Rationale and Design of a Phase 1b Trial Evaluating APG279, the Combination of Half-Life-Extended Anti-IL-13 and Anti-OX40L Monoclonal Antibodies, Compared With Dupilumab in Moderate-to-Severe Atopic Dermatitis

Introduction: Atopic dermatitis (AD) is a chronic skin disease primarily driven by Type 2 inflammation. Other pathways, including Type 1 and Type 3 inflammation, are known to contribute to disease heterogeneity. Monoclonal antibodies (mAb) targeting the IL-13, IL-4/IL-13, or OX40/OX40L pathway have demonstrated therapeutic potential for improving the signs and symptoms of AD, although current therapies require ongoing injections every 2-4 weeks. There remains an unmet need to address the multiple drivers of inflammation in this disease while minimizing injection burden for patients. Rationale: APG279 is a combination of APG777, a half-life-extended anti-IL-13 mAb, and APG990, a half-life-extended anti-OX40L mAb. APG777 was designed for deep and sustained inhibition of IL-13-driven Type 2 inflammation, while APG990 targets the upstream OX40/OX40L interaction with the potential for broad inhibition of Types 1, 2, and 3 inflammation. In phase 1 studies, both mAbs demonstrated favorable safety and pharmacokinetics (PK), with APG777 exhibiting a half-life of 75.3-77.5 days and APG990 demonstrating a half-life of ~60 days (interim results). Objective: This phase 1b, open-label, assessor-blinded, randomized, multicenter, active comparator study (NCT07027527) evaluates the safety, PK, pharmacodynamics (PD), and efficacy of APG279 in adults with moderate-to-severe AD, in comparison to dupilumab. Study Design: Adults (≥18 years) are eligible to participate if they have a diagnosis of AD for ≥1 year and exhibit moderate-to-severe AD (EASI≥16, vIGA-AD≥3, BSA≥10%) at screening and baseline. Participants will be randomized 1:1 to APG279 or dupilumab. The study consists of a 24-week treatment period and a 52-week follow-up. The primary endpoint is the incidence of treatment-emergent adverse events through week 24. Secondary endpoints include PK of APG777 and APG990. Exploratory endpoints include biomarkers, ADA, and efficacy (e.g., EASI-75, vIGA-0/1) throughout the study including the follow-up period. The study is currently enrolling in Canada, Australia, and New Zealand and aims to include ~50 participants. Funding: Apogee Therapeutics, Inc.

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