EVERLAST-A: A Phase 2a Study Design of ORKA-001, a Novel Half-Life Extended IL-23p19 Monoclonal Antibody for Plaque Psoriasis

Abstract

Introduction & Objectives:

The clinical efficacy and safety of monoclonal antibodies targeting IL-23 have been well established in plaque psoriasis. While currently approved therapies have significantly advanced care of psoriasis patients, issues such as frequent injections, fixed-dose regimens, inadequate responses, and loss of efficacy over time remain. Additionally, achieving off-treatment remission remains a key aspiration in psoriasis treatment.

ORKA-001 is a novel half-life extended monoclonal antibody targeting IL-23p19 with similar potency and epitope binding to risankizumab. In non-human primates, ORKA-001 demonstrated a half-life approximately three times longer than that of risankizumab, potentially enabling a dose frequency of once to twice per year. In addition, increased doses of ORKA-001 (vs. risankizumab) could improve efficacy by enabling complete blockade of IL-23 activity within skin. Complete and sustained inhibition of IL-23 with ORKA-001 may deplete tissue-resident memory T cells that have been linked to prolonged skin clearance while off therapy. Here, we outline the innovative study design of EVERLAST-A, a Phase 2a study to evaluate efficacy and safety of ORKA-001 in psoriasis.

Materials & Methods: EVERLAST-A is a multicenter, randomized, double-blinded, placebo-controlled, proof-of-concept, Phase 2a study to evaluate efficacy, safety, and pharmacokinetics (PK) of ORKA-001 in adults with moderate-to-severe plaque psoriasis. The EVERLAST-A study consists of a screening period, a 28-week double-blinded induction period, and a 24-week maintenance period. At baseline, 80 participants will be randomized in a 3:1 ratio to receive either ORKA-001 600 mg or placebo, administered subcutaneously at Weeks 0 and 4. Two maintenance regimens will be evaluated: ORKA-001 300 mg administered every six months and a treatment-free arm, aiming to assess both disease remission and feasibility of once-yearly dosing. The primary endpoint is the proportion of participants achieving PASI 100 at Week 16. Additional endpoints include efficacy measures, quality of life, safety, PK, and biomarker assessments. At Week 52, participants may enter an open-label extension to assess long-term safety and efficacy, including evaluation of six-monthly and once-yearly dosing, as well as the potential for disease remission.

Conclusion:

EVERLAST-A is a Phase 2 proof-of-concept study evaluating efficacy and safety of ORKA-001 in adults with moderate-to-severe psoriasis. The study aims to investigate whether high induction doses of ORKA-001, a novel IL-23p19 inhibitor with an extended half-life, can lead to increased rates of skin clearance and prolonged durability of responses. This dosing strategy could support infrequent individualized dosing and potentially lead to disease remission in some individuals.