Izokibep in patients with active psoriatic arthritis: Latest results from a phase II study

Psoriatic arthritis (PsA) is a chronic, systemic inflammatory, autoimmune disease with a variety of symptoms, most prominently arthritis, dactylitis, and enthesitis, as well as plaque psoriasis and axial skeleton involvement. Current treatments focus on controlling inflammation and include disease-modifying antirheumatic drugs (DMARDs), nonsteroidal anti-inflammatory drugs (NSAIDs), and biologic agents that target different pathways of the immune system.¹ However, there is still a risk of inadequate disease management and the development of new drugs remains urgent.

Interleukin-17A (IL-17A)-mediated immune response plays a pivotal role in PsA. Izokibep (ABY-035) is a novel small molecule IL-17A inhibitor with potent binding affinity for two subunits of IL-17A and serum albumin, allowing for a half-life extension and increased drug concentration in the sites of inflammation, including joints, skin, and nails.² Izokibep was investigated in a phase II clinical trial (NCT04713072) to evaluate its efficacy and safety compared with placebo in patients with active PsA. Frank Behrens presented the first results from this trial at the European Alliance of Associations for Rheumatology (EULAR) 2022 Congress² and we are pleased to provide a summary here.

Study design and patient characteristics

The study was a multicenter, randomized, double-blind, placebo-controlled, and dose-finding clinical trial to investigate the efficacy, safety, pharmacokinetics, and immunogenicity of izokibep versus placebo in patients with active PsA.

A total of 135 patients with a mean age of 48.5 years were enrolled at 22 European sites between June 2020 and July 2021. The patients were randomized to 40 mg izokibep or 80 mg izokibep or placebo (all biweekly) in a 1:1:1 ratio, and ≥50% improvement based on the American College of Rheumatology (ACR) criteria (ACR50) at Week 16 was evaluated as the primary endpoint. In total, 80% of patients received a concomitant conventional synthetic DMARD during the trial. The mean duration of PsA and psoriasis was ~8 years and ~10 years, respectively. Demographics and disease characteristics were balanced among the groups.

Study design and patient characteristics are detailed in Figure 1 and Table 1, respectively.

Figure 1. Study design* 

ACR, American College of Rheumatology; AE, adverse event; PSO-BSA, psoriasis body surface area; CASPAR, Classification Criteria for Psoriatic Arthritis; csDMARD, conventional synthetic disease modifying antirheumatic drug; IBD, inflammatory bowel disease; ISR, injection site reaction; LEI, Leeds Enthesitis Index; NSAID, non-steroidal anti-inflammatory drug; PASI, Psoriasis Area Severity Index; PsA, psoriatic arthritis; PsAID, Psoriatic Arthritis Impact of Disease; Q2W, once every two weeks; SJC66, Swollen Joints out of 66 joints; SAE, severe adverse event; TJC68, Tender Joints out of 68 joints; TNFi, tumor necrosis factor inhibitor.
*Adapted from Behrens.² 

Table 1. Baseline characteristics*

Results

Safety

Treatment-emergent adverse events were reported in 58% of patients and were mostly mild or moderate in severity. No serious adverse events or new onset/flare of inflammatory bowel disease were reported. Two patients discontinued the treatment due to injection site reactions. There were no apparent differences in safety between treatment groups and placebo, with the exception of injection site reactions in the izokibep 40 mg arm. Of note, there was only one mild vulvovaginal candida infection reported, which did not lead to treatment discontinuation. The results of the safety analysis are provided in Table 2.

Table 2. Safety outcomes*

Efficacy

At 16 weeks, the ACR50 response rates were 48% and 52% in the 40 mg and 80 mg groups, respectively, compared with 13% in the placebo group (p = 0.0014 and p = 0.0006, respectively). The ACR20/50/70 response rates by treatment group are presented in Figure 2A. As shown in Figure 2B, both treatment groups demonstrated greatly improved response rates in terms of the ≥75% and ≥90% improvement in Psoriasis Area and Severity Index (PASI-75 and PASI-90, respectively) in patients with a psoriasis body surface area of >3% (izokibep 40 mg, n = 23; izokibep 80 mg, n = 28; and placebo, n = 23).

Figure 2. Response rates according to A ACR and B PASI scores at 16 weeks* 

ACR, American College of Rheumatology; ACR20, ≥20% improvement based on ACR criteria; ACR50, ≥50% improvement based on ACR criteria; ACR70, ≥70% improvement based on ACR criteria; PASI, Psoriasis Area and Severity Index; PASI75, ≥75% improvement in PASI; PASI90, ≥90% improvement in PASI; PASI100, ≥100% improvement in PASI; Q2W, once every two weeks.
*Data from Behrens.²

In addition, resolution of enthesitis (Leeds Enthesitis Index = 0) at Week 16 was 63% for the 40 mg group, 88% for the 80 mg group, and 10% for the placebo group in those with enthesitis at baseline. There were also clinically important improvements in quality of life according to the Psoriatic Arthritis Impact of Disease score at 16 weeks, with the proportion of patients achieving a minimal clinical important improvement at 41% in the 80 mg group versus 12% in the placebo group.

Conclusion

Overall, the results of this study suggest that 16 weeks of izokibep treatment was associated with high response rates (ACR50, PASI75, and PASI90) in patients with PsA, showing a dose-dependent efficacy in the musculoskeletal and cutaneous domains. Izokibep was generally well tolerated and its safety profile was broadly consistent with placebo in this study and with approved IL-17A inhibitors in general. No dose-related adverse events or dose-limiting toxicity were reported, suggesting izokibep could be tested at higher doses. Further larger clinical studies are under development.