Celldex discontinued barzolvolimab development in prurigo nodularis after its Phase 2 trial missed primary and secondary endpoints despite profound mast cell depletion.
Written By: Shaik Yasmeen, PharmD
Reviewed By: Pharmacally Editorial Team
Celldex has halted its Phase 2 clinical program evaluating barzolvolimab in patients with moderate to severe prurigo nodularis (PN) after the study failed to meet its primary efficacy endpoint and key secondary objectives. Although the investigational monoclonal antibody produced rapid and sustained depletion of mast cells, the biological effect did not translate into clinical improvements in itch severity or skin lesions compared with placebo.
The topline results represent a setback for barzolvolimab in PN but do not alter the company’s broader development strategy, which remains focused on chronic spontaneous urticaria (CSU), symptomatic dermographism (SD), cold urticaria (ColdU), and atopic dermatitis (AD).
Barzolvolimab Targets Mast Cells Through KIT Receptor Inhibition
Barzolvolimab is a humanized monoclonal antibody that selectively binds the KIT receptor, a critical signaling pathway required for mast cell survival and function. By inhibiting KIT, the therapy produces systemic mast cell depletion, a mechanism that has shown encouraging efficacy in several mast cell-driven inflammatory diseases.
Prurigo nodularis is a chronic inflammatory skin disorder characterized by intensely itchy, hard nodules that substantially impair quality of life. Current treatment options remain limited, particularly for patients who do not respond adequately to topical therapies.
The new findings indicate that mast cell depletion alone may be insufficient to improve symptoms in PN, highlighting differences in disease biology compared with chronic urticarias.
Phase 2 Trial Missed Primary and Secondary Efficacy Endpoints
The randomized, double-blind, placebo-controlled Phase 2 study (NCT06366750) enrolled 140 adults with moderate to severe prurigo nodularis who had an inadequate response to prescription topical medications or for whom topical treatment was medically inadvisable.
Participants were randomized to receive
- Barzolvolimab 150 mg every four weeks following a 450 mg loading dose
- Barzolvolimab 300 mg every four weeks following a 450 mg loading dose
- Placebo
Treatment continued for 24 weeks, followed by a 16-week observation period without study treatment. Patients with persistent symptoms, including those initially assigned to placebo, could enter an open-label extension.
The primary endpoint evaluated the proportion of patients achieving at least a four-point improvement from baseline on the Worst Itch Numeric Rating Scale (WI-NRS) at Week 12.
Neither dosing regimen demonstrated superiority over placebo. The study also failed to show improvements in key secondary endpoints, including the proportion of patients achieving an Investigator’s Global Assessment for Chronic Nodular Prurigo-Stage (IGA-CPNG-S) score of 0 or 1. No meaningful clinical benefit emerged after extending treatment through Week 24.
Profound Mast Cell Depletion Confirmed Despite Lack of Clinical Benefit
Although efficacy endpoints were not achieved, barzolvolimab produced rapid, profound, and sustained reductions in circulating serum tryptase, a recognized biomarker of systemic mast cell depletion.
The newly introduced 450 mg loading dose accelerated early tryptase suppression, which remained durable throughout treatment. Despite this clear pharmacodynamic effect, reductions in mast cells were not associated with improvements in itch intensity or skin lesion severity.
The disconnect between biological activity and clinical outcomes suggests mast cells may not represent the principal pathogenic driver of prurigo nodularis symptoms.
Safety Profile Remained Consistent with Earlier Studies
Barzolvolimab was generally well tolerated across both treatment groups. The safety profile of the 450 mg loading dose followed by either 150 mg or 300 mg every four weeks was consistent with findings from previous clinical studies, with no new safety concerns reported.
The favorable tolerability supports continued evaluation of the therapy in diseases where mast cells play a more established pathogenic role.
Company Shifts Focus to Late-Stage Mast Cell Programs
Celldex President and Chief Executive Officer Anthony Marucci said the results were disappointing because they did not reproduce the encouraging signal observed in an earlier intravenous Phase 1b study. He noted that the robust reduction in serum tryptase failed to improve symptoms, providing important insights into the biology of prurigo nodularis.
The company will discontinue further development of barzolvolimab in PN and concentrate resources on programs with stronger clinical validation. Topline results from the Phase 3 chronic spontaneous urticaria trials are expected in September or October 2026. Enrollment continues in Phase 3 studies for symptomatic dermographism and cold urticaria, while topline data from the Phase 2 atopic dermatitis trial are anticipated later in 2026.
What This Means for Patients
Patients with prurigo nodularis will not have barzolvolimab as a future treatment option based on the current evidence, as the Phase 2 study failed to improve itch or skin lesions compared with placebo. The results also suggest that mast cells may not be the primary driver of the disease, providing important insights that could guide the development of more effective therapies targeting other biological pathways.
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About the Writer
Shaik Yasmeen (LinkedIn) is a Pharm.D graduate with interests in clinical pharmacy, pharmacovigilance, and medical writing. She has gained experience through hospital clinical postings, patient case reviews, case presentations, and literature evaluation. Passionate about evidence-based healthcare, she is committed to creating accurate and engaging medical content while continuously expanding her professional knowledge.