Methods of treatment of psoriatic arthritis

Abstract

The invention related to methods of treatment of psoriatic arthritis. In certain embodiments, the invention provides compositions and dosing regimen of an IL-17A inhibitor for the treatment of psoriatic arthritis.

Description

METHODS OF TREATMENT OF PSORIATIC ARTHRITIS FIELD OF INVENTION

[0001] The invention is related to methods of treatment of psoriatic arthritis. The invention provides compositions and dosing regimen for treatment of psoriatic arthritis. BACKGROUND

[0002] Psoriatic Arthritis (PsA) is a chronic immune-mediated inflammatory disease characterized by both joint inflammation and skin lesions consistent with psoriasis. It is estimated that approximately 30% of the 125 million people living with psoriasis worldwide will also develop PsA over time. PsA is a disease of multiple clinical manifestations including enthesitis, joint pain, skin lesions and dactylitis. Dactylitis, the inflammation and swelling of entire fingers and toes with a sausage-like appearance (sometimes referred to as "sausage digit") often happens in association with changes to the nails such as small depressions in the nail (pitting), thickening of the nails, and detachment of the nail from the nailbed. Skin changes consistent with psoriasis (e.g., red, scaly, and itchy plaques) frequently occur before the onset of psoriatic arthritis but psoriatic arthritis can precede the rash in 15% of affected individuals. It is classified as a type of seronegative spondyloarthropathy.

[0003] Psoriatic arthritis is an inheritable polygenic disease, with many genes known or theorized to contribute to its clinical presentation (or lack thereof). When someone with the genes for psoriatic arthritis comes into contact with certain substances, these substances may induce an autoimmune reaction, causing the immune system to target normal tissues in the body. The exact strength, location, and clinical effects of this reaction depend on which genes are involved for each individual. The substance that triggers the reaction is typically not known.

[0004] Improvement broadly across all manifestations of disease drives reduction in overall PsA disease activity, and, as expected, also improves overall quality of life – helping patients feel better and function better.SUMMARY OF THE INVENTION

[0005] The current invention relates to methods of treatment of PsA. The invention provides compositions and dosing regimen for treatment of PsA. In certain aspects, the invention provides a method of treatment of PsA by administration to a patient of a composition comprising at least 160 mg of izokibep or a salt thereof. In certain embodiments, wherein the composition comprises 160 mg of izokibep or a salt thereof. In a related aspect, the invention also provides a composition comprising at least 160 mg of izokibep or a salt thereof for use in the treatment of PsA. In another related aspect, the invention provides use of a composition comprising at least 160 mg of izokibep or a salt thereof in the manufacture of a medicament for the treatment of PsA.

[0006] In certain embodiments, the methods of the invention provide that the composition comprising at least 160 mg of izokibep or a salt thereof is administered once weekly (QW) for the treatment of PsA. In certain embodiments, the methods of the invention provide that the composition comprising 160 mg of izokibep or a salt thereof is administered once weekly (QW) for the treatment of PsA.

[0007] In certain embodiments, the methods of the invention provide that the composition comprising at least 160 mg of izokibep or a salt thereof is administered once every 2 weeks (Q2W) for the treatment of PsA. In certain embodiments, the methods of the invention provide that the composition comprising 160 mg of izokibep or a salt thereof is administered once every 2 weeks (Q2W) for the treatment of PsA.

[0008] In certain embodiments, the methods of the invention provide that the composition comprising izokibep is administered as an injection for treatment of PsA. In certain embodiments, the methods of the invention provide that the composition comprising izokibep is administered as an intravenous (IV) infusion for treatment of PsA. In certain embodiments, the methods of the invention provide that the composition comprising izokibep is administered as a subcutaneous (SC) injection for treatment of PsA.

[0009] In certain aspects, the methods of the invention provide that the composition comprising izokibep is administered for a duration for which the therapeutic effect is observed. In certain embodiments, the invention provides that the composition comprising izokibep may be administered for treatment of PsA for a duration of at least 16 weeks. In certain embodiments, the invention provides that the composition comprising izokibep may be administered for thetreatment of PsA for a duration of at least 50 weeks. In certain embodiments, the invention provides that the composition comprising izokibep may be administered for the treatment of PsA for a duration of at least 46 weeks. In certain embodiments, the invention provides that the composition comprising izokibep may be administered for the treatment of PsA for a duration of 51 weeks.

[0010] Beneficially, the invention provides that the compositions comprising at least 160 mg izokibep or a salt thereof are safe and efficacious for the treatment of PsA. The invention recognizes that previously known dosing regimen for izokibep for treatment of PsA do not provide administration of compositions comprising 160 mg izokibep. The methods of the invention are beneficial because they provided an unexpected therapeutic benefit for treatment of PsA. The invention also recognizes that it is unexpected that a composition comprising 160 mg izokibep or a salt thereof would not have significant adverse events and will be generally well tolerated. Surprisingly, administration of compositions comprising 160 mg izokibep or a salt thereof, administered either QW or Q2W, is well-tolerated, and has better efficacy in the treatment of psoriatic arthritis.

[0011] The invention also recognizes that subcutaneous administration of compositions comprising 160 mg izokibep or a salt thereof, administered either QW or Q2W, is well-tolerated. Subcutaneous administration is beneficial because it demonstrates that izokibep could be self- administered by the patients. Moreover, subcutaneous injections are beneficial to be administered to the patients as compared to the other forms of administration because they provide for greater patient convenience for administration of the injections. For example, as compared to other forms of injections, such as intravenous infusion or intramuscular injection, they lead to lesser pain to the patients. In addition, subcutaneous injections lead to lower risk of infection, as compared to intravenous infusion or intramuscular injections.

[0012] In certain embodiments, the methods of the invention alleviate symptoms of PsA. For example, the methods of the treatment lead to complete resolution of enthesitis. In certain embodiments, the methods of the invention results in Psoriasis Area and Severity Index (PASI) score of 100. In certain embodiments, the methods of the invention results in improvement in tender and swollen joints, along with improvement in three of these five parameters: (a) patient global assessment of disease activity; (b) physician global assessment of disease activity; (c) patient pain scale; (d) disability / functional questionnaire and (e) decreased concentration of C- reactive protein correlated to inflammation.BRIEF DESCRIPTION OF DRAWINGS

[0001] FIG.1 provides a depiction of izokibep bound to IL-17A homodimer.

[0002] FIG.2 provides a radar plot for the efficacy of administration of izokibep to certain trial patients.

[0003] FIG.3 provides the design of the Phase 2 trial of izokibep for PsA.

[0004] FIG. 4 summarizes the trial results demonstrating that participants with enthesitis at baseline reported a higher percentage of participant-derived clinically important difference in PsAID with izokibep compared to the overall trial population.

[0005] FIG.5 provides key results from the Phase 2 trial of izokibep at week 46.

[0006] FIG.6 provides modeled data up to 48 weeks predicted consistent evidence of additional exposure response across clinically validated PsA endpoints.

[0007] FIG.7 provides the schema of the Phase 2b / 3 trial for izokibep in treatment of PsA.

[0008] FIG.8 provides observed and simulated PK profiles for 10 mg / kg IV Q2W×4 secukinumab versus simulated profiles for 160 mg izokibep SC QW and Q2W.

[0009] FIG.9 provides the information regarding the baseline characteristics of the patients in the Phase 2 clinical trials.

[0010] FIG. 10A provides the results from the global assessment of disease activity and the average itch NRS score.

[0011] FIG.10B provides pain assessment score and percentage of patients with pain VAS < 30.

[0012] FIG.11 provides SF-36 scores through week 36.

[0013] FIG.12 provides PsAID-9 subdomains for baseline, placebo, izokibep 40 mg, and izokibep 80 mg respectively.

[0014] FIG. 13 provides the results from the Treatment Satisfaction Questionnaire of Medicine (TSQM TSQM-9) Satisfaction survey from the patients.

[0015] FIG. 14 provides the trial design for the double-blind, randomized, placebo-controlled Phase 2 study of izokibep.

[0016] FIG.15 provides the details for the patients enrolled in the trial.

[0017] FIG.16 provides the demographics and baseline characteristics of patients enrolled in the trial.

[0018] FIG.17 provides the data for ACR50 responses for patients receiving izokibep.

[0019] FIG.18 provides the data for ACR70 responses for patients receiving izokibep.

[0020] FIG. 19A and FIG. 19B provide MDA and DAPSA LDA data for patients receiving izokibep.

[0021] FIG.20 provides PASI100 data for patients receiving izokibep.

[0022] FIG.21A provides high LEI enthesitis resolution data for patients receiving izokibep.

[0023] FIG.21B provides SPARCC enthesitis resolution data for patients receiving izokibep.

[0024] FIG.22A provides PsAID-9 data for patients receiving izokibep.

[0025] FIG.22B provides HAQ-DI data for patients receiving izokibep.

[0026] FIG.23 provides the safety data for patients receiving izokibep.

[0027] FIG. 24 outlines the trial design for the double-blind, randomized, placebo-controlled Phase 2b / 3 study of izokibep described herein.

[0028] FIG. 25 provides the patient dispositions and dosing through week 16 of the phase 2b / 3 outlined in Fig.24.

[0029] FIG.26 provides the patient demographics and baseline characteristics of the phase 2b / 3 outlined in Fig.24.

[0030] FIG.27 provides PK data from the study outlined in Fig.24 for 160mg izokibep Q2W in PsA patients compared to exposure in HS patients.

[0031] FIGS 28A-28B provide ACR50 and ACR70 data through week 16 for the trial outlined in Fig.24.

[0032] FIG. 29 provides a comparison of ACR70 data from the trial compared to other dosage regimes and therapies.

[0033] FIG.30 provides PASI90 and PASI100 data through 16 weeks for the trial outlined in Fig. 24.

[0034] FIG.31A shows composite ACR50 and PASI100 scores at the primary endpoint.

[0035] FIG.31B provides MDA data through 16 weeks for the trial outlined in Fig.24.

[0036] FIG.32 provides LEI data through 16 weeks for the trial outlined in Fig.24.

[0037] FIG.33 provides safety data through 16 weeks for the trial outlined in Fig.24. DETAILED DESCRIPTION

[0038] Psoriatic Arthritis (PsA) is a chronic immune-mediated inflammatory disease characterized by both joint inflammation and skin lesions consistent with Psoriasis (PsO). It is estimated that approximately 30% of the 125 million people living with PsO worldwide will also develop PsA over time. PsA causes pain, stiffness and swelling in and around the joints and commonly appears between the prime productivity ages of 30 and 50, but can develop at any time. Common symptoms include: º Arthritis. Stiff joints associated with pain and swelling are common signs of arthritis. The arthritis associated with PsA differs from rheumatoid arthritis based on its location in the distal phalangeal joints of the hands and feet, the pelvis and spine. º Skin lesions. Psoriatic lesions caused by inflammation-driven proliferation of skin cells are also found in PsA but the severity of the joint involvement is often worse for patients than the severity of the skin involvement. º Enthesitis. The enthesis is the tissue at the site where a tendon or ligament inserts into the bone. Enthesitis is inflammation of the enthesis. A common site of enthesitis in PsA is the Achilles tendon. Given the forces that pass through the entheseal tissues, they feature high tensile strength and are not very vascular. Inflammation of the enthesis typically causes pain at rest or with movement possibly leading to swelling of surrounding tissues. The pain associated with enthesitis can result in disability and reduced quality of life due to reduced dexterity and mobility. Enthesitis is believed to be one of the earliest steps in the development of joint inflammation in PsA, which ultimately leads to more serious joint damage. Therefore, early identification of enthesitis and early intervention with an effective treatment could potentially modify the course of a patient’s PsA, avoiding the joint erosion, pain and disability associated with more serious disease. º Dactylitis. Dactylitis is the swelling of digits due to inflammation resulting in pain and reduced range of motion. This symptom is commonly referred to as sausage-shaped digits. Dactylitis, which can be very painful, occurs in approximately 50% of patients with moderate-to-severe PsA. º Spondylitis. Spondylitis is a chronic arthritis caused by inflammation of the joints, tendons, and ligaments of the spine and sacroiliac region.

[0039] PsO and PsA are types of psoriatic disease. Psoriasis is a chronic relapsing / remitting, immune-mediated systemic disease characterized by skin lesions including red scaly plaques,resulting from an abnormally excessive and rapid growth of the epidermal layer of the skin. The most common form is plaque psoriasis, and other disease types include pustular, guttate, and erythrodermic psoriasis (Merola et al, 2016; Raharja et al, 2021).

[0040] Psoriatic arthritis is a chronic, immune-mediated, inflammatory musculoskeletal disease associated with psoriasis, manifesting most commonly with peripheral arthritis, dactylitis, enthesitis, and spondylitis (Singh et al, 2019; Veale and Fearon, 2018). Nail lesions, including pitting and onycholysis, occur in about 80% to 90% of patients with PsA (Sobolewski et al, 2017; Colunga-Pedraza et al, 2021).

[0041] The incidence of PsA in the general population ranges from 3.6 to 7.2 per 100,000 person years. Prevalence estimates in the U.S. range from 0.06% to 0.25%, and in Europe range from 0.05% (Turkey, Czech Republic) to 0.21% (Sweden; Ogdie and Weiss, 2015). The annual incidence of PsA in patients with psoriasis is 2.7% (Singh et al, 2019; Ritchlin et al, 2017), and the reported prevalence of PsA among patients with psoriasis varies between 6% and 41% (Singh et al, 2019; Gladman et al, 2005; Ogdie and Weiss, 2015). In the majority of patients, the skin symptoms develop first, followed by the arthritis; however, in some patients the skin and joint symptoms appear at the same time, and in 10% to 15% the arthritis presents first (Singh et al, 2019; Ritchlin et al, 2017). The common scenario is that PsO has its onset approximately 10 years before PsA (Gladman et al, 2005).

[0042] PsA affects men and women equally (Gladman et al, 1998) and can start at any age. It occurs most often in adults between the ages of 45 and 55 (American College of Rheumatology, 2019; Augustin and Radtke, 2017). Psoriatic arthritis is associated with an adverse impact on health-related quality of life (Adams et al, 2010; American College of Rheumatology, 2019; Husted et al, 2001; Singh and Strand, 2009a) and high health care costs and utilization (American College of Rheumatology, 2019; Javitz et al, 2002; Singh and Strand, 2009b).

[0043] PsA-specific clinical features include the common involvement of distal joints. The condition is also associated with periosteal reaction, enthesitis (observed in 30% to 50% of patients [Kehl et al, 2016]), dactylitis (reported in 40% to 50% of patients [Gladman et al, 2013]), and spinal involvement (Gladman et al, 2005). Most frequent extra-articular manifestations of PsA found in 26% to 33% of the patients are inflammatory bowel disease (IBD; e.g., Crohn’s disease, ulcerative colitis), cardiovascular (e.g., aortic insufficiency, conduction disturbances, majorcardiac events), ocular (uveitis and conjunctivitis), and urogenital (e.g., urethritis, prostatitis, vaginitis); (Peluso et al, 2015).

[0044] Greater disease activity is associated with progressive joint damage and higher mortality (American College of Rheumatology, 2019; Bond et al, 2007; Cresswell et al, 2011; Gladman et al, 1998; Gladman, 2008), being early identification of PsA and early initiation of therapy important for improving long-term outcomes (Gladman, 2012).

[0045] The “treat to target” is disease remission or at least minimal disease activity (MDA) in order to maximize clinical improvement and minimize long-term damage (Mease, 2011). The quality of life and comorbidities of the patients must be taken into account when selecting the therapy. Depending on the predominant involvement (peripheral, axial, dactylitis, enthesitis, skin, nails) the therapy is different (Augustin and Radtke, 2017). There is currently a wide variety of pharmacologic therapies for PsA including symptomatic treatments such as nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular (IA) injections, as well as immunomodulatory therapies (American College of Rheumatology, 2019). Interleukin-17

[0046] Interleukin-17A, which is produced by T-helper (Th)17 and other immune cells, is one of the major proinflammatory cytokines that contributes to the pathogenesis of several inflammatory disorders (Miossec and Kolls, 2012). Dysfunction of the Th17 / IL-17 axis is a source of inflammation in the pathogenesis of psoriasis and PsA, and IL-17A is considered to be involved as a key driver cytokine (Gooderham et al, 2015; Raychaudhuri et al, 2015).

[0047] Interleukin-17A inhibiting agents have demonstrated to be efficacious in the treatment of PsA.

[0048] The clinical development program for secukinumab in PsA included patients with active disease despite current or previous NSAIDs, conventional-synthetic disease-modifying anti- rheumatic drugs (csDMARDs), and / or previous anti-TNF therapy (biological disease-modifying antirheumatic drug [DMARD]). In two pivotal secukinumab studies in 1003 patients with PsA (FUTURE-1 and FUTURE-2), approximately 50% of patients on 150 mg or 300 mg secukinumab (the approved doses) achieved ≥ 20% improvement from baseline in tender and swollen joint counts (and American College of Rheumatology [ACR] 20% [ACR20] response score) after 24 weeks. This was in comparison to approximately 15% ACR20 responders in patients on placebo. Sustained inhibition of radiographic progression and improved quality of life measures were alsoachieved (Patel et al, 2017). Ixekizumab has been shown to be similarly effective in treating PsA in pivotal studies. In SPIRIT-P1 (biologic-naïve patients), 62.1%, 57.9%, and 30.2% of patients treated with ixekizumab 80 mg every 2 weeks (Q2W), every 4 weeks (Q4W), or placebo achieved ACR20 response, respectively. In SPIRIT-P2 (patients who failed anti-TNF therapy), 48.0%, 53.3%, and 19.5% of patients treated with ixekizumab 80 mg Q2W, Q4W, or placebo achieved ACR20 response, respectively (Canadian Agency for Drugs and Technologies in Health 2018). Izokibep:

[0049] Izokibep is a small protein therapeutic designed to inhibit interleukin-17A (IL-17A) with higher potency and the potential for greater tissue penetration due to its markedly smaller size when compared to traditional monoclonal antibodies.

[0050] Izokibep has enhanced potency as it blocks the homodimeric IL-17A target protein by binding to both sub-units simultaneously with a very high affinity. In certain embodiments, KD for izokibep binding to IL-17A is as low as 0.3 pM. Klint et al. Izokibep – Preclinical Development and First-in-Human Study of a Novel IL-17A Neutralizing Affibody Molecule in Patients with Plaque Psoriasis. mAbs. 2023 (manuscript accepted, in publication). FIG. 1 provides a representation of izokibep bound to the IL-17A homodimer. In particular, the two IL-17A binding domains bind to the dimeric IL-17A homodimers at the same time, and the two IL17A binding domains are connected by albumin binding domain.

[0051] Advantageously, the presence of albumin binding domain increases the half-life of izokibep. The half-life of izokibep may be a few days. In certain embodiments, the half-life of izokibep is from about 5 to about 20 days. In certain embodiments, the half-life of izokibep is from about 10 to about 15 days. In certain embodiments, the half-life of izokibep is about 12 days. Importantly, as a result of enhanced half-life of izokibep, it can engage with the pharmacological targets for longer duration. Izokibep also has a well-established safety profile. In certain embodiments of the invention, izokibep has been well-tolerated for patients dosed up to 3 years without any observed increased risk of infection or any significant increase in anti-drug antibodies (ADAs). The presence of or a significant increase in ADAs can impact exposure of the drug and / or the clinical response of the drug in the patients.

[0052] Advantageously, the high potency of izokibep to IL-17A, as well as the small molecular size of izokibep, leads to improved tissue penetration and target engagement and therefore provide the potential for differentiated clinically meaningful benefit for patients. In certain embodiments,the size of izokibep is one-tenth (1 / 10th) of those of typical monoclonal IL-17A antibodies. In certain embodiments, izokibep has rapid and therapeutic effects in patients suffering from Hidradenitis Suppurativa (HS) and PsA.

[0053] In certain embodiments, the bispecific fusion protein is SEQ ID. NO. 1.

[0054] In certain embodiments, the bispecific fusion protein sequence comprises the peptide described in the amino acid sequence below or a fragment thereof:

[0055] In another embodiment of the invention, a pharmaceutical composition comprising a therapeutically effective amount of the bispecific fusion protein, preferably izokibep, is administered to a patient suffering from PsA.

[0056] Another embodiment of the invention provides a pharmaceutical composition of the bispecific fusion protein, preferably izokibep. Preferably, the pharmaceutical composition is an injectable solution. In another embodiment of the invention, the bispecific fusion protein, preferably izokibep, is administered to the patient subcutaneously.

[0057] Izokibep is a small protein therapeutic designed to inhibit interleukin-17A (IL-17A) with high potency and the potential for robust tissue penetration due to its small molecular size, about one-tenth the size of a monoclonal antibody. Izokibep is administered to patients with psoriatic arthritis (PsA). More than 400 patients - some for up to three years - have received izokibep, a small therapeutic protein inhibitor of interleukin- 17A (IL-17A) designed to overcome the limitations of monoclonal antibodies. With high potency and small molecular size, izokibep can reach high drug exposure levels through a single, subcutaneous injection that monoclonal antibodies require IV administration to achieve. The small size of izokibep - about one tenth the size of a monoclonal antibody - enables its potential to reach targeted tissues that may otherwise be inaccessible to the much larger monoclonal antibodies.

[0058] Izokibep has a molecular weight of 18.6 kDa, approximately one-tenth the size of a monoclonal antibody, enabling the potential to reach difficult to penetrate tissues such as denseand poorly vascularized entheses in PsA. In murine skin, izokibep demonstrated robust exposure, increasing over time, compared to secukinumab.

[0059] The lower molecular weight of izokibep (18.6 kDa) compared to traditional monoclonal antibodies (~150 kDa) means that there are more izokibep drug molecules in a given volume. Additionally, as demonstrated in comparative analyses assessing binding affinity, izokibep molecules are also more potent than the currently marketed monoclonal antibodies targeting IL- 17A, secukinumab and ixekizumab. As a result, izokibep can deliver in a single subcutaneous injection exposure levels that the marketed anti-IL-17A monoclonal antibodies require IV infusion to deliver.

[0060] Izokibep is a biologic drug that binds IL-17A with high affinity and with a potency corresponding to clinically tested monoclonal antibodies in terms of blocking the biological activity of IL-17A. Izokibep has the potential to be an efficacious treatment for a variety of IL-17A-related diseases. The smaller size of izokibep compared to monoclonal antibodies offers advantages in terms of required dosing volumes and potential for alternative pharmacological formulations.

[0061] Izokibep is based on a small protein binding to and blocking the biological effect of the cytokine IL-17A. The izokibep protein molecule also contains an albumin-binding domain that confers specific binding to a single site on endogenous serum albumin and thereby prolonging half-life (t½) in the circulation and in tissues after parenteral administration.

[0062] IL-17 inhibitors have already demonstrated efficacy and a favorable safety profile in different inflammatory diseases, including psoriasis, PsA, and axial spondyloarthritis. These include secukinumab (Cosentyx) and ixekizumab (Taltz) in the US, Canada, and the European Union. Route of Administration of izokibep:

[0063] In certain aspects of the invention, izokibep is administered as an injection. In certain embodiments, izokibep is delivered subcutaneously. The concentration of izokibep for Phase 2 trial in PsA was 80 mg / 1 mL and for Phase 3 trial in PsA is 160 mg / 1.5 mL as a single SC injection. The formulation is at neutral pH within a phosphate buffered saline.

[0064] In certain embodiments, compositions comprising izokibep for subcutaneous administration is provided to the patients as a pre-filled syringe. In certain embodiments,compositions comprising izokibep for subcutaneous administration is provided to the patients as a standard autoinjector.

[0065] In certain embodiments, the pharmaceutical compositions comprising izokibep can be administered to a patient by parenteral routes such as injection (e.g., subcutaneous, intravenous, intramuscular, intraperitoneal, infraorbital, intravitreal, intraocular, subconjunctival, retrobulbar, peribulbar, and / or intrathecal injection). Numerous reusable pen and / or autoinjector delivery devices can be used to subcutaneously deliver the pharmaceutical compositions disclosed herein. Examples include, but are not limited to AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25™ pen, HUMALOG™ pen, HUMALIN 70 / 30™ pen (Eli Lilly and Co., Indianapolis, Ind.), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, N.J.), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™, and OPTICLIK™ (sanofi-aventis, Frankfurt, Germany), to name only a few. Examples of disposable pen and / or autoinjector delivery devices having applications in subcutaneous delivery of a pharmaceutical composition disclosed herein include, but are not limited to the SOLOSTAR™ pen (sanofi-aventis), the FLEXPEN™ (Novo Nordisk), and the KWIKPEN™ (Eli Lilly), the SURECLICK™ Autoinjector (Amgen, Thousand Oaks, Calif.), the PENLET™ (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey, L. P.), and the HUMIRA™ Pen (Abbott Labs, Abbott Park, Ill.), to name only a few.

[0066] The use of West SelfDose and SmartDose injection systems to deliver the pharmaceutical compositions disclosed herein is also contemplated herein. The use of a microinfusor to deliver the pharmaceutical compositions disclosed herein is also contemplated herein. As used herein, the term “microinfusor” means a subcutaneous delivery device designed to slowly administer large volumes (e.g., up to about 2.5 mL or more) of a therapeutic composition over a prolonged period of time (e.g., about 10, 15, 20, 25, 30 or more minutes). See, e.g., U.S. Pat. Nos. 6,629,949; 6,659,982; and Meehan et al., J. Controlled Release 46:107-116 (1996). Treatment of PsA with izokibep:

[0067] Patients with PsA associated with mild arthritis are often first treated with nonsteroidal anti-inflammatory drugs (NSAIDs). As the disease becomes moderate-to-severe, so called “anti- rheumatic” drugs such as methotrexate or leflunomide are added to NSAIDs. Once NSAIDs and / or anti-rheumatic therapies fail, biologic treatment is initiated, with the anti-TNF agent adalimumabamongst the most commonly prescribed biologics. While biologics are needed in PsA, anti-TNF agents or anti-IL-17 agents, such as adalimumab, secukinumab or ixekizumab are both recommended alternatives.

[0068] Despite the availability of these therapies, there is still a large unmet need for more effective therapies to treat PsA across all disease features. PsA is a disease of multiple clinical manifestations, including joint swelling / pain, skin irritation, enthesitis and dactylitis-all contributing to reduced quality of life. There remains significant room for an effective therapeutic that addresses all of these manifestations – and therefore improves quality of life – for these patients.

[0069] The current invention methods of treatment of psoriatic arthritis (PsA). The invention provides compositions and dosing regimen for treatment of psoriatic arthritis. In certain aspects, the invention provides a method of treatment of psoriatic arthritis (PsA) by administration to a patient a composition comprising at least 160 mg of izokibep or a salt thereof. In certain embodiments, wherein the composition comprises 160 mg of izokibep or a salt thereof.

[0070] In certain embodiments, the methods of the invention provide that the composition comprising at least 160 mg of izokibep or a salt thereof once weekly for the treatment of PsA. In certain embodiments, the methods of the invention provide that the composition comprising 160 mg of izokibep or a salt thereof once weekly for the treatment of PsA.

[0071] In certain embodiments, the methods of the invention provide that the composition comprising at least 160 mg of izokibep or a salt thereof once every 2 weeks (Q2W) for the treatment of PsA. In certain embodiments, the methods of the invention provide that the composition comprising 160 mg of izokibep or a salt thereof once every 2 weeks (Q2W) for the treatment of PsA.

[0072] In certain embodiments, the methods of the invention provide that the composition comprising izokibep is administered as an injection for treatment of PsA. In certain embodiments, the methods of the invention provide that the composition comprising izokibep is administered as an intravenous infusion for treatment of PsA. In certain embodiments, the methods of the invention provide that the composition comprising izokibep is administered as a subcutaneous for treatment of PsA.

[0073] In certain aspects, the methods of the invention provide that the composition comprising izokibep is administered for a duration for which the therapeutic effect is observed. In certainembodiments, the invention provides that the composition comprising izokibep may be administered for treatment of PsA for a duration of at least 16 weeks. In certain embodiments, the invention provides that the composition comprising izokibep may be administered for treatment of PsA for a duration of at least 50 weeks. In certain embodiments, the invention provides that the composition comprising izokibep may be administered for treatment of PsA for a duration of at least 46 weeks.

[0074] Beneficially, the invention provides that the compositions comprising at least 160 mg izokibep or a salt thereof are safe and efficacious for the treatment of PsA. The invention recognizes that previously known dosing regimen for izokibep for treatment of PsA do not provide administration of compositions comprising 160 mg izokibep. The methods of the invention are beneficial because they provided an unexpected therapeutic benefit for treatment of PsA. The invention also recognizes that it is unexpected that a composition comprising 160 mg izokibep or a salt thereof would not have significant adverse events and will be generally well tolerated. Surprisingly, administration of compositions comprising 160 mg izokibep or a salt thereof, administered either QW or Q2W, is well-tolerated, and has better efficacy in the treatment of psoriatic arthritis.

[0075] The invention also recognizes that subcutaneous administration of compositions comprising 160 mg izokibep or a salt thereof, administered either QW or Q2W, is well-tolerated. Subcutaneous administration is beneficial because it demonstrates that the drug could be self- administered by the patients.

[0076] In certain embodiments, the methods of the invention alleviate the symptoms of PsA. The methods of the treatment lead to complete resolution of enthesitis. In certain embodiments, the methods of the invention results in Psoriasis Area and Severity Index (PASI) score of 100. In certain embodiments, the methods of the invention result in improvement in tender and swollen joints, along with improvement in three of these five parameters: (a) patient global assessment of disease activity; (b) physician global assessment of disease activity; (c) patient pain scale; (d) disability / functional questionnaire and (e) decreased concentration of C-reactive protein correlated to inflammation.

[0077] In a Phase 2 clinical trial, izokibep demonstrated efficacy for treatment of PsA. In the trial, both the 40 mg and 80 mg doses of izokibep were evaluated compared to placebo. At 16 weeks, of the participants receiving izokibep 80 mg administered subcutaneously every two weeks(Q2W), 52% achieved ACR50 response (placebo response rate at 13%, p-value 0.0006), 85% achieved PASI75 response (placebo response at 14%, p-value less than 0.0001), and 88% achieved enthesitis resolution (placebo response at 10%, p-value 0.0001). Of the participants receiving 40 mg administered SC Q2W, 48% achieved ACR50 response (placebo response at 13%, p-value 0.0014), 83% achieved PASI75 response (placebo response at 14%, p-value less than 0.0001), and 63% achieved enthesitis resolution (placebo response at 10%, p-value 0.0143). ACR50 response is defined as a 50% improvement in tender and swollen joints, along with improvement in three of these five parameters: (a) patient global assessment of disease activity; (b) physician global assessment of disease activity; (c) patient pain scale; (d) disability / functional questionnaire and (e) decreased concentration of C-reactive protein correlated to inflammation.

[0078] The Phase 2 PsA trial enrolled 135 participants across 28 European sites in seven countries. The participant characteristics were similar to those of previous trials in this disease. At Week 16, the placebo cohort was transitioned to 80 mg Q2W izokibep and the trial treatment period continued for up to 46 weeks. The results are summarized in FIG.3. As shown in FIG.3, this PsA Phase 2 trial included participants with moderate to severe PsA, with participants that fulfilled the CASPAR criteria, which criteria consist of confirmed inflammatory articular disease (joint, spine, or entheseal) with at least 3 points from the following features: current psoriasis (assigned a score of 2 points; all other features are assigned a score of 1), a history of psoriasis or a family history of psoriasis (unless current psoriasis is present), dactylitis, juxta-articular new bone formation (hands or feet), rheumatoid factor (RF) negativity (except latex test), and psoriatic nail dystrophy. Eligible participants must also have more than 3 tender joints of a possible 68 total and more than 3 swollen joints of a possible 66 total. Eligible participants may have had prior failures to any of anti-inflammatory medications (NSAIDs), disease modifying medications (DMARDs) or tumor necrosis factor inhibitors (TNF inhibitors).

[0079] At 16-weeks, of the participants in the trial receiving izokibep 80 mg administered SC Q2W, 52% achieved ACR50 response versus placebo at 13%, p-value 0.0006, 85% achieved PASI75 response versus placebo at 14%, p-value less than 0.0001, and 88% achieved enthesitis resolution as evaluated by the Leeds Enthesitis Index (LEI) versus placebo at 10%, p-value 0.0001. At 16-weeks, of the participants in the trial receiving izokibep 40 mg administered SC Q2W, 48% achieved ACR50 response versus placebo at 13%, p-value 0.0014, 83% achieved PASI75 response versus placebo at 14%, p-value less than 0.0001, and 63% achieved enthesitis resolution asevaluated by the LEI versus placebo at 10%, p-value 0.0143. Enthesitis is unchecked inflammation of the difficult to treat entheseal tissues and is a marker of disease severity often associated with residual pain and physical dysfunction, negatively impacting quality of life.

[0080] In addition to joints, skin and enthesitis, dactylitis and nail PsO are additional difficult-to- treat manifestations of PsA. Using the Leeds Dactylitis Index-B, we observed that more than 67% of participants had complete resolution of their dactylitis whereas only 27% of placebo participants had resolution at 16 weeks. Multiple measures of participant-reported outcomes were assessed as part of the trial, including the Psoriatic Arthritis Impact of Disease (PsAID) questionnaire developed and validated by GRAPPA (the Group for Research and Assessment for PsA), a preeminent group of rheumatology thought-leaders.

[0081] Using the PsAID questionnaire, participants in the Phase 2 trial reported improvements in all quality-of-life sub-domains of the PsAID questionnaire, including pain, sleep disturbance and functional capacity. Furthermore, it was observed that participants with enthesitis at baseline reported even greater improvement in the measured outcomes than the total trial population that included participants without baseline enthesitis. The proportion of participants receiving 80 mg Q2W with patient-derived clinically important difference from baseline in those with enthesitis was numerically higher at 53% as compared to the total population where 41% reached this threshold.

[0082] In the radar plot in FIG.2, lower scores closer to the center of the figure represent better outcomes. Each spoke represents a participant-reported outcome from the PsAID. Changes in the magnitude of the scores of individual outcomes are represented by the distance from the center point. As reflected, scores moved inward on all participant-reported measures at Week 16 compared to the dotted line representing the baseline. Comparison of izokibep 80 mg versus placebo is shown at statistically significant levels between p<0.01 to p<0.001 and comparison of izokibep 40 mg versus placebo is shown at statistically significant levels between p<0.05 and p<0.01.

[0083] As demonstrated in FIG. 4, participants with enthesitis at baseline reported a higher percentage of participant-derived clinically important difference in PsAID with izokibep compared to the overall trial population. In the same trial, at 46 weeks, of the participants receiving izokibep 80 mg administered SC Q2W, 79% achieved ACR50 response, 50% achieved ACR70 response, 71% achieved PASI100 response and 89% achieved enthesitis resolution. Since all patients onplacebo switched to izokibep 80 mg Q2W after 16 weeks, no p-values were planned or calculated beyond Week 16. Of the participants receiving izokibep 40 mg administered SC Q2W, 50% achieved ACR50 response, 33% achieved ACR70 response, 50% achieved PASI100 response and 83% achieved enthesitis resolution.

[0084] FIG. 5 provides key results of the Phase 2 trial of izokibep in PsA at Week 46. Of the participants who switched at 16 weeks from receiving placebo to receiving izokibep 80 mg administered SC Q2W, 73% achieved ACR50 response, 64% achieved ACR70 response, 67% achieved PASI100 response and 80% achieved enthesitis resolution.

[0085] PASI75 response is defined as a 75% improvement in skin activity and severity response of psoriasis skin lesions, and enthesitis resolution is defined as no active entheseal sites on the Leeds Enthesitis Index (LEI). Enthesitis is unchecked inflammation of the difficult to treat entheseal tissues and is a marker of disease severity often associated with residual pain and physical dysfunction, negatively impacting quality of life. Beyond the placebo-controlled period of 16 weeks and out to 46 weeks, after the placebo group had switched to 80 mg Q2W, no p-values were planned nor have been calculated.

[0086] In certain embodiments, at 46 weeks after administration of izokibep, of the participants receiving izokibep 80 mg administered SC Q2W, 79% achieved ACR50 response, 50% achieved ACR70 response, 71% achieved PASI100 response and 89% achieved enthesitis resolution. Of the participants receiving izokibep 40 mg administered SC Q2W, 50% achieved ACR50 response, 33% achieved ACR70 response, 50% achieved PASI100 response and 83% achieved enthesitis resolution. ACR70 response is defined as a 70% improvement in features noted above for ACR50 response and is considered by some clinicians to be an indicator of significant control of disease activity. PASI100 response is defined as 100% improvement in skin response, or complete resolution of psoriasis skin lesions.

[0087] In certain embodiments, of the participants who switched at 16 weeks from receiving placebo to receiving izokibep 80 mg administered SC Q2W, 73% achieved ACR50 response, 64% achieved ACR70 response, 67% achieved PASI100 response and 80% achieved enthesitis resolution.

[0088] Using the PsAID questionnaire, participants in the Phase 2 trial reported improvements in all quality-of-life sub-domains of the PsAID instrument including pain, sleep disturbance and functional capacity. In the radar plot in FIG. 2, lower scores closer to the center of the figurerepresent better outcomes. Each spoke represents a participant-reported outcome from the PsAID. Changes in the magnitude of the scores of individual outcomes are represented by the distance from the center point. As reflected, scores moved inward on all participant-reported measures at Week 16 compared to the dotted line representing the baseline. Comparison of izokibep 80 mg versus placebo is shown at statistically significant levels between p<0.01 to p<0.001 and comparison of izokibep 40 mg versus placebo is shown at statistically significant levels between p<0.05 and p<0.01. Furthermore, we observed that participants with enthesitis at baseline reported even greater improvement in the measured outcomes than the total trial population that included participants without baseline enthesitis. The proportion of participants receiving 80 mg weekly with participant-reported clinically important difference from baseline in those with enthesitis was numerically higher at 53% as compared to the total population where 41% reached this threshold.

[0089] Also provided herein are results from a randomized, placebo-controlled Phase 2 trial of izokibep in PsA. At 16 weeks, of the participants in this trial receiving izokibep 80 mg administered SC every two weeks (Q2W), 52% achieved ACR50 response, 85% achieved PASI75 response and 88% achieved enthesitis resolution. Of the participants receiving 40 mg administered SC Q2W, 48% achieved ACR50 response, 83% achieved PASI75 response and 63% achieved enthesitis resolution. ACR50 response is defined as a 50% improvement in tender and swollen joints, along with improvement in three of these five parameters: (a) patient global assessment of disease activity; (b) physician global assessment of disease activity; (c) patient pain scale; (d) disability / functional questionnaire and (e) decreased concentration of C-reactive protein correlated to inflammation. PASI75 response is defined as a 75% improvement in skin activity and severity response of psoriasis skin lesions, and enthesitis resolution is defined as no active entheseal sites on the Leeds Enthesitis Index (LEI). Enthesitis is unchecked inflammation of difficult to treat entheseal tissues and is a marker of disease severity often associated with residual pain and physical dysfunction, negatively impacting quality of life. In the same trial, at 46 weeks, of the participants receiving izokibep 80 mg administered SC Q2W, 79% achieved ACR50 response, 50% achieved ACR70 response, 71% achieved PASI100 response and 89% achieved enthesitis resolution. Participants receiving izokibep 40 mg administered SC Q2W, 50% achieved ACR50 response, 33% achieved ACR70 response, 50% achieved PASI100 response and 83% achieved enthesitis resolution. Of the participants who switched at 16 weeks from receiving placebo to receiving izokibep 80 mg administered SC Q2W, 73% achieved ACR50 response, 64%achieved ACR70 response, 67% achieved PASI100 response and 80% achieved enthesitis resolution. ACR70 response is defined as a 70% improvement in features noted above for ACR50 response, and is considered by some clinicians to be an indicator of significant control of disease activity. PASI100 response is defined as 100% improvement in skin response, or complete resolution of psoriasis skin lesions. Safety profile of izokibep

[0090] Izokibep has been administered to more than 700 participants and in some for up to three years. More than 150 participants received doses up to 160 mg and more than 80 participants received up to 160 mg weekly, some out to six months. Izokibep has been generally well-tolerated with localized mild-to-moderate injection site reactions being the most common adverse event. The injection site reactions were generally the size of a quarter to half dollar, and typically presented within the first few injections, after which they generally declined in incidence.

[0091] Injection site reactions were localized reactions, with the majority graded mild-to-moderate in severity, generally the size of a quarter to half dollar, and typically presented within the first few injections, after which they generally declined in incidence. If needed, symptoms were generally managed with ice or topical over-the- counter cortisone cream. In the Phase 2 trial in PsA, trial participant discontinuation rates of approximately 1-2% due to injection site reactions were observed.

[0092] In the Phase 2 trial in PsA, izokibep was well-tolerated – in line with previous trials of izokibep – and no SAEs were reported / observed across all cohorts at Week 16. In the Week 46 data, eight SAEs were reported, one of which (vulvar cancer) was identified by the principal investigator to be potentially drug-related, and seven of which were deemed not to be drug-related. The most common adverse event at Week 16 and Week 46 was injection site reactions. Injection site reactions were localized reactions, with the majority graded mild-to- moderate in severity, generally the size of a quarter to half dollar, and typically presented within the first few injections, after which they generally declined in incidence.

[0093] The table below provides a summary of certain safety related data for izokibep. Table: Safety summary—Phase 1 and Phase 2 PsO trials; Week 16 and Week 46 Phase 2 PsA trial; and Part A Week 12 Phase 2b HS trial Study Current Status DeathsSAE(1)Adverse Events (AEs)(1) Relatedness to study treatment as determined by study investigator.(2) Measurement of injection site reaction in Phase 1 PsO trial was based on patient self- reporting on a questionnaire specifically querying injection site reactions, compared to spontaneous reporting in the Phase 2 trials in PsO and PsA. Measurement of ail other AEs was based on spontaneous reporting.(3) Excludes placebo(4) Injection site reactions could include incidences of injection site pruritis. injection site erythema and / or injection site swelling. (5) Only represents subcutaneous administration cohorts.(6) Measured over the 12-week placebo-controlled period

[0094] Pre-existing antibodies and treatment emergent anti-drug antibodies (ADAs) were detected in participants treated with izokibep in Phase 1 and Phase 2 trials. However, there was no observed correlation between the presence of these antibodies and drug exposures, clinical improvements on standard outcome measures or adverse events.

[0095] Among the more than 400 participants treated with izokibep to date, more than 80 participants have been treated with the 160 mg dose weekly. There has been no observed increasein the incidence of adverse events at this higher dose level compared to lower dose levels, and the 160 mg dose level has been generally well-tolerated. Pharmacodynamic and pharmacokinetic modeling for higher doses:

[0096] Responses for the 80 mg dose exceeded the 40 mg dose on joint, psoriasis, enthesitis and participant- reported outcome measures at 16 weeks in the Phase 2 trial in PsA. Modeling was performed to determine the potential for additional clinical response with higher dosing.

[0097] Surprisingly, the modeling provided that the 160 mg QW dose of izokibep led to a seven- fold increase in the minimum serum concentration (Cmin) and the 160 mg Q2W dose led to a two- fold increase in Cmin both compared to 80 mg Q2W. In general, higher Cmin, or trough circulating drug concentrations, is an important determinant of disease control for chronic inflammatory illnesses.

[0098] As demonstrated in FIG. 6, using industry standard computational PK-PD modeling, the higher 160 mg Q2W and 160 mg QW doses resulted in a projected approximately 10% increase in ACR50 as well as PASI100 responses at Week 16, and predicted a further approximate 10% increase with longer treatment duration over 46 weeks. Similarly modeled data also predicted improved enthesitis resolution at these doses as well as over time. This is presented in FIG.6 by comparing the blue band of exposure and response (response on the y-axis) across any one time point (time on the x-axis) against the pink band. The blue band is intended to reflect the 40 mg and 80 mg exposures and responses modeled from the data observed in our Phase 2 PsA trial through 16 weeks. The PK-PD model based on historical data, predicted the pink band, representing izokibep 160 mg QW and Q2W to be higher than the blue band. The modeling also predicted improvement over time (comparing week 18 in the model to week 48) using any of the doses. We have used this modeling to inform certain of our decisions around designing the duration of trials or dosing used in such trials. Phase 2b / 3 trial for izokibep for treatment of PsA

[0099] An ongoing placebo-controlled Phase 2b / 3 trial of izokibep in PsA is evaluating 160 mg delivered SC QW or Q2W, or 80 mg every four weeks (Q4W). 351 participants with PsA are enrolled in this trial. The primary endpoint of this Phase 2b / 3 trial is the ACR50 response on active therapy versus placebo at 16 weeks. Secondary endpoints including, without limitation, PASI90response, enthesitis resolution and minimal disease activity at 16 weeks will also be evaluated compared to placebo. Following the 16-week placebo-controlled portion, those participants on placebo will switch to active therapy and the trial is expected to continue to 52 weeks.

[0100] This Phase 2b / 3 trial is investigating 160 mg dose QW, 160 mg dose Q2W and 80 mg dose Q4W. The design of this trial is similar to that of the Phase 2 trial: after 16 weeks, participants on placebo will receive izokibep for the remainder of the 52-week trial period. Similar to our completed Phase 2 trial, the primary endpoint of this Phase 2b / 3 trial is the commonly accepted regulatory endpoint of ACR50 at Week 16 and key secondary endpoints include PASI90, enthesitis resolution rates, minimal disease activity and participant reported quality of life. Efficacy and safety will continue to be evaluated up to 52 weeks. Participants meeting the CASPAR criteria and having a tender joint count greater than three based on a possible 68 total count, and having a swollen joint count more than three based on a possible total count of 66, will be enrolled in the trial. Furthermore, to ensure that PsA is the most likely diagnosis, as compared to rheumatoid arthritis, blood test for rheumatoid arthritis (RF and anti-CCP) will be required to be negative. Patients may have had prior failures to any of anti-inflammatory medications (NSAIDs), disease modifying medications (DMARDs) or tumor necrosis factor inhibitors (TNF inhibitors). Further details about the Phase 2b / 3 clinical trial are provided below: A Randomized, Double-blind, Placebo-controlled, Multicenter Phase 2b / 3 Study to Evaluate the Efficacy and Safety of Izokibep in Subjects with Active Psoriatic Arthritis Rationale:

[0101] Izokibep is a small protein molecule that acts as a selective, potent inhibitor of interleukin-17A, to which it binds with high affinity. Izokibep has been investigated in nonclinical and clinical studies including healthy subjects, and subjects with psoriasis and psoriatic arthritis (PsA). The clinical development plan also includes axial spondyloarthritis, uveitis, and hidradenitis suppurativa. This study investigates izokibep in subjects with active PsA, including tumor necrosis factor-alpha inhibitor (TNFi) naïve subjects, and those who had an inadequate response or intolerance to TNFi, or for whom TNFi is contraindicated. The study is intended to be 1 of 2 adequate and well-controlled studies to support a claim of efficacy of izokibep in subjects with PsA. Overall Design:`0102] This is a multicenter, randomized, double-blind, placebo-controlled, Phase 2b / 3 Study to evaluate the efficacy and safety of izokibep in subjects with active PsA who are TNFi naïve, who have had an inadequate response or intolerance to TNFi, or for whom TNFi is contraindicated. This study is being conducted at study sites in North America and Europe. Brief Summary:

[0103] 351 subjects with active PsA enrolled.

[0104] Subjects will be screened within 28 days of study drug administration. Subjects meeting eligibility criteria will be randomized 4:4:4:1 to 1 of 4 treatment groups on Day 1, and will receive via subcutaneous injection: º Group 1 (n = 100): placebo every week (QW) from Day 1 / Week 0 to Week 15, then izokibep 160 mg QW from Week 16 to Week 51. º Group 2 (n = 100): izokibep 160 mg QW from Day 1 / Week 0 to Week 51. º Group 3 (n = 100): izokibep 160 mg every 2 weeks (Q2W) from Day 1 / Week 0 to Week 50, with matching placebo Q2W until Week 51 for the weeks in between izokibep doses to maintain the blind. º Group 4 (n = 25): izokibep 80 mg every 4 weeks (Q4W) from Day 1 / Week 0 to Week 48, with matching placebo QW until Week 51 for the weeks in between izokibep doses to maintain the blind.

[0105] Randomization will be stratified by prior TNFi use (Yes / No) and enthesitis (Leeds Enthesitis Index [LEI] > 0 / LEI = 0). Anticipated enrollment of subjects previously treated with TNFi is 20% to 30%. The number of subjects without enthesitis entering into the study (LEI = 0 at baseline) will be capped at 70%.

[0106] Subjects will complete study assessments according to the study visits outlined in the Schedule of Activities below. The primary endpoint will be assessed at Week 16. The last dose of study drug will be administered on Week 51.

[0107] Starting at Week 24, subjects who do not meet clinical Disease Activity for PsA (cDAPSA) low disease activity (cDAPSA ≤ 14) at 2 consecutive visits (e.g. at Week 20 and Week 24) will be discontinued from study drug and can receive SOC as deemed appropriate by the investigator..

[0108] An End of Treatment visit will be conducted at Week 52. A Safety Follow-up visit will be conducted at Week 59. A pharmacokinetic / anti-drug antibody (PK / ADA) Follow-up and End of Study Visit will be conducted at Week 65.

[0109] For subjects that prematurely discontinue study drug for any reason, the End of Treatment (EOT) visit should be completed within 14 days of withdrawal, and follow-up visits should be completed at 8 weeks (safety follow-up) and 14 weeks (PK and ADA follow-up) after the last dose of study drug, where possible.

[0110] The final analysis of primary and secondary endpoints will be conducted after the last subject has had the opportunity to complete Week 16 assessments or early terminates from the study.

[0111] Number of Subjects: 351 subjects enrolled into this study.

[0112] Intervention Groups and Duration: º Group 1 (n = 100): placebo QW from Day 1 / Week 0 to Week 15, then izokibep 160 mg QW from Week 16 to Week 51. º Group 2 (n = 100): izokibep 160 mg QW from Day 1 / Week 0 to Week 51. º Group 3 (n = 100): izokibep 160 mg Q2W from Day 1 / Week 0 to Week 50, with matching placebo Q2W until Week 51 for the weeks in between izokibep doses to maintain the blind. º Group 4 (n = 25): izokibep 80 mg Q4W from Day 1 / Week 0 to Week 48, with matching placebo QW until Week 51 for the weeks in between izokibep doses to maintain the blind

[0113] Izokibep and matching placebo (collectively referred to as study drug) will be visually indistinguishable to prevent unblinding during preparation or administration of study material.

[0114] Study drug doses are fixed and will not be adjusted for individual subjects during the study.

[0115] FIG.7 provides a schematic representation of the design of the Phase 2b / 3 clinical trials for the treatment of PsA with izokibep. The legends and abbreviations included in FIG. 7 are described below:

[0116] Abbreviations: EOS = End of Study; EOT = End of Treatment; Q2W = every 2 weeks; QW = every week; TNFi = tumor necrosis factor-alpha inhibitor; LEI = Leeds Enthesitis Index a Randomization will be stratified by prior TNFi use (Yes / No) and enthesitis (LEI > 0 / LEI = 0). Anticipated enrollment of subjects previously treated with TNFi is 20% to 30%. The number of subjects without enthesitis entering into the study (LEI = 0 at baseline) will be capped at 70%. b Subjects in Group 1 (placebo QW) will receive placebo weekly until Week 15, then izokibep weekly until Week 51. Subjects in Group 2 (izokibep QW) will receive izokibepweekly. Subjects in Group 3 (izokibep Q2W) will receive izokibep every other week, with matching placebo in between izokibep doses to maintain the blind. Subjects in Group 4 (izokibep Q4W) will receive izokibep every 4 weeks, with matching placebo between izokibep doses to maintain the blind. At Week 16, subjects initially randomized to izokibep who are classified as non-responders (defined as not achieving at least 20% improvement in either or both tender joint count (TJC) and swollen joint count (SJC) at both Week 12 and Week 16) will be switched to izokibep 160 mg QW until the end of the study. c Two follow-up visits will be completed by all subjects at Weeks 59 and 65. For subjects that early terminate the follow-up visits should be completed at 8 weeks and 14 weeks after the last dose of study drug. d At Week 24, rescue therapy should be given to subjects classified as non-responders (defined as not achieving at least 20% improvement in either or both tender joint count (TJC) and swollen joint count (SJC) at both Week 20 and Week 24). e Starting at Week 36, subjects who do not meet clinical Disease Activity for PsA (cDAPSA) low disease activity (cDAPSA ≤ 14) at 2 consecutive visits (e.g., at Week 32, and Week 36) will be discontinued from study drug. Nonclinical studies:

[0117] Assessments of target-binding specificity have demonstrated high specificity and affinity of izokibep to IL-17A and to albumin. The in vitro and in vivo pharmacodynamic evaluations show that izokibep has a 3-to 5-fold higher potency than the anti-IL-17A monoclonal antibody secukinumab on a molar basis and appears to be approximately equipotent to ixekizumab on a molar basis.

[0118] Pharmacokinetic data for intravenous (IV)- and subcutaneous (SC)-administered izokibep have been obtained in rat and monkey. Pharmacokinetic assessments in rat and monkey indicate that the time course of izokibep concentrations after a bolus IV injection and SC injection is well described by a 2- or 3-compartment model. Pharmacokinetic assessments indicate that the elimination rate of izokibep is similar to that of albumin in the respective species.

[0119] Repeated (10 days to 3 months) SC or IV administration of izokibep to cynomolgus monkeys was well tolerated, with no observed adverse effect levels (NOAELs) of 40 mg / kg / dose administered every third day (IV, 28-day study), 20 mg / dose administered every third day (SC,28-day study), and 20 mg / kg / week (SC, 3-month study), being the highest dose levels tested in the respective studies.

[0120] In the 26-week repeated dose toxicity study in cynomolgus monkeys, weekly SC injection of 10, 20, or 40 mg / kg / week izokibep to monkeys for 26 weeks was generally well tolerated. However, due to the presence of local abscessation and systemic sequelae in 1 female administered 40 mg / kg / week, which was considered adverse, the NOAEL for SC administration is considered to be 20 mg / kg / week.

[0121] In the enhanced pre and postnatal developmental toxicity study in cynomolgus monkeys, SC izokibep administration of up to 40 mg / kg / week to pregnant monkeys for approximately 21 weeks was well tolerated. The NOAEL was 40 mg / kg / week.

[0122] The results from the immunotoxicity screening assays do not suggest that izokibep has an intrinsic capacity for immune system activation.

[0123] Metabolism and genotoxicity have not been investigated, since izokibep is a protein molecule and contains only naturally occurring amino acids. Clinical Overview

[0124] A first-in-human multipart clinical study (Study ABY-035-001, EudraCT number 2015-004531-13, NCT02690142) has been conducted with the parenteral formulation of izokibep. Izokibep was administered IV and SC to healthy subjects and plaque psoriasis patients, in doses ranging from 2 mg to 40 mg in a single- or multiple-dose regimen.

[0125] A Phase 2 dose-finding study in subjects with moderate to severe plaque psoriasis was recently completed with up to 3 years of exposure (Study ABY-035-002, EudraCT number 2017-001615-36, NCT03591887).108 subjects were randomized into 5 dose groups: 2 mg, 20 mg, 80 mg, and 160 mg izokibep or placebo. The treatment period consisted of an induction period (12 weeks), an optimization period (12 weeks), and an individualization period including 4 weeks follow-up (28 weeks), and 2 further years of extension. The induction period was double blind and placebo controlled.

[0126] The primary endpoint of the study was the proportion of patients that achieved a Psoriasis Area and Severity Index (PASI) response of 90% (PASI90) after 12 weeks of treatment. The PASI90 at 12 weeks was 71.4% and 59.1% in subjects treated with 80 mg and 160 mg Q2W of izokibep, respectively. In the lower dose groups, 2 mg and 20 mg izokibep, only 5.0% and 19.0% of subjects, respectively, reached the primary endpoint. None of the subjects receiving placeboreached PASI90 response at Week 12. At Week 24, PASI90 responses were comparable between the initial 80 mg and 160 mg treatment groups. The safety and efficacy data obtained from the 52-week core period of the study with izokibep suggest a favorable benefit-risk profile in plaque psoriasis.

[0127] A Phase 2 clinical trial in subjects with active PsA has recently been completed (Study ABY-035-202). Study ABY-035-202 is a dose-finding trial of 40 mg or 80 mg izokibep or placebo SC Q2W. The primary endpoint is the ACR 50% (ACR50) response at Week 16; further key secondary endpoints comprise other ACR responses, PASI scores, enthesitis endpoints, proportion of subjects achieving MDA, adverse events (AEs; safety), and izokibep blood levels (PK), and ADA assessments.

[0128] The primary endpoint of ACR50 at 16 weeks was met with 52% response rate in subjects receiving 80 mg Q2W of izokibep versus 13% for placebo (p-value = 0.0006). Subjects receiving 40 mg Q2W had an ACR50 response rate of 48% at 16 weeks. The PASI response of 75%, in subjects with a minimum psoriasis body surface area (BSA) ≥ 3% at baseline, at 16 weeks was 85% and 83% in subjects treated with 80 mg and 40 mg Q2W, respectively versus 14% for those receiving placebo. In subjects with enthesitis at baseline utilizing the Leeds Enthesitis Index (LEI), resolution of enthesitis was achieved by 88% of subjects receiving 80 mg Q2W, 63% of subjects receiving 40 mg Q2W of izokibep and 10% receiving placebo. Safety Overview

[0129] In the first-in-human study in healthy subjects and subjects with psoriasis (Study ABY- 035-001), doses of up to 40 mg IV and SC of izokibep (n = 62) were well tolerated, with no deaths or treatment-related serious AEs (SAEs).

[0130] Intravenous administration (single doses up to 40 mg in 46 subjects in total) resulted in the following treatment-emergent AEs (TEAEs) by preferred term: oropharyngeal pain (10.9%), nasopharyngitis (6.5%), diarrhea (4.3%), and headache (4.3%). A further 9 TEAEs were reported, which affected 1 subject each (2.2% each). Subcutaneous administration (single and multiple doses up to 40 mg in 21 subjects in total) resulted in the following TEAEs by preferred term: injection site reaction (61.9%) and injection site pain (28.6%). A further 11 TEAEs were reported, which affected 1 subject each (5.2% each). The majority of the injection site reactions were of mild intensity and required no treatment or limited therapy.

[0131] Surprisingly, in the Phase 2, 52-week core period in subjects with plaque psoriasis (ABY- 035-002), multiple doses of up to 160 mg Q2W SC of izokibep (n = 108) were well tolerated with no deaths or treatment-related SAEs. A total of 65 subjects (60.2%) experienced at least 1 izokibep-related TEAE. The most common izokibep-related TEAEs (n / %) were injection site reaction (42 / 38.9%), nasopharyngitis (13 / 12.0%), diarrhea (7 / 6.5%) and fatigue (6 / 5.6%) consistent with the first-in-human study.

[0132] In the Phase 2, randomized, double-blind, placebo-controlled clinical trial in subjects with active PsA (ABY-035-202), doses of 40 mg and 80 mg Q2W were well tolerated. Safety evaluation showed no serious or severe AEs up to Week 16. Treatment-emergent AE rate overall was 52.3% for placebo, 65.9% for 40 mg Q2W and 55.3% for 80 mg Q2W. The most common AEs (≥ 5% in either arm with active treatment) were injection site reaction or erythema, headache, hyperkalemia, and upper respiratory tract infection. Three patients had AEs of special interest: 2 subjects experienced injection site reaction and 1 subject experienced vulvovaginal candidiasis. Pharmacokinetics

[0133] Following SC administration of single izokibep doses in the first–in-human study (Study ABY-035-001), median time to maximum observed concentration (tmax) was 60 hours postdose. After reaching maximum observed plasma concentration (Cmax), plasma levels of izokibep declined in an apparent mono or biphasic manner with the geometric mean t½being 278 hours which was similar to that after IV administration (288 hours). Individual t½ estimates ranged from 199 to 464 hours and 220 to 340 hours for SC and IV treatments, respectively. The absolute SC bioavailability after a 40-mg dose of izokibep was estimated to 77%. In general, as assessed by the geometric percent coefficient of variation (CV%) low between-subject variability was noted for area under the concentration-time curve (AUC) extrapolated to infinity (AUC0-∞) and Cmaxfor both dose routes, with values ranging from 20% to 22% and 14% to 15%, respectively.

[0134] Following 40 mg repeated SC doses, maximum plasma concentrations occurred at a median tmax of 48.0 hours postdose on Days 1 and 29 (individual range: 24.0 to 71.0 hours postdose). On Day 85, median tmaxwas slightly later at 71.6 hours postdose (individual range: 66.6 to 73.1 hours postdose). After reaching Cmaxon Day 85, plasma concentrations of izokibep declined in an apparent mono or biphasic manner with a geometric mean t½ of 279 hours with individual patients ranging from 229 to 423 hours. Predose trough izokibep plasma concentrations showed that steady state was achieved by Day 71, following 5 doses of izokibep administeredQ2W. There was evidence of accumulation following repeated dosing by Day 85 with geometric mean accumulation ratio, based on AUC over the dose interval (AUC0-τ) of 1.95, and individual patients ranging from 1.35 to 5.09. Between-patient variability, based on geometric CV%, was moderate on the monitored study days for AUC0-τwith values ranging from 29.4% to 36.0%, and low-to-moderate for Cmaxwith values ranging from 20.4% to 28.8%. Risk Assessment:

[0135] Izokibep is a biologic drug that binds IL-17A with high affinity and with a potency corresponding to clinically tested monoclonal antibodies in terms of blocking the biological activity of IL-17A. º IL-17A inhibitors, including secukinumab at 10 mg / kg and 30 mg / kg and ixekizumab as well as izokibep at doses up to 160 mg SC, do not appear to have dose-limiting AEs. º Class effects and potential risks seen with other IL-17 inhibitors have not been identified with izokibep. Given the small numbers of subjects treated to date, class effects and potential risks of IL-17 inhibitors will be explicitly monitored (ie, events of special interest) and have been taken into consideration in the development of inclusion and exclusion criteria. These events include Candida infections and IBD. º Non-serious, mild-to-moderate injection site reactions are the most common adverse event reported in association with subcutaneous administration of izokibep. These are typically self-resolving; however, additional measures to mitigate / manage injection site reactions include the following: allow study drug to warm to room temperature prior to administration, about 15 to 20 minutes.No genotoxicity or carcinogenicity is foreseen as izokibep is a protein consisting of natural amino acids. However, since no data are available at this stage of clinical development on possible effects on the reproductive system, the following precautionary measure will be taken: º Females of childbearing potential as well as reproductive female partners of male subjects must use an adequate method of contraception while participating in the clinical study until 8 weeks after the last dose of study drug. Pregnancy testing will be performed at regular intervals prior to, during treatment and after the end of treatment (ie, 8 weeks after last investigational medicinal product dosing).

[0136] Benefit Assessment:

[0137] The safety, efficacy, and PK data obtained in clinical trials with izokibep in healthy volunteers and in patients with psoriasis and PsA suggest a favorable benefit-risk profile. Based on results from the izokibep Phase 2 randomized, double-blind, placebo-controlled clinical trial in subjects with active PsA and published data showing efficacy and safety for other IL-17 inhibitors in patients with PsA, the benefit-risk relationship in these patients appears favorable and justifies clinical development of izokibep in PsA as well.

[0138] Overall Benefit: Risk Conclusion:

[0139] The following considerations are important for the benefit-risk assessment: ^ Only subjects with active PsA will be enrolled. Subjects must have had an inadequate response to NSAIDs or a DMARD, demonstrated intolerance to, or have a contraindication to NSAIDs or a DMARD for treatment of their PsA. Subjects previously treated with TNFi, or TNFi naïve, are eligible. ^ The inclusion and exclusion criteria will ensure that subjects who might be predisposed to a higher risk of drug-related TEAEs are either excluded or identified and treated with caution. Class effects seen with other IL-17 inhibitors have been taken into account when designing the eligibility criteria. Subjects with active infections will be excluded from participating in the study. ^ Subjects will be monitored at the study site for at least 1 hour after administration of izokibep at designated visits. ^ No subjects will be solely on placebo for more than 16 weeks. At Week 24, subjects defined as non-responders should receive rescue therapy. At Week 36 and beyond, subjects not achieving low disease activity will discontinue study drug and can receive SOC as judged appropriate by the investigator, excluding other IL-17 inhibitors. Details are provided below. ^ Placebo treatment will be limited to 16 weeks. After Week 16, subjects randomized to placebo will begin blinded active treatment (izokibep 160 mg QW) in order to potentially derive benefit from the disease-relevant effect of IL-17 inhibition. ^ Starting at Week 24, subjects who do not meet clinical Disease Activity for PsA (cDAPSA) low disease activity (cDAPSA ≤ 14) at 2 consecutive visits (e.g. at week 20 and Week 24) will be discontin ed from study drug and can receive SOC as deemed appropriate by the investigator.

[0140] Given the known possibility of disease progression if PsA goes untreated, subjects across all treatment arms of this study will be allowed to continue methotrexate, leflunomide, sulfasalazine, apremilast, hydroxychloroquine, corticosteroids, or NSAIDS during the study provided the dose has been stable. Additionally, subjects must have had an inadequate response to NSAIDs, DMARDs, or TNFi, or demonstrated intolerance to, or have a contraindication to NSAIDs, DMARDs, or TNFi for treatment of their PsA. Prior treatment failure and the use of concomitant background medications / treatments to mitigate the risk of progression of disease in the placebo group, and a short-term exposure to placebo to 16 weeks all justify a placebo cohort.

[0141] Participation in the study is voluntary. Each subject may refuse to participate or withdraw from the study, at any time, without penalty or loss of benefits to which the subject is otherwise entitled.

[0142] Taking into account the measures taken to minimize risk to subjects participating in this study, the lack of clear dose-limiting AEs associated with izokibep at the doses under study, and the pre-existing data on the effects of izokibep and other IL-17 inhibitors in PsA, the potential risks identified in association with izokibep in this study are justified by the anticipated benefits that may be afforded to subjects with PsA. Objectives, Endpoints, and Estimands: Objectives Endpoints^ Proportion of subjects achieving 90% or ^ PASI90 at Week 16 greater reduction in PASI score from= body surface area; cDAPSA = Change in Clinical Disease Activity in Psoriatic Arthritis; CRP = C-reactive protein; DAPSA = Disease Activity in Psoriatic Arthritis; DAS28 = Disease Activity Score in 28 joints; FACIT-F = Functional Assessment of Chronic Illness Therapy – Fatigue; HAQ- DI = Health Assessment Questionnaire – Disability Index; LDI = Leeds Dactylitis Index; LEI = Leeds Enthesitis Index; MCS=Mental Component Summary; MDA = Minimal Disease Activity; mNAPSI = modified Nail Psoriasis Severity Index; mTSS = modified total Sharp score; NRS = numeric rating scale; PASDAS = Psoriatic Disease Activity Score; PASI = Psoriasis Area and Severity Index; PCS=Physical Component Summary PsAID = Psoriatic Arthritis Impact of Disease; SAE = serious adverse event; SF-36 = 36-Item Short Form Survey; SPARCC =Spondyloarthritis Research Consortium of Canada; TEAE = treatment-emergent adverse event; VLDA = very low disease activity. Primary Estimand:

[0143] The 5 components of the estimand to address the primary objective: º Treatment: izokibep versus placebo. º Population of interest: subjects with PsA who meet all inclusion / exclusion criteria. º Variable of interest: achievement of ACR50 after 16 weeks of treatment. º Summary measure: response rate, achievement of ACR50 (Yes / No). º Intercurrent event handling: treatment policy strategy, with all subjects included in the analysis regardless of treatment discontinuation, concomitant medication / rescue medication, protocol deviations, or other actions. Secondary Estimand(s) The 5 components of the estimand to address each secondary objective are as follows. First secondary objective: º Treatment: izokibep versus placebo. º Population of interest: subjects with PsA who meet all inclusion / exclusion criteria who have at least 3% BSA affected at baseline. º Variable of interest: achievement of PASI90 after 16 weeks of treatment. º Summary measure: response rate, achievement of PASI90 (Yes / No). º Intercurrent event handling: treatment policy strategy, with all subjects included in the analysis regardless of treatment discontinuation, concomitant medication, protocol deviations, or other actions. Second secondary objective: º Treatment: izokibep versus placebo. º Population of interest: subjects with PsA who meet all inclusion / exclusion criteria who have enthesitis at baseline (LEI > 0). º Variable of interest: resolution of enthesitis after 16 weeks of treatment. º Summary measure: response rate, achievement of LEI = 0 (Yes / No).º Intercurrent event handling: treatment policy strategy, with all subjects included in the analysis regardless of treatment discontinuation, concomitant medication, protocol deviations, or other actions. Third secondary objective: º Treatment: izokibep versus placebo. º Population of interest: subjects with PsA who meet all inclusion / exclusion criteria. º Variable of interest: achievement of MDA after 16 weeks of treatment. º Summary measure: response rate, achievement of MDA (Yes / No). º Intercurrent event handling: treatment policy strategy, with all subjects included in the analysis regardless of treatment discontinuation, concomitant medication, protocol deviations, or other actions. Fourth secondary objective: º Treatment: izokibep versus placebo. º Population of interest: subjects with PsA who meet all inclusion / exclusion criteria. º Variable of interest: achievement of ACR20 after 16 weeks of treatment. º Summary measure: response rate, achievement of ACR20 (Yes / No). º Intercurrent event handling: treatment policy strategy, with all subjects included in the analysis regardless of treatment discontinuation, concomitant medication, protocol deviations, or other actions. Fifth secondary objective: º Treatment: izokibep versus placebo. º Population of interest: subjects with PsA who meet all inclusion / exclusion criteria who have a Psoriatic Arthritis Impact of Disease (PsAID) score of at least 3 at baseline. º Variable of interest: change in PsAID after 16 weeks of treatment. º Summary measure: response rate, improvement in PsAID of at least 3 units (Yes / No). º Intercurrent event handling: treatment policy strategy, with all subjects included in the analysis regardless of treatment discontinuation, concomitant medication, protocol deviations, or other actions. Sixth secondary objective: º Treatment: izokibep versus placebo.º Population of interest: subjects with PsA who meet all inclusion / exclusion criteria. º Variable of interest: Health Assessment Questionnaire – Disability Index (HAQ-DI) change from baseline. º Summary measure: mean change from baseline in HAQ-DI. º Intercurrent event handling: treatment policy strategy, with all subjects included in the analysis regardless of treatment discontinuation, concomitant medication, protocol deviations, or other actions. Study design:

[0144] This is a multicenter, randomized, double-blind, placebo-controlled, Phase 2b / 3 study. The plan is to evaluate the efficacy and safety of izokibep in subjects with active PsA who are TNFi naïve, who have had an inadequate response or intolerance to TNFi, or for whom TNFi is contraindicated.

[0145] 351 subjects with active PsA were enrolled. The study consists of up to a 28-day (4-week) screening period, a 51-week treatment period, and a follow-up period with visits at 8 weeks and 14 weeks after the last dose of study drug to assess safety and immunogenicity.

[0146] Subjects meeting eligibility criteria will be randomized into 1 of 4 treatment groups in a 4:4:4:1 ratio as follows: º Group 1 (n = 100): placebo QW from Day 1 / Week 0 to Week 15, then izokibep 160 mg QW from Week 16 to Week 51. º Group 2 (n = 100): izokibep 160 mg QW from Day 1 / Week 0 to Week 51. º Group 3 (n = 100): izokibep 160 mg Q2W from Day 1 / Week 0 to Week 50, with matching placebo Q2W until Week 51 for the weeks in between izokibep doses to maintain the blind. º Group 4 (n = 25): izokibep 80 mg Q4W from Day 1 / Week 0 to Week 48, with matching placebo QW until Week 51 for the weeks in between izokibep doses to maintain the blind.

[0147] The first dose of study drug (ie, izokibep or placebo) will be administered on Day 1 (Week 0).

[0148] Randomization will be stratified by any prior treatment with a systemic TNFi (Yes / No) and enthesitis (LEI > 0 / LEI = 0). Anticipated enrollment of subjects previously treated with TNFi is 20% to 30%. The number of subjects without enthesitis entering into the study (LEI = 0 at baseline) will be capped at 70%.

[0149] The primary endpoint will be assessed at Week 16. The last dose of study drug will be administered on Week 51.

[0150] An End of Treatment visit will be conducted at Week 52. A Safety Follow-up visit will be conducted at Week 59. A PK / anti-drug antibody (ADA) Follow-up and End of Study Visit will be conducted at Week 65.

[0151] For subjects that early terminate, the End of Treatment visit should be completed within 14 days of withdrawal and follow-up visits should be completed at 8 weeks and 14 weeks after the last dose of study drug, where possible.

[0152] The final analysis of primary and secondary endpoints is conducted after the last subject has had the opportunity to complete Week 16 assessments or early terminates from the study. Analysis of data at later timepoints may occur after all subjects have had the opportunity to complete that timepoint. Scientific Rationale:

[0153] The design of this clinical study was chosen to evaluate izokibep in subjects with active PsA previously treated with TNFi, or TNFi naïve. The primary aim of the study is to evaluate the safety and efficacy of izokibep administered SC at a dose of 160 mg QW and 160 mg Q2W for the treatment of active PsA. The primary endpoint of ACR50 response will be evaluated after all subjects have the opportunity to complete the 16-week placebo-controlled study period. After Week 16, subjects randomized to placebo will receive blinded active treatment (izokibep 160 mg QW) until Week 51. Long-term efficacy beyond Week 16 will be explored up to Week 52 and safety will be explored up to the End of Study visit at Week 65.

[0154] Standard statistical procedures will be utilized in this study. Efficacy measurements in this study have been selected or designed to assess disease activity in subjects with active PsA. All clinical and laboratory procedures in this study are standard and generally accepted.

[0155] Males and females ≥ 18 years and ≤ 75 years with active PsA who meet all inclusion criteria and who do not meet any of the exclusion criteria are eligible for this study. The population being studied represents a population normally seen in clinical practice. This ensures the activity of izokibep can be evaluated across a distribution of disease severity in the study. Dose:

[0156] The doses of izokibep are: 80 mg SC Q4W, 160 mg SC QW and 160 mg SC Q2W administered from Day 1 (Week 0) through Week 51 in subjects randomized to izokibep. Subjectsrandomized to placebo will switch to active treatment at Week 16 and will receive izokibep 160 mg QW until Week 51.

[0157] The selection of the dosing regimen is informed by the following facts. The 80 mg Q4W and 160 mg dose groups will support dose-response analyses along with the 40 mg Q2W dosing in the prior phase 2 study. A dose of 160 mg QW has 10-fold margin for Cmaxand 9-fold margin for AUC0-τ based on NOAEL from nonclinical cynomolgus monkey toxicity studies (data provided in the Table below). Table: Cmaxand AUC0-τat NOAEL in Cynomolgus Monkey Versus Predicted Exposure Levels in Man and Respective Margins Parameter NOAEL Predicted in Subjects Margin (20 mg / kg / week) at Steady State (160 mg ax=maximum observed plasma concentration; h = hour; NOAEL = no observed adverse effect level; QW = once a week.

[0158] Finally, based on PK modeling of the izokibep and secukinumab plaque psoriasis data and the available data with secukinumab in uveitis, the sponsor aimed to approximate the observed exposure of 10 mg / kg secukinumab IV Q2W (administered on 4 occasions) with the 160 mg QW SC dose of izokibep as shown in FIG.8 and the Table below: Table: Predicted Exposure at Steady State for 160 mg Izokibep SC QW Parameter Unit Value Unit Value ge= average observed plasma concentration; Cmax= maximum observed plasma concentration; Cmin= minimum observed plasma concentration; h = hour; QW = once a week; SC = subcutaneous.

[0159] Current agents leave considerable room to improve responses, with ACR 50 responses in 35 to 50% of patients at 24 weeks and less than 60% at 52 weeks. Population pharmacokinetic modeling with IV and SC data from Phase 1 and 2 izokibep studies in healthy volunteers, plaque psoriasis, and PsA predict that meaningfully higher ACR50, ACR70, and PASI100 responses may be observed with izokibep 160mg QW and Q2W regimens when compared with 40 mg and 80 mg Q2W regimens in the treatment of PsA, with improvement in responses increasing with longer duration of treatment (FIG.6). Achieving higher levels of response, such as ACR70 for a majority of patients remains an unmet need and modelling from the phase 2 data with 40 mg and 80 mg Q2W suggests higher levels of response are possible. Furthermore, in the clinical setting, izokibep has not demonstrated dose-limiting safety / tolerability up to 160 mg QW with multiple doses across multiple indications, with up to 3 years of exposure, so that safety data available to date suggests the higher doses proposed here are unlikely to lead to additional safety risks.

[0160] The doses of izokibep used in this study supports the maximum likelihood of demonstrating the potential efficacy for izokibep in subjects with active PsA within an acceptable safety profile. Measures have also been taken to ensure the well-being of subjects by applying appropriate inclusion and exclusion criteria to recruit a broad population that is most likely to benefit from treatment, while excluding subjects with an unacceptable risk to enter the study. Further, during the study, measures are in place to monitor the safety of subjects on a regular basis. End of Study Definition:

[0161] The primary completion for the study is the date all subjects have had the opportunity to complete the Week 16 assessment for the purpose of the primary endpoint. A subject will be considered to have had the opportunity to complete the Week 16 assessment if the subject has the Week 16 assessment, has a visit after Week 16, or permanently discontinues the study before Week 16.

[0162] The end of the study is defined as the date of the last scheduled procedure including the last follow-up visit (i.e., Week 65) for the last subject in the study globally. A subject is considered to have completed the study if the subject has completed all periods of the study including the last scheduled procedure. Study Population

[0163] Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not permitted.Inclusion criteria:

[0164] Subjects are eligible to be included in the study only if all of the following criteria apply: General he eExclusion Criteria:

[0165] Subjects are excluded from the study if any of the following criteria apply: Disease-related Medical Conditions in al al ns nt to al is of A reLifestyle considerations:

[0166] Limited alcohol consumption (to < 2 per day, < 7 alcoholic drinks per week) is encouraged amongst participants. An alcoholic drink is defined as a 6 oz (175 mL) glass of wine, a 1 oz (30 mL) glass of hard liquor (e.g., whiskey), or an 8 oz (250 mL) glass of beer. Study Drug(s), prior and concomitant therapy:

[0167] Study drug is defined as any investigational intervention(s), marketed product(s), placebo, or medical device(s) intended to be administered to a study subject according to the study protocol.

[0168] Any medication or vaccine (including over-the-counter or prescription medicines, recreational drugs, vitamins, and / or herbal supplements) that the subject is receiving at the time of enrollment or receives during the study must be recorded along with: º reason for use; º dates of administration including start and end dates; and º dosage information including route, dose, and frequency.

[0169] The medical monitor should be contacted if there are any questions regarding concomitant or prior therapy. Prior therapies:

[0170] Any treatments for PsA since initial diagnosis (as determined through medical history records or through subject interview) prior to study entry will be recorded in the source documents and on the eCRF, along with the reason for discontinuation.

[0171] A detailed history of prior DMARDs, biologics, and steroids use, response, and reason for discontinuation will be collected. Concomitant therapies:

[0172] Subjects will be allowed to continue the following concomitant medications / treatments during the study provided the dose has been prior to Day 1 and within the acceptable limits listed below, and must remain unchanged throughout the study unless subject qualifies for rescue medication: º methotrexate ≤ 25 mg / week; º leflunomide ≤ 20 mg / day; º sulfasalazine ≤ 3 g / day; º apremilast ≤ 60 mg / day; º hydroxychloroquine ≤ 400 mg / day; º corticosteroids equivalent to prednisone ≤ 7.5mg / day;º NSAIDs; and º Low potency opioid medications (tramadol or combination formula of paracetamol with codeine or with hydrocodone).

[0173] Use of methotrexate in combination with leflunomide is prohibited. Concomitant medications should be used in alignment with the approved label in the respective country, and per doses permitted per inclusion criteria. Prohibited medications:

[0174] The following medications are prohibited from enrollment through Week 52, unless otherwise specified for rescue therapy or after study drug discontinuation: 1. all other biologic therapies with a potential therapeutic impact on PsA including but not limited to: a. IL-17 receptor inhibitors (e.g., secukinumab, ixekizumab, bimekizumab, brodalumab) – prohibited from enrollment through Safety Follow up or EoS even if study drug is discontinued early; b. biologics with potential for or known association with progressive multifocal leukoencephalopathy (i.e., natalizumab, rituximab, efalizumab); and c. TNFi (e.g., adalimumab, etanercept, infliximab, golimumab). 2. IM or oral gold 3. cytotoxic agents (e.g., cyclophosphamide, D-penicillamine) 4. any other immunomodulatory therapy (e.g., cyclosporine, azathioprine, tacrolimus, IV gamma-globulin, or Prosorba column therapy) 5. JAK inhibitors (e.g., tofacitinib, upadacitinib) 6. other conventional systemic DMARDs (csDMARDs) (other than methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine with stable doses) 7. IA hyaluronic acid injections 8. IA, IM, or IV corticosteroids including adrenocorticotropic hormone. Corticosteroid injections into trigger points, tender points, bursae, or entheses are not permitted unless meeting rescue criteria. 9. other psoriasis treatments not listed above (e.g., any other biological therapies, mycophenolate mofetil, retinoids, fumarates, or phototherapy [e.g., PUVA, UVA, UVB, high potency topical corticosteroids])10. medium or high potency narcotic analgesics (e.g., morphine or morphine-derived medications, fentanyl, hydromorphone, levorphanol, meperidine, methadone, or hydrocodone). Tramadol or combination formula of paracetamol with codeine or with hydrocodone are permitted at stable doses and as rescue therapy. 11. live vaccines (during the study and for 12 weeks following the last dose of study drug) 12. any investigational agents. Table: Study Drug(s) Administered: Izokibep and Placebo Investigational drug Placebo D I kib Pl b i kib e re ). d d s, at d he d m to to er yAbbreviations: EDTA = ethylenediaminetetraacetic acid; IL = interleukin; NaCl = sodium chloride; SC = subcutaneous. Dosage, Administration, and Schedule: Izokibep and Placebo:

[0175] Study drug (izokibep 80 mg Q4W, izokibep 160 mg QW, izokibep 160 mg Q2W or placebo) will be dosed by SC injection. Study drug vials for placebo and izokibep will be visually indistinguishable.

[0176] Study drug doses are fixed and will not be adjusted for individual subjects during the study. Throughout treatment period, 2 SC injections are to be given for each study drug administration. The anatomical sites for administration of study drug are the upper arm, upper thigh, or abdomen.

[0177] At the study site, only authorized investigational site study staff members are to administer study drug. Subjects should be monitored for at least 1 hour after study drug administrations at the following visits: Day 1 / Week 0, Week 1, Week 2, Week 16, Week 17, and Week 18.

[0178] Subjects will be randomized to 1 of 4 dosing groups as follows: º Group 1 (n = 100): placebo QW from Day 1 / Week 0 to Week 15, then izokibep 160 mg QW from Weeks 16 to Week 51. º Group 2 (n = 100): izokibep 160 mg QW from Day 1 / Week 0 to Week 51. º Group 3 (n = 100): izokibep 160 mg Q2W from Day 1 / Week 0 to Week 50, with matching placebo Q2W until Week 51 for the weeks in between izokibep doses to maintain the blind. º Group 4 (n = 25): izokibep 80 mg Q4W from Day 1 / Week 0 to Week 48, with matching placebo QW until Week 51 for the weeks in between izokibep doses to maintain the blind. Preparation, handling, storage, and accountability:

[0179] Appropriate temperature conditions should be maintained during transit for all study drug received, and any discrepancies are reported and resolved before use of the study drug.

[0180] Only subjects randomized in the study may receive study drug. All study drug must be stored prior to dispensing in a secure, environmentally controlled, and monitored (manual or automated) area in accordance with the labeled storage conditions with access limited to the investigator and authorized site staff.

[0181] Further guidance and information for the final disposition of unused study drugs are provided in the Pharmacy Manual. Randomization Subjects will be randomized to the study drug (izokibep QW, izokibep Q2W with alternating Q2W placebo, izokibep Q4W with placebo at other weeks, to maintain the blind or placebo QW) on Day 1 by IXRS system.

[0182] Randomization will be based on a schedule generated by the sponsor or sponsor designee before the start of the study and will be centrally executed using the IXRS system. The subject, site personnel, and sponsor / Contract Research Organization (CRO) study personnel and designees will be blinded to the randomization treatment group assignment (i.e., izokibep or placebo) and matching placebo administered on the weeks in between izokibep doses for the izokibep Q2W and Q4W arms will be used to blind the dosing schedule (QW or Q2W or Q4W). The randomization dates are to be documented in the subject’s medical record.

[0183] Randomization will be stratified by any prior treatment with a systemic TNFi (Yes / No) and enthesitis (LEI > 0 / LEI = 0).

[0184] Izokibep and matching placebo will be visually indistinguishable to prevent unblinding during preparation or administration of study material.

[0185] Discontinuation: In rare instances, it may be necessary for a subject to permanently discontinue study drug. The reason for permanent discontinuation of study drug will be documented. If study drug is permanently discontinued, the subject will be encouraged to remain in the study to be evaluated for safety and efficacy. Subjects should continue to complete study assessments, where possible, with the exception of study drug administration. Reasons for removal from study drug include any of the following: º subject request º death º lost to follow-up º termination of study by sponsor º emergency unblinding º liver chemistry stopping criteria º serious infections º the subject becomes pregnant while on study drugº malignancy º subject develops CTCAE v5.0 grade 3 or higher SAE or AE(s) that is considered by the º investigator to be related to study drug º subject develops an illness that, in the opinion of the Investigator, would interfere with his or her continued participation, if the risk of continuing with study drug outweighs the potential benefit º subject uses prohibited concomitant medications that may present a risk to the safety of the subject in the opinion of the Investigator or the Medical Monitor º subject is non-compliant with TB prophylaxis (if applicable) or develops active TB at any time during the study º subject is significantly non-compliant with study procedures which would put the subject at risk for continued participation in the trial as determined by the Investigator or Medical Monitor º subjects with disease progression or not responding to treatment are to be withdrawn from study drug treatment based on Investigator's discretion º Starting at Week 24, subjects who have not met clinical Disease Activity for PsA (cDAPSA) low disease activity (cDAPSA ≤ 14) at 2 consecutive visits (e.g. at Week 20 and Week 24) will be discontinued from study drug and can receive standard of care treatment as deemed appropriate by the Investigator.

[0186] Subjects with newly diagnosed IBD during the study must: discontinue study drug and be followed-up until resolution of active IBD symptoms and be referred, as appropriate, to a health care professional treating IBD, such as a gastroenterologist.

[0187] If the subject has a clinical laboratory value meeting any of the following criteria, study drug must be interrupted. The laboratory test must be repeated in 1 to 2 weeks at a scheduled or unscheduled visit. The option to restart study drug after interruption, if felt warranted by the Investigator, should be discussed with, and cannot be implemented, before agreement from the Medical Monitor: º neutrophil count < 1.0 × 109 / L º platelets < 50,000 / mm3º hemoglobin < 8.5 g / dL with decrease of at least 2 g / dL from Baseline º creatinine > 2 × Baselineº any other laboratory abnormality that in the Investigator’s judgement could indicate a medical condition that puts the subject’s safety at risk and that cannot be readily treated (e.g., hyperkalemia)

[0188] Liver-Chemistry Shopping Criteria: Discontinuation of study drug for abnormal liver tests is required by the investigator when a subject meets 1 of the conditions outlined in the algorithm or in the presence of abnormal liver chemistries not meeting protocol-specified stopping rules if the investigator believes that it is in the best interest of the subject. Study-discontinuation / withdrawal from the study:

[0189] Reasons for removal of a subject from the study are: º termination of study by sponsor º death º withdrawal of consent from study º lost to follow-up

[0190] Withdrawal of consent from study - A subject may withdraw from the study at any time without jeopardizing subsequent medical care. At the time of discontinuing from the study, if possible, an early discontinuation visit should be conducted for data to be collected at the time of study discontinuation and follow-up and for any further evaluations that need to be completed.

[0191] The subject will be permanently discontinued from the study drug and the study at that time. If the subject withdraws consent for disclosure of future information, the sponsor may retain and continue to use any data collected before such a withdrawal of consent. Lost to follow-up: A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits and is unable to be contacted by the study site. Study Assessments and Procedures American College of Rheumatology Response Criteria:

[0192] The ACR criteria are standard criteria to measure the effectiveness of various arthritis medications or treatments in clinical trials. The ACR criteria were developed for rheumatoid arthritis but now are also frequently used for primary outcome measure in PsA clinical trials (American College of Rheumatology, 2019).

[0193] The ACR criteria are reported as percentage (%) improvement, comparing disease activity at 2 discrete timepoints (baseline and postbaseline comparison). The ACR criteria are indicated as:º ACR20 is ≥ 20% improvement º ACR50 is ≥ 50% improvement; ACR50 responders include ACR20 responders º ACR 70% (ACR70) is ≥ 70% improvement; ACR70 responders include ACR20 and ACR50 responders

[0194] The ACR20 criteria require that the subject experiences an improvement in the following parameters compared to baseline: º ≥ 20% reduction in TJC68 º ≥ 20% reduction in SJC66 º ≥ 20% reduction in 3 of 5 additional measures: º Subject’s Assessment of Pain º Subject’s Global Assessment of Disease Activity º Investigator’s Global Assessment of Disease Activity º HAQ-DI º Acute phase reactant (C-reactive protein [CRP]).

[0195] Analyses of ACR50 and ACR70 include the same criteria as ACR20, with the use of a higher percentage improvement (50% and 70%, respectively) instead of 20% (European Medicines Agency, 2007).

[0196] The proportion of subjects achieving ACR20, ACR50, and ACR70 will be evaluated at Week 16. Disease Activity Score in 28 Joints:

[0197] The Disease Activity Score in 28 joints (DAS28)-CRP was developed to measure disease activity in subjects with rheumatoid arthritis. It is a composite score derived from the following measures (Mease, 2011): º 28 tender joint count º 28 swollen joint count º CRP º Subject’s Global Health Assessment (corresponds to Subject’s Global Assessment of Disease Activity)

[0198] Generally, remission is considered achieved if the score is between 0 and < 2.6. Low activity corresponds to 2.6 to < 3.2. Moderate activity is between 3.2 and ≤ 5.1, while high activity is strictly above 5.1.

[0199] Change in DAS28-CRP composite score will be evaluated at Week 16. Disease Activity in Psoriatic Arthritis:

[0200] The Disease Activity in Psoriatic Arthritis (DAPSA) is a composite score calculated by summing the following variables (Mease, 2011): º 68 tender joint count º 66 swollen joint count º Subject’s Assessment of Pain º Subject’s Global Assessment of Disease Activity º CRP level in mg / dL. Change in DAPSA and clinical DAPSA (cDAPSA); sum of the above variables, but omitting CRP) composite scores will be evaluated at Week 16. Proportion achieving DAPSA and cDAPSA low disease activity (DAPSA / cDAPSA ≤ 14) and remission (DAPSA / cDAPSA ≤ 4) will be evaluated starting at Week 16. Psoriatic Arthritis Disease Activity Score:

[0201] The Psoriatic Disease Activity Score (PASDAS) is a weighted index comprising the following assessments: º 68 tender joint count º 66 swollen joint count º Subject’s Global Assessment of Disease Activity º Investigator’s Global Assessment of Disease Activity º 36-Item Short Form Survey (SF-36) º Leeds Enthesitis Index º Leeds Dactylitis Index º CRP level in mg / dL.

[0202] The score range of the PASDAS is 0 to 10, with worse disease activity represented by higher scores. Change in PASDAS index will be evaluated at Week 16. Minimal Disease Activity and Very Low Disease Activity

[0203] The criteria for MDA were developed for rheumatoid arthritis, but a PsA-specific definition of MDA has been constructed (Coates et al, 2010). These criteria were validated and are now considered as a step towards “treatment to target” in PsA, i.e., the goal of achieving remission or low disease activity state (Coates et al, 2010; Mease, 2011).

[0204] A subject is classified as in MDA when 5 of the following 7 criteria are met (Mease, 2011): º 68 tender joint count ≤ 1 º 66 swollen joint count ≤ 1 º PASI ≤ 1 or BSA ≤ 3% º Subject’s Pain Assessment (visual analogue scale [VAS]) ≤ 15 mm º Subject’s Global Activity VAS ≤ 20 mm (corresponds to Subject’s Global Assessment of Disease Activity) º HAQ-DI ≤ 0.5 º Tender entheseal points ≤ 1 site out of 6 sites included in LEI.

[0205] A subject is classified as in very low disease activity (VLDA) when all 7 criteria described above are met.

[0206] The proportion of subjects achieving MDA and VLDA will be evaluated at Week 16. Subject’s Global Impression of Change:

[0207] Subjects will complete a global impression of change questionnaire at the designated study visits.

[0208] The questionnaire consists of 1 self-administered item that assesses change in disease activity. Subjects will be asked to indicate their impression of change compared with start of treatment. Subject’s Global Assessment of Disease Activity:

[0209] Subject’s global health assessment will be evaluated at the designated study visits using a VAS.

[0210] The VAS is a horizontal line, 100 mm in length, with anchor statements on the left (0 mm) and on the right (100 mm). The subject will be asked to place a single vertical line through the VAS at the point that best corresponds to their feeling of disease activity.

[0211] The score is obtained by measuring the distance from 0 to the line drawn by the subject. Subject’s Assessment of Pain (VAS)

[0212] Pain will be assessed by the subject at the designated study visits using a VAS.

[0213] The VAS is a horizontal line, 100 mm in length, with anchor statements on the left (0 mm) and on the right (100 mm). The subject will be asked to place a single vertical line through the VAS at the point that best corresponds to their feeling of pain.

[0214] The score is obtained by measuring the distance from 0 to the line drawn by the subject. Subject’s Assessment of Spinal Pain (NRS)

[0215] Spinal pain will be assessed by the subject at the designated study visits using a numeric rating scale (NRS).

[0216] The subject will be asked to circle the number between 0 and 10 that fits best to their spinal pain intensity, with “0” indicating “no pain” and 10 indicating “worst imaginable pain”. Widespread Pain Index

[0217] The Widespread Pain Index (WPI) is a self-report measure used to assess bodily distribution of pain and to specifically quantify the degree of widespread body pain and assess for centralized pain features. The WPI assesses the presence of pain in 19 designated body locations over the past 7 days (e.g., neck, right upper arm, left lower leg). Each location is equal to a score of 1. Items are summed to yield a total score, with higher scores indicating greater widespread pain (Dudeney et al, 2019).

[0218] The WPI will be presented in local language and is to be completed by the subject at the designated study visits. Health Assessment Questionnaire – Disability Index

[0219] The HAQ-DI questionnaire is a patient-reported outcome that is self-administered by the subject. It covers 8 sections: dressing, arising, eating, walking, hygiene, reach, grip, and activities.

[0220] The HAQ-DI will be presented in local language and is to be completed by the subject at the designated study visits. Psoriatic Arthritis Impact of Disease

[0221] The PsAID is a questionnaire developed by EULAR to assess the subject’s physical and psychological domains related to PsA. The questionnaire used in clinical trials consists of 9 questions (PsAID-9; Gossec et al, 2014).

[0222] The PsAID-9 score gives a number between 0 and 10. A higher score on the PsAID-9 indicates more impact of the disease. A score below 4 out of 10 is considered a patient-acceptable status. A change of 3 or more points is considered a relevant absolute change.

[0223] The PsAID-9 questionnaire will be presented in local language and is to be completed by the subject at the designated study visits.

[0224] The subject should complete the questionnaire before site personnel perform any clinic assessments and before any interaction with the site personnel has occurred to avoid biasing the subject’s response. Short Form-36

[0225] The acute Short Form-36v2 Health Survey (SF-36) is 36-item questionnaire that measures 8 dimensions related to functioning and well being including physical functioning, role-function, bodily pain, general health, vitality, social functioning, role-emotional, and mental health.

[0226] The SF-36 questionnaire will be presented in local language and is to be completed by the subject at the designated study visits.

[0227] The subject should complete the questionnaire before site personnel perform any clinic assessments and before any interaction with the site personnel has occurred to avoid biasing the subject’s response. Functional Assessment of Chronic Illness Therapy-Fatigue

[0228] The FACIT measurement system was originally developed to assess health-related quality of life in subjects with chronic illnesses. The additional questions of the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) survey were compiled to assess anemia-related fatigue (Mease, 2011).

[0229] The FACIT-F comprises 13 items in total and each item is answered based on a 5-point Likert scale. Responses of “not at all”, “a little bit”, “somewhat”, “quite a bit”, and “very much” are available for each question, and correspond to scores of 0, 1, 2, 3, and 4, respectively.

[0230] The FACIT-F questionnaire will be presented in local language and is to be completed by the subject at the designated study visits. Joint Assessments

[0231] Joints are palpated for the purpose of determining if they are tender and / or swollen, the latter implying the presence of active synovitis, and both implying the presence of inflammation (Mease, 2011).

[0232] Joint assessment will be performed at the designated study visits for 68 tender and 66 swollen joint count. The tender and swollen joint counts will be used to determine the response (ACR) and disease activity (DAS28-CRP, DAPSA, PASDAS, MDA, and VLDA).

[0233] The table below shows an overview of the joints assessed for tenderness and swelling (Sokka and Pincus, 2005), and of which joint counts will be used for each composite measure.

[0234] A rule of thumb is to apply approximately 4 kg / cm2of pressure (enough to blanch the tip of the examiner’s fingernail) at the joint line (Mease, 2011). To ensure the most accurate assessment of change, the joint counts should be undertaken by the same person in each individual subject where possible.

[0235] If corticosteroids were injected into joints or enthesitis sites as rescue medication, these joints need to be considered as “not assessable” for the following 12 weeks.

[0236] Documentation of the total number of tender joints and total number of swollen joints will be done on a joint count worksheet. Table: Tender and Swollen Joint Counts ACR / DAPSA / PASDAS / DAS28 MDA / VLDA n tPIP joints I-V (toes) 10 joints 10 joints 10 joints 10 oints Abbreviations: ACR = American College of Rheumatology; DAPSA = Disease Activity inL = left; MCP = metacarpophalangeal; MDA = Minimal Disease Activity; MTP = metatarsophalangeal; PASDAS = Psoriatic Disease Activity Score; PIP = proximal interphalangeal; R = right; VLDA = very low disease activity. Global Assessment of Disease Activity

[0237] Global health assessment related to subject’s disease activity will be evaluated at the designated study visits using VAS.

[0238] The VAS is a horizontal line, 100 mm in length, with anchor statements on the left (0 mm) and on the right (100 mm).

[0239] The score is obtained by measuring the distance from 0 to the line drawn by the investigator. Psoriasis Area and Severity Index and Affected Body Surface Area

[0240] Psoriasis Area and Severity Index is an index used to express the severity of psoriasis. Because its performance characteristics are diminished in subjects with low lesional burden, it is not typically calculated in subjects with < 3% BSA involvement with psoriasis lesions (Mease, 2011).

[0241] After start of treatment, PASI will only be assessed if psoriasis affects > 3% of subject’s BSA at baseline. The BSA assessment measures the total area of the body affected by psoriasis.

[0242] Psoriasis Area and Severity Index evaluates the severity of erythema, induration, and desquamation in 4 body sections (head, arms, trunk, and legs).

[0243] Psoriasis Area and Severity Index and affected BSA will be assessed at the designated study visits. Modified Nail Psoriasis Severity Index

[0244] The Nail Psoriasis Severity Index is a numeric, reproducible, objective, simple tool for evaluation of nail psoriasis (Rich and Scher, 2003). Nail bed psoriasis includes onycholysis, splinter hemorrhages, hyperkeratosis, and “oil-drop change”, while nail matrix psoriasis includes pitting, leukonychia, lunular red spots, and nail plate crumbling (Mease, 2011).

[0245] A modification of this system, the modified Nail Psoriasis Severity Index (mNAPSI), is a shorter and more feasible scoring system that has demonstrated excellent interrater reliability andhas been used in PsA clinical trials (Mease, 2011; Cassell et al, 2007). For each fingernail, 7 groups of features are evaluated: pitting, onycholysis and oil-drop dyschromia, nail plate crumbling, leukonychia, splinter hemorrhages, hyperkeratosis, and red spots in the lunula. Pitting, onycholysis and oil-drop dyschromia, and crumbling (including fragmentation and horizontal ridging of the nail bed) are graded from 0 to 3 in severity. Leukonychia, splinter hemorrhages, hyperkeratosis, and red spots in the lunula are graded as either present or absent.

[0246] An mNAPSI will be calculated at the designated study visits. Leeds Enthesitis Index and Spondyloarthritis Research Consortium of Canada Enthesitis Index

[0247] The LEI and the Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index are both used to assess enthesitis in subjects with PsA. The LEI assesses 6 entheseal sites, while the SPARCC Enthesitis Index assesses enthesitis at 16 anatomical sites (see Table below). Tenderness on examination will be recorded as either present (1) or absent (0) for each of the sites, for an overall score range of 0 to 6 (LEI) and 0 to 16 (SPARCC Enthesitis Index). Higher count represents greater enthesitis burden (Mease, 2011).

[0248] If corticosteroids were injected into enthesitis sites or joints as rescue medication, these joints need to be considered as “not assessable” for the following 12 weeks. Table: Entheseal sites assessed for enthesitis according to SPARCC and LEI SPARCC LEI s)Research Consortium of Canada. Leeds Dactylitis Index

[0249] Using the Leeds Dactylitis Index, one can quantify the size and tenderness of a swollen digit, enabling differentiation between tender and nontender dactylitis. Each of 20 digits (ie, all fingers and toes) will be evaluated for size (circumference close to the base measured in millimeter) and tenderness. For use in clinical trials, circumferences of the affected and contralateral digits are measured using a measuring tape or a precalibrated loop. The circumference of the affected digits, circumference of contralateral digits, and tenderness of affected fingers are all assessed for a total score (Mease, 2011; Kaeley et al, 2018).

[0250] The presence or absence of tenderness at 20 digits and the circumference of each digit will be assessed and documented by the investigator at the designated study visits.

[0251] Adverse Events, Serious Adverse Events, and Other Safety Reporting: The definitions of AEs and SAEs is included below. Adverse events will be reported by the subject (or, when appropriate, by a care giver).

[0252] Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event Information: All SAEs will be collected from the signing of the ICF until the 8-week follow-up visit(s). All AEs will be collected from the first dose of study drug until the 4 weeks after the last dose of study drug. Medical occurrences that begin before the start of study drug but after obtaining informed consent will be recorded as medical history / current medical conditions, not as AEs. All SAEs will be recorded and reported to the sponsor or designee immediately and under no circumstance should this exceed 24 hours from the knowledge of the event.

[0253] Method of Detecting Adverse Events and Serious Adverse Events - Care will be taken not to introduce bias when detecting AEs and / or SAEs. Open-ended and nonleading verbal questioning of the subject is the preferred method to inquire about AE occurrences.

[0254] Follow-up of Adverse Events and Serious Adverse Events: After the initial AE / SAE report, proactive follow up with each subject at subsequent visits / contacts should be conducted. All SAEs and AEs of special interest will be followed until resolution, stabilization, the event is otherwise explained, or the subject is lost to follow-up. Events of Special Interest

[0255] Based on the class effects or potential risks with IL-17 inhibitors, the following events of special interest (preferred term) will be monitored: ^ Candida infection; and ^ Inflammatory bowel disease.

[0256] In addition, based on the potential risk with an IL-17 receptor inhibitor the following events of special interest will also be monitored: º suicidal ideation; º malignancies; º major cardiovascular and cerebrovascular events; º TB; º infections (including opportunistic infections and serious infections); º cytopenias; and º hypersensitivity reactions.

[0257] Adverse Events and Serious Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting Definition of Adverse Events AE Definition º d º alEvents Meeting the AE Definition º r ºDefinition of SAERecording and Follow-up of Adverse Event and / or Serious Adverse Event AE and SAE RecordingAssessment of Causality he ng ed le or s, ed al ry reExample 1: Improvement in Patient-Reported Outcomes in Patients With Active Psoriatic Arthritis up to Week 46 – Phase 2 RCT Results Methods:

[0258] This randomized controlled trial evaluated izokibep 80 or 40 mg every 2 weeks (Q2W) to 46 weeks / study termination in patients with active PsA. The original placebo arm switched to izokibep 80 mg Q2W at week 16. Patient -reported outcome (PRO) endpoints included: º Psoriatic Arthritis Impact of Disease (PsAIDPsAID)-9, º Health Assessment Questionnaire Disability Index (HAQ HAQ-DI), º 36 -item Short Short-Form Health Survey (SF SF-36), º Treatment Satisfaction Questionnaire of Medicine (TSQM TSQM-9), and single items for pain, itch, º and patient global assessment of disease activity.

[0259] The analyses was conducted for up to 46 weeks.

[0260] Patients: Overall, 135 patients were randomized and treated at 28 European sites from June 2020 to Dec. 2022, outlined in FIG. 9. After the study, 96 / 102 (94%) and 59 / 62 (95%) patients had evaluable data at weeks 32 and 46, respectively.

[0261] Safety: The data demonstrated that izokibep was generally well tolerated at both 40- and 80 mg doses. Apart from predominantly mild injection-site reactions / erythema, there were no significant differences in the rates of treatment-emergent adverse events between active treatment groups and placebo.

[0262] No dose-related effects were identified in the trials. Results

[0263] The data from the Phase 2 study through week 46 is provided in FIG.10A and FIG.10B. FIG.10A provides the results from the global assessment of disease activity and the average itch NRS score. FIG.10B provides pain assessment score and percentage of patients with pain VAS < 30. The FAS, observed means by visit for global assessment of disease activity, itch, and pain. FAS, observed data in pain VAS <30 post -hoc analysis. Exploratory endpoints: Patient Patient- reported outcomes at week 16, 32 and 46. * P<0.025. P<0.001. For global assessment of disease activity, itch, and pain: 0=none and 100 / 10=very poor / worst.

[0264] FIG.11 provides SF-36 scores through week 46 for patients receiving izokibep.

[0265] As evident from the results provided in FIG. 10A, FIG. 10B, and FIG. 11, patient- perceived disease activity and symptoms decreased with izokibep, with clear differentiation from placebo at week 16. Itch and pain reduction were maintained on izokibep treatment through 46 weeks, with an observed dose response. Indeed, more than 70% of patients achieved marked pain control in izokibep 80 mg at week 46.

[0266] The SF-36 scores provided in FIG.11 demonstrate that health-related QoL improved with izokibep (as compared to placebo) at week 16, and subsequently the benefit was maintained through week 46.

[0267] HAQ-DI also improved from the baseline. HAQ-DI ≥ 0.35, the minimal clinically important difference, was achieved in most patients receiving izokibep treatment.

[0268] The results provided in FIG.12 also demonstrate consistent-dose dependent improvements across all PsAID-9 subdomains. These were evident with izokibep at weeks 16 and 46, with the largest effects observed for pain, fatigue, functional capacity, and skin problems.

[0269] The results provided in FIG. 13 also demonstrate that treatment satisfaction (TSQM-9) was higher among patients receiving izokibep (as compared to patients receiving placebo) at week 16 and maintained through week 46.

[0270] Thus, as evident from the results provided above, izokibep demonstrated clinically meaningful, dose-dependent continuing improvements to 46 weeks across all studied PROs in patients with active PsA.

[0271] Moreover, these results demonstrate that the ongoing Phase 2b / 3 PsA study explores higher doses to maximize the potential benefits of izokibep for treatment and / or relief of symptoms associated with PsA.

[0272] Example 2: Izokibep Demonstrates Major Disease Control on ACR70, PASI100 and Enthesitis Resolution in Patients With Active Psoriatic Arthritis Treated Through 46 Weeks

[0273] The trial design for the double-blind, randomized, placebo-controlled Phase 2 study of izokibep is provided in FIG.14. The screening / eligibility criteria includes: º Moderate active PSA º ≥ 3 TJC68 and ≥ 3 SJC66 º Previous failure of NSAID or csDMARD or TNFi º One concomitant csDMARD allowed º Prior anti–IL-17 exposure excluded

[0274] The treatment was stratified by concomitant csDMARD use, previous TNFi exposure, and country.

[0275] Highlighted Endpoints for the trial: Efficacy: • Primary: ACR50 at weeks 12 and 16 (izokibep 80 mg vs placebo) • ACR70 • Minimal Disease Activity • PASI100 • DAPSA Low Disease Activity • Enthesitis LEI / SPARCC Resolution Safety: º TEAEs; º Other AEs of interest, º Laboratory assessment; º Vital signs; and º Physical examination

[0276] Details for patients in the trial are summarized in FIG.15.

[0277] The patients who were excluded at screening prior to start of the trial included patients that were excluded due to positive rheumatoid factor, positive anti-CCP antibody, and due to positive tuberculosis test.

[0278] As noted in FIG.15, in the placebo cohort, 1 patient discontinued treatment prior to week 16, and 22 patients discontinued treatment after week 16, but prior to week 46; in the izokibep 40 mg cohort, 2 patients discontinued treatment prior to week 16, and 25 patients discontinued treatment after week 16 but prior to week 46; and in the izokibep 80 mg cohort, 1 patient discontinued treatment prior to week 16, and 25 patients discontinued treatment after week 16, but prior to week 46.

[0279] Premature termination of trial affected approximately up to 75 of 135 randomized subjects.

[0280] FIG.16 provides the demographics and baseline characteristics of patients enrolled in the trial:

[0281] The data provided in FIG.17 demonstrates that ACR50 responses showed early separation and were further improved with izokibep 80 mg doses through week 46. The data provided demonstrates that large majority of patients achieved ACR50 response at week 46 for patients receiving 80 mg izokibep. * in FIG.17 indicates that p < 0.05 and ** indicates p < 0.001. The datafor weeks 1-16 is modeled by non-responder imputation (NRI). The data for weeks 16-46 is observed data. The table below further provides the ACR50 data for patients receiving izokibep.

[0282] The data provided in FIG.18 demonstrates that ACR70 response improved further from Week 16 to Week 46 on izokibep 80-mg doses. The data provided demonstrates that large majority of patients achieved ACR50 response at week 46 for patients receiving 80 mg izokibep. * in FIG. 18 indicates that p < 0.05 and ** indicates p < 0.001. The data for weeks 1-16 is modeled by non- responder imputation (NRI). The data for weeks 16-46 is observed data.

[0283] The data provided in FIG. 19A and FIG. 19B demonstrates that patients receiving izokibep have improved MDA and DAPSA LDA from week 16 to week 46. The data provided in FIG.19B provides DAPSA LDA for patients achieving score of ≤ 14. * in FIG.19A indicates that p < 0.05.

[0284] The data provided in FIG. 20 includes skin clearance (PASI1000) data. The provided in FIG.20 demonstrates that skin clearance, as measured by PASI100, improved further from week 16 to week 46 on izokibep 80-mg doses. Over 70% patients receiving 80 mg izokibep had PASI100 at week 46. * in FIG.20 indicates that p < 0.05.

[0285] FIG.21A provides high LEI enthesitis resolution data and FIG. 21B provides SPARCC enthesitis resolution. As maintained in the data demonstrated by high LEI enthesitis resolution at week 16 was maintained through week 46 and the SPARCC enthesitis resolution improved through week 46.

[0286] FIG.22A and FIG.22B provides the data for clinically meaningful reduction in disease burden and improvements in physical function to week 46. The data provided in FIG.22A (PsAID - data) and FIG.22B (HAQ-DI) data demonstrate that patients receiving izokibep have clinically meaningful reductions in disease burden and improvements in physical functions through week 46.

[0287] FIG.23 provides the safety data from week 16 to week 46. As demonstrated in the data in FIG.23, there is no material change in safety data from week 16 and week 46 for patients receiving izokibep. Indeed, the data demonstrates that there were no important differences across dosage groups compared to placebo except for injection site reactions. Even for the injection site reactions, there was a clear reduction observed for number of reactions in week 16 to week 46, as compared to the injection site reactions from week 1 to week 16. The data further demonstrates that the safety profile of izokibep is consistent with other approved IL17 inhibitors. There were no new observed onset or flare of IBD.

[0288] The data from the trials demonstrates that izokibep has high levels of disease control across multiple domains. In particular, izokibep 80 mg dose has high levels of disease control across multiple domains.

[0289] The outcomes improved significantly over from week 16 to week 46 on izokibep 80-mg dose. At week 46: º >75% achieved ACR50 º >50% achieved ACR70 º >50% achieved MDA º >60% achieved DAPSA Low Disease Activity º PASI100 (skin clearance) achieved by >70% of patients at week 46 º The data demonstrates that enthesitis resolution was achieved in most patients. º Early high LEI resolution rate achieved by ≥80% of patients was maintained through week 46. º SPARCC enthesitis resolution rate improved to approximately 70% of patients at week 46

[0290] Clinically meaningful improvements in disease burden (PsAID-9) and physical function (HAQ-DI) were provided by izokibep administered to the patients.

[0291] Finally, izokibep was generally well tolerated, and no new safety concerns were observed during the trials. In particular, no important differences were observed across dosage groups compared to placebo, except for injection site reactions.Example 3: Ongoing Global Izokibep Phase 2b / 3 Clinical Trial in Patients With Active Psoriatic Arthritis Treated Through 24 Weeks

[0292] This example outlines a Phase 2b / 3 clinical trial assessing izokibep in patients with active PsA. The Phase 2b / 3 clinical trial (NCT05623345) is a global, multi center, randomized double- blind, placebo-controlled, trial evaluating the safety and efficacy of izokibep dosed subcutaneously 160 mg every week (QW) or every two weeks (Q2W) and 80 mg every four weeks (Q4W) versus placebo.351 adult patients with active PsA were enrolled across 71 sites in the United States and Europe and randomized across the four arms. Dose sequencing in the 160 mg Q2W and 80 mg Q4W arms was impacted by a third-party programming error. The range of pharmacokinetic data from both the 160 mg QW and Q2W arms in PsA demonstrated comparable exposures to the same dose levels from the Phase 2b HS study.

[0293] The trial design for the double-blind, randomized, placebo-controlled Phase 2b / 3 study of izokibep is provided in Fig.24.

[0294] As explained below, this Phase 2b / 3 clinical trial of izokibep in psoriatic arthritis (PsA) met its primary endpoint of ACR50 at week 16 with high statistical significance. Results from the 160 mg weekly (QW) and every other week (Q2W) arms showed improved magnitude of responses on higher hurdle endpoints such as ACR70, PASI100 and minimal disease activity relative to the Phase 280 mg Q2W dose. This is notable given a higher baseline disease burden in the Phase 2b / 3 trial population, relative to the Phase 2 trial. Izokibep was well-tolerated with a favorable safety profile consistent with previous experience and the IL-17A class, without evidence of the safety liabilities observed with targeting IL-17 more broadly than selectively targeting IL-17A. The trial had a low study discontinuation rate of < 3%. Mild-to-moderate injection site reactions (ISRs) were observed with discontinuations due to ISR < 2%. There were two cases of mild candida – one in the placebo arm and one in the 160 mg QW arm – and no cases of suicidal ideation / behavior.

[0295] Pre-specified analyses continue to support the potential for differentiation in enthesitis resolution. Consistent high magnitude absolute responses were demonstrated in the Phase 2- comparable population (baseline Leeds Enthesitis Index (LEI) 1 or 2) although enthesitis resolution overall was not statistically significant due to high placebo response. Izokibep achieved clinically meaningful resolution in patients with the highest burden of enthesitis (baseline LEI 3- 6) relative to placebo an effect not previously reported by other agents. These positive Phase 2b / 3data reinforce the potential demonstrated in Phase 2 for izokibep to provide meaningful benefit in treating the debilitating signs and symptoms of active psoriatic arthritis in the joints and skin, as well as enthesitis where the results in the most severe patients are encouraging. Observations from the Phase 246-week data that there is no safety limitation to long-term treatment with izokibep and that longer duration of therapy demonstrated the potential for even further improvements over time. The positive PsA results in the phase 2b / 3 study at week 16 and the magnitude of responses provide an indication that the 160 mg Q2W delivers superior clinical responses that are reported with currently-marketed IL-17A agents, and responses comparable to those reported by the only currently-marketed IL-17A / F agent, but without the associated liabilities of the IL-17A / F agent. Notably, further improvement over time in partial week 24 data recorded to date. Across indications, it has been observed that clinically meaningful and potentially differentiated benefits from izokibep. Consistent responses have been seen in high order efficacy measures such as ACR70 and PASI100 in PsA and HiSCR100 in HS that move patients toward disease resolution. This reinforces use of izokibep as an important therapy.

[0296] The screening / eligibility criteria includes: ^ Moderate active PSA assessed using the ClASsification criteria for PsA (CASPAR) ^ > 3 TJC68 and > 3 SJC66 ^ Negative screen results for Rheumatoid Factor and Cyclic Citrullinated Peptide ^ Previous failure of NSAID or csDMARD or TNFi

[0297] Highlighted Endpoints for the trial include: Efficacy (all measured at week 16): • Primary: ACR50 (≥50% improvement based on American College of Rheumatology criteria); • PASI90; • Resolution of enthesitis (Leeds Enthesitis Index [LEI] = 0); • Minimal Disease Activity (MDA); • ACR20 (≥20% improvement based on American College of Rheumatology criteria); • PsAID Response (PsA Impact of Disease); and • Health Assessment Questionnaire Disability Index (HAQ-DI) change from baseline. Safety: ^ TEAEs, events of interest, and SAEs ^ Laboratory values and vital signs at collected time points ^ Treatment-emergent anti-drug antibodies (ADAs)

[0298] As shown in Fig.24, this randomized controlled trial evaluates izokibep 160 mg every 2 weeks (Q2W) for 52 weeks, every week (QW) for 52 weeks, and an arm that received the placebo for 16 weeks followed by izokibep 160 mg (QW) for 36 weeks in patients with active PsA.

[0299] The dispositions of the trial participants are outlined in Fig.25. As shown in Fig.25, there were two patients that discontinued treatment on the Placebo arm, two patients that discontinued treatment on the izokibep 160mg Q2W arm, and six patients that discontinued treatment on the izokibep 160mg QW arm.

[0300] The patients who were excluded at screening prior to start of the trial included patients that were excluded due to positive rheumatoid factor, positive anti-CCP antibody, and due to positive tuberculosis test.

[0301] Fig.26 provides the demographics and baseline characteristics of patients enrolled in the trial.

[0302] As described in Fig.27, all enrolled participants received the correct aggregate amounts of drug and / or placebo. PK samples were collected at every visit and demonstrated: (i) 160mg Q2W PsA PK exposure was comparable to 160mg Q2W HS PK; (ii) 160 mg Q2W PK is much lower than 160 mg QW, as expected, per dose level; and (iii) the low overlap between dose amounts provides confidence in interpretability.

[0303] Figs. 28A-28B provides ACR50 and ACR70 data from the participants at 16 weeks and into week 24 with high statistical significance. Week 16 data are from the full analysis set using prespecified non-responder imputation (NRI). *P<0.05; **P<0.01; ***P<0.0001 (Cochran- Mantel-Haenszel test). Preliminary week 24 partial data shown is an interim cut at time of Primary Endpoint of n=87 participants (vs. n=333 in week 16 dataset); not complete week 24 dataset. As additional participants progress through week 24, these responses will be further assessed.

[0304] As shown in Fig.28A, the study met primary endpoint of ACR50 at 16 weeks with high statistical significance—the registrational endpoint of ACR50 in joints showed rapid and robust improvement. Further, 160mg Q2W appears to be optimal dose for treating PsA with izokibep. As shown in Fig.28B, a significant response was achieved for the high hurdle of ACR70. The ACR70 data demonstrates deeper levels of response that continue to improve over time.

[0305] (2) As observed data after week 16. Preliminary Wk 24 partial data shown is an interim cut at time of Primary Endpoint of n=87 participants (vs. n=333 in Wk 16 dataset); not complete Wk 24 dataset. As additional participants progress through Wk 24, they will be assessed in kind.

[0306] Fig.29 shows ACR70 data for trial participants compared to data from trials for placebo, placebo followed by izokibep or a currently marketed IL-17A or IL-17A / F agent (e.g., bimekizumab), and another IL-17A or IL-17A / F agent alone. As the data indicates, izokibep at the 160 mg dose (QW / Q2W) shows a comparatively strong response in the highest-hurdle, joint response (ACR70) without the safety liabilities of IL-17A / F inhibition.

[0307] Significant responses were also indicated as shown in the PASI90 and PASI100 data (Fig 30), a composite ACR50 and PASI100 score at the primary endpoint (Fig. 31A), and Minimal Disease Activity (Fig.31B). Fig.32 provides data showing LEI data during the course of the study. As shown, izokibep demonstrated resolution despite the high burden of enthesitis in the participants. The data reveals consistent, high magnitude enthesitis responses in the trial participants, which were a comparable population to that of the phase 2 population (Example 2).

[0308] Thus, as shown, significant responses achieved for the high hurdles of ACR70, PASI90, PASI100 and Minimal Disease Activity. Improvement in magnitude of responses relative to Phase 2 notable given higher burden of disease in the Phase 2b / 3 trial participants relative to the prior Examples.

[0309] Fig. 33 provides a summary of safety data from the trial. As shown, izokibep has a favorable safety profile. The most common TEAE included injection site reaction, erythema, and pruritus. Most commonly reported TEAEs occurred in ≥5.0% of patients in any group to week 16.

[0310] In summary, at this interim point, the present study has met the primary endpoint of ACR50 at 16 weeks versus placebo with high statistical significance and shows 160mg Q2W to be an optimal dosing regimen. Significant responses achieved for the high hurdles of ACR70, PASI90 and 100, as well as Minimal Disease Activity. The data also revealed a marked improvement in magnitude of responses relative to Phase 2 notable given higher burden in Phase 2b / 3. Further, higher clinical responses were indicated for izokibep than currently-marketed IL-17A agents, and responses comparable to a currently-marketed IL-17A / F agent without evidence to date for increased risk of infection or suicidal ideation and behavior. Pre-specified analyses continue to support the potential for differentiation in enthesitis resolution. Consistent high magnitude responses in Phase 2-comparable population were also observed although enthesitis resolution overall was not statistically significant due to high placebo response. A resolution of enthesitis achieved in patients with the highest burden, which is an effect not previously reported by other agents. Finally, preliminary week 24 partial data further support continued improvement over timein resolution of key parameters and consistent with Phase 2 trial responses improving through week 46-52. Abbreviations and Definitions Abbreviation DefinitionIncorporation by Reference

[0311] References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, publicly accessible databases, have been made throughout this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Equivalents

[0312] Various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including references to the scientific and patent literature cited herein. The subject matter herein contains important information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.Schedule of ActivitiesAbbreviations: ACR = American College of Rheumatology; ADA = anti‐drug antibodies; AE = adverse  event; anti‐CCP = anti‐cyclic citrullinated peptide; BSA = body surface area; DAS28 = Disease Activity  Score in 28 joints; ECG = electrocardiogram; EOT = end of treatment; FACIT‐F = Functional Assessment of  Chronic Illness Therapy – Fatigue; FU = follow‐up; HADS = Hospital Anxiety and Depression Scale; HAQ‐DI  = Health Assessment Questionnaire – Disability Index; HBcAb = hepatitis B core antibody; HBsAb =  hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus;   HCV = hepatitis C virus; HDL = high‐density lipoprotein; HIV = human immunodeficiency virus;  mNAPSI = modified Nail Psoriasis Severity Index; PASI = Psoriasis Area and Severity Index; PK =  pharmacokinetic; PsA = psoriatic arthritis; PsAID = Psoriatic Arthritis Impact of Disease; SAE =  serious adverse event; SF‐36 = Short Form‐36; SPARCC = Spondyloarthritis Research Consortium of  Canada; TB = tuberculosis; W = week; WOCBP = women of childbearing potential.  a   Visit / dosing windows of ±3 days on either side of the scheduled visits / dosing are permitted. In  case of a delayed or missed dose, the investigator should return subjects on the original visit / dosing  schedule in relation to Day 1 for subsequent doses. The window of ±3 days is relative to Day 1 and  applicable for all subsequent visits / dosing. The minimum of time between doses should be no less than  4 days and no more than 10 days. Subjects do not need to return to the clinical site for dosing on  weeks without study visits noted above if subject / caregiver completes study drug administration at  home. See footnote “r” below.  b  Visit window of ±5 days. For subjects who prematurely discontinue study drug, the End of  Treatment (EOT) visit should be completed within 14 days of withdrawal and follow‐up visits should be  completed at 8 weeks (Safety FU) and 14 weeks (PK & ADA FU) after the last dose of study drug, where  possible. Subjects should continue to complete study assessments as outlined above where possible,  with the exception of study drug administration. Anti‐drug antibody sample and PK sample collection  will not need to be completed if study drug is prematurely discontinued other than at the PK & ADA FU  visit.   c   All subjects who do not achieve cDAPSA low disease activity (cDAPSA <14) for 2 consecutive  visits starting at Week 24 (e.g., at Week 20 and Week 24) will be required to discontinue study drug as  described. Participation in the study should be continued, with EOT visit and assessments as described  herein and in footnote b and n.   d  Vital signs include measurements of temperature, respiratory rate, systolic and diastolic  blood pressure, and pulse. Measurements should be taken in a sitting position after 5 minutes’ rest. e Electrocardiograms in triplicate will be recorded after subject has been supine for at least 5 minutes.  f Chest x‐ray (posterior / anterior or anterior / posterior) will be performed at screening in subjects who  do not have a chest x‐ray available within 3 months of screening. Women of childbearing potential  must have a negative pregnancy test before an x‐ray is performed.  g  Serious adverse events should be recorded from the signing of informed consent through  the Safety Follow‐up visit (i.e., 8 weeks after the last dose of study drug); adverse events will be  recorded from Day 1 (i.e., administration of study drug) until 4 weeks after the last dose of study  drug. h Joint assessment will be performed for ACR66 / 68 and DAS28 joints for swollen and tender  joint counts.  i   Radiographs of hands / wrists / feet will be done on all subjects who discontinue from the study  drug or the study at Week 16 or later and it has been at least 12 weeks from the time the last  radiographs were obtained.  Radiographs should be obtained as close as possible to the EOT date.   j  Hepatitis B surface antigen will be conducted. A positive result for the HBsAg will be  exclusionary. Samples negative for HBsAg will be tested for HBsAb and HBcAb. If test results are  positive for HBcAb or HBsAb, then HBV DNA polymerase chain reaction will be performed and any  result that meets or exceeds detection sensitivity will be exclusionary.  k   QuantiFERON test (or equivalent) for TB will be performed. Note: T‐SPOT testing may be  allowed after consultation with medical monitor.  lSerum pregnancy test required for screening and urine pregnancy test required at all other  times for WOCBP. Local authorities may require more frequent pregnancy testing.  mFecal calprotectin at screening only required if subject has: a) Prolonged or recurrent diarrhea  b) Prolonged or recurrent abdominal pain  c) blood in stool or d) any other symptoms in the opinion of  the Investigator that may be suggestive of IBD  nPharmacokinetic and anti‐drug antibody blood sampling will be taken prior to administration of  study drug (predose) on dosing days. For subjects who prematurely discontinue study treatment for  any reason, follow‐up sampling should be taken at a PK & ADA FU visit 14 weeks after the last dose of  study drug where possible, but do not need to be completed at other timepoints. oSubjects will be monitored at the study site for at least 1 hour after study drug  administrations for the following visits: Day 1 / Week 0, Week 1, Week 2, Week 16, Week 17, and  Week 18. pAfter Week 4, subjects may perform home dosing of study drug at weeks without study visits  (see footnote “a”) and do not need to return to the clinical site on those weeks. Subjects may begin  self‐administration of study drug from Week 5. Subjects will be trained on study drug handling and  self‐administration of study drug at the study visits prior to beginning self‐administration. Subject’s  caregiver or designee can also be trained on home dosing based on subject’s preference. qLast dose of study drug will be administered on Week 51. rA dosing diary will be completed for every home dosing administration. References Izokibep [Investigator’s Brochure]. 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Review: Enthesitis: New insights into pathogenesis, diagnostic modalities, and treatment. Arthritis Rheumatol.2016;68(2):312-322. Langley R, Feldman S, Han C, et al. Ustekinumab significantly improves symptoms of anxiety, depression, and skin-related quality of life in patients with moderate-to-severe psoriasis: Results from a randomized, double-blind, placebo-controlled phase 3 trial. J Am Acad of Dermatol. 2010; 63(3):457-465. Mease PJ. Measures of Psoriatic Arthritis: Tender and Swollen Joint Assessment, Psoriasis Area and Severity Index (PASI), Nail Psoriasis Severity Index (NAPSI), Modified Nail Psoriasis Severity Index (mNAPSI), Mander / Newcastle Enthesitis Index (MEI), Leeds Enthesitis Index (LEI), Spondyloarthritis Research Consortium of Canada (SPARCC), Maastricht Ankylosing Spondylitis Enthesis Score (MASES), Leeds Dactylitis Index (LDI), Patient Global for Psoriatic Arthritis, Dermatology Life Quality Index (DLQI), Psoriatic Arthritis Quality of Life (PsAQOL), Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT‐F), Psoriatic Arthritis Response Criteria (PsARC), Psoriatic Arthritis Joint Activity Index (PsAJAI), Disease Activity in Psoriatic Arthritis (DAPSA), and Composite Psoriatic Disease Activity Index (CPDAI). Arthritis Care & Research.2011;63(11):64-85. Merola JF, Li T, Li WQ, Cho E, Qureshi AA. Prevalence of psoriasis phenotypes among men and women in the USA. 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Claims

Claims:

1. A method of treatment of psoriatic arthritis (PsA) by administration to a patient a composition comprising at least 160 mg of izokibep or a salt thereof.

2. The method of claim 1, wherein the composition comprises 160 mg of izokibep or a salt thereof.

3. The method of claims 1 or 2, wherein the composition is administered once weekly.

4. The method of claims 1 or 2, wherein the composition is administered once in 2 weeks (Q2W).

5. The method of claim 2, wherein the composition comprises 160 mg izokibep and the composition is administered once every two weeks (Q2W).

6. The method of claim 2, wherein the composition comprises 160 mg izokibep and the composition is administered once every week (QW).

7. The method of claims 5 or 6, wherein the composition is administered as an injection.

8. The method of claim 7, wherein the composition is administered as an intravenous (IV) infusion.

9. The method of claim 7, wherein the composition is administered as a subcutaneous injection.

10. The method of claim 7, wherein the composition is administered for at least 16 weeks.

11. The method of claim 7, wherein the composition is administered for at least 50 weeks.

12. The method of claim 7, wherein the composition is administered for at least 46 weeks.

13. The method of claim 7, wherein the administration of the composition results in alleviating of symptoms of psoriatic arthritis (PsA).

14. The method of claim 13, wherein the method results in complete resolution of enthesitis.

15. The method of claim 13, wherein the method results in Psoriasis Area and Severity Index (PASI) score of 100.

16. The method of claim 13, wherein the method results in improvement in tender and swollen joints, along with improvement in three of these five parameters: (a) patient global assessment of disease activity; (b) physician global assessment of disease activity; (c) patient pain scale; (d) disability / functional questionnaire and (e) decreased concentration of C-reactive protein correlated to inflammation.

17. A composition comprising at least 160 mg of izokibep or a salt thereof for use in the treatment of psoriatic arthritis (PsA).

18. A composition for use according to claim 17, wherein the composition comprises 160 mg of izokibep or a salt thereof.

19. A composition for use according to claim 17 or claim 18, wherein the treatment is as defined in any one of claims 3-16.

20. Use of a composition comprising at least 160 mg of izokibep or a salt thereof in the manufacture of a medicament for the treatment of psoriatic arthritis (PsA).

21. Use according to claim 20, wherein the composition comprises 160 mg of izokibep or a salt thereof.

22. Use according to claim 20 or claim 21, wherein the treatment is as defined in any one of claims 3-16.

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