EP262, an MRGPRX2 Antagonist for the Treatment of Atopic Dermatitis: Results From the Phase 2 Randomized EASE Study

INTRODUCTION: Mas-related G protein-coupled receptor X2 (MRGPRX2) levels are elevated in patients with atopic dermatitis (AD). EP262, a small-molecule MRGPRX2 receptor antagonist, significantly diminished AD development in humanized mouse models of AD. In the EASE study, the safety, tolerability, and pharmacodynamics of EP262 were compared with placebo in patients with AD. METHODS: Patients aged 18-80 years with AD, 3%-20% affected body surface area, and validated Investigator's Global Assessment for AD (vIGA-AD) score ≥ 3 were randomized 2:1 to receive 150 mg EP262 or placebo once daily for 6 weeks. The primary endpoint was safety and tolerability. The secondary endpoint was change from baseline to Week 6 in gene expression signature and skin histology. Exploratory efficacy endpoints included Eczema Area and Severity Index (EASI), vIGA-AD, and Peak Pruritus Numerical Rating Scale (PP-NRS). RESULTS: Of 32 randomized patients (median [range] age, 41.0 [18-70] years), treatment-emergent adverse events (TEAEs) were reported in 19.0% of patients who received EP262 and 63.6% who received placebo, with none considered treatment-related. No grade ≥ 3 or serious TEAEs were observed, and no TEAEs led to dose interruptions or treatment discontinuations. No genes were differentially expressed between baseline lesional or nonlesional samples and Week 6 lesional samples. Differences in epidermal thickness were not meaningful between groups following treatment. No improvement was observed at Week 6 between EP262 and placebo in EASI (mean percentage change from baseline, - 14.9% vs - 40.7%), vIGA-AD (patients scoring 0/1 with ≥ 2-point improvement from baseline, 21.1% vs 27.3%), or PP-NRS scores (mean percentage change from baseline, - 26.7% vs - 25.1%). CONCLUSIONS: EP262 was well tolerated in patients with AD. No meaningful differences were observed in gene expression, skin thickness, or efficacy measures in patients who received EP262 versus placebo. TRIAL REGISTRATION: Clinicaltrials.gov identifier, NCT06144424 (registered on November 16, 2023).