Phase 1 Clinical Data of ORKA-001, a Novel Half-Life Extended IL-23p19 Monoclonal Antibody with Potential for Once-Yearly Dosing in Plaque Psoriasis

Abstract

Introduction & Objectives: ORKA-001 is a novel half-life extended monoclonal antibody targeting IL-23p19 with similar potency and epitope binding to risankizumab. ORKA-001’s extended half-life has the potential to enable once-yearly dosing, increased efficacy, and extended off-treatment remission in psoriasis. Here, 24-week results of the First in Human (FIH) Phase 1 study of ORKA-001 in healthy volunteers are presented.

Materials & Methods:  This Phase 1, double-blinded, placebo-controlled, randomized FIH study evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single ascending doses (SAD) of ORKA-001 in 24 healthy adult volunteers. Participants were randomized 6:2 to receive a single subcutaneous (SC) dose of ORKA-001 or placebo across three ascending dose-level cohorts: 300 mg, 600 mg, and 1200 mg. Participants were admitted to a Clinical Research Unit, where they remained until Day 4 and then returned to the clinic for follow-up safety and PK assessments over one year.

Results: Eight participants were dosed in each of the 3 cohorts: 6 with ORKA-001 and 2 with placebo. Baseline characteristics were typical of a healthy volunteer population. Half-life of ORKA-001 was approximately 100 days. Individual PK profiles showed no indication of anti-drug antibodies (ADAs​). In an ex vivo assay, serum from subjects dosed with ORKA-001 potently inhibited IL-23-mediated STAT3 signaling for 24 weeks (study duration to date). The study remains blinded; however, no serious or severe adverse events (AEs) were reported, and no discontinuations occurred. AEs reported in >2 participants were headache, upper respiratory tract infection, and transient erythema at the injection site.​ All of these events were mild. No dose-dependent trends in AEs were observed.

Conclusion: PK and PD results in this Phase 1 study of ORKA-001 support the potential for once-yearly dosing while maintaining trough antibody concentrations above approved IL-23 targeting antibodies like risankizumab. In addition, the PK profile supports evaluation of higher antibody exposures that may allow ORKA-001 to achieve higher rates of skin clearance than that of the current standard of care and long-term off-treatment remission in some patients. ORKA-001 was well-tolerated across all dose levels, with a favorable safety profile consistent with the IL-23p19 inhibitor class. These attributes are being further explored in an ongoing Phase 2a study, EVERLAST-A, which is evaluating efficacy and safety of ORKA-001 in adults with moderate-to-severe psoriasis.