CA2366785C - Soluble tumor necrosis factor receptor treatment of medical disorders - Google Patents

Abstract

The invention pertains to methods 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.

Description

SOLUBLE TUMOR NECROSIS FACTOR RECEPTOR TREATMENT OF
MEDICAL DISORDERS

FIELD OF THE INVENTION
The invention pertains to methods for treating various medical disorders that are characterized by abnormal or excessive TNFa levels by administering compositions containing a TNFa antagonist, preferably a soluble TNF receptor. The TNFa inhibitor may be administered in combination with other biologically active molecules.

BACKGROUND OF THE INVENTION

The pleiotropic cytokine tumor necrosis factor alpha (TNF(x) 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 TNFa, the p55 and p75 TNF receptors mediate the binding to cells of homotrimers of TNF(3, which is another cytokine associated with inflammation and which shares structural similarities with TNFa (e.g., see Cosman, Blood Cell Biochem 7:51-77, 1996).
TNF(3 is also known as lymphotoxin-a (LT(x).

It has been proposed that a systemic or localized excess of TNFa contributes to the progression of numerous medical disorders. For example, patients with chronic heart failure have elevated levels of serum TNFa, 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 TNFa (see, for example, Feldman et al., Transplantation Proceedings 30:4126-4127, 1998).
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 d 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 TNFa, IL-6 and TGF(3 (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.
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.
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 TNFa production or its release from cultured cells (see, for example, U.S. 5,691,382, U.S. 5,834,485, U.S. 5,420,154, U.S.
5,563,143, U.S. 5,869,511 and U.S. 5,872,146), as well as with various combination therapies involving TNF antagonists (for example, see U.S. 5,888,511 or U.S. 5,958,413) Conflicting results have been reported regarding the role of TNFa in psoriasis.
Some investigators have proposed that overproduction of TNFa 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 TNFa, 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 TNFa exacerbates psoriasis. For example, some investigators have reported that treatment with TN-Fa 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).

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+ T
cells and MHC class II antigens in their synovial membranes and synovial fluid, as well as increased expression of the cytokine TNFa. In addition, both diseases are associated with prominent synovial vascular changes.
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"d Ed., Mosby, 1998, 21.1-21.8).
Studies have shown that levels of TNFa, Il-10, 11-8 as well as TNF 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.
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". DMARDs currently used include methotrexate, sulfasalazine, gold, azathioprine, cyclosporine, antimalarials, steroids and colchicine, as well as many others that are used less frequently.
However, one group found that long-term administration of 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 (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 psoriatic arthritis could be treated with truncated TNFa receptors or with a combination of methotrexate and antibodies against TNFa (WO 98/01555; WO
98/0537).

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).

It has been suggested that the suppression of TNFct might be beneficial in patients suffering from various disorders characterized by abnormal or excessive TNFa 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
Provided herein are methods for treating a number of medical disorders characterized by abnormal TNFa expression by repeatedly administering an antagonist of TNFa, such as TNFR:Fc, for a period of time sufficient to induce a sustained improvement in the patient's condition.

According to one aspect of the present invention, there is provided a physiologically acceptable composition for treating ordinary psoriasis in a human patient who is suffering from ordinary psoriasis, which comprises: (a) a chimeric protein comprising a soluble TNFa receptor derived from TNFRp75 and an Fc portion of an antibody, and (b) a physiologically acceptable carrier, excipient or diluent, wherein the soluble TNFa receptor can bind to TNFa.

According to another aspect of the present invention, there is provided use of a chimeric protein in the manufacture of a medicament for therapeutic treatment of ordinary psoriasis, wherein the chimeric protein comprises a soluble TNFu receptor derived from TNFRp75 and an Fc portion of an antibody, wherein the soluble TNFu receptor can bind to TNFc.

According to still another aspect of the present invention, there is provided a physiologically acceptable composition for treating ordinary psoriasis in a pediatric human patient who is suffering from ordinary psoriasis, which comprises: (a) a chimeric protein comprising a soluble TNFu receptor derived from TNFRp75 and an Fc portion of an antibody, and (b) a physiologically acceptable carrier, excipient or diluent, wherein the composition comprises a maximum of 25 mg of the chimeric protein, and wherein the soluble TNFa receptor can bind to TNFO.

According to yet another aspect of the present invention, there is provided a physiologically acceptable composition for treating ordinary psoriasis in an adult human patient who is suffering from ordinary psoriasis, which comprises: (a) a chimeric protein comprising a soluble TNFa receptor derived from TNFRp75 and an Fc portion of an 4a antibody, and (b) a physiologically acceptable carrier, excipient or diluent, wherein the composition comprises 25 or 50 mg of the chimeric protein, and wherein the soluble TNFa receptor can bind to TNFu.

DETAILED DESCRIPTION OF THE INVENTION

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 TNFa.

For purposes of this disclosure, the terms "illness", "disease", "medical condition", "abnormal condition" and the like are used interchangeably with the term "medical disorder".

The subject methods involve administering to the patient a soluble TNFa antagonist that is capable of reducing the effective amount of endogenous biologically 4b active TNFa, such as by reducing the amount of TNFa produced, or by preventing the binding of TNFa to its cell surface receptor (TNFR). Antagonists capable of inhibiting this binding include receptor-binding peptide fragments of TNFa, antibodies directed against TNFa, and recombinant proteins comprising all or portions of receptors for TNFa 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.

Preferred embodiments of the invention utilize soluble TNFRs as the TNFa antagonist. 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 TNFa 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. 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 TNFa.
Antagonists derived from TNFRs compete for TNFa with the receptors on the cell surface, thus inhibiting TNFa from binding to cells, thereby preventing it from manifesting its biological activities. Binding of soluble TNFRs to TNFa or LTa can be assayed using ELISA or any other convenient assay. This invention provides for the use of TNFR:Fc in the manufacture of a medicament for the treatment of numerous diseases.
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 multimer that is capable of binding a TNFa and/or LTa molecule and preventing it from binding to cell-bound receptors. Chimeric proteins used as antagonists include proteins that contain portions of both an antibody molecule and a TNFR. A preferred TN-Fa antagonist 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 TNFa 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,. Etanercept is currently sold by Immunex Corporation under the trade name ENBREL. Because the p75 receptor protein that it incorporates binds not only to TNFc , but also to the inflammatory cytokine LTa, etanercept can act as a competitive inhibitor not only of TNFa, but also of LTa. This is in contrast to-antibodies directed against TNF, which cannot inhibit LTa. 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 chimeric proteins derived from the fusion of the Fc portion of IgG to the extracellular regions of TNF receptor molecules other than the p55 and p75 TNFRs.
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, admixed with such a polymer, 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. Soluble forms of TNFRs including monomers, fusion proteins (also called "chimeric proteins), dimers, trimers or higher order multimers, are particularly useful in formulating TNF antagonists.
To treat a medical disorder characterized by abnormal or excess expression of TNFa, a molecule comprising a TNFa-binding soluble TNFa receptor, preferably TNFR:Fc, is administered to the patient 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 to four weeks. The degree of improvement is determined based on signs or symptoms, and may also employ questionnaires that are administered to the patient, such as quality-of-life questionnaires.
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 less prior to administration of the first dose of the etanercept or other TNFa inhibitor.
Preferably, the baseline examination is done within about 60 days of administering the first dose. If the TNFa 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.
Improvement is induced by repeatedly administering a dose of TNFR:Fc or other TNFa 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.
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.
Any efficacious route of administration may be used to therapeutically administer TNFR:Fc or other TNFa 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 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.
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 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. 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. In accordance with appropriate industry standards, preservatives may also be added, such as benzyl alcohol. 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.
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/m2, and preferably is about 5-12 mg/m2. Alternatively, a flat dose may be administered, whose amount may range from 5-100 mg/dose. If the dose is to be administered more than one time per week, an exemplary dose range for a flat dose is about 20-30 mg per dose. If the dose is to be given one time per week or less often than one time per week, an exemplary dose range is about 25-60 mg per 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 is administered repeatedly. 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 time 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.
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.

The invention further includes the administration of TNFR:Fc concurrently with one or more other drugs that are administered to the same patient, each drug being administered according to a regimen suitable for that medicament. This encompasses pre-treatment, simultaneous treatment, sequential treatment and alternating regimens.
Examples of such drugs include but are not limited to antivirals, antibiotics, analgesics, corticosteroids, antagonists of inflammatory cytokines, DMARDs and non-steroidal anti-inflammatories. Additionally, TNFR:Fc may be combined with a second TNF
antagonist, including an antibody against TNF or TNFR, additional TNFR derivatives, or other molecules that reduce endogenous TNF levels, such as inhibitors of the TNFa converting enzyme (see e.g., U.S. 5,594,106). In further embodiments, TNFR:Fc is administered in combination with pentoxifylline or thalidomide.
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. The TNFR:Fc and other cytokine inhibitor may be administered as separate compositions, and these may be administered by the same or different routes. Examples of cytokine inhibitors used in combination with TNFR:Fc include those that antagonize, for example, TGF(3, IFNy, 11-6 or 11-8. The combination of TNFR:Fc and IFNy-lb, for example, is useful in treating idiopathic pulmonary fibrosis and cystic fibrosis. Other combinations for treating the hereindescribed diseases include the use of TNFR:Fc with compounds that interfere with the binding of RANK and RANK-ligand, such as soluble forms of RANK-ligand, or soluble forms of RANK, including RANK:Fc. For example, the combination of TNFR:Fc and RANK:Fc are 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. TNFa inhibitors such as TNFR:Fc also may be administered in combination with 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. In addition, TNFR:Fc may be administered in combination with soluble forms of an receptor (such as IL-17R:Fc), IL-18 binding protein, or antibodies against CD30-ligand or against CD4.
The present invention also relates to the disclosed TNF inhibitors and combination therapies for use in medicine. The use in medicine may involve the treatment of any of the medical disorders as described herein. The TNF inhibitors may be in the form of compounds, compositions or combination therapies. Where the compounds are used together with one or more other components, the compound and the one or more other components may be administered simultaneously, separately or sequentially (usually in pharmaceutical format).
The present invention also relates to the use of TNF inhibitors (as disclosed), such as TNFR:Fc, in the manufacture of a medicament for the prevention or therapeutic treatment of each medical disorder disclosed herein.
The disclosed TNF 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. Furthermore 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 infection.
Cardiovascular disorders are treatable with the disclosed TNF 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.
In addition, the subject TNF 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.
Provided also are methods for using TNF inhibitors, compositions or combination therapies to treat various disorders of the endocrine system. For example, the TNF
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).
Conditions of the gastrointestinal system also are treatable with TNF
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 ulcers, including gastric and duodenal ulcers.
Included also are methods for using the subject TNF 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.
Also provided herein are methods for using TNF 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
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 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.
Various lymphoproliferative disorders also are treatable with the disclosed TNF
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.

In addition, the subject TNF 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.
Other conditions treatable by the disclosed TNF 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.
The disclosed TNFa 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.
In addition, the disclosed TNF inhibitors, compositions and combination therapies are used to treat various disorders that involve hearing loss and that are associated with abnormal TNFa 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. Also treatable with the disclosed TNF inhibitors, compositions and combination therapies is cholesteatoma, a middle ear disorder often associated with hearing loss.
In addition, the subject invention provides TNF 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 with the compounds, compositions and combination therapies of the invention is temporal mandibular joint dysfunction (TMJ).
The following pulmonary disorders also can be treated with the disclosed TNF
inhibitors, compositions and combination therapies: adult respiratory distress syndrome (ARDS) caused by a variety of conditions, 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); 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 fibrosis, including idiopathic pulmonary fibrosis and radiation-induced pulmonary fibrosis; pulmonary sarcoidosis; and allergies, including allergic rhinitis, contact dermatitis, atopic dermatitis and asthma.
Other embodiments provide methods for using the disclosed TNF inhibitors, compositions or combination therapies to treat a variety of rheumatic disorders. These include adult and juvenile rheumatoid arthritis; scleroderma; systemic lupus erythematosus; gout; osteoarthritis; polymyalgia rheumatica; seronegative spondylarthropathies, including ankylosing spondylitis, and Reiter's disease.
The subject TNF 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.
The TNFa 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 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).
Disorders involving the skin or mucous membranes also are treatable using the disclosed TNF 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 inhibitors, compositions and combination therapies are acne; acne rosacea; alopecia areata; 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.
Disorders associated with transplantation also are treatable with the disclosed TNF
inhibitors, compositions or combination therapies, such as graft-versus-host disease, and complications resulting from solid organ transplantation, such as heart, liver, skin, kidney or other transplants.
Ocular disorders also are treatable with the disclosed TNF inhibitors, compositions or combination therapies, including rhegmatogenous retinal detachment, and inflammatory eye disease, including inflammatory eye disease associated with smoking and macular degeneration.
TNF 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.
In addition, the disclosed TNF inhibitors, compositions and combination therapies are useful for treating obesity, including 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 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.
The disclosed TNF 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.
In addition to human patients, soluble TNFRs are useful in the treatment of 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 TNFc -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/m2, or more preferably, from 5-mg/m2. For small animals, such as dogs or cats, a suitable dose is 0.4 mg/kg.
TNFR:Fc (preferably constructed from genes derived from the recipient species), 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.
Provided herein are methods of treating or preventing psoriatic lesions that involve administering to a human patient a therapeutically effective amount of a soluble TNFR. A preferred soluble TNFR for this purpose is TNFR:Fc. The treatment is effective against psoriatic lesions that occur in patients who have ordinary psoriasis or psoriatic arthritis.
Patients are defined as having ordinary psoriasis if they lack the more serious symptoms of psoriatic arthritis (e.g., distal interphalangeal joint DIP
involvement, enthesopathy, spondylitis and dactylitis), but exhibit 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).
In treating ordinary psoriasis, TNFR:Fc is administered in an amount and for a time sufficient to induce an improvement in the patient's condition as measured according to any indicator that reflects the severity of the patient's psoriatic lesions. One or more such indicators may be assessed for determining whether the amount of TNFR and duration of treatment is sufficient. In one preferred embodiment of the invention, the TNFR:Fc is administered in an amount and for a time sufficient to induce an improvement over baseline in either the psoriasis area and severity index (PASI) or the Target Lesion Assessment Score. In another embodiment, both indicators are used.
When PASI score is used as the indicator, treatment is regarded as sufficient when the patient exhibits an at least 50% improvement in his or her PASI score, or alternatively, when the patient exhibits an at least 75% improvement in PASI score. Using the Psoriasis Target Lesion Assessment Score to measure sufficiency of treatment involves determining for an individual psoriatic lesion whether improvement has occurred in one or more of the following, each of which is separately scored: plaque elevation; amount and degree of scaling or degree of erythema; and target lesion response to treatment.
Psoriasis Target Lesion Assessment Score is determined by adding together the separate scores for all four of the aforementioned indicia, and determining the extent of improvement by comparing the baseline score the score after treatment has been administered.
A satisfactory degree of improvement in psoriasis patients is obtained by administering the TNFR:Fc one or more times per week. For example, the TNFR:Fc may be administered one time, two times or three or more times per week. Treatment may be continued over a period of at least one week, for two weeks, three weeks, four weeks or longer. Treatment may be discontinued after the patient improves, then resumed if symptoms return, or alternatively, the treatment may be administered continuously for an indefinite period. A preferred route of administration is subcutaneous injection. In one preferred method for treating adult psoriasis patients, the amount of TNFR:Fc administered by injection is 5-12 mg/m2, or a flat dose of either 25 mg or 50 mg. In one preferred embodiment of this method, a dose of 25 mg is injected two times per week, and in another preferred embodiment, a dose of 50 mg is injected one time per week. In a preferred method of treating pediatric psoriasis patients, the dose administered by injection is 0.4 mg/kg, up to a maximum dose of 25 mg.
TNFR:Fc may be used to treat ordinary psoriasis in combination with one, two, three or more other medications that are effective against psoriasis. These additional medications may be administered before, simultaneously with, or sequentially with the TNFR:Fc. Drugs suitable for combination therapies of psoriasis include pain medications (analgesics), including but not limited to acetaminophen, codeine, propoxyphene napsylate, oxycodone hydrochloride, hydrocodone bitartrate and tramadol. In addition, the TNFR:Fc or other TNFR mimic may be administered in combination with methotrexate, sulfasalazine, gold salts, azathioprine, cyclosporine, antimalarials, oral steroids (e.g., prednisone) or colchicine. Non-steroidal anti-inflammatories may also be coadministered with the TNFR

mimic, including but not limited to: salicylic acid (aspirin); ibuprofen; indomethacin; celecoxib; rofecoxib;
ketorolac; nambumetone; piroxicam; naproxen; oxaprozin;
sulindac; ketoprofen; diclofenac; and other COX-1 and COX-2 inhibitors, salicylic acid derivatives, propionic acid derivatives, acetic acid derivatives, fumaric acid derivatives, carboxylic acid derivatives, butyric acid derivatives, oxicams, pyrazoles and pyrazolones, including newly developed anti-inflammatories.

Moreover, the 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, it may be administered in combination with one or more of the following compounds: minocycline; misoprostol; oral colagen; penicillamine; 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.

Psoriasis moreover may be treated by TNFR:Fc administered in combination with one or more of the following topically applied compounds: 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 by TNFR:Fc in combination with the following therapies: plasmapheresis;
phototherapy with ultraviolet light B; psoralen combined with ultraviolet light A (PUVA); and sunbathing.

It is understood that the response by individual patients to the aforementioned medications or combination therapies may vary, and the most efficacious combination of drugs for each patient will be determined by his or her physician.

For practical use, storage, transportation or the like, the composition may be put in a commercial package including a container in which the composition is contained.
Such a commercial package usually also includes a written matter which is associated with the composition and describes indications of the composition and how it should be taken.

The following example is provided to illustrate the advantages of various embodiments of the invention, and is not intended in any way to limit the scope of the disclosure.

18a EXAMPLE
TNFR:Fc Treatment of Patients with Psoriatic Arthritis 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.
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.
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 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.
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 >_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.
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 >_30% was scored as an "improvement," and an increase in swelling of >_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.
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 _>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).
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; l=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+DI)Al 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 (-90% improvement);
2=marked response (-75% improvement); 3=moderate response (-50% improvement);
4=slight response (-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.
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 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.

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 C (36-46 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 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), (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.
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 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 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 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 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 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.
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 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 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 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 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 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 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

Claims (21)

CLAIMS:

1. A physiologically acceptable composition for treating ordinary psoriasis in a human patient who is suffering from ordinary psoriasis, which comprises:

(a) a chimeric protein comprising a soluble TNF.alpha.
receptor derived from TNFRp75 and an Fc portion of an antibody, and (b) a physiologically acceptable carrier, excipient or diluent, wherein the soluble TNF.alpha. receptor can bind to TNF.alpha..

2. The composition of claim 1, wherein the chimeric protein forms a dimer, trimer, or higher order multimer.

3. The composition of claim 1, wherein the chimeric protein forms a dimer.

4. The composition of claim 1, wherein the chimeric protein is TNFR:Fc.

5. The composition of any one of claims 1 to 4, which is a lyophilizate.

6. The composition of any one of claims 1 to 4, which is a liquid.

7. The composition of any one of claims 1 to 6, wherein the composition is for injection and wherein the patient is an adult and the amount of the chimeric protein to be injected each time is 5 to 12 mg/m2.

8. The composition of any one of claims 1 to 6, wherein the composition is for injection and wherein the patient is an adult and the amount of the chimeric protein to be injected each time is a flat dose of about 20 to 30 mg.

9. The composition of claim 8, wherein the patient is an adult and the amount of the chimeric protein to be injected each time is a flat dose of 25 mg.

10. The composition of any one of claims 1 to 6, wherein the composition is for injection and wherein the patient is an adult and the amount of the chimeric protein to be injected each time is a flat dose of about 25 to 60 mg.

11. The composition of claim 10, wherein the patient is an adult and the amount of the chimeric protein to be injected each time is a flat dose of 50 mg.

12. The composition of any one of claims 1 to 11, wherein the chimeric protein is TNFR:Fc and wherein said composition is in a sustained release form selected from the group consisting of TNFR:Fc that is encapsulated in a biocompatible polymer, TNFR:Fc that is admixed with a biocompatible polymer, and TNFR:Fc that is encased in a semi-permeable implant.

13. Use of a chimeric protein in the manufacture of a medicament for therapeutic treatment of ordinary psoriasis, wherein the chimeric protein comprises a soluble TNF.alpha.
receptor derived from TNFRp75 and an Fc portion of an antibody, wherein the soluble TNF.alpha. receptor can bind to TNF.alpha..

14. The use of claim 13, wherein the chimeric protein is TNFR:Fc.

15. A physiologically acceptable composition for treating ordinary psoriasis in a pediatric human patient who is suffering from ordinary psoriasis, which comprises:

(a) a chimeric protein comprising a soluble TNF.alpha.
receptor derived from TNFRp75 and an Fc portion of an antibody, and (b) a physiologically acceptable carrier, excipient or diluent, wherein the composition comprises a maximum of 25 mg of the chimeric protein, and wherein the soluble TNF.alpha. receptor can bind to TNF.alpha..

16. The composition of claim 15, wherein the chimeric protein is TNFR:Fc.

17. A physiologically acceptable composition for treating ordinary psoriasis in an adult human patient who is suffering from ordinary psoriasis, which comprises:

(a) a chimeric protein comprising a soluble TNF.alpha.
receptor derived from TNFRp75 and an Fc portion of an antibody, and (b) a physiologically acceptable carrier, excipient or diluent, wherein the composition comprises 25 or 50 mg of the chimeric protein, and wherein the soluble TNF.alpha. receptor can bind to TNF.alpha..

18. The composition of claim 17, wherein the chimeric protein is TNFR:Fc.

19. A commercial package comprising:

(a) a container containing the composition of any one of claims 1 to 12, and (b) a written matter which is associated with the composition and describes use of the composition for treating ordinary psoriasis in a human patient.

20. The commercial package of claim 19, wherein the container comprises the composition of claim 4.

21. The commercial package of claim 20, wherein the written matter describes that the composition can be taken by the human patient in combination with a therapy selected from the group consisting of phototherapy with ultraviolet light B, psoralen combined with ultraviolet light A, plasmapheresis and sunbathing.