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.