Izokibep for use in a treatment of psoriatic arthritis

Abstract

The invention is related to methods of treatment of active psoriatic arthritis (PsA). In certain embodiments, the invention provides pharmaceutical compositions of izokibep and uses thereof for treatment of active psoriatic arthritis.

Description

[0001] METHODS FOR TREATMENT OF PSORIATIC ARTHRITIS FIELD OF INVENTION

[0002] The invention is related to methods of treatment of active psoriatic arthritis (PsA). The invention provides pharmaceutical compositions and uses thereof for treatment of active psoriatic arthritis.

[0003] BACKGROUND

[0004] Psoriatic arthritis (PsA) is a chronic, systemic, immune-mediated, inflammatory musculoskeletal disease characterised by multidomain manifestations, including peripheral arthritis, psoriasis (PsO), enthesitis, spine involvement, dactylitis and nail abnormalities, with PsA increasing in prevalence with PsO duration.1, 2PsA is associated with a risk of increased mortality due to cardiovascular events and other comorbidities.3, 4PsA appears to be driven by T-cell activation associated with the secretion of proinflammatory cytokines such as interleukin (IL)- 17, tumour necrosis factor (TNF)-a and IL-23.5IL-17A is a critical effector cytokine in PsA that affects different cellular targets within the skin and joints by promoting inflammation, coagulation and structural damage to the osseous, cartilaginous and entheseal elements of the joint, which can lead to pain and reduced physical function.6'8Agents that target proinflammatory cytokines have greatly improved the treatment landscape for PsA, but less than 50% of patients achieve a >50%

[0005] improvement from baseline based on American College of Rheumatology (ACR) criteria (ACR50) response at six months9'13; additionally, remission rates are low and treatment discontinuations due to inadequate response or intolerance are common.14'17Enthesitis, dactylitis and nail disease resolution remain key areas of unmet need.15, 18, 19

[0006] Izokibep is a small protein therapeutic designed to inhibit IL-17A with high affinity (KD 0.3 pM).20Izokibep’s small size (18.6 kDa) has the potential to enhance access to inflamed tissues and may overcome limitations associated with the larger monoclonal antibodies of approximately 150 kDa in size, including poor tissue distribution.20Further, izokibep possesses an albumin-binding domain, which increases its half-life.20The simultaneous binding of izokibep to both subunits of IL-17A enhances its inhibitory capacity when compared with the monomeric precursor or other IL-17A-directed therapies.20Prior studies in PsO, including a phase 2 trial (NCT03591887), have established that izokibep was efficacious and well tolerated for up to three years.21The aim of this study was to evaluate the efficacy and safety of izokibep versus placebo in adults with active PsA.

[0007] SUMMARY OF THE INVENTION

[0008] 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 treating active psoriatic arthritis (PsA) in a patient in need thereof, comprising administrating to the patient a composition comprising a therapeutically effective amount of izokibep, wherein the therapeutically effective amount is about 40 to about 80 mg about every two weeks. In certain embodiments, the methods of the invention provide that the patient has demonstrated an insufficient response to at least one of a nonsteroidal anti-inflammatory drug (NSAID), a conventional synthetic disease-modifying antirheumatic drug (csDMARD), and a tumour necrosis factor inhibitor (TNFi). In certain embodiments, the methods of the invention provide that the patient is rheumatoid factor and anti-cyclic citrull inated peptide antibody negative. In certain embodiments, the methods of the invention provide that the patient has a history of or current plaque psoriasis (PsO). In certain embodiments, the methods of the invention provide that the patient does not have a history of or current autoimmune disease other than PsA or PsO. In certain embodiments, the methods of the invention provide that the therapeutically effective amount is about 40 mg. In certain embodiments, the methods of the invention provide that the therapeutically effective amount is about 80 mg. In certain embodiments, the methods of the invention provide that the izokibep is administered as a subcutaneous injection.

[0009] In certain embodiments, the methods of the invention provide that the izokibep is administered for at least about 16 weeks. In certain embodiments, the methods of the invention provide that the izokibep is administered for at least about 30 weeks. In certain embodiments, the methods of the invention provide that the izokibep is administered for at least about 46 weeks. In certain embodiments, the methods of the invention provide that the method results in alleviation of symptoms of PsA. In certain embodiments, the methods of the invention results in complete resolution of enthesitis. In certain embodiments, the methods of the invention results in complete resolution of dactylitis. In certain embodiments, the methods of the invention results in a Psoriasis Area and Severity Index (PASI) score of 75, wherein the patient had >3% body surface area (BSA) involvement at baseline. In certain embodiments, the methods of the invention results in a Psoriasis Area and Severity Index (PASI) score of 100, wherein the patient had >3% body surface area (BSA) involvement at baseline. In certain embodiments, the methods of the invention results in a Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index score of 0, wherein the patient had a SPARCC score of >0 at baseline. In certain embodiments, the methods of the invention results in a Leeds Enthesitis Index (LEI) score of 0, wherein the patient had an LEI score of >0 at baseline. In certain embodiments, the methods of the invention results in reduction of at least one step, of at least two steps, of at least three steps, of at least four steps, of at least five steps of the Leeds Enthesitis Index (LEI) score wherein the patient had an LEI score of >0 at baseline. In certain embodiments, the methods of the invention result in at least 50%, at least 60%, at least 70%, at least 80% at least 90% reduction of the Leed’s Dactylitis Index-Basic (LDI-B) score wherein the patient had an LDI-B score of >0 at baseline. In certain embodiments, the methods of the invention results in a Leed’s Dactylitis Index-Basic (LDI-B) score of 0, wherein the patient had an LDI-B score of >0 at baseline. In certain embodiments, the methods of the invention results in a Nail Psoriasis Severity Index (NAPSI) score of 0 for a target nail specified at baseline. In certain embodiments, the methods of the invention results in improvement in tender and swollen joints, along with improvement in at least three of the following 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.

[0010] In a related aspect, the invention also provides a pharmaceutical composition for use in the treatment of active psoriatic arthritis (PsA), wherein the composition comprises about 80 mg / mL of izokibep, and wherein the composition is formulated as a solution for injection.

[0011] In another related aspect, the invention provides use of a pharmaceutical composition, comprising about 80 mg / mL of izokibep formulated as a solution for injection, in the manufacture of a medicament for the treatment of active psoriatic arthritis (PsA). In a certain embodiment, the invention provides use of a pharmaceutical composition comprising 80 mg / mL of izokibep. In a certain embodiment, the invention provides use of a pharmaceutical composition comprising about 80 mg / mL of izokibep or comprising 80 mg / mL of izokibep, and wherein the treatment is as described herein. STUDY OVERVIEW

[0012] Objectives To evaluate the efficacy and safety of izokibep, a small protein therapeutic designed to inhibit interleukin- 17A, in patients with active psoriatic arthritis (PsA) over 46 weeks.

[0013] Methods This phase 2, multicentre, placebo-controlled RCT randomised adult patients with active PsA 1:1:1 to izokibep 40mg, izokibep 80mg or placebo every two weeks for 16 weeks; placebo-treated patients then switched to izokibep 80mg. The primary endpoint was ACR50 at week 16 for izokibep 80mg versus placebo. Additional efficacy endpoints and treatment-emergent adverse events (TEAEs) were evaluated to 16 weeks (placebo-controlled) and then to 46 weeks.

[0014] Results Of 172 patients screened, 135 were randomised to izokibep 40mg (n=44), izokibep 80mg (n=47) or placebo (n=44). ACR50 response rates modelled and controlling for covariates were significantly higher for izokibep 80mg versus placebo at week 16 (52% versus 13%; two- sided p=0.0006) and week 12 (50% versus 6%; pO. OOOl); lower rates were observed for izokibep 40mg (48% and 43% for weeks 16 and 12, respectively). Additional analyses of joints, psoriasis, enthesitis, dactylitis and quality of life outcomes supported the efficacy of izokibep. Continued improvement to week 46 was shown for the 80mg doses. TEAE rates were generally similar across treatment groups except for injection site reactions.

[0015] Conclusions Izokibep resulted in clinically meaningful improvements over placebo across all disease domains and the 80mg dose showed continued improvements to week 46. There were no unexpected safety risks identified. Izokibep’s small size and high potency have the potential for further improved disease control justifying additional investigation of higher doses.

[0016] Trial registration number NCT04713072; ClinicalTrials.gov identifier METHODS

[0017] Study design

[0018] This phase 2, multicentre, randomised, double-blind, placebo-controlled, parallel-group study at 28 European clinical sites (Austria, Belgium, Czech Republic, Germany, Hungary, Poland and Spain) recruited adult patients with active PsA. The trial was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Guidance for Good Clinical Practice. Ethics approval was obtained from national and site-specific independent ethics committees at participating sites and all patients provided written consent.

[0019] The study included a screening period of up to four weeks, a 16-week, placebo-controlled, double-blind treatment period, a subsequent 28-week treatment period in which patients in the placebo arm were switched to active treatment (izokibep 80 mg every two weeks [Q2W]) and an end of treatment visit scheduled two weeks after the last dosing (week 46; supplemental figure SI); blinding with respect to doses was maintained during the entire 46-week study period. An interactive web response system, overseen by an unblinded team member, was used for randomisation of eligible patients to treatment at baseline, using 1:1:1 randomisation to one of three parallel treatment groups: izokibep 40 mg, izokibep 80 mg and placebo, stratified by concomitant conventional synthetic disease-modifying antirheumatic drug (csDMARD) use (yes / no), previous TNF inhibitor (TNFi) exposure (yes / no) and country. Doses of izokibep and placebo were prepared and injected by an independent, unblinded, authorised member of the site team to maintain the blinding of study patients, the site personnel caring for the patient and the sponsor. Unblinding was allowed only in case of a medical emergency to treat a patient’s adverse event (AE) and done in consultation with the medical monitor. Izokibep (40 mg as a 0.5-mL injection or 80 mg as a 1-mL injection) and placebo (0.9% saline solution in a single-use vial) were administered as subcutaneous injections at clinical study sites at baseline and subsequently Q2W. Safety was assessed at every study visit. Efficacy outcomes were assessed at baseline and every four weeks (Q4W), with additional assessments at weeks 2, 18 and 46 (end of treatment visit).

[0020] There were two major amendments to the initial protocol. Amendment 1 allowed patients to continue treatment Q2W after week 16 instead of switching to treatment Q4W as originally planned. Amendment 2 established premature termination of treatment following the completion of all patients through the 16-week placebo-controlled period and was undertaken to allow acceleration of further dose-ranging studies with izokibep in PsA.

[0021] Patients

[0022] Patients aged 18 to 75 years who met the Classification criteria for Psoriatic Arthritis (CASPAR), had active PsA (>3 tender [of 68] and >3 swollen [of 66] joints) and had an insufficient response to nonsteroidal anti-inflammatory drugs (NSAIDs), csDMARDs or TNFi were enrolled. Patients were required to have a history of or current plaque PsO. Patients with a history of or current relevant immune-mediated diseases other than PsO or PsA (including uncontrolled inflammatory bowel disease [IBD]) and those having previous exposure to any IL- 17 / IL-l 7 receptor inhibitors were excluded. Full inclusion and exclusion criteria are provided in the supplemental methods (section SI). During the study, patients were allowed to continue stable use of one csDMARD and oral glucocorticoid up to 7.5 mg of a prednisolone equivalent and use of NSAIDs as needed. Other systemic PsA or any PsO therapies, except for topical mild glucocorticoids in selected areas, were not allowed. Outcomes

[0023] The primary endpoint was the percentage of patients achieving an ACR50 response at week 16 versus placebo. Other ranked endpoints in hierarchical order were ACR50 response at week 12, followed by >20% improvement (ACR20) and >70% improvement (ACR70) in ACR criteria at week 16, ACR20 and ACR70 at week 12 and minimal disease activity (MDA) responses at week 16 and 12. The izokibep 80-mg dose versus placebo was evaluated for the above endpoints prior to the izokibep 40-mg dose versus placebo, and then the izokibep 80-mg and 40-mg doses versus placebo were evaluated at week 8.

[0024] Additional efficacy endpoints measured included tender and swollen joint counts based on 68 and 66 joints, respectively, Psoriasis Area and Severity Index (PASI) score and >75% / >90% / l 00% reduction from baseline in PASI (PAS 175 / 90 / 100) response rates in patients with >3% body surface area (BSA) involvement at baseline, Nail Psoriasis Severity Index for a target nail (specified at baseline), patient’s pain, patient’s global assessment, physician’s global assessment, Disease Activity Score in 28 joints (DAS28) using C-reactive protein (CRP), Disease Activity in Psoriatic Arthritis (DAPSA), Health Assessment Questionnaire Disability Index (HAQ-DI) score and percentage of patients with a >0.35-unit improvement from baseline, Psoriatic Arthritis Impact of Disease based on 9 numerical rating scales (PsAID-9) score and percentage of patients with a >3-unit improvement from baseline, enthesitis indices including the Leeds Enthesitis Index (LEI) and the Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index, and Leed’s Dactylitis Index-Basic (LDI-B).22’23Safety outcomes included treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (SAEs), TEAEs leading to withdrawals, AEs of special interest (Candida infection, IBD, staphylococcal skin infection and moderate or severe injection site reactions) and TEAEs based on clinically relevant abnormal laboratory results. TEAEs were coded by the Medical Dictionary of Regulatory Activities (Version 22.1) and defined as any AE occurring or worsening on or after the first dose of the study drug up to week 46 or patient discontinuation.

[0025] Statistical analyses

[0026] A sample size of 129 patients was calculated to provide 80% power of the primary endpoint assuming an estimated 35% ACR50 response rate at week 16 in the izokibep 80-mg group and a 10% placebo response rate, as informed by prior ixekizumab PsA studies’24, 25and estimating a dropout rate of 5% prior to 16 weeks. Efficacy analyses were conducted on the full analysis set (FAS), which included all randomised patients with at least one documented dose of study drug and at least one post-baseline ACR efficacy assessment and used a one-sided Z-test with pooled variance at a significance level of 2.5%. Corresponding two-sided p values are reported for ease of interpretability. Summaries of demographics, baseline disease characteristics and efficacy analyses are presented for the FAS. The safety-evaluable population included all randomised patients with at least one documented dose of study drug.

[0027] The analysis for the 16-week primary endpoint was comparison of ACR50 response rates between the 80-mg group and placebo, followed by a comparison between these groups at week 12, tested sequentially in a logistic generalised estimating equation regression model with previous TNFi exposure, concomitant csDMARD use, country, treatment, visit (weeks 8, 12 and 16; week 4 was omitted due to convergence issues with the model) and treatment by visit interaction as fixed adjustment factors. Patients were considered non-responders for binary endpoints if they did not meet clinical response criteria or had missing clinical response data at the respective time point. For primary and secondary endpoints during the 16-week placebo- controlled period, missing data were imputed using non-responder imputation (NRI). Other endpoints that were not part of the primary and secondary analyses set are presented as observed data. Due to the change in the design subsequent to all patients completing the 16-week placebo- controlled period, all analyses beyond week 16 are presented as observed data, as NRI was no longer an appropriate form of analysis given that the vast majority of discontinuations were due to the sponsor’s decision to terminate the study and not related to patients’ choice to discontinue (figure 1).

[0028] This trial was registered with EudraCT (number 2019-003405-94) prior to enrolment of the first patient and subsequently registered with ClinicalTrials.gov (NCT04713072).

[0029] BRIEF DESCRIPTION OF THE FIGURES

[0030] Figure 1 Trial profile. *Includes n=11 (30%) due to positive rheumatoid factor or positive anti-CCP antibody and n=6 (16%) due to positive tuberculosis test. fThe study was amended and terminated due to the sponsor’s decision to continue exploring the effective dose range in the next phase 2b / 3 trial; as a result, 17 patients in the placebo / izokibep 80-mg group, 21 patients in the izokibep 40-mg group and 20 patients in the izokibep 80-mg group did not reach the week 46 visit. JTwo patients in the placebo / izokibep 80-mg group, two patients in the izokibep 40-mg group and four patients in the izokibep 80-mg group had visits outside of the predefined week 46 window (day 322±6) and were not included in the week 46 analysis. CCP, cyclic citrullinated peptide.

[0031] Figure 2 Percentages of patients achieving (Figure 2A) ACR20, (Figure 2B) ACR50, (Figure 2C) ACR70 and (Figure 2D) MDA from week 0 to week 46. Non-responder imputation until week 16; logistic regression model with fixed factors (pooled) at weeks 8 to 16; observed data after week 16.

[0032] Asterisks (*) indicate significance within the hierarchical test chain and daggers (f ) indicate significance in descriptive test results in analyses of modelled NRI data for izokibep versus placebo during the placebo-controlled period. * / fTwo-sided p<0.05. ** / tfTwo-sided p<0.001. ACR20 / 50 / 70, >20% / >50% / >70% improvement from baseline based on American College of Rheumatology criteria; MDA, minimal disease activity; NRI, non-responder imputation; PBO, placebo; Q2W, every two weeks.

[0033] Figure 3 Percentages of patients achieving (Figure 3A) PASI75, (Figure 3B) PASI100, (Figure 3C) LEI=0 in patients with LEI >0 at baseline and (Figure 3D) SPARCC=0 in patients with SPARCC >0 at baseline from week 0 to 46. Data shown are observed data. PASI analyses were conducted in patients with >3% BSA at baseline.

[0034] Asterisks indicate statistically significant differences for izokibep versus placebo during the placebo-controlled period. P values (two sided) for PASI values were determined based on modelled observed data. P values (two sided) for enthesitis resolution analyses (LEI and SPARCC) were determined by Fisher’s exact test of observed data in post hoc analyses.

[0035] *Descriptive p<0.05. **Descriptive p<0.001. BSA, body surface area; LEI, Leeds Enthesitis Index; PASI, Psoriasis Area and Severity Index; PBO, placebo; Q2W, every two weeks;

[0036] SPARCC, Spondyloarthritis Research Consortium of Canada.

[0037] Figure 4 PsAID-9 subdomain mean values at week 16 (model adjusted) and week 46 (observed). Asterisks indicate statistically significant differences in analyses of modelled data for izokibep versus placebo during the placebo-controlled period. *Two-sided descriptive p<0.05. **Two- sided descriptive p<0.001. PsAID-9, Psoriatic Arthritis Impact of Disease based on 9 numerical rating scales; Q2W, every two weeks.

[0038] Figure 5 Clinical trial design. Figure 5 is also referred to as Supplementary Figure SI and / or Supplemental Figure SI in the application text. *Premature termination of the trial during treatment period II affecting approximately up to 75 of 135 randomised patients.

[0039] ^FUEOT. *FUS via phone call.§FUP in women of childbearing potential. ^FUPK / ADA at trial completion visit. ACR50, >50% improvement from baseline based on American College of Rheumatology criteria; D, day; FUEOT, end of treatment visit; FUPK / ADA, follow-up of pharmacokinetics and anti-drug antibodies; FUs, follow-up of safety; FUUP, follow-up visit for pregnancy test; Q2W, every 2 weeks; S, screening; V, visit.

[0040] Figure 6 DAPSA LDA (including remission) responses over 46 weeks (observed data). Figure 6 is also referred to as Supplementary Figure S2 and / or Supplemental Figure S2 in the application text. DAPSA LDA and remission were defined as scores <14; analyses were conducted post hoc. DAPSA LDA, Disease Activity in Psoriatic Arthritis low disease activity; PBO, placebo; Q2W, every 2 weeks.

[0041] Figure 7 PASI90 responses over 46 weeks in patients with >3% BSA at baseline (observed data). Figure 7 is also referred to as Supplementary Figure S3 and / or Supplemental Figure S3 in the application text. *Two-sided p<0.05; **p<0.001 in analyses of modelled data for izokibep versus placebo. BSA, body surface area; PASI90, 90% reduction from baseline in Psoriasis Area and Severity Index; PBO, placebo; Q2W, every two weeks. RESULTS

[0042] Efficacy and safety of izokibep in patients with active psoriatic arthritis: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial

[0043] Interleukin (IL)- 17 inhibitors reduce symptoms and improve quality of life in patients with psoriasis and psoriatic arthritis (PsA). IL- 17 inhibitors currently in clinical use for PsA are monoclonal antibodies of approximately 150 kDa in size with near peak efficacy at approximately six months.

[0044] This randomised, double-blind, phase 2 study is the first evaluation of izokibep, a small protein therapeutic designed to inhibit IL-17A, in patients with PsA. Because of its small size (18.6 kDa), high affinity for IL-17A (KD 0.3 pM), and albumin-binding domain, this molecule may have an advantage over antibodies in penetrating inflamed tissues and improving levels of efficacy.

[0045] Subcutaneous izokibep every other week resulted in significant improvements in PsA disease activity in adults with active PsA compared with placebo over 16 weeks of treatment, with continued improvements to week 46, while being generally well tolerated.

[0046] Rates of enthesitis resolution at 16 weeks were particularly high.

[0047] The findings support the continued development of izokibep as a novel therapeutic agent for PsA. Higher doses are being explored in a clinical trial to assess whether greater levels of disease control might be possible. Patient characteristics

[0048] From August 4, 2020, to June 9, 2021, 172 patients were screened for the study and 135 patients (62 [46%] male; 73 [54%] female) were randomised to izokibep 40 mg Q2W (n=44), izokibep 80 mg Q2W (n=47) or placebo (n=44; figure 1). All randomised patients received at least one dose of study drug and had at least one ACR data point and safety information; thus, the FAS and safety sets were identical.

[0049] Baseline characteristics were comparable between treatment groups with a mean (standard deviation [SD]) age of 48.5 (12.0) years and a mean (SD) PsA duration of 7.1 (7.8) years (table 1). In the overall patient population, evaluation of baseline disease activity showed a mean (SD) of 9.9 (6.6) swollen and 16.7 (10.4) tender joints, 98% of patients had plaque PsO, 77% had enthesitis per SPARCC Enthesitis Index (>0, 18 evaluated sites [0-16 scale]), 32% had enthesitis per LEI (>0, six evaluated sites [0-6 scale]) and 19% had dactylitis. Discontinuation rates were low (4 patients during the first 16 weeks; figure 1) and similar between treatment groups. The overall mean compliance as judged by the clinician based on visit attendance was 98% during the first 16 weeks and similar across the treatment groups.

[0050] Efficacy outcomes for the 16-week placebo-controlled period

[0051] For comparisons of izokibep 80 mg and placebo, ACR50 response rates as determined by the logistic regression model at week 16 were 52% (95% confidence interval [CI] 32, 71) for izokibep 80 mg versus 13% for placebo (95% CI 6, 28; two-sided p=0.0006) and 50% (95% CI 30, 69) versus 6% (95% CI 2, 17; pO. OOOl) at week 12, respectively (table 2; figure 2). The endpoint of ACR20 response rates for izokibep 80 mg versus placebo at week 16 was also achieved (75% versus 26%; pO. OOOl), but the subsequent hierarchical endpoint, ACR70 response rates for izokibep 80 mg versus placebo at week 16 (20% versus 5%; p=0.0678), was not met (table 2, figure 2).

[0052] In subsequent analyses, izokibep 40 mg resulted in higher ACR20 / 50 / 70 response rates than placebo at weeks 8, 12 and 16 (table 2, figure 2). Approximately 40% of izokibep-treated patients achieved MDA at week 16 versus 5% for placebo (table 2, figure 2). For both doses, increases in ACR20 responses were evident at the earliest clinical visit (2 weeks; figure 2). In analyses of additional key efficacy outcomes, the 80-mg dose led to lower disease activity scores versus the 40-mg dose as measured by TJC68, SJC66, DAPSA, DAS28-CRP and physician’s global assessment (table 3). For DAPSA, low disease activity (<14) was reached in more than 20% of patients at week 4 with active treatment and improved to more than 40% at week 16, with higher values for the 80-mg versus 40-mg dose observed at the week 16 time point (supplemental figure S2).

[0053] In analyses assessing additional PsA domains, izokibep was associated with higher rates of PASI75 / 90 / 100 response in patients with BSA >3% at baseline versus placebo at week 16 (table 3, figure 3, supplemental figure S3). Almost 40% of patients treated with izokibep achieved PASH 00 at week 16 versus 5% for placebo. Domains assessing nails, dactylitis and enthesitis showed large improvements for izokibep 80 and 40 mg relative to placebo during the 16-week study period (table 3, supplemental table S2). Higher rates of LEI resolution at 16 weeks were observed for the izokibep 80-mg group (15 / 17 [88%]) compared with the izokibep 40-mg group (10 / 15 [67%]) and placebo (1 / 9 [11%]) in patients with LEI >0 at baseline, and these findings were consistent with improvements in the SPARCC Enthesitis Index (table 3, figure 3). Marked mean reductions were observed in LDI-B scores at week 16 in patients with baseline dactylitis (table 3). Across patient-reported outcomes, patient-reported pain, patient-reported itch, HAQ-DI and the PsAID-9 questionnaire showed clinically important dose-dependent improvements at week 16 versus placebo (table 3). Izokibep 80 mg achieved statistically significant improvements over placebo for all nine PsAID-9 domains at week 16 (figure 4); for all domains, greater improvements were observed for izokibep 80 mg versus 40 mg except for “skin problems,” which showed similar levels of change.

[0054] Efficacy outcomes during long-term treatment (to week 46)

[0055] The study was terminated once the last enrolled patient passed the 16-week primary time point, although many patients already had visits beyond 16 weeks. Patient numbers were balanced across treatment groups and not related to dose assignment, as expected since study closure was administrative and not related to patients’ choice. Of the original 135 patients randomised, 59 (44%) had available week 46 data (figure 1).

[0056] Patients who started on izokibep 80 mg generally showed continuing improvements to week 46, with 81% attaining an ACR50 response, 52% attaining ACR70, 71% attaining PASI100 and 89% attaining LEI complete resolution (figures 2 and 3). In patients initially randomised to the 80-mg group, improvements over time were generally seen in all outcome measures, including ACR20 / 50 / 70 and MDA scores (figure 2), PASI75 / 90 / 100 (figure 3, supplemental figure S3) and composite disease activity scores (DAPSA, DAS28-CRP; supplemental table S3). Responses were typically higher for izokibep 80 mg versus 40 mg for clinical and patient-reported outcomes (figures 2, 3 and 4, supplemental table S3). Patients who switched from placebo to izokibep 80-mg Q2W therapy showed responses mirroring the continuous 80-mg Q2W group by approximately week 24 (figures 2 and 3) and at all time points beyond (supplemental table S3). Those originally randomised to izokibep 40 mg typically maintained responses between weeks 16 to 46 (figures 2 and 3).

[0057] SPARCC enthesitis outcomes also showed continued improvements with week 46 resolution rates for the original 80-mg dose (72%) and 40-mg dose (77%) paralleling the LEI resolution rates (figure 3). At week 46, all seven patients with LDI-B >0 at baseline achieved dactylitis resolution (supplemental table S3). The mean values of all PsAID-9 subdomains continued to improve further from week 16 to 46, with responses for the 80-mg dose groups exceeding those in the 40-mg group (figure 4).

[0058] Safety

[0059] By week 16, 26 (55%) and 29 (66%) patients in the izokibep 80-mg and 40-mg groups, respectively, and 23 patients (52%) in the placebo group reported at least one TEAE (table 4). Treatment-related TEAEs were reported in 17 patients (36%) in the izokibep 80-mg group and 24 patients (55%) in the izokibep 40-mg group versus 9 (21%) patients in the placebo group; the different rates were primarily due to injection site reactions / injection site erythema related to izokibep treatment. All TEAEs were of mild or moderate severity, and no relationship between izokibep dose and the incidence or severity of TEAEs was observed. Treatment with izokibep 40 mg was discontinued in 2 / 44 (5%) patients due to TEAEs (one injection site reaction and one injection site erythema; table 4). There were no treatment discontinuations due to TEAEs in the izokibep 80-mg group or placebo group. Injection site reactions were the most frequently reported TEAEs with izokibep (80 mg, 26%; 40 mg, 27% versus 0% for placebo), followed by injection site erythema, hyperkalaemia and upper respiratory tract infections. Hyperkalaemia events in the absence of clinical correlates were reported at specific clinical sites and were hypothesised to be related to blood sample management. No deaths occurred during the study and there were no SAEs during the placebo-controlled period. There was one case of mild vulvovaginal candidiasis in the izokibep 40-mg group that resolved within two weeks.

[0060] Between weeks 16 and 46, the rates of injection site reactions decreased in the izokibep groups (to 15% and 12% for the 80- and 40-mg groups, respectively), and were 16% in placebo- randomised patients switched to izokibep 80 mg. Izokibep continued to be well tolerated for up to 46 weeks and no new safety signals were observed. There were three treatment discontinuations due to TEAEs overall (1 per treatment group) after week 16. One treatment discontinuation in the izokibep 40-mg group was due to hepatic enzyme increased (initially reported in the first 16 weeks, with a persistent increase leading to discontinuation between weeks 16 and 46). One treatment discontinuation in the 80-mg group was due to a human papillomavirus-associated vulvar intraepithelial neoplasia (diagnosed after laser excision) after approximately four months of treatment, a latency period considered too short to be related to the drug product. One treatment discontinuation in the placebo to 80-mg group resulted from an injection site reaction, which was moderate in intensity and considered related to treatment. Seven patients experienced eight SAEs between weeks 16 and 46 (placebo to 80-mg group, n=3; 80-mg group, n=3; 40-mg group, n=l; supplemental table S4). There was no pattern to the SAEs observed and 6 / 7 patients were reported as recovered / resolved by end of study (the status of one was unknown).

[0061] DISCUSSION IL-17A is a key driver of immune-mediated inflammatory disorders including PsO and PsA.6In this phase 2, randomised, double-blind, placebo-controlled study, izokibep, a small protein therapeutic designed to inhibit IL-17A, significantly improved musculoskeletal and skin symptoms in adult patients with active PsA and an inadequate response to csDMARDs, TNFi or NSAIDs. An ACR50 response at week 16, the primary efficacy endpoint, was achieved by 52% and 48% of patients in the izokibep 80- and 40-mg groups, respectively, compared with 13% of placebo-treated patients. At week 16, approximately 40%- of patients in the izokibep treatment groups achieved MDA, which is a widely used measure of multidimensional disease control.26, 27More than 80% of izokibep-treated patients with a baseline BSA >3% achieved a PASI75 response at week 16 (versus 14% of placebo-treated patients), and complete skin clearance (PASH 00 response) was observed in almost 40% of izokibep-treated patients (versus 5% of placebo-treated patients). The PASI data for izokibep are in line with those reported for other anti-IL-17A agents in PsA.11, 13’24>25-28-30

[0062] Improvements in efficacy outcomes observed at week 16 generally increased further with the higher 80-mg dose and were maintained with the lower 40-mg dose to week 46. Patients treated with placebo during the initial 16-week period showed rapid improvements in symptoms when switched to izokibep 80 mg.

[0063] Recent reports have highlighted a higher symptom burden in patients with PsA who have enthesitis31; the response of enthesitis to therapy is reduced compared with skin and joint outcomes32and enthesitis is associated with a lower probability of achieving remission or low disease activity.33In our study, patients with clinical enthesitis showed excellent responses to izokibep as evaluated by resolution of enthesitis by both SPARCC and LEI. The enthesitis resolution rate (LEI=0) of 88% with izokibep 80 mg at week 16 compares favourably with LEI rates reported in clinical trials of bimekizumab at week 16 and secukinumab and ixekizumab at week 24 or later.11, 13>24-25>28>34=35We also observed marked and rapid reductions in dactylitis throughout this study. The large effects with izokibep in hard to treat tissues may be related to its unique abilities to penetrate inflamed tissues (related to its small molecular size and albumin trafficking to sites of inflammation) and high binding affinity to IL-17A (KD 0.3 pM).20, 36, 37The clinical safety profile of izokibep in this study indicated good tolerability similar to other therapies targeting the IL-17A pathway such as the monoclonal antibodies secukinumab and ixekizumab, with lower rates of fungal infections than are seen with the IL-17A& F inhibitor bimekizumab.11’!3’28>29’38In this trial, injection site reactions and injection site erythema were the predominant TEAEs reported with izokibep; these were typically mild in severity, resolved rapidly and were more prevalent with earlier injections. Injection site reactions uncommonly lead to discontinuation. There were otherwise no important differences in TEAEs versus placebo. Studies of IL-17 inhibitors in PsA have reported higher risks of Candida infections, injection site reactions and IBD associated with these agents.38'42In our study, one patient in the izokibep 40-mg group had mild vulvovaginal candidiasis (1% with izokibep). Infection rates were low and comparable to placebo over 16 weeks, and no cases of IBD were reported.

[0064] The currently approved IL-17A inhibitors do not have a clear dose-limiting AE profile, and empirical evidence has demonstrated their short- and long-term safety in patients with PsA.38'40Based on published data for other IL- 17 inhibitors, the benefit-risk relationship in patients with PsA appears favourable for izokibep and highlights the potential opportunity for enhanced therapeutic effects on PsA symptoms, including difficult to treat domains such as enthesitis and dactylitis. The lack of dose-related AEs with izokibep, dose-related improvements in clinical signs and symptoms and sustained efficacy support the potential for investigating higher doses in future trials, including those being conducted for other inflammatory conditions. Izokibep is currently being studied in patients with uveitis (NCT05384249 [phase 2b]), hidradenitis suppurativa (NCT05355805 [phase 2b]; NCT05905783 [phase 3]) and PsA (NCT05623345 [phase 2b / 3]). Data from these trials will provide further information on the benefits of izokibep in the management of chronic inflammatory diseases.

[0065] Limitations of this study include a modest sample size, consistent with the phase 2 stage of investigation. Patient numbers beyond 16 weeks declined related to the administrative decision to terminate the trial following the last patient reaching the 16-week primary endpoint; this decision was made to accelerate further dose exploration to understand whether even greater responses might be achieved with higher doses without dose-related safety events. The study was not designed to compare izokibep doses.

[0066] CONCLUSION

[0067] In this phase 2 study in patients with active PsA, izokibep, a small protein therapeutic designed to inhibit IL-17A with high affinity, showed differentiated high levels of response across multiple measures of joint, PsO and quality of life. Improvements began as early as two weeks and were continued or maintained through the end of the study; dose-related improvements were observed at later time points in patients exposed to izokibep 80 mg. Clinical responses in patients with enthesitis appeared to be favourable compared to current therapies, although no head-to-head studies have been performed. The safety profile of izokibep was generally consistent with other IL-17A inhibitors, and event rates were mostly similar to placebo with the exception of injection site reactions. Our study supports further investigation of the clinical potential of izokibep for achieving even greater disease control and quality of life goals in patients with active PsA. References

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[0109] 42. Penso L, Bergqvist C, Meyer A, et al. Risk of inflammatory bowel disease in patients with psoriasis and psoriatic arthritis / ankylosing spondylitis initiating interleukin- 17 inhibitors: a nationwide population-based study using the French National Health Data System. Arthritis Rheumatol 2022;74:244-52. Table 1 Baseline characteristics of randomised patients

[0110] Izokibep

[0111] All patients Characteristic Placebo

[0112] (n=44) 40 mg Q2W 80 mg Q2W (N=135)

[0113] (n=44) (n=47)

[0114] Age, years 47.6 (12.6) 47.6 (12.5) 50.1 (10.9) 48.5 (12.0) Sex

[0115] Male 22 (50%) 21 (48%) 19 (40%) 62 (46%) Female 22 (50%) 23 (52%) 28 (60%) 73 (54%) Race, White* 44 (100%) 44 (100%) 47 (100%) 135 (100%) Ethnicity*

[0116] Hispanic or Latino 0 1 (2%) 1 (2%) 2 (1%) Not Hispanic or Latino 44 (100%) 43 (98%) 46 (98%) 133 (99%) BMI, kg / m228.2 (4.7) 30.2 (5.2) 28.5 (4.5) 29.0 (4.8) PsA duration, years 7.8 (9.2) 7.3 (7.9) 6.4 (6.2) 7.1 (7.8) Previous anti-TNF exposure 4 (9%) 5 (11%) 8 (17%) 17 (13%) Concomitant csDMARD use 35 (80%) 35 (80%) 38 (81%) 108 (80%) Concomitant methotrexate use 25 (57%) 31 (70%) 32 (68%) 88 (65%) Plaque PsO, years 18.5 (14.6) 16.7 (12.0) 18.8 (14.5) 18.0 (13.7) Plaque PsO 44 (100%) 42 (95%) 46 (98%) 132 (98%) Nail PsO 34 (77%) 34 (77%) 36 (77%) 104 (77%) TJC68 16.4 (11.3) 16.7 (10.3) 17.0 (9.7) 16.7 (10.4) SJC66 9.2 (6.4) 10.1 (7.0) 10.4 (6.4) 9.9 (6.6) DAPSA score 47.1 (25.1) 47.1 (20.6) 46.3 (21.1) 46.8 (22.2) DAS28-CRP 4.5 (0.9) 4.5 (1.0) 4.5 (1.1)+4.5 (1.0) Physician’s global assessment

[0117] 64.1 (15.6) 61.4 (14.8) 64.0 (18.0) 63.2 (16.2) VAS, mm

[0118] CRP, mg / 1 9.3 (12.1) 8.3 (8.0) 6.0 (7.7) 7.8 (9.5) SPARCC Enthesitis Index score

[0119] SPARCC >0 33 (75%) 34 (77%) 37 (79%) 104 (77%) Mean value in patients with

[0120] 3.6 (3.3) 3.4 (2.6) 3.2 (2.5) 3.4 (2.8) SPARCC >0

[0121] LEI LEI >0 10 (23%) 16 (36%) 17 (36%) 43 (32%) Mean value in patients with

[0122] 1.5 (0.5) 1.7 (0.5) 1.4 (0.5) 1.5 (0.5) LEI >0

[0123] LDI-B

[0124] LDI-B >0 11 (25%) 9 (20%) 6 (13%) 26 (19%)

[0125]

[0126] Izokibep

[0127] Placebo All patients Characteristic

[0128] (n=44) 40 mg Q2W 80 mg Q2W (N=135) (n=44) (n=47)

[0129] Mean value of LDI-B in

[0130] patients with baseline 22.1 (16.3) 18.6 (12.7) 29.5 (13.1) 22.6 (14.5) dactylitis

[0131] PASI

[0132] Patients with >3% of BSA- 23 (52%) 23 (52%) 28 (60%) 74 (55%) PsO

[0133] PASI (in patients with >3%

[0134] 11.1 (7.0) 10.2 (6.8) 8.1 (4.9) 9.7 (6.3) ofBSA-PsO)

[0135] BSA affected by PsO, % 8.7 (11.0) 8.0 (11.7) 8.5 (10.1) 8.4 (10.9) NAPSI score (target nail)* 3.7 (2.1) 3.5 (2.4) 3.7 (2.5) 3.7 (2.3) DLQI total sum score 8.4 (7.5) 7.9 (7.0) 9.3 (6.7) 8.5 (7.1) PsAID-9 5.7 (1.7) 5.8 (2.1) 6.0 (1.6) 5.9 (1.8) HAQ-DI score 1.2 (0.6) 1.2 (0.6) 1.3 (0.5) 1.3 (0.6) Pain VAS, mm562.3 (18.9) 61.5 (20.4) 64.4 (20.3) 62.8 (19.8) Patient’s global assessment

[0136] 59.9 (19.7) 58.5 (21.4) 62.2 (20.1) 60.2 (20.3) VAS, mm5

[0137] Itch NRS (average)14.4 (2.4) 4.2 (2.9) 4.8 (2.4) 4.5 (2.6)

[0138]

[0139] Data are mean (SD) or n (%).

[0140] ’As reported by the patient.

[0141] ^Evaluable n=46.

[0142] ^Evaluable n=35 in each treatment group (total N=105).

[0143] §From 0=none / very well to lOO^wvorst imaginable / very poor.

[0144] ^From 0=none to 10=worst imaginable.

[0145] BMI, body mass index; BSA, body surface area; CRP, C-reactive protein; csDMARD, conventional synthetic disease-modifying antirheumatic drug; DAPSA, Disease Activity in Psoriatic Arthritis; DAS28-CRP, Disease Activity Score in 28 joints with C-reactive protein; DLQI, Dermatology Life Quality Index (from 0=no impact to 30=extreme impact on quality of life); HAQ-DI, Health Assessment Questionnaire Disability Index (from 0=without any difficulty to 3=unable to do); LDI-B, Leeds Dactylitis Index-Basic; LEI, Leeds Enthesitis Index; NAPSI, Nail Psoriasis Severity Index; NRS, numerical rating scale; PASI, Psoriasis Area and Severity Index; PsA, psoriatic arthritis; PsAID-9, Psoriatic Arthritis Impact of Disease based on 9 numerical rating scales; PsO, psoriasis; Q2W, once every two weeks; SD, standard deviation; SJC66, swollen joint count based on 66 joints; SPARCC, Spondyloarthritis Research Consortium of Canada; TJC68, tender joint count based on 68 joints; TNF, tumour necrosis factor; VAS, visual analogue scale Table 2 Primary and secondary efficacy outcomes

[0146] Outcome Hierarchical Week Placebo Izokibep 40 mg Izokibep 80 mg rank (N=44) (N=44) (N-47) (placebo Modelled NRI rate Modelled NRI rate Two- Modelled NRI rate Two- versus (95% CI) (95% CI) sided (95% CI) sided izokibep p value p value 80 mg) versus versus placebo'' pl ace ho Primary outcomes

[0147] 13% 48% 52

[0148] ACR50 1 16 0.0014 %

[0149] 0.0006 (6. 28) (29. 68 ) (32. 71 )

[0150] 6% 43% 50%

[0151] ACR50 2 12 0.0002

[0152] (2, 17) (25. 62) (30, 69) <0.0001 Secondary outcomes

[0153] 26% 60% 75%

[0154] ACR20 3 16 0.0028 <0.0001

[0155] (14.44). (40. 77) (57, 88) _

[0156] 5% 32% 20%

[0157] ACR70 4 16 0.0101 0.0678

[0158] . CLJ8) (17. 53) (M3j

[0159] Secondary outcomes

[0160] 36% 65% 82%

[0161] ACR20 NA 12 0.0086 <0.0001

[0162] (20. 55) 80). X67>91).

[0163] 5% 27% 18%

[0164] ACR70 NA 12 0.0176 0.0831

[0165] (1, 18) (13, 46). (7, 36).

[0166] 5% 42% 39%

[0167] MDA NA 16 0.0020 0.0032

[0168] (1, 20) (24, 62) (22, 59)

[0169] 3% 23% 20%

[0170] MDA NA 12 0.0285 0.0434

[0171] (0, 17) (IL. nr (9, 38)

[0172] 4% 31% 40%

[0173] ACR50 NA 8 0.0039 0.0012

[0174] (1, 16) (17, 50) (21, 62)

[0175] 33% 60% 69%

[0176] ACR20 NA 8 0.0179 0.0015

[0177] (18, 52) 140, 77)._. (50,.831 _

[0178] 2% 24% 7%

[0179] ACR70 NA 8 0.0243 0.3186

[0180] (0, 15) (11, 43) _

[0181] 3% 28% 22%

[0182] MDA NA 8 0.0143 0.0316

[0183]

[0184] (0, 17) (15, 47) (11, 40) Modelled response rates using NRI for primary and secondary outcomes are shown in hierarchical order. Two-sided p values <0.05 were considered statistically significant and are shown in bold. The fourth ranked outcome failed to be statistically significant (two-sided p value >0.05), so a formal statistical analysis could not be performed on subsequent ranked outcomes and additional statistical analyses were descriptive only, including all comparisons of izokibep 40 mg and placebo.

[0185] ACR20 / 50 / 70, >20% / >50% / >70% improvement from baseline based on American College of Rheumatology criteria; CI, confidence interval; MDA, minimal disease activity; NA, not applicable; NRI, non-responder imputation. Table 3 Key efficacy endpoints at week 16 (observed data)

[0186] Outcome Placebo (N=44) Izokibep 40 mg (N=44) Izokibep 80 mg (N=47) n / N or Percent n / N or Percent Two-sided n / N or Percent Two-sided n or mean n or mean p value versus n or mean p value (SD) (SD) placebo* (SD) versus placebo* TJC68 43 10.7 (9.1) 42 7.1 (7.7) <0.0001 46 5.6 (6.8) <0.0001 SJC66 43 5.0 (5.7) 42 2.4 (3.7) <0.0001 46 1.7 (2.7) <0.0001 SPARCC Enthesitis Index

[0187] Mean value in patients with

[0188] 32 2.8 (2.6) 33 1.2 (1.7) <0.0001 36 1.2 (2.0) <0.0001 SPARCC >0 at baseline1'

[0189] SPARCC=0 for patients with 6 / 32 19% 15 / 33 45% 0.0344 20 / 36 56% 0.0028 SPARCC >0 at baseline1'

[0190] LEI

[0191] Mean value in patients with LEI >0

[0192] 9 1.3 (0.7) 15 0.5 (0.7) 0.0191 17 0.2 (0.7) 0.0006 at baseline1'

[0193] LEI=0 for patients with LEI >0 at 1 / 9 11% 10 / 15 67% 0.0143 15 / 17 88% 0.0001 baseline1

[0194] LDI-B

[0195] Mean score in patients with LDI-B 17.6

[0196] 10 9 2.0 (4.0) <0.0001 6 4.4 (8.1) <0.0001 >0 at baseline (15.9)

[0197] LDI-B=0 in patients with LDI-B >0 Not 3 / 10 30% 7 / 9 78% Not calculated 4 / 6 67%

[0198] at baseline1calculated PASI in patients with >3% BSA at

[0199] baseline

[0200] PASI75 3 / 22 14% 19 / 23 83% <0.0001 23 / 27 85% <0.0001 PASI90 3 / 22 14% 13 / 23 57% 0.0009 13 / 27 48% 0.0022 PASI 100 1 / 22 5% 9 / 23 39% 0.0029 10 / 27 37% 0.0013

[0201]

[0202] Outcome Placebo (N=44) Izokibep 40 mg (N=44) Izokibep 80 mg (N=47) n / N or Percent n / N or Percent Two-sided n / N or Percent Two-sided n or mean n or mean p value versus n or mean p value (SD) (SD) placebo'’ (SD) versus placebo* NAPSI score (target nail) 36 2.7 (2.1) 33 1.2 (1.4) <0.0001 36 1.8 (2.2) 0.0028 Patient-reported outcomes5

[0203] 4.79 3.63 3.42

[0204] PsAID-9 (0-10) 43 42 0.0022 46 <0.0001

[0205] (2.06) (2.50) (2.35)

[0206] PsAID-9 >3-unit improvement^15 / 43 12% 13 / 42 31% 0.0418 19 / 46 41% 0.0017

[0207] 1.08 0.84 0.86

[0208] HAQ-DI (0-3) 43 42 0.0166 46 0.0001

[0209] (0.59) (0.70) (0.67)

[0210] Not HAQ-DI >0.35-unit improvement11111 / 43 26% 18 / 42 43% Not calculated 25 / 46 54%

[0211] calculated 49.6 35.0 34.3

[0212] Patient’s global assessment (0-100) 43 42 0.0030 46 0.0001

[0213] (22.7) (27.8) (26.4)

[0214] 51.3 35.3 33.4

[0215] Patient’s pain assessment (0-100) 43 42 0.0007 46 <0.0001

[0216] (24.5) (27.6) (26.0)

[0217] Average Itch NRS (0-10) 43 3.7 (2.9) 42 2.3 (2.5) 0.0053 46 2.7 (2.1) 0.0008 Composite and global scores

[0218] 34.1 22.3 17.7

[0219] DAPSA composite score 43 42 <0.0001 44 <0.0001

[0220] (19.0) (16.3) (12.0)

[0221] 3.87 2.93 2.85

[0222] DAS28-CRP 43 42 <0.0001 44 <0.0001

[0223] (1.06) (1.15) (0.90) Physician’s global assessment (0- 44.8 20.3 16.5

[0224] 43 42 <0.0001 46 <0.0001 100) (23.4) (17.4) (14.3)

[0225]

[0226] Results for additional efficacy endpoints during the placebo-controlled period are presented in supplementa table S2.

[0227] * Two-sided p values <0.05 were considered statistically significant. tThe subpopulation with enthesitis at baseline was not pre-specified in the study protocol. Two-sided p values for enthesitis resolution analyses (LEI and SPARCC) were determined by Fisher’s exact test of observed data in post hoc analyses.

[0228] JDactylitis resolution in the subpopulation with dactylitis at baseline was not pre-specified in the study protocol.

[0229] §Lower scores are better for all patient-reported outcomes.

[0230] ^The analysis was not pre-specified in the study protocol.

[0231] BSA, body surface area; csDMARD, conventional synthetic disease-modifying antirheumatic drug; DAPSA, Disease Activity in Psoriatic Arthritis; DAS28-CRP, Disease Activity Score in 28 joints with C-reactive protein; HAQ-DI, Health Assessment Questionnaire Disability Index; LDI-B, Leeds Dactylitis Index-Basic; LEI, Leeds Enthesitis Index; NAPSI, Nail Psoriasis Severity Index; NRS, numeric rating scale; PASI, Psoriasis Area and Severity Index; PASI75 / 90 / 100, >75% / 90% / l 00% reduction from baseline in PASI; PsAID-9, Psoriatic Arthritis Impact of Disease based on 9 numerical rating scales; SD, standard deviation; SJC66, swollen joint count based on 66 joints; SPARCC, Spondyloarthritis Research Consortium of Canada; TJC68, tender joint count based on 68 joints; TNFi, tumour necrosis factor inhibitor. Table 4 Treatment-emergent adverse events

[0232] Placebo-controlled period (weeks Long-term treatment (weeks 16-46)

[0233] 0-16)

[0234] Placebo Izokibep Izokibep Placebo Izokibep Izokibep TEAEs 40 mg 80 mg to 40 mg 80 mg izokibep

[0235] (N=44) (N=44) (N=47) 80 mg (N=42) (N=46)

[0236] (N=43)

[0237] Any TEAE 23 (52%) 29 (66%) 26 (55%) 22 (51%) 24 (57%) 27 (59%) Serious TEAEs 0 0 0 3 (7%) 1 (2%) 3 (7%) Severe TEAEs 0 0 0 3 (7%) 0 2 (4%) Deaths 0 0 0 0 0 0 TEAEs assessed as

[0238] 9 (20%) 24 (55%) 17 (36%) 15 (35%) 13 (31%) 14 (30%) possibly drug related

[0239] Discontinuations due

[0240] 0 2 (5%) 0 1 (2%) 1 (2%) 1 (2%) to TEAEs

[0241] TEAE by preferred term (in >5% of patients in any group and any period)

[0242] 12 (27%) 12 (26%)

[0243] Injection site

[0244] 0 (none (none 7 (16%) 5 (12%) 7 (15%) reaction

[0245] severe) severe)

[0246] 8 (18%) 5 (11%)

[0247] Injection site

[0248] 0 (none (none 5 (12%) 6 (14%) 5 (11%) eiythema

[0249] severe) severe)

[0250] Nasopharyngitis 0 1 (2%) 2 (4%) 2 (5%) 3 (7%) 4 (9%) Headache 4 (9%) 0 4 (9%) 2 (5%) 1 (2%) 4 (9%) Gamma- glutamyltransferas 1 (2%) 0 0 2 (5%) 0 3 (7%) e increased

[0251] Back pain 0 0 0 2 (5%) 3 (7%) 2 (4%) Hypertension 4 (9%) 2 (5%) 0 1 (2%) 0 2 (4%) Hyperkalaemia 2 (5%) 3 (7%) 2 (4%) 0 4 (10%) 1 (2%) Upper respiratory

[0252] 1 (2%) 2 (5%) 3 (6%) 0 3 (7%) 1 (2%) tract infection

[0253] Arthralgia 1 (2%) 0 0 1 (2%) 3 (7%) 1 (2%) Diarrhoea 3 (7%) 0 2 (4%) 1 (2%) 0 0 Corona virus

[0254] 2 (5%) 1 (2%) 1 (2%) 2 (5%) 2 (5%) 3 (7%) infection

[0255] Placeb o-controlled period Long-term treatment 'weeks 0-16' (weeks 16-46) AEs of special

[0256] Plac Izokibep Izokibep Izokibep 40 mg Izokibep 80 mg interest ebo

[0257] (N=44) 40 mg 80 mg (N=42) (N=89)*

[0258]

[0259] (N=44) (N=47) Injection site

[0260] 0 2 (5%) 0 1 (2%) 1 (1%) reaction

[0261] Injection site

[0262] 0 0 0 1 (2%) 0 erythema

[0263] Candidiasis 0 1 (2%)t0 0 0 Groin abscess 0 0 0 0 1 (1%)

[0264]

[0265] Data are from the safety-evaluable set and presented as the number (%) of patients with the AE.

[0266] ’Data were pooled from placebo to izokibep 80-mg and izokibep 80-mg treatment groups from weeks 16 to 46.

[0267] ^Mild vulvovaginal candidiasis resolving within two weeks while the patient stayed on therapy.

[0268] AE, adverse event; TEAE, treatment-emergent adverse event. SUPPLEMENTAL MATERIAL

[0269] Supplemental material referred to in the application can be found in the following section below, such as supplemental section SI (“Inclusion and exclusion criteria”) as well as supplemental tables S2, S3 and S4. Supplemental figures (Supplemental figures SI, S2, and S3) are available in the Figures (see also the section BRIEF DESCRIPTION OF THE FIGURES for further information concerning the figure numbering of the supplemental figures). Supplemental Section SI Inclusion and exclusion criteria

[0270] Inclusion criteria

[0271] 1. Patient who has given his / her signed declaration of consent and data protection declaration 2. At least 18 years and less than 75 years of age at the screening visit

[0272] 3. Psoriatic arthritis (PsA) with inflammatory musculoskeletal disease (joint, spine or entheseal) with the presence of >3 points from the five categories of the Classification Criteria for Psoriatic Arthritis at any time point in medical history

[0273] 4. Active PsA defined by:

[0274] a. >3 swollen joints out of 66 joints (swollen joint count based on 66 joints[SJC66]) at the screening visit and baseline visit

[0275] b. >3 tender joints out of 68 (tender joint count based on 68 joints [TJC68]) at the screening visit and baseline visit

[0276] 5. Precedent failure or insufficient treatment response to at least one of the following PsA treatments:

[0277] a. Non-steroidal anti-inflammatory drug

[0278] b. Conventional synthetic disease-modifying antirheumatic drug (csDMARD; i.e.

[0279] methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, cyclosporine A) c. Tumour necrosis factor inhibitor (TNFi; e.g. adalimumab, infliximab, etanercept, golimumab, certolizumab)

[0280] 6. Rheumatoid factor and anti-cyclic citrullinated peptide antibody negative

[0281] 7. Presence or history of plaque psoriasis (PsO)

[0282] 8. For females of childbearing potential only: negative serum human chorionic gonadotropin test at screening visit

[0283] 9. Willingness and capability of using adequate contraceptive methods from the screening visit until 14 weeks after the last izokibep dose

[0284] a. Female of childbearing potential should use a highly efficient method of contraception but this is not necessary for females of non-childbearing potential permanently sterilised or post-menopausal (i.e. at least 12 consecutive months with amenorrhea without other known or suspected medical cause)

[0285] b. Male who has a female partner of childbearing potential should use a highly efficient method of contraception

[0286] c. Adequate contraceptive method defined as the following:

[0287] i. A method with less than 1% failure rate (e.g. permanent sterilisation, hormone implants, hormone injections, some intrauterine devices, vasectomised partner)

[0288] OR

[0289] ii. The use of two methods of contraception (e.g. one barrier method [condom, diaphragm, cervical / vault caps] with spermicide and one hormonal contraceptive [e.g. combined oral contraceptives, patch, vaginal ring, injectables and implants])

[0290] 10. Willingness and capability of complying with all trial procedure requirements as per the investigator’ s j udgement

[0291] Exclusion criteria

[0292] Medical and surgical history

[0293] 1. Underlying conditions, which in the investigator’s opinion significantly immunocompromise the patient and / or place the patient at unacceptable risk for receiving an immunomodulatory therapy

[0294] 2. History of or current relevant autoimmune diseases (e.g. rheumatoid arthritis, primary ankylosing spondylitis, systemic lupus erythematosus) other than PsO or PsA

[0295] 3. History of or current fibromyalgia or pain syndrome

[0296] 4. Uncontrolled inflammatory bowel disease

[0297] 5. Presence or history of recurrent or medically important infections in the last 6 months prior to the baseline visit (e.g. due to bacterial, mycobacterial, invasive fungal, parasitic, viral other opportunistic infections that required medical / pharmaceutical intervention [i.e. prescription of antibiotics and / or hospitalisation])

[0298] 6. Clinically relevant Candida infection requiring systemic treatment within the last 6 months prior to the baseline visit

[0299] 7. History or any signs of lymphoproliferative disease or a known malignancy or a history of malignancy within the previous 5 years (with the exception of basal cell or squamous cell carcinoma of the skin that had been fully excised with no evidence of recurrence) 8. Insufficiently controlled heart failure as assessed by the investigator

[0300] 9. Current uncontrolled arterial hyper- or hypotension

[0301] Laboratory examinations and body measurements

[0302] 10. Positive test for subclinical / latent tuberculosis infection (i.e. positive QuantiFERON-TB® Gold test or equivalent product) or chest X-ray suggestive of tuberculosis at the screening visit

[0303] 11. Positive test for human immunodeficiency virus (HIV) to hepatitis B (HBV) or hepatitis C (HCV) at the screening visit

[0304] a. HIV antibody (any test)

[0305] b. HBV surface antigen

[0306] c. Anti-HCV antibody

[0307] 12. Alanine aminotransferase or aspartate aminotransferase level >2.5 times the upper limit of normal at the screening visit

[0308] 13. Estimated glomerular filtration rate (eGFR) <60 mL / min / 1.73 m2according to the Chronic Kidney Disease-Epidemiology Collaboration equation at the screening visit 14. Body mass index (BMI) >40 kg / m2or <16 kg / m2

[0309] Medication to drug use and special behavioural patterns

[0310] 15. Previous exposure to izokibep or any other interleukin-(IL)17i or IL- 17 receptor inhibitor (e.g. secukinumab, ixekizumab, brodalumab)

[0311] 16. History of hypersensitivity or allergy to izokibep or its excipients

[0312] 17. Exposure to IL- 12 / 23 inhibitors within 12 weeks, TNFi within 8 weeks (except etanercept within 2 weeks), csDMARD within 6 weeks and / or systemic and / or intraarticular glucocorticoid and / or Janus kinase inhibitors (JAKi) within 4 weeks prior to the baseline visit (apart from one csDMARD or oral glucocorticoids, if on a chronic and stable dose at the baseline visit)

[0313] 18. Previous failure to more than two TNFi or any exposure to more than four TNFi

[0314] 19. Failure to JAKi or previous exposure to more than two JAKi (e.g. tofacitinib)

[0315] 20. Current use of more than one csDMARD

[0316] 21. Ongoing or 4 weeks prior to the baseline visit systemic PsO treatments (e.g. biological therapies, mycophenolate mofetil, azathioprine, tacrolimus, retinoids, fumarates, apremilast or phototherapy [e.g. psoralen and ultraviolet A, ultraviolet A, ultraviolet B, (UVB), UVB311])

[0317] 22. Use of high potency opioid analgesics (e.g. methadone, hydromorphone, morphine) 23. Live vaccination within 12 weeks prior to the baseline visit to or intend to have a live vaccination during the course of the study or within 15 weeks of completing treatment in this clinical trial to or have participated in a vaccine clinical trial within 12 weeks prior to the baseline visit

[0318] 24. Participation in another clinical trial within 30 days prior to the screening visit or administration of another investigational medicinal product within five half-lives (for biologies, 6 months or five half-lives, whichever is longer) prior to the baseline visit 25. Evidence or indication of drug and / or alcohol abuse or dependence according to the judgement of the investigator

[0319] Other exclusion criteria

[0320] 26. Females who are currently pregnant, who intend to become pregnant during the course of the trial or who are breastfeeding

[0321] 27. Previous randomisation in the current clinical trial

[0322] 28. Patient is an investigator to trial site or sponsor personnel directly affiliated with this clinical trial and / or their immediate families (partner, spouse, parent, child or sibling, whether biological or legally adopted)

[0323] 29. Any medical or psychiatric condition which, in the investigator’s opinion, would preclude the patient from adhering to the protocol or completing the clinical trial per protocol 30. Patient is considered to belong to a vulnerable population (e.g. placed under guardianship, imprisoned) This page intentionally left blank. Supplemental Table S2 Additional pre-specified efficacy outcomes during the placebo-controlled study period (up to week 16, observed data)

[0324] PBO (N=44) Izokibep 40 mg (N=44) Izokibep 80 mg (N=47) Outcome Week n Mean SD n Mean SD p value n Mean SD p value vs vs PBO* PBO* Musculoskeletal and inflammatory endpoints

[0325] TJC68 score 8 41 10.5 7.5 42 9.0 10.5 0.0108 46 7.4 7.2 0.0014

[0326] 12 42 10.9 8.7 43 8.1 8.9 <0.0001 46 6.0 6.7 <0.0001 SJC66 score 8 41 6.0 6.2 42 3.5 4.1 0.0002 46 3.7 4.7 <0.0001

[0327] 12 42 5.1 5.2 43 2.6 3.4 <0.0001 46 2.3 3.4 <0.0001 ESR (mm / h) 8 41 23.0 16.4 43 16.4 17.0 0.0135 47 14.8 10.0 0.0013

[0328] 12 42 21.9 16.0 43 16.4 15.1 0.0847 46 13.8 10.0 0.0017 16 43 23.6 16.3 42 16.3 19.4 0.0081 46 14.7 10.1 0.0003 CRP (mg / L) 8 40 8.36 9.18 42 4.20 5.57 <0.0001 47 3.05 3.13 <0.0001

[0329] 12 42 9.47 11.75 43 4.09 4.89 <0.0001 46 3.48 4.18 <0.0001 16 43 8.33 9.13 42 5.76 9.89 0.0098 44 3.15 3.78 <0.0001 Psoriasis-related endpoints

[0330] NAPSI score (target 8 35 2.9 1.9 35 1.9 1.8 0.0132 39 2.1 2.0 0.0591 nail).

[0331] Patient-reported outcomes

[0332] Worst Itch NRS score 16 43 3.6 2.9 42 2.2 2.5 0.0048 46 3.0 2.3 0.0194 DLQI sum score 16 43 7.1 7.8 42 3.0 3.5 0.6412 46 3.9 4.1 0.5907 Composite and global disease activity outcomes

[0333] DAPSA 16 43 25.77 16.06 42 16.51 14.81 <0.0001 46 14.08 11.47 <0.0001 clinical score

[0334] DAS28-ESR score 16 43 4.27 1.26 42 3.11 1.36 <0.0001 46 3.15 1.07 <0.0001

[0335]

[0336] ’Adjusted for previous TNFi exposure, concomitant csDMARD use, country, treatment, visit and treatment by visit interaction. Two-sided p values <0.05 were considered statistically significant.

[0337] CRP, C -reactive protein; csDMARD, conventional synthetic disease-modifying antirheumatic drug; DAPSA, Disease Activity in Psoriatic Arthritis; DAS28, Disease Activity Score in 28 joints; DLQI, Dermatology Life Quality Index; ESR, erythrocyte sedimentation rate; NAPSI, Nail Psoriasis Severity Index; NRS, numerical rating scale; PBO, placebo; SD, standard deviation; SJC66, swollen joint count based on 66 joints; TJC68, tender joint count based on 68 joints; TNFi, tumour necrosis factor inhibitor. Supplemental Table S3 Selected efficacy outcomes at weeks 32 and 46 (observed data)

[0338] Placebo— > Izokibep 80 mg‘ Izokibep 40 mg Izokibep 80 mg

[0339] Outcome Week 32 Week 46 Week 32 Week 46 Week 32 Week 46

[0340] n Value n Value n Value n Value n Value n Value Musculoskeletal endpoints

[0341] LDI-B for patients 8 0.64 (1.81) 5 0.00 (0.00) 6 0.00 (0.00) 4 0.00 (0.00) 4 0.00 (0.00) 3 0.00 (0.00) with LDI-B >0 at

[0342] baseline

[0343] LDI-B=0 for 8 7 (88%) 5 5 (100%) 6 6 (100%) 4 4 (100%) 4 4 (100%) 3 3 (100%) patients with LDI-B

[0344] >0 at baseline1'

[0345] SPARCC El in 24 1.6 (2.4) 16 0.8 (1.8) 26 0.6 (0.9) 13 0.5 (0.9) 26 1.0 (2.1) 18 0.9 (2.1) patients with

[0346] SPARCC El >0 at

[0347]

[0348] baseline1LEI in patients with 8 0.3 (0.7) 5 0.4 (0.9) 12 0.4 (0.7) 6 0.3 (0.8) 15 0.3 (0.7) 9 0.2 (0.7)

[0349] LEI >0 at baseline1

[0350] Psoriasis-related endpoints

[0351] PAS190- 13 8 (62%) 11 10 (91%) 17 13 (76%) 9 6 (67%) 19 15 (79%) 14 11 (79%) NAPSI score (target 25 1.3 (1.7) 17 0.5 (1.1) 29 0.7 (1.2) 12 0.7 (1.3) 27 1.1 (1.4) 16 1.0 (2.1) nail)

[0352] Patient-reported outcomes

[0353] PsAID-9 31 3.15 (2.12) 21 2.25 (2.12) 32 3.11 (2.16) 17 3.21 (2.53) 33 2.67 (1.89) 21 2.28 (2.00) HAQ-DI 31 0.87 (0.67) 21 0.77 (0.72) 32 0.76 (0.65) 17 0.74 (0.66) 33 0.79 (0.65) 21 0.77 (0.64) Patient’s pain 31 35.0 (21.9) 21 21.0 (23.2) 32 33.2 (26.3) 17 37.4 (30.1) 33 27.4 (21.6) 21 19.0 (20.3) assessment

[0354]

[0355] Placebo— ^Izokibep 80 mg* Izokibep 40 mg Izokibep 80 mg

[0356] Outcome Week 32 Week 46 Week 32 Week 46 Week 32 Week 46

[0357] n Value n Value n Value n Value n Value n Value Patient’s global 31 32.9 (21.2) 21 18.6 (20.2) 32 33.1 (26.0) 17 38.1 (31.5) 33 25.8 (21.4) 21 19.1 (21.2) assessment

[0358] Average Itch NRS 31 1.6 (1.9) 21 1.6 (2.0) 32 2.2 (2.4) 17 2.9 (2.6) 33 2.4 (2.1) 21 1.7 (2.0) Composite and global disease activity outcomes

[0359] DAPSA composite 31 16.92 21 11.55 32 14.74 17 15.69 33 13.30 (9.38) 20 10.91

[0360] score (11.86) (10.68) (13.03) (13.18) (9.35)

[0361] DAPSA clinical 31 13.40 21 8.91 32 11.50 17 12.90 33 9.75 (8.36) 21 7.15

[0362] score (11.84) (10.80) (12.01) (12.46) (7.40)

[0363]

[0364] DAS28-CRP 31 2.71 (0.88) 21 2.20 (0.86) 32 2.52 (1.00) 17 2.50 (1.01) 33 2.48 (0.91) 20 2.09 (0.89) DAS28-CRP <2.6 31 17 (55%) 21 16 (76%) 32 17 (53%) 17 10 (59%) 33 20 (61%) 20 15 (75%) (remission^

[0365] DAS-ESR score 31 2.98 (1.04) 21 2.37 (0.97) 31 2.72 (1.26) 17 2.76 (1.16) 33 2.59 (1.10) 21 2.15 (1.04) Physician’s global 31 16.5 (14.2) 21 10.7 (13.0) 32 13.7 (13.1) 17 17.5 (18.1) 33 10.2 (9.8) 21 7.5 (9.1)

[0366] assessment

[0367]

[0368] Values are presented as n (%) or mean (SD).

[0369] ‘Placebo patients were switched to izokibep 80 mg Q2W at week 16.

[0370] Subgroup analyses not pre-specified in the study protocol.

[0371] ?In patients with >3% BSA at baseline.

[0372] BSA, body surface area; DAPSA, Disease Activity in Psoriatic Arthritis; DAS, Disease Activity Score; DAS28-CRP, Disease Activity Score in 28 joints with C-reactive protein; ESR, erythrocyte sedimentation rate; HAQ-DI, Health Assessment Questionnaire Disability Index; LDI-B, Leeds Dactylitis Index-Basic; LEI, Leeds Enthesitis Index; NAPSI, Nail Psoriasis Severity Index; NRS, numerical rating scale; PAST, Psoriasis Area Severity Index; PsAID, Psoriatic Arthritis Impact of Disease; Q2W, every two weeks; SD, standard deviation; SPARCC El, Spondyloarthritis Research Consortium of Canada Enthesitis Index.

[0373]

[0374] Supplemental Table S4 Serious adverse events

[0375] Serious adverse event Number of patients Treatment Trial period Outcome Unstable angina 1 Izokibep 40 mg 16 to 46 weeks Recovered / resolved Hepatitis E infection 1 Placebo to izokibep 80 mg 16 to 46 weeks Recovered / resolved Intercostal neuralgia 1 Placebo to izokibep 80 mg 16 to 46 weeks Recovered / resolved Concussion* 1 Placebo to izokibep 80 mg 16 to 46 weeks Recovered / resolved Ulna fracture* 1 Placebo to izokibep 80 mg 16 to 46 weeks Recovered / resolved COVID-19-associated pneumonia 1 Izokibep 80 mg 16 to 46 weeks Recovered / resolved Ligament injury 1 Izokibep 80 mg 16 to 46 weeks Recovered / resolved Vulval cancer1.1 Izokibep 80 mg 16 to 46 weeks Unknown

[0376]

[0377] " The same patient experienced both a concussion and fracture of the ulna.

[0378] t57-year-old woman with longstanding PsA treatment. The event was initially reported as early-stage, highly differentiated, squamous human papillomavirus-associated cell carcinoma of the vulva (pTla, Gl, LO, VO). After laser excision, the event was downgraded to vulval intraepithelial neoplasia (uVIN3). After approximately 4 months of izokibep exposure, this latency period is considered too short to be a treatment-related effect.

[0379] COVID-19, coronavirus disease 2019; PsA, psoriatic arthritis.

Claims

CLAIMS1. A method of treating active psoriatic arthritis (PsA) in a patient in need thereof, comprising administering to the patient a composition comprising a therapeutically effective amount of izokibep, wherein the therapeutically effective amount is about 40 to about 80 mg about every two weeks.

2. The method of claim 1, wherein the patient has demonstrated an insufficient response to at least one of a nonsteroidal anti-inflammatory drug (NSAID), a conventional synthetic diseasemodifying antirheumatic drug (csDMARD), and a tumour necrosis factor inhibitor (TNFi).

3. The method of claim 1, wherein the patient is rheumatoid factor and anti-cyclic citrullinated peptide antibody negative.

4. The method of claim 1, wherein the patient has a history of or current plaque psoriasis (PsO).

5. The method of claim 1, wherein the patient does not have a history of or current autoimmune disease other than PsA or PsO.

6. The method of claim 1, wherein the therapeutically effective amount is about 40 mg.

7. The method of claim 1, wherein the therapeutically effective amount is about 80 mg.

8. The method of claim 1, wherein the izokibep is administered as a subcutaneous injection.

9. The method of claim 1, wherein the izokibep is administered for at least about 16 weeks.

10. The method of claim 1, wherein the izokibep is administered for at least about 30 weeks.

11. The method of claim 1, wherein the izokibep is administered for at least about 46 weeks.

12. The method of claim 1, wherein the method results in alleviation of symptoms of PsA.

13. The method of claim 12, wherein the method results in complete resolution of enthesitis.

14. The method of claim 12, wherein the method results in complete resolution of dactylitis.

15. The method of claim 12, wherein the method results in a Psoriasis Area and Severity Index (PASI) score of 75, wherein the patient had >3% body surface area (BSA) involvement at baseline.

16. The method of claim 12, wherein the method results in a Psoriasis Area and Severity Index (PASI) score of 100, wherein the patient had >3% body surface area (BSA) involvement at baseline.

17. The method of claim 12, wherein the method results in a Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index score of 0, wherein the patient had a SPARCC score of >0 at baseline.

18. The method of claim 12, wherein the method results in reduction of at least one step, of at least two steps, of at least three steps, of at least four steps, of at least five steps of the Leeds Enthesitis Index (LEI) score wherein the patient had an LEI score of >0 at baseline.

19. The method of claim 12, wherein the method results in a Leeds Enthesitis Index (LEI) score of 0, wherein the patient had an LEI score of >0 at baseline.

20. The method of claim 12, wherein the method results in at least 50%, at least 60%, at least 70%, at least 80% at least 90% reduction of the Leed’s Dactylitis Index-Basic (LDI-B) score wherein the patient had an LDI-B score of >0 at baseline.

21. The method of claim 12, wherein the method results in a Leed’s Dactylitis Index-Basic (LDI-B) score of 0, wherein the patient had an LDI-B score of >0 at baseline.

22. The method of claim 12, wherein the method results in a Nail Psoriasis Severity Index (NAPSI) score of 0 for a target nail specified at baseline.

23. The method of claim 12, wherein the method results in improvement in tender and swollenjoints, along with improvement in at least three of the following 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.

24. A pharmaceutical composition for use in the treatment of active psoriatic arthritis (PsA), wherein the composition comprises about 80 mg / mL of izokibep, and wherein the composition is formulated as a solution for injection.

25. Use of a pharmaceutical composition, comprising about 80 mg / mL of izokibep formulated as a solution for injection, in the manufacture of a medicament for the treatment of active psoriatic arthritis (PsA).

26. Use according to claim 25, wherein the pharmaceutical composition comprises 80 mg / mL of izokibep.

27. Use according to claim 25 or 26, wherein the treatment is as defined in any one of claims 1-

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