DESIGN OF A PHASE 2A, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF MK-6194, AN INTERLEUKIN-2 MUTEIN, IN ADULT PARTICIPANTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS

PV264 / #825 Poster Topic: AS24 - SLE-Treatment Background/Purpose Regulatory T cell (Treg) dysfunction is a key feature of systemic lupus erythematosus (SLE). Preliminary studies expanding Tregs in patients with SLE using low-dose interleukin 2 (IL-2) have demonstrated promising results. However, use of IL-2 is limited due to its short half-life requiring frequent injections and the narrow therapeutic window for Treg selectivity poses the risk of activating other immune responses (eg, pathogenic T effector, natural killer [NK] cells). Compounding these challenges, SLE is immunologically and clinically heterogenous with a high variability in disease activity and organ system involvement. Interpretation of SLE trial results is further complicated by various background treatments, imperfect outcome measures, and need for experienced investigators. Therefore, there are challenges to the development of treatments for Treg expansion in SLE. MK-6194 is an IL-2 mutein with enhanced Treg selectivity, increased affinity for the alpha chain of the IL-2 receptor (CD25) and decreased affinity for the beta chain (CD122), which is Fc-conjugated for increased half-life. In a phase 1 trial, subcutaneous (SC) MK-6194 was generally well tolerated (up to a single dose of 10 mg; up to doses of 5 mg every 2 or 4 weeks) by healthy participants with no serious adverse events (AEs) or dose-limiting toxicities. Injection site erythema was the most common AE. A dose-dependent increase in Treg number was observed, peaking between Days 8–11 with no attenuation after repeated injections and minimal impact on non-Treg or NK cell numbers. These data support further evaluation of MK-6194 as a potential treatment for SLE. To test this hypothesis in a phase 2a SLE trial, analysis of past trials highlights the importance of accurate assessment of eligible patients with clinically significant disease activity and limited background therapy. Methods This multicenter, randomized, double-blind, placebo-controlled phase 2a trial is currently enrolling eligible adults (Table) with moderate-to-severe SLE (Figure) randomized (1:1:1) to receive SC placebo or MK-6194 in 1 of 2 dosing regimens for 52 weeks (main trial period) followed by a double-blind long-term extension ( NCT06161116 ). The primary efficacy endpoint is the proportion of participants with Systemic Lupus Erythematosus Responder Index-4 (SRI-4) response at Week 28. The primary safety endpoint is the number of AEs and AEs leading to trial discontinuation. Secondary endpoints include SRI-4 response at Week 52, British Isles Lupus Assessment Group-Based Composite Lupus Assessment (BICLA) and Cutaneous Lupus Erythematosus Disease Area and Severity Index-50 (CLASI-50) responses at Weeks 28 and 52, and change from baseline in tender/swollen joint counts. Exploratory endpoints include immunologic parameters, pharmacokinetics/pharmacodynamics, anti-drug antibodies, and biomarker parameters. Patient eligibility and accuracy of disease activity scoring throughout the trial will be adjudicated by an experienced, blinded clinical team. Table. Inclusion/exclusion criteria Figure. Trial design and key endpoints Results The trial is actively recruiting approximately 270 participants in 17 countries across North America, Latin America, Europe, the Middle East and Asia-Pacific regions. Estimated primary trial completion will be April 2027. Conclusions This currently recruiting phase 2a trial was designed to address challenges in the development of Treg expansion therapy for SLE. MK-6194, a novel IL-2 mutein, was developed for Treg selectivity with longer half-life. The trial protocol utilized knowledge gained from past SLE publications to increase the likelihood of interpretable data.