CHRONIC hives symptoms improved with experimental oral EP262, but neither dose outperformed placebo in a randomized trial. The Phase II CALM-CSU study found no significant additional benefit for disease activity, itch, or hive severity after six weeks of treatment alongside stable daily H1 antihistamines.
Chronic spontaneous urticaria (CSU) causes itchy wheals, angioedema, or both for more than six weeks without a known external trigger. EP262 targets Mas-related G protein–coupled receptor X2 (MRGPRX2), a receptor on skin mast cells associated with immunoglobulin E (IgE)-independent degranulation.
The multicenter, double-blind study randomized 113 adults to oral EP262 50 mg, EP262 150 mg, or placebo once daily. Eligible patients were aged 18–80 years, had CSU for at least six months, and had a Urticaria Activity Score over seven days (UAS7) of at least 16 despite receiving stable daily H1 antihistamines. Overall, 107 patients completed treatment.
The primary endpoint was the change in UAS7 from baseline to Week 6. This patient-reported measure combines itch intensity and hive counts.
Least squares mean UAS7 reductions were 10.4 points with placebo, 8.4 points with EP262 50 mg, and 12.0 points with EP262 150 mg. Neither dose differed significantly from placebo. The estimated differences versus placebo were 1.99 points for 50 mg (90% CI: −1.96 to 5.94; p=0.4059) and −1.53 points for 150 mg (90% CI: −5.49 to 2.42; p=0.5213).
Weekly itch and hive severity scores also improved across all groups without significant treatment differences. Exploratory efficacy outcomes followed the same pattern.
Both EP262 doses were generally well tolerated. No serious treatment-emergent adverse events occurred, and no treatment-related events were Grade 3 or higher. Vital signs, electrocardiograms, and laboratory assessments showed no clinically meaningful safety patterns.
A planned second study component evaluating a lower dose was terminated following the lack of efficacy. Small sample size, short treatment duration, and limited population diversity constrain interpretation.
For clinicians, these findings do not establish EP262 as an effective addition to antihistamines for chronic hives at the doses and duration studied. They also leave unanswered whether other treatment durations or patient populations could yield different results.
Reference
Metz M et al. MRGPRX2 antagonism in chronic spontaneous urticaria: Phase 2 randomized CALM-CSU study results. Allergy. 2026;doi:10.1111/all.70547.
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