medwireNews: The small protein therapeutic izokibep that inhibits interleukin (IL)-17A significantly reduces disease activity in people with active psoriatic arthritis (PsA), according to the results of a phase 2 study.
The primary end point of achieving an ACR50 response – more than 50% improvement in American College of Rheumatology (ACR) criteria – at 16 weeks was achieved in 52% of the 47 people who were randomly assigned to receive treatment with izokibep 80 mg, and 48% of the 44 people who were treated with izokibep 40 mg, but just 13% of the 44 people treated with placebo.
Moreover, izokibep treatment was associated with “significant and clinically meaningful improvements over placebo across multiple disease domains,” report Peter Taylor (University of Oxford, UK) and fellow investigators in the Annals of the Rheumatic Diseases.
Other endpoints, which were tested in a hierarchical order, included: ACR50 at 12 weeks; ACR20 and ACR70 at week 16 and at week 12, respectively; minimal disease activity (MDA) at week 16 and at week 12; and ACR50, ACR20, ACR70, and MDA at week 8.
For almost all of these ranked endpoints, izokibep 80 mg and 40 mg were associated with significantly greater improvements than placebo. The exceptions were for ACR70 at weeks 16, 12, and 8, and MDA at week 8 with the 80 mg dose of izokibep versus placebo.
The researchers explain that, compared with existing IL-17 monoclonal antibodies for PsA, “izokibep’s unique properties, including its small size (18.6kDa), high affinity for IL-17A (equilibrium dissociation constant [KD] 0.3 pM), and albumin-binding domain, may provide an advantage over antibodies in penetrating inflamed tissues to improve levels of efficacy.”
The trial plan consisted of a 4-week screening period, a 16-week double-blind phase, and a subsequent 28-week treatment period when people who had been allocated to placebo were switched to receive izokibep 80 mg. A protocol amendment, however, meant that the study was terminated after the last participant had completed the 16-week double-blind phase.
Throughout the trial izokibep or matching placebo were administered via subcutaneous injection every 2 weeks. Safety was assessed at every visit, with efficacy assessments undertaken at baseline, week 2, then every 4 weeks, and additionally at weeks 18 and 46.
The study’s 135 participants, 54% of whom were women, were recruited from 28 centers throughout Europe. All met Classification Criteria for Psoriatic Arthritis and had active PsA, defined as having at least three tender and three swollen joints, current or past plaque psoriasis, and an insufficient response to nonsteroidal anti-inflammatory drugs, conventional synthetic disease-modifying antirheumatic drugs, or tumor necrosis factor inhibitors.
Similar baseline characteristics were recorded across the study groups. The mean age was 48.5 years and the mean duration of PsA was 7.1 years. The mean number of tender and swollen joints were a respective 16.7 and 9.9, and 98% of patients had psoriasis. Enthesitis was recorded in 77% using the SPARCC Enthesitis Index and in 32% using the Leeds Enthesitis Index (LEI); 19% had dactylitis.
Taylor et al report “large improvements” in nail dystrophy, dactylitis, and enthesitis with izokibep 80 mg and 40 mg versus placebo during the 16-week double-blind phase of the study. For instance, enthesitis resolution using the LEI occurred in a respective 88%, 67%, and 11%.
There were also significantly greater improvements comparing the 80 and 40 mg doses of izokibep with placebo in the percentage of people who achieved a 75% reduction in the Psoriasis Area and Severity Index score from baseline (85 and 83 vs 14%), as well as a 90% reduction (48 and 57 vs 14%) and a 100% reduction (37 and 39 vs 5%).
“There were no unexpected safety risks identified,” say the researchers. The most common treatment-emergent adverse events (TEAEs) associated with izokibep 80 mg and 40 mg use were injection site reactions (26% and 27% of participants at 16 weeks, respectively) and injection site erythema (11% and 18%), which did not occur in the placebo-treated group. All TEAEs were of mild or moderate intensity and no dose-response relationships were seen.
“The findings support the continued development of izokibep as a novel therapeutic in PsA,” says the team.
“Higher doses are being explored in a clinical study to assess whether greater levels of disease control might be possible.”
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