Anti‐KIT Barzolvolimab for Chronic Spontaneous Urticaria

ABSTRACT Background Chronic spontaneous urticaria (CSU) is characterized by mast cell (MC)‐mediated wheals and/or angioedema without identifiable triggers and is driven by MC activation. Barzolvolimab—a monoclonal anti‐KIT antibody—depletes MCs by inhibiting activation of KIT by stem cell factor. We evaluated multiple ascending doses in patients with CSU. Methods Phase 1b double‐blind placebo‐controlled trial (NCT04538794) in adults with moderate‐to‐severe (urticaria activity score over 7 days [UAS7] ≥ 16) antihistamine–refractory CSU treated with intravenous barzolvolimab for 12 weeks with a 12‐week follow‐up in four sequentially enrolled cohorts (randomized 4:1 barzolvolimab:placebo): 0.5 mg/kg, Q4W ( n = 9); 1.5 mg/kg, Q4W ( n = 8); 3 mg/kg, Q8W ( n = 9); and 4.5 mg/kg, Q8W ( n = 9). Primary and secondary objectives were safety and disease activity (UAS7 and urticaria control test [UCT]). Pharmacokinetics and pharmacodynamics were assessed. Results Patients had high mean (range) baseline CSU activity, with UAS7 = 29.6 (16.3–42.0) for barzolvolimab‐treated, UAS7 = 35.8 (19.0–42.0) for placebo‐treated, and 44% prior omalizumab use. Multiple doses of barzolvolimab were well tolerated. Hair color change was the commonest adverse event in barzolvolimab‐treated patients. Across barzolvolimab doses, rapid symptom reduction within 1 week was observed and sustained during 12 weeks; 71% of patients achieved a well‐controlled (UAS7 ≤ 6) response and 57% a complete response (UAS7 = 0). Additionally, 77% of barzolvolimab‐treated patients achieved a well‐controlled response (UCT ≥ 12) and 43% a complete response (UCT = 16) by Week 12. The kinetics of disease activity paralleled tryptase suppression, indicative of MC inhibition. Patients with and without prior omalizumab treatment responded similarly. Conclusions This study supports barzolvolimab as a promising treatment for CSU.