WO2006018832A1 - Tnf-binding protein-1 in the treatment of psoriasis - Google Patents

Abstract

The treatment of psoriasis by administering an anti-TNF-alpha agent is here described. Such a treatment is performed according to specific doses, regimens and route of administration. In particular the anti-TNF-alpha agent is recombinant human TNF-binding protein-1 (r-hTBP-1) and the psoriasis is defined as moderate to severe or associated with psoriatic arthritis.

Description

TNF-BINDING PROTEIN-I IN THE TREATMENT OP PSORIASIS

FIELD OF THE INVENTION

This invention relates to the treatment of psoriasis by administering an anti-TNF-alpha 5 agent according to specific doses, regimens and route of administration. In particular the anti-TNF-alpha agent is recombinant human TNF-binding protein-1 (r-hTBP-1).

BACKGROUND OF THE INVENTION PSORIASIS

10 Psoriasis is an inflammatory skin disorder that affects between 1 and 2% of the population. It is characterised by an increased proliferation of the epidermis, and presents as well-defined thickened erythematous patches typically covered with a silver scale. Psoriatic arthritis (PsA), an inflammatory arthritis and the most serious disorder associated with psoriasis, affects an estimated 25% of patients with psoriasis. PsA

15 typically involves the distal interphalangeal joints. Current therapies for psoriasis and PsA are unsatisfactory, as none are curative; moreover, the most effective agents are associated with potentially serious side effects. In all cases, psoriasis is a chronic condition that requires long-term medication.

20 Although the aetiology and pathology of psoriasis and PsA is not well understood, the discovery that T-cells and inflammatory cytokines are centrally involved in the development of psoriasis and PsA is leading to the development of new biological therapeutic agents to treat these conditions.

25 CONVENTIONAL TREATMENT FOR PSORIASIS

Present treatments for psoriasis and PsA, consisting of drug therapies and phototherapies, may clear lesions and relieve uncomfortable symptoms of the disease, but remissions are usually short-lived and most patients experience at least one exacerbation or relapse per year.

3_.0

Topical therapies are often the initial therapeutic choice for mild-to-moderate psoriasis. Emollients and moisturisers are the first choice because they cause few side effects; they are also often used as pre-treatments for, or in combination with, other active topical agents. Keratolytic agents act by reducing hyperkeratosis and softening psoriatic scales, aiding in their removal. As with emollients, keratolytic agents are often used to supplement other therapies.

Corticosteroids are the most common treatment for psoriasis. Numerous forms of corticosteroids are available, depending on the required potency. Systemic absorption of very potent corticosteroids can cause skin atrophy, and abrupt withdrawal can cause the disease to flare. The relapse rate has been reported to vary from 35-80%, depending on the formulation and treatment regimen used.

Topical retinoids (vitamin A analogues) work by interacting with receptors that regulate gene expression within the cell, i.e., the fundamental mechanism of cell growth and differentiation. They are applied only once daily and approximately 50-60% of patients will achieve a good response after 12 weeks of treatment. The efficacy of topical retinoids can be enhanced with concomitant high-potency corticosteroids.

Systemic therapies are frequently the therapeutic choice for moderate-to-severe psoriasis. They include phototherapy, retinoids, methotrexate and immunosuppressive drugs such as cyclosporin.

Phototherapy with ultraviolet A or B light (PUVA or PUVB) is thought to block DNA replication, thereby decreasing skin proliferation. Phototherapy with UVA, has been shown to be effective; however, its use is associated with the development of skin cancer, and is therefore limited to carefully selected patients with extensively disabling psoriasis and to those over 50 years of age.

The use of systemic retinoids is mainly limited to the treatment of severe and less common forms of psoriasis. These drugs are anti-inflammatory agents that decrease skin proliferation. However, their use is associated with severe side effects, which include liver damage and foetal abnormalities.

Methotrexate is a folic acid analogue that inhibits DNA synthesis, thus stopping rapid cell division, such as that found in untreated psoriatic lesions. It is generally reserved for very severe and refractory psoriasis, as its use is associated with liver toxicity. Immunosuppressive drugs such as cyclosporin function by inhibiting T-cells. Cyclosporin is generally used for severe plaque psoriasis; however, its use is limited to refractory patients because of its side effects, which include renal toxicity, paresthesia and hirsutism.

TUMOUR NECROSIS FACTOR-ALPHA

Tumour necrosis factor-alpha (TNF-alpha).is a cytokine with pleiotropic biologic effects. The secreted form of human TNF-alpha is a 17 kD non-glycosylated protein, circulating as a 51 kD homotrimer that is mainly produced by fibroblasts, monocytes, macrophages and T and B cells. The production of TNF-alpha is triggered by a variety of stimuli, including endotoxins, superantigens, osmotic stress and radiation. TNF-alpha secretion is also influenced by pro-inflammatory and anti-inflammatory cytokines; for example, interferon-gamma is an important synergistic stimulant for TNF-alpha production, whereas IL-10 is a suppressor of this production. The production of TNF-alpha is regulated at the transcriptional, translational, and post- translational levels, suggesting the need for protection against unregulated TNF-alpha release. TNF-alpha is translated as a 26kD precursor protein that contains a long signal peptide. The enzyme that cleaves the propeptide to yield the mature form is a specific metalloproteinase. Unprocessed TNF-alpha remains membrane-bound, and is biologically active upon contact with neighbouring cells.

TNF-alpha plays a pivotal role in the immune response and in inflammatory reactions. It is able to recruit circulating inflammatory cells to local tissue sites of inflammation, to enhance the production of pro-inflammatory cytokines, to induce oedema (capillary leakage/endothelial damage), to activate coagulation, to induce vasodilatation through the pre-kallikrein/bradykinin system, and to mediate granuloma formation.

SOLUBLE TNF RECEPTORS

TNF-alpha exerts its multiple effects on cell function by binding to specific transmembrane receptors (TNFR). TNFR are of 2 types: p55 (type I) and p75 (type II), respectively 55 ^"and 75 kD(1 ;2). Both type I and Il receptors are also receptors for lymphotoxin alpha (also known as TNF-beta). Each receptor contains a specific intracellular (cytoplasmic) domain for signal transduction, suggesting different roles, a transmembrane domain and an extracellular domain that shares some homology through the presence of 4 cysteine-rich repeats(3). Soluble forms of both receptors have been isolated(4-6) and have been demonstrated to arise from the shedding of the extracellular portions of the membrane-bound type I and Il molecules. These soluble forms of the type I and type Il receptors are referred to as TNF-binding protein-1 (TBP-1) and TNF-binding . protein-2. (TBP-2) respectively, and retain the capacity to bind TNF.

The TNF-binding proteins (TBPs) exist naturally in body fluids including serum, urine, colostrum, milk(7) and synovial fluid, and can reach serum levels up to the ng/mL range in certain diseases, such as myocardial failure or sepsis syndrome. Thus, the serum concentrations of TBPs are about 1000-fold higher than those of TNF, which are in the pg/mL range. Soluble TNF- binding proteins act by competing with the cell surface receptors for TNF-alpha and TNF-beta molecules. Many of the biological effects of TNF are blocked by TBPs. The presence of TNF-binding proteins in biological fluids is detected by their ability to compete with the binding of TNF-alpha and TNF-beta to specific cell receptors, and is measured by their ability to inhibit TNF-alpha and TNF-beta cell lytic activity.

RECOMBINANT HUMAN TUMOUR NECROSIS FACTOR-BINDING PROTEIN-1 (r- hTBP-1)

A recombinant form of the human TNF-binding protein-1 (r-hTBP-1) is produced in Chinese Hamster Ovary (CHO) cells. Its approved International Non-proprietary Name (INN) is onercept. It is a glycoprotein, consisting of 161 amino acids (lacking the first 19 amino acids in the fully expressed molecule) and containing 24 fully-paired cysteine residues and three potential N-glycosylation sites (Asn 14, Asn 105 and Asn 111). The molecular weight of the polypeptide portion is about 18.2kD. The main structure of the N-linked glycane is a bi-antennary oligosaccharide complex type, fucosilated with a varying sialylation rate.

TBP-1 IN THE TREATMENT OF PSORIASIS

Psoriasis is a disease state in which TNF-alpha, a pro-inflammatory cytokine, is present in increased concentrations in skin lesions. In inflamed skin, keratinocytes and inflammatory cells both produce large amounts of TNF. Therefore, psoriasis has been an appropriate therapeutic target for anti-TNF agents. To date, two phase Il studies with onercept have been conducted in this indication. In a first study, a total of 126 patients with psoriasis and psoriatic arthritis were randomly allocated to receive treatment with either 50 mg onercept subcutaneous (SC) injection 3 times per week, 100 mg onercept SC injection 3 times per week or matching placebo over a 12-week period. Patients were followed up for a further 8 weeks.

The results indicated that subcutaneous onercept at 50 mg or 100 mg given three times a week induces dose-dependent improvements in manifestations of psoriasis and psoriatic arthritis including skin lesions, arthritic symptoms and systemic inflammation.

Onercept had a positive effect on psoriatic arthritis, with significant improvements in Psoriatic Arthritis Response Criteria (PsARC), American College of Rheumatology (ACR) 20 and ACR 50 response rates compared to placebo. With respect to cutaneous psoriasis, the pre-defined primary endpoint, Psoriasis Area and Severity Index (PASI) 75% response, did not show significant difference between onercept and placebo at either dose level. However, clinically significant effects were seen on secondary endpoints. In particular, the difference between onercept 100 mg and placebo in PASI 50% response rate was close to statistical significance, and PASI 50% response was achieved faster in onercept-treated patients compared to placebo patients. Onercept showed effects on markers of systemic inflammation, including reductions in Erythrocyte Sedimentation Rate (ESR), C-Reactive Protein (CRP) and lnterleukin-6 (IL-6) plasma levels. Onercept also induced a marked and statistically significant decrease in lesional T-cells and an increase in circulating T-cells fhttp://www.forrelease.com/D20030622/nvsu004.P2.06222003082356.09126.htlm and S.N. Nikas, Current Opinion in Investigational Drugs (2003, 4(11): 1369-76)) ]

These results indicated that the therapeutic window of onercept wasn't fully explored or characterised. It was considered necessary to determine whether higher doses or different treatment regimens would result in better efficacy with respect to cutaneous measures while still providing a favourable risk-benefit ratio. Subsequently, a second study was performed to evaluate the safety and efficacy of onercept in patients with moderate to severe plaque psoriasis. One hundred and thirty patients were randomised to receive either onercept 150 mg three times a week (TIW) and matching placebo four times per week, or onercept 100 mg daily, or matching placebo daily for 12 weeks. At the end of the treatment period, patients were followed up for a further 12 weeks in the absence of therapy.

Onercept given at a dose of 150 mg TIW induced a marked reduction in the signs and symptoms of psoriasis, as shown by the 54% PASI 75 response measured at week 12, compare to 12% in patients receiving placebo (p<0.001). A PASI 50 response was achieved by 74% of patients receiving onercept 150 mg TIW, compared to 26% in placebo patients (p<0.001).

OTHER ANTI-TNF-ALPHA AGENTS IN THE TREATMENT OF PSORIASIS Recent clinical studies have demonstrated the efficacy of both Enbrel® (a soluble decoy receptor) and Remicade® (an anti-TNF monoclonal antibody). Enbrel is now approved in the USA for the treatment of patients with moderate to severe psoriasis and has just received a positive opinion from the CHMP in Europe based on data from 2 phase III studies (Leonardi et a/ 2003 NEJM 394:2014-2022 and Gottlieb et at 2003 Arch. Dermatol. 139:1627-1632.

In another study(10), Remicade^® was tested in 33 patients with moderate to severe plaque psoriasis who were randomly assigned to receive intravenous placebo (n=11), Remicade^® 5 mg/kg (n=11), or Remicade^® 10 mg/kg (n=11) at weeks 0, 2, and 6. Patients were assessed at week 10 for the primary endpoint (good, excellent, or clear rating on the Physician's Global Assessment [PGA]). Of the 33 patients enrolled, three dropped out. Eighty-two percent (82%) of patients in the Remicade^® 5 mg/kg group were responders, compared with 18% in the placebo group, and 91% patients in the Remicade^® 10 mg/kg group were responders. The median time to response was 4 weeks for patients in both Remicade^® groups.

Remicade^® was also tested in six patients with progressive joint disease and psoriatic skin lesions that were unresponsive to methotrexate therapy(11). PASI score was determined before and 10 weeks after initiation of therapy. Improvement of psoriatic skin lesions was observed in all patients.

DESCRIPTION OF THE INVENTION A more complete evaluation of the whole set of results coming from the phase Il clinical studies with onercept has demostrated that higher weekly doses (like 100 mg daily) do not result in comparable efficacy results. The improvement in PASI was delayed in this group compared to what was observed in the onercept 150 mg TIW group, although it tended to reach a similar level at the end of the treatment period and especially during the follow-up period. These results do not support the use of doses as high as 100 mg daily.

Moreover, the data coming from the 12-week follow-up period (period in which the administration of the medicament is suspended) demonstrated that the beneficial effect of onercept was well maintained after administration cessation, with 61% of patients who received onercept 150 mg TIW during the treatment period and achieved a PASI 75, maintaining that response through to Week 24 of the follow-up period. Indeed, the proportion of patients with PASI 75 at the end of the follow-up was 43%, compared to 54% at the end of the treatment period. This result indicates that onercept interferes with disease pathways that are not reactivated shortly after treatment cessation.

Therefore the main object of the present invention is the use of r-hTBP-1 together with a pharmaceutically acceptable excipient for the manufacture of a medicament in the therapeutic treatment of psoriasis, wherein the medicament is to be subcutaneously administered three times per week at a dose of 100 to 150 mg per injection for intermittent periods of 12 weeks up to 52 weeks, thus alternating periods of administration of the medicament with periods of non-administration.

Typically the therapy for psoriasis according to the present invention will comprise a first treatment (FT) period, in which r-hTBP-1 is administered as indicated above and a second period, known as an observation (OB) period, in which no r-hTBP-1 is administered. Typically each of these periods will be at least 12 weeks long. At the end of the OB period, another treatment period, known as re-treatment (RT), will begin under the same conditions applied during the FT. The advantages of the present invention with respect to all the other known psoriasis treatments are the following:

- Contrary to the other anti-TNF-alpha agents reported in the Background of the Invention, r-hTBP-1 is the recombinant version of a product which is naturally occurring in the human body and which is considered to be the natural inhibitor for TNF. Therefore treatment with r-hTBP-1 has very low safety and immunogenicity risks.

The intermittent administration allows reducing the overall dosage of the active ingredient administered to a patient over long periods of time, thereby further decreasing toxicity risks and patients inconvenience due to repeated injections.

The dose comprised between 100 and 150 mg to be administered subcutaneously three times per week represents the optimal r-hTBP-1 treatment in terms of efficacy, patient compliance and safety.

According to a preferred embodiment of the invention the patients subject to the intermittent treatment of the present invention are those, who failed to respond to at least another previous treatment.

According to a further preferred embodiment of the invention the patients subject to the intermittent treatment of the present invention represent a sub-population of the whole set of psoriasis patients.

Therefore, another object of the present invention is the use of r-hTBP-1 together with a pharmaceutically acceptable excipient for the manufacture of a medicament in the treatment of psoriasis, wherein the medicament is to be subcutaneously administered three times per week at a dose of 100 to 150 mg per injection for intermittent periods of

12 weeks up to 52 weeks, thus alternating periods of administration of the medicament with periods of non-administration and wherein the medicament is administered to patients, who could be defined as PASI 75 responders at the end of a first 12 weeks administration period.

Preferably each period (of treatment and of non-treatment) is 12 weeks long. More preferably the period of non-treatment and the period of treatment is 16 weeks long. The preferred doses per injection are 100 or 150 mg.

According to another preferred embodiment of the invention the psoriasis treated with the present invention is from moderate to severe or associated with psoriatic arthritis.

According to a further preferred embodiment of the invention r-hTBP-1 is produced from transformed mammalian cells, such as CHO (Chinese Hamster Ovary) cells.

Another object of the present invention is a method of therapeutically treating psoriasis comprising administering to a patient in need of such treatment an effective amount of recombinant human Tumor-Necrosis-Binding-Binding Protein-1 (r-hTBP-1), wherein the medicament is to be subcutaneously administered three times per week at a dose of 100 to 150 mg per injection for intermittent periods of 12 weeks up to 52 weeks, thus alternating periods of administration of the medicament with periods of non- administration.

One example of the treatment according to the present invention is illustrated in Figure 1.

DEFINITIONS

"Therapeutic treatment" within the context of this invention refers to any beneficial effect on progression of disease, including attenuation, reduction, decrease or diminishing of the pathological development after onset of disease.

"Pharmaceutically acceptable" is meant to encompass any carrier, which does not interfere with the effectiveness of the biological activity of the active ingredient and that is not toxic to the host to which is administered. For example, for parenteral administration, the above active ingredients may be formulated in unit dosage form for injection in vehicles such as saline, dextrose solution, serum albumin and Ringer's solution. Besides the pharmaceutically acceptable carrier, the compositions of the invention can also comprise minor amounts of additives, such as stabilisers, excipients, buffers and preservatives. An "effective amount" refers to an amount of the active ingredients that is sufficient to affect the course and the severity of the diseases described above, leading to the reduction or remission of such pathology. The effective amount will depend on the route of administration and the condition of the patient.

"A week" refers to a period of time of or about 5, 6 or 7 days.

"Psoriasis" is intended to be a common chronic, recurrent disease characterized by dry, well-circumscribed, silvery, scaling papules and plaques of various sizes. In generic terms psoriasis can be characterized by type and degree of severity. The categorization of psoriasis into the degrees of severity: mild, moderate afid severe is a useful tool for determining an effective form of therapy in individual cases. It is also a criteria used by psoriasis research programs seeking patient volunteers to describe eligible candidates. Each category is defined in terms of percent of the body's surface affected by psoriasis: - Mild psoriasis is defined as affecting less than 5% of the body's surface Moderate psoriasis is defined as affecting 5-30% Severe psoriasis is defined as affecting greater than 30%. As a general estimate, the palm of the hand is thought to represent 1% of the body's surface.

More specifically the severity of the disease and the efficacy of therapies are evaluated by physicians according to some internationally recognized parameters, criteria and scores. For psoriasis the following indexes, criteria ,and scores are internationally applied by physicians during clinical trials and accepted by the Health Authorities.

"PASI" means Psoriasis Area and Severity Index. It is determined by a physician after a visit to a patient and after having completed a Table like that reported in Figure 2. Physicians are also asked to report at the end of the treatment a % improvement of the PASI. This is calculated according to the following formula: % IMPROVEMENT - »» ^ - WeekX2PΛSl _{χ m}

Study DayO PASI

The same evaluator should perform all PASI determinations for any individual subject throughout the study. According to the present invention "PASI 75 responders" are intended as those subjects having achieved at least 75% improvement of the PASI after the initial treatment period (12 weeks).

Subjects having achieved from 50 to 74% improvement of the PASI after the initial treatment period (12 weeks) are considered "partial responders" and subjects having achieved less than 50% improvement of the PASI after the initial treatment period are considered as "non responders".

"Psoriatic BSA" represents the percentage of total body surface (BSA) affected by psoriasis. This is to be calculated using the following Table 1. Table 1

In practice the body has been divided into four segments, which are listed in column one of the above table and their approximate percentage of the entire body area is in column two. These approximate percentages are used as references and they represent the maximum that can be reported in the sixth column. The areas of the body segments affected (columns three and five) are to be determined using the "rule of palm" ("rule of palm" reference is based on the size of the patient's palm and not the assessor's palm). The percentages of anterior and posterior sites affected by psoriasis are to be determined as percentages of the total BSA. The final row and column are to be used to sum the totals of the four body segments and to calculate the total BSA.

Another score to determined is the "Physician's Global Assessment (PGA)". PGA represents the evaluation by the physicians of the global response of all psoriatic lesions to therapy. It will be evaluated compared with the baseline condition using Study Day 1 photographs and using the categories reported in the following Table 2. Table 2

The PGA score should, at a minimum, include and reflect a global consideration of erythema, scaling, plaque thickness and percentage of total body surface area affected by psoriasis.

There is also a "static PGA" (sPGA). For the determination of the sPGA, the degree of overall lesion severity will be evaluated using the categories of the following Table 3: Table 3

The sPGA score should be selected using the descriptors that best describe the overall appearance of the lesions. It is not necessary that all three criteria be fulfilled. In some patients, either scale or erythema will dominate the clinical presentation. In those cases, the sPGA score should be based on a combination of plaque elevation and the dominant feature (either erythema or scale). Because plaque elevation is the most robust finding, it should be the dominant feature influencing the sPGA rating for indeterminant cases. "Nail Psoriasis Severity Index" (NAPSI) is a score used to measure the advancement of the disease in the nails. It is calculated as follows.

The nail is divided with imaginary horizontal and longitudinal lines into quadrants. Each nail is given a score for nail bed psoriasis (0-4) and nail matrix psoriasis (0-4) depending on the presence of any of the features of nail psoriasis in that quadrant. Nail Matrix Psoriasis consists of any of the following: pitting leukonychia, red spots in the lunula, and nail plate crumbling. A score from 0 (absent) to 4 (present in all 4 quadrants of the nail) is given for the nail matrix psoriasis.

Nail Bed Psoriasis is the presence or absence of any of the following: onycholysis, splinter hemorrhages, oil drop (salmon patch) discoloration, and nail bed hyperkeratosis. A score from 0 (absent) to 4 (present in all 4 quadrants of the nail) is given for the nail bed psoriasis.

The target nail is graded for nail matrix psoriasis and nail bed psoriasis. The sum of these two scores is the total score for that nail (0-8). Each nail is evaluated, and the sum of all the nails is the total NAPSI score. The sum of the scores from all nails is 0-80. At any time the matrix or nail bed score can be assessed independently if desired

The sum of the total score of all involved fingernails is the total NAPSI score for that patient at that time.

The "Itching scale" is completed by the patients by asking them to circle the number (from 0 to 10) that best represents his/her itching at the visit time-

"Psoriatic Arthritis" (PsA) is intended to be an inflammatory arthritis associated with psoriasis of the skin or nails.

"Psoriatic Arthritis Response Criteria" (PsARC) is used to evaluate the efficacy of a treatment of PsA (12; 13).

To have such a response, a patient had to show improvement in at least two of the following "American College of Rheumatology" (ACR) categories (at least one being a joints score), with worsening in none:

Physician's Global Assessment of disease activity: improvement was defined as decrease by at least one unit and worsening as increase by at least one unit. - Patient's Global Assessment of disease activity: improvement was defined as decrease by at least one unit and worsening as increase by at least one unit.

Tender joints score: improvement was defined as decrease by at least 30% and worsening as increase by at least 30%. - Swollen joints score: improvement was defined as decrease by at least 30% and worsening as increase by at least 30%.

Response according to American College of Rheumatology (ACR) criteria requires improvement in both tender and swollen joint counts and in at least three of the other five outcomes (Patient's Assessment of Pain, Patient's and Physician's Global Assessments, Patient's Assessment of Physical Function and acute phase reactant). Response levels are determined by the amount of improvement achieved: ACR 20% response corresponded to at least 20% improvement in each of these outcomes, ACR 50% response to at least 50% improvement, and so on.

Various aspects and embodiments of the present invention will now be described in more details by way of Examples, which make reference to the following Figures. It will be appreciated that modification of details may be made without departing from the scope of the invention.

LIST OF ABBREVIATIONS

ACR American College of Rheumatology

ALT Alanine aminotransferase

ANOVA Analysis of variance

ANCOVA Analysis of covariance

AST Aspartate aminotransferase

B-cell B lymphocyte

BSA Body surface area

CAM Cell-adhesion molecule

CHO Chinese hamster ovary

CD- Cluster differential (e.g., CD4+ cell, CD8+ cell, etc.)

CRP C-reactive protein

DMARD(s) Disease modifying anti-rheumatic drug(s)

DLQI Dermatology life quality index

DNA Deoxyribonucleic acid

ESR Erythrocyte sedimentation rate

HCV Hepatitis C virus hCG Human chorionic gonadotropin

IL- lnterleukin (e.g., IL-1, IL-6, etc.)

IM Intramuscular

ITT Intention to treat

IV Intravenous

IVRS Interactive voice recognition system MAb Monoclonal antibody

MHC Major histocompatibility complex mg Milligram mL Miliilitre

MMP Metalloproteinase

MTX Methotrexate

NAPSI Nail Psoriasis Severity Index

NSAID(s) Non-steroidal anti-inflammatory drug(s)

OTC Over-the-counter

PASI Psoriasis area and severity index

PGA Physician's global assessment

PsARC Psoriatic Arthritis Response Criteria

SPGA Static physician's global assessment

PsA Psoriatic arthritis

PsA-GA Psoriatic Arthritis Global Assessment

PT Prothrombin time

PUVA Psoralen-ultraviolet lightA

PUVB Psoralen-ultraviolet light B

RA Rheumatoid arthritis

RT Re-treatment period

SC Subcutaneous

SRB Safety review board

TB Tuberculosis

TBP-1 Tumour necrosis factor binding protein-1

T-cell T lymphocyte

TGF-beta Transforming growth factor-beta

TIW Three times per week

TNF-alpha Tumour necrosis factor alpha

TNFR Tumour necrosis factor Receptor

ULN Upper limit of normal DESCRIPT1ON OF THE FIGURES

Figure 1 : This drawing illustrates by way of flow-chart an exemplary intermittent treatment according to the present invention.

Figure 2: This figure reports the details of the Table that the physicians have to complete in order to calculate the PASI.

EXAMPLES

EXAMPLE 1 - TREATMENT OF PATIENTS WITH ACTIVE PSORIASIS AND PSORIATIC ARTHRITIS

This study was conducted in 28 clinical centres in 14 countries.

Phase of development: Clinical phase Il

Objectives:

Primary: to evaluate safety and therapeutic response in both skin and joints of two different regimens of onercept in patients with plaque psoriasis and active psoriatic arthritis (PsA). Secondary: to assess the effects of onercept on disease progression, area of skin involvement, biological markers of inflammation, bone turnover, blood lipid profile and haematological parameters and to establish the pharmacokinetics of onercept in this population.

Methodology:

Multi-centre, randomised, double-blind, placebo-controlled Phase Il study of onercept (recombinant human tumour necrosis factor-alpha binding protein-1 [TBP-1]) in patients with active plaque psoriasis and active psoriatic arthritis, consisting of

12 weeks of treatment and 8 weeks of follow-up.

Eligible patients were randomised in equal allocation to receive 100 mg onercept,

50 mg onercept or matching placebo, administered subcutaneously 3 times a week for 12 weeks. Randomisation was stratified by disease severity and centre. Each dose was given as 2 subcutaneous injections: 2 injections of 50 mg onercept, 2 injections of placebo, or one injection of each.

Cutaneous disease was evaluated using the Psoriasis Area and Severity Index (PASI), the Physician's Global Assessment (PGA) and measurement of psoriatic body surface area (PBSA). Articular disease was evaluated using the Psoriatic Arthritis Response Criteria (PsARC) and American College of Rheumatology (ACR) criteria, including tender and swollen joint counts, patient assessment of pain and disability, patient and physician assessment of global disease activity and measurement of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). In some centres, ultrasound examination, enthesial screen and arthroscopy/synovial biopsy were performed. Treatment period visits took place on Days 15 and 29 and at the end of Weeks 8 and 12. A follow-up visit took place 4 weeks after the last injection, and for patients who completed treatment, a final study visit took place 8 weeks after the last injection, involving only disease activity assessments. Adverse events were to be reported up to 30 days after the last injection of study drug. At the end of the study,-¹ any ongoing adverse events were to be followed until resolution or until 30 days after the last dose of study drug, whichever came first. Stable regimens of prednisone (<10 mg/day) and/or one non-steroidal anti- inflammatory drug (NSAID) were allowed during the study, as were emollients and moisturisers, salicylic acid preparations for scalp lesions and low-potency topical corticosteroids for lesions on the face, groin or axillae (topical steroids were not to be used within 24 hours before a study assessment). Oral but not topical antihistamines could be used for itching, but had to be withheld for 24 hours before study visits. If additional treatment was required or if the patient experienced a relapse, this was to be considered a treatment failure and the patient was to be withdrawn from the trial.

Number of patients: Planned: 126 patients (30 centres). Enrolled: 127 patients randomised and 126 treated in 25 centres.

Diagnosis and main criteria for inclusion: Psoriasis and psoriatic arthritis. Patients with cutaneous psoriasis that had failed one recognised treatment and active psoriatic arthritis (PsA) that had failed at least one disease-modifying anti-rheumatic drug (DMARD) were recruited for the study. Major inclusion criteria were: - Disease duration of more than 6 months.

- Plaque psoriasis covering ≥5% of body surface area, with Psoriasis Area and Severity Index (PASI) score of 8 or more. (Patients with guttate, erythrodermic or pustular psoriasis as sole or predominant form of the disease were excluded.) - Active arthritis with at least 3 swollen joints and tenderness or pain on movement of at least 3 joints (or periarticular areas). Patients with arthritis mutilans and wheelchair-bound or bedridden patients were excluded.

Major exclusion criteria were: - Any previous use of chlorambucil or cyclophosphamide or use of biologies, other experimental treatments, disease-modifying anti-rheumatic drugs (DMARDs), intra-articular corticosteroids, topical therapies, oral retinoids or phototherapy within specified times before study entry.

- Antibodies against double-stranded DNA. - History of active tuberculosis (TB) or evidence of active TB or other active severe infection (or non-severe infection at the Investigator's discretion). Inadequate bone marrow reserve, renal function or hepatic function. Other major concomitant illness incompatible with the study, such as congestive heart failure, history of blood dyscrasia, history of cancer in the previous 5 years (with the exception of adequately treated basal cell carcinoma of the skin) or central nervous system demyelinating disorder. Written informed consent was obtained from all patients before any study-related procedures were performed. Potentially fertile female patients were required to practice contraception during the study, and pregnant and breastfeeding women were excluded.

Test product, dose and mode of administration, batch numbers:

Onercept solution for injection, given subcutaneously three times a week (tiw) at either

50 mg or 100 mg. Batch numbers used: 01 PC01 , 01PC02, 02PC01 , 02PC02.

Reference product, dose and mode of administration, batch numbers:

Placebo to match onercept solution for injection, given subcutaneously three times a week. Batch numbers used: 01 F101 , 01F102.

Duration of treatment: Twelve (12) weeks, followed by 8 weeks of follow-up. Criteria for evaluation:

Efficacy: For the cutaneous component, Psoriasis Area and Severity Index (PASI) scores, skin biopsy findings, body surface area affected by lesions,_, and Physician's Global Assessment (PGA). For the arthritic component, Psoriatic Arthritis Response Criteria (PsARC) and American College of Rheumatology (ACR) scores and subscale scores. Needle arthroscopies and synovial biopsies were performed in selected centres.

Safety: Incidence and severity of adverse events, with special attention to serious adverse events and infection-related adverse events; local tolerability, premature study withdrawal due to adverse events, routine haematology, blood chemistry and urinalysis, blood lipid profile, changes in vital signs and physical examination findings, occurrence of antibodies to tumour necrosis factor-alpha binding-protein-1 (TBP-1), and concomitant medications used during the study.

Statistical methods:

The primary analysis population was the intent-to-treat (ITT) population (N=126). The per-protocol population (N=115) excluded patients with major protocol violations and those who withdrew prematurely for reasons unrelated to efficacy. Patients who withdrew from the study or experienced treatment failure were considered non- responders thereafter. Safety was assessed in all randomised patients who received any study medication (N=126), analysed as treated.

Efficacy endpoints were defined separately for cutaneous psoriasis and for psoriatic arthritis. The primary cutaneous endpoint was the proportion of patients showing at least 75% improvement in PASI score (PASI 75% response) between baseline and

Week 12. The primary articular endpoint was the proportion of patients achieving a

PsARC response between baseline and Week 12.

Secondary endpoints were:

- Cumulative proportion of PASI 75% responders and duration of PASI 75% response.

- Proportion of patients achieving PASI 50% response, time to first PASI 50% response and cumulative proportion of PASI 50% responders over time.

- Numbers of patients relapsing after a PASI 75% or PASI 50% response at Week 12 and times to relapse. - Changes from baseline in PASI and in individual PASI parameters

(erythema, induration and scale).

- Cumulative proportion of patients with deterioration of PASI by ≥25% from baseline ('paradoxical response'). - Changes from baseline in psoriatic body surface area (PBSA) and individual PBSA components (head, upper limbs, trunk, lower limbs).

- Physician's Global Assessment (PGA) over time and proportion of patients with a PGA of 'cleared' or 'almost cleared.' - Change in skin biopsy from Study Day 1 to Week 12.

Cumulative proportion of PsARC responders over time.

- Duration of PsARC response.

- Proportions of patients achieving ACR 20, ACR 50 and ACR 70 response. Evolution of individual ACR parameters over time. - Proportion of patients with both PASI 50% and PsARC responses at

Week 12.

- Evolution of biological markers over time.

Both primary endpoints (PsARC response and PASI 75% response), selected secondary endpoints and safety outcomes for the 12-week treatment period were analysed after all patients had completed the treatment period (TP). The remaining analyses were performed and the final report was written after all patients had completed the 8-week follow-up period (FP).

Summary statistics were presented by treatment group. Confidence intervals (95%) for the mean/median were calculated where appropriate. P-values were calculated using two-sided tests. As this was an early phase Il study, there was no adjustment for multiplicity. The primary analysis of the primary endpoints (proportions of patients with PASI 75% response and PsARC response) compared the onercept dose with the best response rate (the 'best dose') to placebo. For all secondary endpoints, onercept

50 mg, onercept 100 mg and the combined onercept groups were compared to placebo.

The primary endpoints were to be analysed using the Cochran-Mantel-Haenszel test, adjusted for geographical region and baseline PASI score (PASI 8-12 and PASI >12). However, due to the small number of responses, the primary cutaneous endpoint was analysed using Fisher's exact test instead. Effects of geographical region and baseline severity were examined for this outcome using exact logistic regression.

Continuous secondary endpoints were analysed using ANOVA. If normality assumptions were not met, transformations of the endpoints or ANOVA on the ranks were performed. Binary and categorical secondary endpoints were analysed using the Cochran-Mantel-Haenszel test or Fisher's exact test, as appropriate. Confidence intervals for categorical data were calculated using the exact method of Armitage. Randomisation was stratified by disease severity (PASI 8-12 or PASI >12), and analyses of selected cutaneous outcomes were adjusted for baseline PASI score. Where appropriate, tests for trends were performed using the Jόnckheere-Terpstra test, the Cochran-Armitage test for trend or Cuzick's test for trend. Summary and Conclusions:

In this study, 84 patients were treated with onercept 50 mg or 100 mg tiw for up to 12 weeks. Twenty-two (22) patients discontinued during the treatment phase, primarily due to treatment failure. The number of such discontinuations was greater in the placebo group compared to the onercept groups, and placebo patients accounted for the majority of treatment failures. Efficacy results:

The primary cutaneous endpoint, PASI 75% response at Week 12, did not show statistically significant differences between treatments (4.8% for placebo, 7.1% for onercept 50 mg and 7.1% for onercept 100 mg). PASI 50% response was higher for onercept than for placebo (21.4% for placebo, 26.2% for onercept 50 mg and 40.5% for onercept 100 mg; p=0.063 for 100 mg vs. placebo). Median time to first PASI 50% response was shorter in onercept recipients (56.0 days for each onercept group compared to 111.5 days for placebo), and median decrease in PASI at Week 12 was also higher in onercept patients. Cumulative percentages of patients reaching a Physician's Global Assessment (PGA) rating of 'fair' or better at Week 12 were 33.3% for placebo, 47.6% for onercept 50 mg and 51.2% for onercept 100 mg. Percentages of patients reaching a PGA rating of 'clear' or 'almost clear' at Week 12 did not differ significantly. Skin biopsy results also showed a trend towards reduction in lesion severity. In particular, a significant decrease was seen in dermal CD3 T-cell count after onercept therapy. There was also a dose-dependent increase in circulating T-cell counts after onercept therapy.

PsARC response at Week 12 (the primary articular endpoint) differed significantly between the onercept and placebo groups: 45.2% for placebo, 66.7% for onercept 50 mg and 85.7% for onercept 100 mg (p<0.001 for onercept 100 mg vs. placebo). The effect of onercept on PsARC response was time- and dose-dependent. Assessment using ACR criteria also showed time- and dose-dependent improvement in joint disease. ACR 20 response rates (corresponding to at least 20% improvement in both tender and swollen joint counts and in at least three of the other five ACR components [Patient's Assessment of Pain, Patient's and Physician's Global Assessments, Patient's Assessment of Physical Function and acute phase markers]) were 31% for placebo, 59.5% for onercept 50 mg and 66.7% for onercept 100 mg. ACR 50 response rates (corresponding to at least 50% improvement in the criteria mentioned for ACR 20) were 2.4% for placebo, 28.6% for onercept 50 mg and 26.2% for onercept 100 mg. Most individual ACR components were significantly affected by onercept.

- A panel of biological markers of systemic inflammation was evaluated, as well as less specific markers of inflammation such as CRP and ESR:

- At the end of treatment (Week 12), IL-6 plasma levels were reduced by 4.8% in the placebo group, 19.4% in the onercept 50 mg group and 55.8% in the onercept 100 mg onercept groups compared to baseline.

- Onercept significantly reduced plasma vascular endothelial growth factor (VEGF) levels: VEGF was reduced by 3.4% in the placebo group, 13.7% in the onercept 50 mg group and 16.8% in the onercept 100 mg group compared to baseline.

- Onercept also reduced ESR and plasma levels of CRP, particularly in patients with elevated values at baseline. In patients with baseline CRP ≥15 mg/L, CRP was decreased by a median of 55.3% in onercept 50 mg patients and 75.0% in onercept 100 mg patients at Week 12, compared to a median increase of 0.2% in placebo patients. In patients with baseline ESR

≥28 mm/hr, median decreases of 33.3% and 42.3% in ESR levels were seen in the onercept 50 mg and 100 mg groups at Week 12, compared to a median increase of 14.3% in the placebo group.

Onercept did not show effects on the other markers of inflammation assessed. In particular, it did not appear to induce any of the pro-inflammatory markers assessed or to reduce anti-inflammatory mediators.

Safety results:

Total exposure in the treated population was approximately 6440 days, or 920 patient- weeks. Injection site events were the only adverse events reported by 5% or more of onercept patients: they appeared to be dose-related, and were not seen in placebo patients. No other adverse events were reported by more than two patients in any treatment group, and the majority of events were mild to moderate in intensity. No other trends in adverse events were noted. There was no evidence of increased incidence of infections, malignancies or blood dyscrasias with onercept treatment, although the size of the study must be considered. There were no reports of cardiac failure or demyelinating disorders. Four serious adverse events were reported in three patients: only one, in a placebo patient, was considered possibly related to study treatment.

No significant trends were noted in results of routine laboratory assessments. Onercept did not appear to be associated with renal or hepatic impairment. Group values of liver function tests, including Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST), were stable over time, although individual patient abnormalities were noted in all treatment groups. Results of renal function tests were similarly stable. Overall, there was some evidence of anaemia, which was expected in this population; this did not appear to worsen during the study. White blood cell counts, including CD3 cell subsets, showed no signs of immunosuppression as a result of onercept treatment. Some minor transient eosinophil elevations were seen in the onercept groups, but these were not considered clinically significant.

There was no evidence of increased autoimmune response in onercept-treated patients. While approximately 15% of onercept-treated patients developed antibodies to TBP-1 , the clinical significance of these antibodies remains unknown.

Conclusions:

Altogether, the results of the current study indicate that subcutaneous onercept at 50 mg or 100 mg given three times a week induces dose-dependent improvements in manifestations of psoriasis and psoriatic arthritis including skin lesions, arthritic symptoms and systemic inflammation. Onercept had a clear effect on psoriatic arthritis, with significant improvements in PsARC, ACR 20 and ACR 50 response rates compared to placebo. With respect to cutaneous psoriasis, the pre-defined primary endpoint, PASI 75% response, did not show significant differences between onercept and placebo at either dose level. However, clinically significant effects were seen on secondary endpoints. In particular, the difference between onercept 100 mg and placebo in PASI 50% response was close to statistical significance, and PASI 50% response was achieved faster in onercept- treated patients compared to placebo patients. Onercept showed effects on markers of systemic inflammation, including reductions in ESR, CRP and IL-6 plasma levels. Onercept also induced a marked and statistically significant decrease in lesional T-cells and an increase in circulating T-cells.

At the doses tested, onercept showed a good safety profile. The only adverse events that affected >5% of treated patients were injection site erythema and injection site reaction; these appeared to be dose-related and were not seen in placebo patients. No other adverse events were reported by more than two patients in any treatment group, and the majority of events were mild to moderate in intensity. Four (4) serious adverse events occurred during the trial, of which only one - in a placebo patient - was considered potentially treatment-related. There was no evidence of increased incidence of infections, malignancies or blood dyscrasias with onercept treatment, and no reported events suggested development or worsening of cardiac failure or demyelinating disorders. White blood cell counts, including CD3 cell subsets, showed no signs of immunosuppression resulting from onercept treatment, and there was no evidence of increased autoimmune response. While approximately 15% of onercept- treated patients developed antibodies to TBP-1 , the clinical significance of these antibodies remains unclear, and preliminary analysis did not suggest an impact of antibody formation on efficacy. No new safety concerns were identified. Taken together, these results indicate that the therapeutic window of onercept has not yet been fully explored or characterised. It is necessary to determine whether higher doses will result in better efficacy with respect to cutaneous measures while still providing a favourable risk-benefit ratio.

EXAMPLE 2 - TREATMENT OF PATIENTS WITH MODERATE TO SEVERE PSORIASIS Title of study: A multicentre, randomised, double-blind, placebo controlled phase Il study of subcutaneously administered onercept in the treatment of patients with moderate to severe psoriasis

Phase of development: Clinical Phase Il

Objectives: The objective of the study was to evaluate the safety and therapeutic efficacy of two different treatment regimens of onercept (compared to matching placebo) in patients who had moderate to severe psoriasis and had failed at least one recognised treatment. Methodology: In this double-blind, placebo-controlled multicentre study, adult patients with moderate to severe plaque psoriasis who satisfied the study's entry criteria were randomised in equal allocation to receive one of three study treatments: - Onercept 100 mg daily,

- Onercept 150 mg three times a week alternating with matching placebo four times a week, or Matching placebo daily. Each daily dose of study drug consisted of two subcutaneous injections. Treatment was given for 12 weeks, followed by 12 weeks of follow-up observation. Patients were evaluated at Weeks 2, 4, 8 and 12 of the treatment period and Weeks 4, 8 and 12 of follow-up (minor safety assessments took place at Weeks 1, 6 and 10 of treatment). The primary assessment of efficacy took place at the end of treatment, at Week 12. Efficacy was assessed in terms of changes over time in the Psoriasis Area and Severity Index (PASI) score, the Physician's Global Assessment (using photographs taken at the first treatment visit for reference), the percentage of body surface area affected by psoriasis, quality of life measures (the SF-36 Health Survey and the Dermatology Life Quality Index (DLQI)) and biological markers of inflammation (erythrocyte sedimentation rate and C-reactive protein). The primary efficacy endpoint was the PASI 75% response rate at Week 12, defined as the proportion of patients showing at least 75% improvement in PASI score at Week 12 compared to baseline. Safety was assessed in terms of the incidence and severity of adverse events, the occurrence of serious adverse events and permanent treatment discontinuation due to adverse events, local tolerability, changes in clinical laboratory values, changes in vital signs and physical examination findings, concomitant medication use and formation of antibodies to the study drug. Because of safety concerns arising in connection with other anti-TNF therapies, special attention was given to adverse events related to infection. Blinded safety data were monitored throughout the study by a Safety Review Board (SRB), which consisted of company personnel, who were not directly involved in the conduct of the study.

Number of patients: It was planned to enrol 126 patients in approximately 10 centres. A total of 130 patients were enrolled in 9 centres. Diagnosis and main criteria for inclusion: The study enrolled adult patients with moderate to severe plaque psoriasis. Entry criteria included plaque psoriasis covering more than 10% of total body surface area, a Psoriasis Area and Severity Index score of 12.0 or more, disease duration of at least 6 months and outpatient status at the time of study entry. Potentially fertile women were required to practice contraception during the study. Patients were excluded if they: had received chlorambucil or cyclophosphamide, were taking lithium or antimalarial therapy, had received systemic biologies, experimental treatments, systemic corticosteroids, immunosuppressants, phototherapy, retinoids, topical psoriasis medications or multiple NSAIDs within specified periods before study entry, had significant concurrent illnesses, had evidence of ^"skin diseases other than psoriasis or dominant forms of psoriasis other than plaque psoriasis and had a clinically significant psoriasis flare at the time of screening or study entry. Written informed consent was obtained from all patients before any study-related procedures were performed.

Test products, dose and mode of administration, batch numbers: Onercept (recombinant human TBP-1), given as either 150 mg three times a week (alternating with matching placebo four times a week) or onercept 100 mg daily by subcutaneous injection.

Batch numbers: 100 mg daily: 02VN01, 02VN02, 02VN03; 150 mg TIW: 02VN01 , 02VN02, 02VN03, 02VM04, 02V101, 02V102, 02V103, 02V104.

Duration of treatment: 12 weeks, followed by 12 weeks of follow-up.

Reference products, dose and mode of administration, batch numbers: Placebo to match onercept solution for injection, given subcutaneously either four times a week

(alternating with onercept 150 mg three times a week) or daily.

Batch numbers: 02V101 , 02V102, 02V103, 02V104.

Criteria for evaluation:

Efficacy: Psoriasis Area and Severity Index (PASI) scores, body surface area affected by lesions, Physician's Global Assessment (PGA), quality of life assessment

(SF-36 Health Survey and DLQI). Safety: Incidence and severity of adverse events, with special attention to serious adverse events and infection-related adverse events; local tolerability, premature study withdrawal due to adverse events, changes in laboratory findings, vital signs and physical examination findings, occurrence of anti-TBP-1 antibodies, and concomitant medications used during the study.

Statistical methods: The primary analysis population was the Intent-To-Treat (ITT) population (N=130). The Per-Protocol population (N=113) excluded patients with major protocol violations. Patients who discontinued from the study or experienced treatment failure were considered to be non-responders thereafter. Safety was assessed in all randomised patients who received any study medication (N=130), analysed as treated. The primary efficacy endpoint was the proportion of patients with at least a 75% improvement in PASI score between baseline and Week 12. Secondary endpoints were:

- Proportion of patients with PASI 90% and PASI 50% response between baseline and Week 12.

- Proportion of patients achieving PASI 50%, PASI 75% and PASI 90% responses by Visit. - Time to PASI 75% and PASI 50% response, analysed by Kaplan-Meier method and log rank test for comparison of treatment groups.

- Mean percentage change from baseline in PASI over time.

- Duration of PASI 75% response from occurrence (earliest at Week 2). Evolution of individual PASI parameters over time. - Changes in the Physician's Global Assessment (PGA).

Proportion of patients with a Physician' Global Assessment of 'cleared' or 'almost cleared'.

- Percentage change in the percentage of body surface area affected by psoriasis over time. - Median time to relapse for patients with PASI 75% and PASI 50% at Week

12.

- Proportion of patients with PASI 75% and PASI 50% showing a relapse after the end of treatment.

- Changes in SF 36 Health Survey and DLQI quality of life questionnaires. A relapse was defined as loss of at least 50% of the improvement in the PASI score achieved between baseline and end of the 12-week treatment phase. The primary endpoint (PASI 75%), selected secondary endpoints and safety outcomes for the 12-week treatment period were analysed after all patients had completed the treatment phase. The remaining analyses were performed and the final report written after all patients had completed the 12-week follow-up phase. The analysis of follow-up efficacy data excluded patients who did not complete the treatment phase. In addition to this, a sensitivity analysis based on the full ITT population was performed on the proportion of patients responding. Summary statistics were presented for each treatment group. For all summaries, 95% confidence intervals for the mean/median were calculated. P-values were¹ calculated for all statistical tests performed, using two-sided tests where appropriate. No adjustments for multiplicity were incorporated in the analyses. The primary efficacy endpoint was analysed using the Cochran-Mantel-Haenszel (CMH) test. Exploratory analyses were to be preformed using logistic regression including any covariates that could be considered to have prognostic or predictive effect. The primary comparison was between the onercept dose with the best rate and placebo. Additionally, the second best dose and the combined onercept groups were compared with placebo, and the two active doses were compared. Continuous secondary endpoints were analysed using ANOVA. If normality assumptions were not met, transformation of the data or ANOVA on the ranks were performed. Binary and categorical endpoints were analysed using the CMH test. Tests for trends were performed using the Cochran-Armitage test, the Jonckheere-Terpstra test or the Cuzick's test, as appropriate. Confidence intervals for categorical data were based on the exact method of Armitage. Time to event endpoints were described using Kaplan-Meier estimates and log-rank tests where appropriate.

Summary and Conclusions:

In this study, 87 patients were treated with onercept at doses of 150 mg three times per week (TIW; n=43) or 100 mg daily (n=44), and 43 patients received placebo. During the 12-week treatment phase, 16 patients discontinued: 6 treated with placebo, 3 treated with onercept 150 mg TIW and 7 treated with onercept 100 mg daily. The main reason, for 7 patients overall, was adverse events. During the follow up phase 20 patients discontinued, with the main reason being lack of efficacy or treatment failure. Efficacv results: The primary endpoint, the proportion of patients with PASI 75% response at the end of the 12-week treatment period, was seen in 53.5% (95%CI 37.7%,68.8%) of patients treated with onercept 150 mg TIW, 25.0% (95%CI 13.2%,40.3%) of patients treated with onercept 100 mg daily and 11.6% (95%CI 3.9%,25.1%) of patients given placebo. The response with onercept 150 mg TIW was significantly greater than that with placebo. The difference between onercept 100 mg daily and placebo was not statistically significant, but the difference between onercept 100 mg daily and onercept 150 mg TIW was (p=0.007). For all onercept patients combined a PASI 75% response was seen in 39.1% of patients, which was significantly better (p=0.001) than placebo.

The improvement in PASI 75% with onercept 150 mg TIW was maintained through the follow-up phase; at Week 24, when patients had been off treatment for 12 weeks, 42.5% of those treated with onercept 150 mg TIW had a PASI 75% response, compared with 10.8% of those who had been given placebo (p=0.002). During the follow-up phase, the patients who had been treated with onercept 100 mg daily continued to improve and at the Week 24 endpoint, 35.1% had a PASI 75% response; this was significantly better (p=0.014) than with placebo and not significantly different compared with the onercept 150 mg TIW group. A more conservative estimate of PASI 75% during the follow-up phase including all patients estimated the proportion at Week 24 to be 39.5% for patients who had been treated with onercept 150 mg TIW. The corresponding estimate for patients treated with onercept 100 mg daily was 29.5%. A PASI 50% response was seen at Week 12 in 74.4% of patients treated with onercept 150 mg TIW, 54.5% of patients treated with onercept 100 mg daily and 25.6% of the placebo-treated group. The PASI 50% response was significantly greater than placebo for both onercept 150 mg TIW (p<0.001) and onercept 100 mg daily (p=0.006). The median time to reach a first PASI 50% response was 8.1 weeks with onercept 150 mg TIW, which was significantly less than the median of 24.1 weeks for the placebo group. The median time for a first PASI 50% response with onercept 100 mg daily was 12.1 weeks; this was significantly less (p=0.015) than placebo but significantly longer (p=0.017) than with onercept 150 mg TIW. At Week 24, a PASI 50% response was seen for 62.5% of patients who had received onercept 150 mg TIW, 54.1% of patients who had received onercept 100 mg daily and 35.1% of patients who had received placebo. The PASI 50% response rate with onercept 150 mg TIW was significantly better than with placebo (p=0.017).

A PASI 90% response was seen at Week 12 in 20.9% of patients treated with onercept 150 mg TIW and 7.0% of patients treated with placebo; the difference was not significantly different (p=0.063). However, during the follow-up period the proportion of patients with a PASI 90% response increased in the onercept-treated patients and declined in those given placebo; at Week 24, 22.5% of patients who had been treated with onercept 150 mg TIW had a PASI 90% response, which was significantly greater (p=0.033) than the 5.4% of placebo patients. The PASI 90% response at Week 24 was also significantly greater (p=0.023) with onercept 100 mg daily (24.3% of patients) compared with placebo.

The mean percentage improvement in PASI score at Week 12 was 66.4% in patients treated with onercept 150 mg TIW; this was significantly greater (p<0.001) than the 24% improvement seen with placebo. The mean improvement with onercept 100 mg daily was 50.3%, which was also significantly better (p=0.002) than placebo. When the percentage improvement from baseline was assessed over time, the earliest visit at which a greater improvement was seen with onercept 150 mg TIW compared with placebo was at Week 2 The percentage improvement at the end of follow-up was 67.6% with onercept 150 mg TIW and 59.5% with onercept 100 mg daily; these rates were both significantly better than the 37.7% improvement seen with placebo.

Assessment of percentage of body surface area affected by psoriasis showed an improvement at Week 12 with both onercept 150 mg TIW (59.5% improvement) and onercept 100 mg daily (38.3%) compared with placebo (19.5%). The Physician's Global Assessment at the end of treatment was 'cleared' or 'almost cleared' for 52.4% of patients treated with onercept 150 mg TIW compared with 12.2% of patients given placebo (p<0.001). With onercept 100 mg daily, the proportion with a PGA of cleared/almost cleared was 26.2%, which was not significantly different from that with placebo. The median improvement in DLQI total score at Week 12 was 55% with onercept 150 mg TIW, 50% with onercept 100 mg daily and 8% with placebo. The percentage improvement for each onercept-treated group was significantly greater than that with placebo. Median improvements in DLQI total score at Week 24 were 52% in the onercept 150 mg TIW group, 57% in the onercept 100 mg daily group and 25% in the placebo group, although the interpretation of these estimates was hindered due to 25% of patients with missing data. For SF36 total score, median improvements at Week 12 were 16% with onercept 150 mg TIW, 11% with onercept 100 mg daily and 4% with placebo. The improvement with 150 mg TIW was significantly greater than that with placebo (p=0.020).

Safety results: Mean onercept exposure time was 80.7 days at 150 mg TIW and 77.5 days at 100 mg daily, giving a total exposure time of 496 patient-weeks for onercept 150 mg TIW and 487 patient-weeks for onercept 100 mg daily. The mean total dose of onercept administered over that time was 5294 mg per patient for the onercept 150 mg TIW group and 7719 mg per patient for the onercept 100 mg daily group.

The overall rate of treatment emergent adverse events was 19.9 events per 100 patient-weeks; the rate was higher in the two onercept-treated groups compared with the placebo group. The most common adverse event was injection site erythema, which was reported for 13 patients treated with onercept 150 mg TIW and 14 patients treated with onercept 100 mg daily, but none of the placebo patients. When injection site reactions were excluded from the analysis, the overall rate of adverse events was reduced to 15.0 events per 100 patient-weeks and the rates for the three treatment groups were very similar. Apart from injection site events, the most commonly reported (≥10% in any treatment group) treatment-emergent adverse events were: increased levels of alanine aminotransferase and aspartate aminotransferase, and influenza, which were more frequently reported in the onercept 100 mg daily group, and psoriasis aggravated, which showed a similar incidence among the treatment groups. The majority of events were mild to moderate in severity; 11 events were considered to be sever (3.8% of all events) and one event (small cell lung cancer in a placebo-treated patient) was classified as very severe. Of the severe and very severe events, 9 were considered possible related to study treatment. There was no evidence of demyelinating disorder, serious blood dyscrasias or cardiac failure associated with onercept; the incidences of infections did not indicate any concern with regard to increases with onercept treatment. No clinically relevant trends were noted in routine laboratory assessments. While the total white blood cell counts did not appear to change, differential counts indicated a slight increase in eosinophils during onercept treatment. Group values for liver function test results, including serum ALT and AST levels, did not indicate any particular trends with onercept treatment, although individual patient abnormalities were noted. Antibodies to TBP-1 were present in approximately 70% of onercept-treated patients at the end of the treatment period; no formal analysis was performed to compare response to treatment between patients who did and did not develop antibodies. The use of topical medications for psoriasis treatment was similar across the three^* treatment groups. Very few patients experienced treatment failure during the study. In the treatment phase, treatment failure occurred for only 1 patient treated with placebo and 1 patient treated with onercept 150 mg TIW; during the follow-up period, treatment failure was recorded for 23 patients, 12 of whom had received placebo.

Conclusions: Overall, the results from this study indicated that subcutaneous administration of onercept induced significant improvements in plaque psbriasis. At the end of the 12-week treatment period, a PASI 75% response was seen in 54% of patients treated with onercept 150 mg TIW, compared with only 12% of patients who received placebo. Onercept at a dose of 100 mg daily induced a PASI 75% response in 25% of patients during treatment and took longer to achieve an effect than onercept 150 mg TIW. A PASI 50% response was seen in a significantly greater proportion of patients in both onercept-treated groups compared with placebo. At the end of the 12-week follow-up phase, onercept-treated patients improved or maintained the original response; at Week 24, 43% of those treated with onercept 150 mg TIW had a PASI 75%, which was significantly greater than the 11% of placebo- treated patients. For patients treated with onercept 100 mg daily the proportion with a PASI 75% response at the end of follow-up increased to 35%, which was significantly greater than with placebo. The time taken to achieve a PASI response indicted that it took longer to develop with onercept 100 mg daily compared with onercept 150 mg TIW. The median time at which a first PASI 75% response was seen was 12.1 weeks with onercept 150 mg TIW but no median time could be evaluated for onercept 100 mg daily or placebo; the median time to first PASI 50% response was significantly less at 8.1 weeks with onercept 150 mg TIW than the 12.1 weeks with onercept 100 mg daily. When percentage improvements in PASI score were assessed, the earliest time at which a difference from placebo was observed was 2 weeks with onercept 150 mg TIW. The earliest time for a difference between onercept 100 mg daily and placebo was 8 weeks.

During treatment both onercept doses produced a significantly greater improvement than placebo in quality of life assessed from the DLQl and SF36 questionnaires. At the two doses examined in this study, onercept treatment was associated with a very good safety profile. No new adverse events were identified that might reasonably be associated with onercept treatment. Laboratory parameters showed no clear patterns of change compared with placebo. The main treatment-emergent adverse event was injection site erythema, which affected only the patients treated with onercept. The majority of adverse events were mild to moderate in severity; 11 events were classified by the Investigator as severe and one was classified as very sever; 9 of these were possibly related to treatment but they were mostly individual events that occurred in one or two patients each. Among the onercept-treated patients there was no evidence of any clinically relevant increase in adverse events considered to be related to anti-TNF therapies. White blood cell counts did not show signs of immunosuppression due to onercept treatment; differential counts suggested a slight increase in eosinophils, which was not considered clinically relevant and resolved on cessation of treatment. While approximately 70% of patients developed antibodies to TBP-1, the clinical significance is not established and there was no indication that this affected efficacy. A single report of hypersensitivity reaction occurred in a patient treated with onercept 100 mg daily, who was negative for anti-TBP-1 antibodies. Overall, the results of this study indicated that onercept was well tolerated and was effective in the treatment of patients with moderate to severe plaque psoriasis. No new safety concerns were identified for onercept treatment in this patient population.

EXAMPLE 3 - INTERMITTENT THERAPEUTIC TREATMENT AS CLAIMED This is a multicentre, randomized, double blind, placebo controlled Phase III study to evaluate the safety and efficacy of onercept 150 mg TIW SC administered in subjects with moderate to severe plaque psoriasis. It is expected to randomise at least 840 subjects in approximately 70-80 investigational centres. The maximum duration of study participation will be 56 weeks (including safety follow-up) with four distinct periods as highlighted below:

First Treatment (Weeks 1-12): Beginning on SD1 , all randomised subjects will be stratified by baseline PASI score (≤20, >20), by prior treatment for psoriasis (naive to systemic treatment versus prior systemic treatment), and by region. Treatment will be administered for a maximum of 12 weeks. Each randomised subject will receive comprehensive instructions from the study centre staff on the self-administration of study drug. Study staff will administer the first dose so the subject can be observed following treatment.

At the end of the double blind 12-week treatment period, all subjects will undergo a series of required cutaneous assessments to determine their treatment response. Subjects will be classified as responders (those who achieve at least a 75% improvement in their PASI compared to baseline) or partial/non-responders (those who achieve less than a 75% improvement in their PASI, compared to baseline).

At Week 12

Partial and non-responders will enter an OL treatment period, where they will receive onercept 150mg injected by the SC route TIW. At the end of this 40-week OL treatment period subjects will enter a 4-week SF period.

Responders will enter a 24-week OB period. Upon relapse (defined as loss of at least 50% of the improvement achieved between baseline and the end of the 12-week FT period) or at the end of the 24-week OB period, which ever occurs first, subjects will be re-randomised, in a 1:1 ratio, into a 12-week RT period to receive either onercept 150mg or matching placebo, administered by SC injection TIW.

Open Label (OU: Partial responders (≥50-74% decrease in PASI) and non- responders (<50% decrease in PASI) at Week 12 of the FT period will proceed directly to the 40-week OL treatment period and receive 150 mg TIW active medication for the remainder of the study. Unless there are reasons for treatment discontinuation, the subject may receive onercept for a maximum of 40 weeks during this period. It is anticipated that approximately 550 subjects will enter the 40-week OL treatment period.

Observation (OB): At the end of the 12-week FT period, responders (≥75% decrease in PASI) will enter the OB study period. Treatment is discontinued during the OB period until the subject relapses or reaches 24 weeks of observation, whichever occurs first. Relapse is defined as a decrease of ≥50% from the optimal improvement in PASI during the FT period (between baseline and Week 12). It is anticipated that approximately 230 responders will enter the 24-week OB period. Re-treatment (RT): Subjects who have relapsed during the OB period or reached Week 24 of the OB period without relapsing, will subsequently enter the 16-week RT period. It is anticipated that 200 subjects will be enrolled in the double blind RT period. Each subject will be re-randomized using IVRS to receive onercept 150 mg TIW or matching placebo in a 1:1 ratio (100:100 subjects). Randomisation will be stratified by previous treatment during the FT period (placebo, onercept 150 mg), by whether the subject has relapsed during the OB period (yes or no). During the RT period, blinded study drug will be administered by SC injection TIW for up to 16 weeks of treatment.

Following their completion of the RT or OL treatment periods or at the time of early termination, subjects will enter a 4-week SF period that will signify his or her completion of the study. Subjects will then discuss with their doctor other available alternative treatments.

Subjects

It is estimated that 1 ,008 subjects with moderate to severe plaque psoriasis will be screened to obtain 840 eligible subjects meeting all eligibility criteria.

Entry Criteria Inclusion Criteria

To be eligible for inclusion into this study, the subjects must fulfill all of the following criteria before randomisation at Study Day 1 (SD1):

- Written informed consent, given prior to any study-related procedure not part of the subject's normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to his or her future medical care.

- Between the ages 18 and 75 years, inclusive.

- Female subjects must be neither pregnant nor breast-feeding, and must lack childbearing potential, as defined by either: - Being post-menopausal (i.e. at least 12 months past last menses) or surgically sterile, or

Using an effective form of contraception (i.e. condoms, oral contraceptives or IUD). - Confirmation that the subject is not pregnant must be established by a negative urinary hCG test within 7 days before SD1. A pregnancy test is not required if the subject is post-menopausal or surgically sterile.

- An outpatient status at the time of enrolment. - Plaque psoriasis for at least 12 months.

- Plaque psoriasis covering at least 10% of total body surface area and a PASI score of 12.0 or more.

- Candidate for phototherapy or systemic therapy.

- Static Physician's Global Assessment (sPGA) of 3 or more. Exclusion Criteria

To be eligible for inclusion in this study, the subjects must not meet any of the following criteria:

- Use of more than one NSAID or having a change in NSAID regimen during the 28 days before SD 1. - Previous systemic treatment with biologies, including interferon, and/or cytokines/anti-cytokines (e.g., anti-TNF-alpha, anti-CD4, IL-10, IL-1ra, anti- CD11a, etc.) within 3 months before SD1.

- Participation in any other investigational study or experimental therapeutic procedure considered to interfere with the study within 3 months before SD1 (exceptions to be discussed with Sponsor).

- Treatment with any systemic corticosteroids or intra-articular corticosteroid injection during the 28 days before SDl

- Any previous treatment with chlorambucil or cyclophosphamide.

- Treated with cyclosporine or methotrexate or oral retinoids within 28 days prior to SD1.

- Treatment with topical therapies (vitamin D derivatives, corticosteroids) within 14 days before SD1.

Phototherapy within 28 days before SD1.

- Use of tanning booths within 14 days before SD1. - Abnormal liver function, defined by a total bilirubin ≥ 1.2 times the upper limit of normal values, aspartate aminotransferase, alanine aminotransferase or alkaline phosphatase level ≥ 1.5 times the upper limit of normal values. Inadequate bone marrow reserve, defined as: o Leukocytes ≤ 3.5 x 10⁹/L, or o Thrombocytes ≤ 100 x 10⁹/L, or o Haemoglobin ≤ 5.5 mmol/L (8.9 g/dL).

- Abnormal renal function, defined by serum creatinine >150 micromol/L. Seropositivity for human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV).

Planned major surgery within the treatment period of the study.

- History of cancer in the preceding 5 years (except adequately treated basal cell carcinoma of the skin or squamous cell carcinoma in situ of the skin). History of active tuberculosis, current active tuberculosis or current treatment or prophylactic therapy for tuberculosis.

- Active severe infection (or non-severe infection at the discretion of the Investigator).

- Opportunistic infection in the 3 months preceding SD1.

Clinically significant (at the discretion of the Investigator) and serious abnormalities on electrocardiography or chest X-ray.

Other serious concomitant disorders incompatible with the study. In particular, subjects with congestive heart failure, prior or current history of blood dyscrasia or central nervous system demyelinating disorders should not be included in the study. - History of or current drug (including narcotics) abuse, or current active problems with alcohol abuse.

Requirement for immunisation, allergy desensitisation or vaccination during the entire study period (it is recommended that these are scheduled at least

14 days prior to SD1 or >3 months after the last injection of study drug). - Guttate, erythroderma or pustular psoriasis as sole or predominant form of psoriasis.

Evidence of skin conditions other than psoriasis (e.g., eczema) that would interfere with psoriasis disease assessments.

Clinically significant psoriasis flare during screening or at the time of enrolment necessitating immediate relief (at the Investigator's discretion).

Live or killed virus or bacteria vaccines (within 14 days before SD1).

- Wheelchair-bound or bedridden status. Previous use of onercept. Treatment Phase

The treatment phase is divided into 4 distinct periods: First treatment (FT) period of 12 weeks duration with onercept 150mg TIW or matching placebo by SC administration. At the end of Week 12, subjects with <75% improvement in PASI from baseline will enter the 40-week Open Label (OU period. Subjects with ≥75% improvement in PASI will enter a 24-week Observation (OB) period. Subjects responding who maintain their PASI improvement during the OB period (i.e. do not experience a clinical relapse as defined by a decrease of >50% from the optimal improvement in PASI during the FT period (between baseline and Week 12)) will enter the Re-treatment (RT) period at the end of Week 24 (of the OB period). However, if a subject experiences a clinical relapse between Weeks 13-36 of the study then they will immediately" enter the RT period.

Following their completion of the RT or OL treatment periods or at the time of early termination, subjects will enter a 4-week SF period that will signify his or her completion of the study.

First Treatment Period (Weeks 1-12)

The following assessments will be performed during the FT period at Weeks 1 , 2, 4, and 8:

- Complaint-directed physical examination, body weight and vital signs.

- Laboratory tests: haematology, blood chemistry, and standard urinalysis.

- PASI and sPGA.

- PGA at Weeks 4 and 8 only. - Blood sample for central analysis of anti-TBP-1 antibodies at week 4 only.

- Review of adverse events, concomitant medications and procedures.

- PK/PD subjects only: Pre-dose and 6-12 hours post-dose at week 4. Pre- dose and 24-36 hours post-dose at week 8.

Week 12 or Early Termination

Completion by the subject of the quality of life questionnaire (SF-36, itching scale and DLQI).

Complete physical examination including body weight and vital signs.

- Laboratory tests: haematology, blood chemistry, and standard urinalysis. - Blood samples for anti-TBP-1 antibody.

- Half-body photographs of the most severely affected areas.

- PASI₁ PGA and sPGA.

- NAPSI if nail involvement. - Psoriatic Arthritis Global Assessment (PsA-GA) for subjects with active psoriasis arthritis only. Review of adverse events, concomitant medications and procedures

- PK/PD subjects only: The final PK blood sample will be collected post-dose at Week 12.

Observation Period (Weeks 13-36)

Unless the subject relapses, study visits will remain at the same 4-week time interval as the FT period. At Weeks 16, 20, 24, 28 and 32 the following assessments will be performed: - Complaint-directed physical examination including vital signs and weight.

- Complete physical examination including body weight and vital signs at Week 24 only.

Laboratory tests: haematology, blood chemistry, and standard urinalysis.

Blood samples for anti-TBP-1 antibody at Week 16 only. - PASI, PGA and sPGA.

Review of adverse events, concomitant medications and procedures.

Upon relapse please collect the following in addition to the above assessments:

Cutaneous disease history, including new forms of psoriasis.

Re-treatment Period (Weeks 37-56)

During this period, study visits will occur at Weeks 40, 44, 48 and 52 and the following assessments will be performed:

- Completion by the subject of the quality of life questionnaire (SF-36, itching scale and DLQI) at Week 52 only.

- Complaint-directed physical examination including vital signs and weight at Weeks 40, 44 and 48 only.

- Complete physical examination including body weight and vital signs at Week 52 only. - Laboratory tests: haematology, blood chemistry, and standard urinalysis.

- Blood samples for anti-TBP-1 antibody at Week 52 only.

- PASI and sPGA.

- PGA at Week 52 only. - NAPSI if nail involvement at Week 52 only.

- Psoriatic Arthritis Global Assessment (PsA-GA) for subjects with active psoriasis arthritis at Week 52 only.

Review of adverse events, concomitant medications and procedures.

- PK subjects only: PK blood samples will be collected at Weeks 40, 44 and 52.

Open Label Period (Weeks 13-52)

During this period, study visits will occur at Weeks 16, 20, 24, 28, 32, 36, 40, 44, and 48 and the following assessments will be performed: - Completion by the subject of the quality of life questionnaire (SF-36, itching scale and DLQI) at Week 52 only.

- Complaint-directed physical examination including vital signs and weight.

- Complete physical examination including body weight and vital signs at Weeks 24, 36 and 52 only. - Laboratory tests: haematology, blood chemistry, and standard urinalysis.

- Blood samples for anti-TBP-1 antibody at Week 52 only.

- PASI, PGA and sPGA at Weeks 24, 36 and 52 only.

- NAPSI if nail involvement at Week 52 only.

- Review of adverse events, concomitant medications and procedures.

Safety Follow-up or Post treatment Period

Following their completion of the RT or OL treatment periods or at the time of early termination, a post treatment safety follow-up visit will occur. During this visit the following assessments will be performed: - Complaint-directed physical examination including vital signs and weight.

- Laboratory tests: haematology, blood chemistry, and standard urinalysis. Blood samples for anti-TBP-1 antibody.

Review of adverse events, concomitant medications and procedures. Efficacy Observations and Measurements Markers of disease progression

Markers of disease progression will be collected throughout the study according to the schedule of assessments. The psoriasis specific disease assessments (PASI, PGA, sPGA, NAPSI, PsA-GA) are considered as reference to follow psoriasis progression. They are widely used by dermatologists and recognised as efficacy markers by the FDA and EMEA.

Investigational Product The investigational product for the study is onercept 150 mg or matching placebo.

Description of Investigational Products

Onercept will be supplied as a colourless, sterile solution for injection in pre-filled glass syringes in strength of 150mg/1.05 ml_. Excipients are sodium chloride, sodium phosphate buffer, sodium hydroxide, and phosphoric acid.

The placebo pre-filled syringes will have the same composition as the 150mg pre-filled syringes but without active ingredient.

Each syringe will contain an overfill of 0.04 ml to allow an extractable volume of 1.05 ml_. The syringes used are 2.25 mL with fixed 25G needles.

Dosage and Administration

Assignment to treatment group will be done through IVRS. The allocated treatment (150mg of onercept or matching placebo) will be administered by SC injection TIW preferably on the same days each week. The sites of SC injection should be alternated, e.g., the outside of the thighs and the various quadrants of the anterior abdominal wall. At the discretion of the Investigator, the subject or a family member may be taught to administer the SC injections. The subject or family should receive instructions in proper injection technique in order to minimise injection site reactions, and must prove to be proficient at giving SC injections.

No dose changes of the investigational product are allowed throughout the study.

Packaging and Labelling

The packaging and label will be in accordance with applicable regulatory requirements. The study drug will be packed in monthly kits containing 12 syringes, a sufficient amount to treat a subject for a month, and emergency kits containing 3 syringes.

Preparation, Handling and Storage Investigational product will be stored at 2°C to 8⁰C in a secure location until use, ideally in a locked monitored refrigerator.

Each dose of investigational product will consist of one injection of 1.05 ml. (1 pre-filled syringe).

Before injection, syringes will be brought to room temperature (20 - 25°C) by removing them from the refrigerator until they reach the desired temperature (at least 15 minutes after).

The investigational product should not be shaken before use.

Study drug will be dispensed by the Investigator or by a staff member specifically authorised by the Investigator. Each subject will receive proper instructions regarding the storage, handling, and administration of study drug before leaving the investigational centre on SD1.

Efficacy Analyses Primary efficacy endpoint The primary endpoint of this study is the proportion of subjects with at least a 75% improvement in the PASI score between baseline and Week 12 (FT period). This will be abbreviated as PASI 75.

Percentage improvement at Week 12 (FT period) is defined as:

(Baseline PASI value - Week 12 PASI value) * 100

Baseline PASI value

Response status at the end of the FT period will be determined as follows:

Responder: Any subject whose PASI score has decreased >75% from baseline (SD1) to Week 12 (FT period).

- Partial responder: Any subject whose PASI score has decreased >50% but <75% from baseline (SD1) to Week 12 (FT period). - Non-responder: Any subject whose PASI score has decreased <50% from baseline (SD1) to Week 12 (FT period).

Subjects who withdraw from the study prior to Week 12 (FT period) will be considered as not having achieved a 75% improvement in the PASI for analysis of the primary efficacy endpoint, thereby maintaining the denominator of the ITT population.

Principal Secondary Endpoint

The principal secondary endpoint is: - The proportion of subjects attaining a PGA rating of Cleared or Almost

Cleared at Week 12 (FT period).

Other secondary endpoints

- Mean percentage improvement of PASI from baseline (SD1) to Week 12 (FT period).

- Proportion of subjects with at least a 90% improvement in the PASI score between baseline and Week 12 (FT period).

- Mean percentage improvement from baseline (SD1) in the itching scale at Week 12 (FT period). - Mean improvement from baseline (SD1) in the DLQI quality of life assessment at Week 12 (FT period).

To ensure an overall type I error rate of α=0.05 (two-sided) for the analysis of the five secondary efficacy endpoints, the Hochberg-Bonferroni multiple comparisons procedure (Hochberg 1988) will be used to adjust for multiple comparisons.

Tertiary endpoints

Time to PASI 75 during the FT period.

- Mean improvement from baseline (SD1) in the SF-36 quality of life assessments at Week 12 (FT period).

- Time to relapse in the OB period for subjects achieving PASI 75 response at Week 12 (FT period).

Mean improvement from baseline (SD1) in NAPSI at Week 12 (FT period). - For PASI 75 responders receiving re-treatment after 24 weeks of observation or relapse, the proportion of subjects with at least a 75% improvement in the PASI score between baseline (SD1) and Week 12 of the

RT period. The proportion of PASI 75 responders at Week 16 of the RT period will also be evaluated.

For PASI 75 responders receiving re-treatment after 24 weeks of observation or relapse, the mean percentage PASI improvement from baseline (SD1) to Week 12 of the RT period. The mean percentage PASI improvement at Week 16 of the RT period will also be evaluated.

Statistical methodology

All efficacy endpoints will be analysed using the ITT population. Only the primary and secondary efficacy endpoints will be analysed using the PP population additionally. All safety analyses will be performed using the safety population. All statistical tests will be two-sided using a 0.05 significance level unless otherwise specified.

Model assumptions and potential interactions will be assessed for all analyses. If model assumptions are not met, analyses will be performed on transformed (e.g. log transformed, ranked) data. Further details regarding model assumptions and interactions will be given in the statistical analysis plan.

Primary efficacy endpoint

The primary endpoint will be analysed using a logistic regression model including effects for treatment and the factors used in the randomisation (PASI score at baseline, prior treatment for psoriasis and region). The adjusted odds ratio and associated 95% confidence interval of being PASI 75 in the onercept treatment group vs. placebo will be estimated based on the logistic regression model.

Primary efficacy endpoint - additional analyses The generalisability of the primary endpoint results will be examined by categories of sex, age group, baseline PASI, previous treatment for psoriasis, region, body weight, duration of psoriasis, and age at disease diagnosis assuming that there are sufficient numbers of subjects in any given category. The robustness of the primary analysis will be examined using a Cochran-Mantel- Haenszel test stratified by the randomisation factors and Fisher's exact test on the proportion of PASI 75 responders. In addition an analysis based on counts rather than proportions of subjects within categories of PASI response at Week 12 (FT Period) (< 50%, >50% - < 75%, >75% - <90%, > 90%) will be performed and analysed using a Jonckheere-Terpstra 2-sided test.

Additional logistic regressions on the primary endpoinf response (PASI 75 response at Week 12) will compare treatments and include any covariates that may be considered to have prognostic or predictive effect. Possible covariates to consider include sex, age group, body weight, duration of psoriasis, and age at disease diagnosis.

Subjects who withdraw from the study prior to Week 12 (FT period) wiϊl be asked to return at the scheduled Week 12 visit and complete all PASI assessments regardless of any concomitant medication received from the time of withdrawal. An additional analysis will therefore be performed on all non-missing Week 12 values to assess the sensitivity of the primary analysis to potential bias associated with informative withdrawal. Other approaches regarding the imputation of missing responses will be outlined in the statistical analysis plan.

Secondary efficacy endpoints The principal secondary endpoint (proportion of subjects attaining a PGA rating of Cleared or Almost Cleared at Week 12 (FT period) will be analyzed using a logistic regression model including effects for treatment and the factors used in the FT randomisation (PASI score at baseline, prior treatment for psoriasis and region).

The mean percentage improvement of PASI from baseline (Study Day 1) to Week 12 (FT period) will be analysed using an ANCOVA model on ranked data including effects for treatment and the factors used in the FT randomisation (PASI score at baseline, prior treatment for psoriasis and region).

The proportion of subjects with at least a 90% improvement in the PASI score between baseline and Week 12 (FT period) will be analysed using a logistic regression model including effects for treatment and the factors used in the FT randomisation (PASI score at baseline, prior treatment for psoriasis and region). If the analysis is degenerate due to the sparseness of data, a Fisher's Exact test will be performed instead.

The mean percentage improvement from baseline (Study Day 1) in the itching scale at Week 12 (FT period) will be analysed using an ANCOVA model on ranked data including effects for treatment and the factors used in the FT randomisation (PASI score at baseline, prior treatment for psoriasis and region).

The mean improvement from baseline (Study Day 1) in the DLQI quality of life assessment at Week 12 (FT period) will be analysed using the Wilcoxon rank-sum test.

Tertiary efficacy endpoints

Tertiary efficacy endpoints will be analyzed as follows:

Continuous endpoints will be summarised with appropriate summary statistics including the mean, median, standard deviation, minimum and maximum. Graphical representations of the primary and selected secondary endpoints will be prepared. Further statistical analyses will be performed using parametric and non-parametric methods (ANCOVA, Wilcoxon rank-sum test), depending on the distribution of the data. If necessary, data will be transformed (e.g. log transformed, ranked) to satisfy normality assumptions.

Categorical endpoints will be tabulated (with the frequency and proportion in each treatment group, by visit if appropriate). Binary and multinomial endpoints will be analysed using logistic regression, CMH or Fisher's exact test (adjusted for the randomisation stratification variables), as appropriate. Exact confidence intervals (95%) for the proportion of subjects with a response will be calculated and presented. Odds ratios produced by logistic regression modelling will be adjusted for the variables in the model. Survival curves for time-to event endpoints will be estimated using the Kaplan-Meier method. Modelling will be performed using Cox's proportional hazards model. The assumption of proportional hazards will be investigated. Descriptive statistics will be provided for the efficacy endpoints obtained during the OL period. Further detail of the analysis of efficacy and safety endpoints will be detailed in the Statistical Analysis Plan.

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Claims

1. Use of recombinant human Tumor-Necrosis-Binding-Binding Protein-1 (r-hTBP-

1) together with a pharmaceutically acceptable excipient for the manufacture of a medicament in the therapeutic treatment of psoriasis, wherein the medicament is to be subcutaneously administered three times per week at a dose of 100 to 150 mg per injection for intermittent periods of 12 weeks up to 52 weeks, thus alternating periods of administration of the medicament with periods of non-administration.

2. The use of claim 1, wherein the medicament is administered to patients, who failed to respond to at least another previous treatment.

3. The use of claim 1 , wherein the medicament is administered to patients, who were defined as "PASI 75 responders" at the end of a first 12 weeks treatment period.

4. The use of claim 1 , wherein each period of treatment and of non-treatment is 12 weeks long.

5. The use of claim 1 , wherein the psoriasis treated is from moderate to severe or associated with psoriatic arthritis.

6. The use of any preceding claims, wherein the r-hTBP-1 is produced from . transformed mammalian cells, such as Chinese Hamster Ovary (CHO) cells.

7. The use of any preceding claims, wherein the r-hTBP-1 is administered at a dose of 150 mg per injection.

8. The use of any preceding claims, wherein the r-hTBP-1 is administered at a dose of 100 mg per injection.

9. A method of therapeutically treating psoriasis comprising administering to a patient in need of such treatment an effective amount of recombinant human Tumor-Necrosis-Binding-Binding Protein-1 (r-hTBP-1), wherein the medicament is to be subcutaneously administered three times per week at a dose of 100 to 150 mg per injection for intermittent periods of 12 weeks up to 52 weeks, thus alternating periods of administration of the medicament with periods of non- administration.