared; 1=almost
cleared (.about.90% improvement); 2=marked response (.about.75%
improvement); 3=moderate response (.about.50% improvement);
4=slight response (.about.25% improvement); 5=condition unchanged;
6=condition worsened. The patient's Target Lesion Assessment Score
was determined by summing the plaque, scaling, erythema and target
lesion response scores for the monitored lesion. If the monitored
lesion worsened, the percentage change from baseline was recorded
as a negative number.
[0079] Treatment and placebo groups were compared in accord with
the measurements described above, as well as for demographic and
background characteristics; premature discontinuation rate; pain
medication requirements; toxicities; serious adverse events; side
effects reported by patients; number of weeks on drug until
subjects met criteria for improvement, and response according to
PsA subtype. Results were analyzed using standard statistical
methods.
Dosing Regimen
[0080] Recombinant human TNFR:Fc (etanercept) from Immunex
Corporation was used in this study. The gene fragments encoding the
etanercept polypeptides were expressed in a Chinese hamster ovary
(CHO) expression vector.
[0081] TNFR:Fc was supplied as a sterile lyophilized powder
containing 10 mg or 25 mg TNFR:Fc; 40 mg mannitol, USP; 10 mg
sucrose, NF; and 1.2 mg tromethamine (TRIS), USP per vial. Patients
received either a dose of 25 mg of etanercept or a placebo. Vials
of etanercept or identically-appearing placebo were reconstituted
by aseptic injection of 1.0 mL Bacteriostatic Water for Injection,
USP, (containing 0.9% benzyl alcohol), and was not filtered during
preparation or prior to administration. If storage was required,
the reconstituted solutions were stored at 2-8.degree. C.
(36-46.degree. F.) in the original vial or in a plastic syringe for
a period of no longer than 28 days. Dose was not changed during the
study. Study drug was given twice weekly at approximately the same
time of day.
Results
[0082] Study drug was well tolerated in all patients, and adverse
events were consistent with this population and were equally
distributed among both treatment groups. As illustrated in Tables
1-4, etanercept induced a significant improvement as compared with
the placebo group in Psoriatic Arthritis Response (Table 1), ACR20
(Table 2), ACR50 (Table 3), PASI score, 50% improvement (Table 4),
PASI score, 75% improvement (Table 5) and improvement in Target
Lesion Assessment Score (Table 6). The fractions shown in Tables
1-5 represent numbers of patients. For example, the first entry in
Table 1, which is "4/30," indicates that 4 of 30 patients in the
placebo group scored as "improved" according to the Psoriatic
Arthritis Response measurements. The tables include P-values for
the differences between the two study groups, the groups being
labeled as "PLACEBO" and "TNFR:Fc." All of the tables include data
calculated after the first four weeks of the open label extension
portion of the study ("EXTENSION"), during which all of the
patients in both study groups received etanercept.
[0083] Table 1 shows the number of patients in each treatment group
who scored as "improved" according to the Psoriatic Arthritis
Response scoring system described above. By four weeks, there was a
highly significant difference between etanercept and placebo
groups. Moreover, after being switched to etanercept during the
extension, those patients who had received placebo during the
blinded portion of the study were seen to exhibit an improvement
over baseline (Table 1, Placebo, EXTENSION). These results indicate
that etanercept acts rapidly to alleviate many aspects of psoriatic
arthritis.
TABLE-US-00001 TABLE 1 Psoriatic Arthritis Response Placebo TNFR:Fc
P-value 4 weeks 4/30 (13%) 23/30 (77%) 0.000 8 weeks 7/30 (23%)
25/30 (83%) 0.000 12 weeks 6/30 (20%) 26/30 (87%) 0.000 EXTENSION
17/23 (74%) 21/25 (84%) 0.356
[0084] Tables 2 and 3, respectively, illustrate the study results
for the ACR20 and ACR50 endpoints. For either measure, a
significant difference between etanercept and placebo groups was
observed at all three time points during the blinded portion of the
study. Given the differences between test and placebo groups after
only four weeks of treatment (P=0.000 for ACR20 and P=0.011 for
ACR50), these data suggest that notable improvement in ACR scores
occurred within the etanercept group very soon after treatment was
initiated, possibly after a single dose of etanercept. During the 4
week extension period, during which all of the patients received
etanercept, a striking improvement in both ACR20 and ACR50 was seen
in those patients who had received placebo during the first 12
weeks (Tables 2 and 3).
TABLE-US-00002 TABLE 2 ACR20 Response Placebo TNFR:Fc P-value 4
weeks 1/30 (3%) 18/30 (60%) 0.000 8 weeks 3/30 (10%) 19/30 (63%)
0.000 12 weeks 4/30 (13%) 22/30 (73%) 0.000 EXTENSION 11/23 (48%)
18/25 (72%) 0.093
TABLE-US-00003 TABLE 3 ACR50 Response Placebo TNFR:Fc P-value 4
weeks 0/30 (0%) 6/30 (20%) 0.011 8 weeks 1/30 (3%) 11/30 (37%)
0.001 12 weeks 1/30 (3%) 15/30 (50%) 0.000 EXTENSION 7/23 (30%)
11/25 (44%) 0.316
[0085] The results of the psoriasis evaluations are presented in
Tables 4-6. Tables 4 and 5, respectively, present the numbers and
percentages of patients in each group who exhibited a 50% or 75%
improvement in PASI score, while Table 6 presents Target Lesion
Assessment scores, these latter being denoted as percent
improvement over baseline. The data in Tables 4-6 clearly indicate
that etanercept induced an improvement in psoriasis for a large
percentage of the patients who received it. When single lesions
were evaluated (Table 6), the improvement in psoriasis was even
more apparent than when PASI scores were used (Tables 4 and 5). It
is notable also that, for either PASI scores (Tables 4 and 5) or
Psoriasis Target Lesion Assessment Score (Table 6), the scores of
the placebo group improved after these patients were switched to
etanercept during the extension.
[0086] Though not shown in Table 6, Target Lesion Assessment Scores
for patients who were concurrently receiving methotrexate (14 of
the 30 patients in the etanercept group, and 14 patients in the
placebo group) were compared with the scores of those patients who
did not take methotrexate. Little difference in this index was
noted between the patients who received methotrexate and those who
did not receive it.
TABLE-US-00004 TABLE 4 PASI Score - 50% Improvement Placebo TNFR:Fc
P-value 4 weeks 0/19 (0%) 4/19 (21%) 0.037 8 weeks 1/19 (5%) 7/19
(37%) 0.019 12 weeks 4/19 (21%) 8/19 (42%) 0.165 EXTENSION 6/16
(38%) 6/15 (40%) 0.856
TABLE-US-00005 TABLE 5 PASI Response Rate 75% Improvement Placebo
TNFR:Fc P-value 4 weeks 0/19 (0%) 1/19 (5%) 0.264 8 weeks 0/19 (0%)
2/19 (11%) 0.153 12 weeks 0/19 (0%) 4/19 (21%) 0.037 EXTENSION 1/16
(6%) 4/15 (27%) 0.113
TABLE-US-00006 TABLE 6 Psoriasis Target Lesion Assessment (Percent
Improvement or Worsening Compared with Baseline) Placebo TNFR:Fc
P-value 4 weeks Mean (SD) 2.7 (27.6) 21.2 (35.2) 0.120 Median 0.0
14.3 MIN--MAX -50.0 -50.0 -33.3 -100.0 N 19 19 8 weeks Mean (SD)
-7.5 (25.3) 28.5 (34.1) 0.003 Median 0.0 29.2 MIN--MAX -50.0 -20.0
-33.3 -100.0 N 17 18 12 weeks Mean (SD) 9.5 (23.2) 45.7 (31.6)
0.001 Median 0.0 50.0 MIN--MAX -25.0 -50.0 -16.7 -100.0 N 16 19
EXTENSION Mean (SD) 28.9 (41.2) 47.1 (35.8) 0.263 Median 36.7 50.0
MIN--MAX -100.0 -66.7 -33.3 -100.0 N 16 15
* * * * *