Barzolvolimab: A Comprehensive Clinical and Scientific Review of a Novel Mast Cell-Depleting Antibody

Executive Summary

Barzolvolimab (CDX-0159) is an investigational, humanized monoclonal antibody being developed by Celldex Therapeutics that represents a paradigm shift in the treatment of mast cell-mediated inflammatory diseases. It is classified as a potent and highly specific inhibitor of the receptor tyrosine kinase KIT (c-Kit). The drug’s novel mechanism of action is not to merely suppress downstream inflammatory pathways but to target the root cellular driver of these conditions—the mast cell—by blocking KIT signaling, which is essential for mast cell survival, differentiation, and activity. This upstream intervention results in the profound and rapid depletion of mast cells, a pharmacodynamic effect that has translated into remarkable clinical efficacy in diseases where these cells are the primary pathological effectors.

The clinical development program for Barzolvolimab, structured as a "pipeline in a product," is most advanced in chronic urticaria. In a landmark Phase 2 study in patients with moderate to severe Chronic Spontaneous Urticaria (CSU) refractory to antihistamines, Barzolvolimab demonstrated unprecedented efficacy. The treatment led to rapid symptom control, with statistically significant and clinically meaningful improvements observed as early as one week. Complete response rates (defined as the complete absence of itch and hives, UAS7=0) reached up to 51% at 12 weeks and deepened to 71% after 52 weeks of therapy. Most notably, the therapeutic benefit was remarkably durable, with up to 41% of patients remaining in complete remission 28 weeks after their final dose, suggesting a potential disease-modifying effect. Similar profound efficacy was observed in Chronic Inducible Urticaria (CIndU), where 95% of patients achieved a complete response to provocation tests after a single dose.