Celldex Therapeutics reported topline results from its Phase 2 study of barzolvolimab in eosinophilic esophagitis (EoE), delivering important scientific insights about the role of mast cells in this chronic inflammatory disease of the esophagus. While the study successfully met its primary endpoint of mast cell depletion, the profound reduction in mast cells did not translate to clinical benefit, providing direct evidence that mast cells are not primary drivers of EoE pathogenesis.
Primary Endpoint Achievement with Statistical Significance
The randomized, double-blind, placebo-controlled study enrolled 65 patients with active, moderate to severe EoE who were randomly assigned to receive either barzolvolimab 300 mg every 4 weeks or placebo. The primary endpoint measured the absolute change from baseline to Week 12 in peak esophageal intraepithelial mast cell count.
Barzolvolimab demonstrated profound mast cell depletion capabilities. Peak mast cell counts (CD117 positive cells) per high power field at baseline were 50.3 in the placebo arm and 55.4 in the barzolvolimab arm. At Week 12, the absolute change from baseline was -2.7 for placebo compared to -36.0 for barzolvolimab, representing a difference of -33.3 (95% CI: -44.1, -22.6; p<0.0001).
Mast cells defined by tryptase staining also showed profound decreases at Week 12 in barzolvolimab-treated patients, with sustained and deepening decreases observed at Week 28.
Clinical Outcomes Remain Unchanged Despite Mast Cell Depletion
Despite achieving approximately 65% reduction in esophageal mast cells, barzolvolimab failed to demonstrate clinical improvement across multiple measures. No definitive evidence of improvement in EoE symptoms was observed as measured by the Dysphagia Symptom Questionnaire (DSQ) (p=0.33). Similarly, endoscopic scoring of EoE-related inflammation and fibrosis (EREFS) showed no difference compared to placebo (p=0.95).
The study also found no difference in histological reduction of esophageal intraepithelial infiltration of eosinophils (p=0.57), suggesting that mast cell depletion does not impact the characteristic eosinophilic inflammation that defines the condition.
Safety Profile and Future Development Plans
Barzolvolimab demonstrated a favorable safety profile at the 300 mg every 4 weeks dosing regimen, consistent with prior studies. An unblinded review of all available data through the full treatment period (28 weeks) and full study (44 weeks) confirmed that clinical and safety outcomes were consistent at these timepoints.
"As we explore barzolvolimab's full potential as a mast cell depleting agent, we are ultimately defining which diseases are mast cell driven," said Anthony Marucci, President and Chief Executive Officer of Celldex Therapeutics. "While we are disappointed in the clinical outcome in EoE, we are proud of our role in advancing the science for patients who need more effective treatment options."
Implications for Mast Cell-Targeted Therapy Development
Based on these results, Celldex will not advance barzolvolimab development in EoE. However, the company emphasized that the results support future development of KIT- or SCF-targeted therapies in other gastrointestinal indications where mucosal mast cells are believed to play an important role.
The company continues advancing barzolvolimab's development pipeline, with enrollment ongoing across four studies, including two Phase 3 studies in chronic spontaneous urticaria and Phase 2 studies in atopic dermatitis and prurigo nodularis. Celldex is also finalizing plans to initiate a Phase 3 program in inducible urticaria that will include both cold urticaria and symptomatic dermographism.
Mechanism of Action and Therapeutic Rationale
Barzolvolimab is a humanized monoclonal antibody that binds the receptor tyrosine kinase KIT with high specificity and potently inhibits its activity. KIT is expressed in various cells, including mast cells, which mediate inflammatory responses such as hypersensitivity and allergic reactions. KIT signaling controls the differentiation, tissue recruitment, survival and activity of mast cells.
The study was designed based on research suggesting that mast cells could play an important role in EoE pathogenesis. Identifying the key drivers of EoE has challenged the field, and this study provides valuable mechanistic insights by demonstrating that profound mast cell depletion alone is insufficient to improve clinical outcomes in this condition.
