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Clinical Trial
. 2025 Aug;80(8):2178-2186.
doi: 10.1111/all.16598. Epub 2025 May 26.

Anti-KIT Barzolvolimab for Chronic Spontaneous Urticaria

Marcus Maurer  1   2 , Martin Metz  1   2 , John Anderson  3 , Neetu Talreja  4 , Diane Young  5 , Elizabeth Crowley  5 , Margo Heath-Chiozzi  5 , Rick Ma  5 , Elsa Paradise  5 , Thomas Hawthorne  5 , Diego Alvarado  5 , Jonathan A Bernstein  6
Affiliations
Clinical Trial

Anti-KIT Barzolvolimab for Chronic Spontaneous Urticaria

Marcus Maurer et al. Allergy. 2025 Aug.

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.

Keywords: anti‐KIT; chronic urticaria; hives; mast cell; monoclonal antibody; stem cell factor.

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Conflict of interest statement

Diego Alvarado, Diane Young, Elizabeth Crowley, Elsa Paradise, Rick Ma, Thomas Hawthorne, and Margo Heath‐Chiozzi are full‐time employees of Celldex Therapeutics and may hold stock and/or stock options. Martin Metz reports being a speaker and/or advisor for AbbVie, Advanz, ALK Abello, Allegria, Almirall, Amgen, AstraZeneca, Argenx, Astria, Attovia, Berlin‐Chemie, Celldex, Celltrion, DeepApple, Escient, Galderma, GSK, Incyte, Jasper, Lilly, Novartis, Pfizer, Regeneron, Sanofi, Santa Ana Bio, Septerna, Teva, ThirdHarmonic Bio, and Vifor. John Anderson is a speaker bureau member for CSL Behring, Pharming, BioCryst, Takeda, AstraZeneca, and GSK; has received consulting fees from CSL Behring, Pharming, BioCryst, Pharvaris, Ionis, Takeda, and Novartis; and is a clinical trial investigator for BioCryst, CSL Behring, Pharvaris, Kalvista, Biomarin, Astria, Takeda, Novartis, and Celldex. Neetu Talreja has been an investigator for 9Meters, AbbVie, Allakos, Amgen, Anaptybio Inc., Arena, ARS, AstraZeneca, Biohaven, Braintree, Celldex, Eli Lilly, Escient, GlaxoSmithKline, Gossamer, Incyte, Janssen, Knopp, Nerre, Novartis, Pearl Therapeutics, Pfizer, Phathom, Regeneron, Sanofi, Teva, and Upstream. She has also sat on advisory board(s) and been a medical consultant for Celldex, Novartis, and Regeneron. Jonathan A. Bernstein has been a PI, consultant, and speaker for Novartis, Genentech, AstraZeneca, Sanofi, Regeneron, BioCryst, CSL Behring, Takeda/Shire, Pharming, and GSK; PI and consultant for Celldex, Cogent, Escient, Jasper, Amgen, Roche, Ionis, Kalvista, Allakos, Biomarin, and Blueprint Medicine; PI for Allergy Therapeutics, Telios, Intellia, Aretrea, Pharvaris, Astria; PI for Teva; and consultant for Incyte, Astria, ONO, Cycle, Escient, Pharvaris, and TLL.

Figures

FIGURE 1
FIGURE 1
Change from baseline in UAS7 and UCT and percentage of responders for UAS7 = 0 and UAS7 ≤ 6 according to barzolvolimab dose. (A) UAS7 mean ± SE shown from baseline to Week 24. UAS7 describes urticaria activity, with lower scores representing low urticaria activity and higher scores representing high urticaria activity. (B) UCT mean ± SE shown from baseline to Week 24. Higher scores represent greater urticaria control, with a score of ≥ 12 indicating well‐controlled disease (shaded light green). (C) Percentage of patients who were urticaria free (UAS7 = 0) from baseline to Week 24. (D) Percentage of patients who were well controlled (UAS7 ≤ 6) from baseline to Week 24. Abbreviations: Q4W, every 4 weeks; SE, standard error; UAS7, urticaria activity score over 7 days; UCT, urticaria control test.
FIGURE 2
FIGURE 2
Change from baseline in serum barzolvolimab concentrations, serum tryptase percentage of baseline, and plasma SCF fold change over baseline according to barzolvolimab dose. (A) Serum barzolvolimab concentrations mean ± GeoSD, from baseline to Week 24, dotted red line indicates lower limit of quantitation 0.07 ug/mL. (B) Serum tryptase mean percentage of baseline ± SE. (C) Plasma SCF mean fold change over baseline ± SE. Abbreviations: GeoSD, geometric standard deviation; SCF, stem cell factor; SE, standard error.
FIGURE 3
FIGURE 3
Change from baseline in UAS7 and UCT in barzolvolimab‐treated patients according to omalizumab naivety or experience. (A) UAS7 mean ± SE in omalizumab‐naive and ‐experienced patients from baseline to Week 24. UAS7 calculated over 7 consecutive days describes urticaria activity, with lower scores representing low urticaria activity and higher scores representing high urticaria activity. (B) UCT mean ± SE in omalizumab‐naive and ‐experienced patients from baseline to Week 24. Higher scores represent greater urticaria control, with a score of ≥ 12 indicating well‐controlled disease. Pooled data from saturating doses (1.5, 3.0, and 4.5 mg/kg). Abbreviations: Q4W, every 4 weeks; SE, standard error; UAS7, urticaria activity score over 7 days; UCT, urticaria control test.
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