Celldex Therapeutics announced positive results from its Phase 2 clinical trial of barzolvolimab in patients with chronic inducible urticaria (CIndU), specifically cold urticaria (ColdU) and symptomatic dermographism (SD). The study, which included patients symptomatic despite antihistamine treatment, demonstrated that barzolvolimab met all primary and secondary endpoints with high statistical significance.
Key Findings from the Phase 2 Trial
The primary endpoint, the percentage of patients with a negative provocation test at Week 12, was significantly higher in the barzolvolimab groups compared to placebo. For cold urticaria, 46.9% (150 mg q4w) and 53.1% (300 mg q8w) of patients achieved a negative provocation test (p=0.0023 and p=0.0011, respectively) compared to 12.5% in the placebo group. In symptomatic dermographism, 57.6% (150 mg q4w) and 42.4% (300 mg q8w) achieved a negative provocation test (p<0.0001 and p=0.0003, respectively) compared to 3.2% in the placebo group.
Secondary endpoints, including responder analyses, improvements in Critical Temperature and Critical Friction Thresholds (CTT and CFT), changes in WI-NRSprovo (itch associated with provocation test) and Urticaria Control Test, were also achieved at Week 12.
Specifically, in cold urticaria, patients treated with barzolvolimab experienced improvements in Critical Temperature Thresholds of -8.82°C (p<0.0001) and -9.61°C (p<0.0001) for the 150 mg q4w and 300 mg q8w groups, respectively, compared to -0.30°C in the placebo group. In symptomatic dermographism, improvements in Critical Friction Thresholds were -2.46 pins (p<0.0001) and -2.27 pins (p=0.0002) for the 150 mg q4w and 300 mg q8w groups, respectively, compared to -0.82 pins in the placebo group.
Safety and Tolerability
Barzolvolimab was well-tolerated, with a favorable safety profile consistent with prior studies. Most adverse events were grade 1 (mild). The most common treatment-emergent adverse events in barzolvolimab-treated patients were hair color changes (13%) and neutropenia (10%), which are mechanism-related (KIT) and expected to be reversible. The rate of infections was similar between barzolvolimab-treated patients and placebo, with no association between neutropenia and infections.
Study Design and Patient Population
The Phase 2 study was a randomized, double-blind, placebo-controlled trial evaluating two dose regimens of barzolvolimab in patients with CIndU who remained symptomatic despite antihistamine therapy. A total of 196 patients were randomized into two cohorts (97 with ColdU and 99 with SD) and assigned to receive subcutaneous injections of barzolvolimab at 150 mg every 4 weeks, 300 mg every 8 weeks, or placebo during a 20-week treatment phase, followed by a 24-week follow-up phase. The study also included an Open Label Extension.
Expert Commentary
"Chronic inducible urticaria is a devastating disease for patients who despite constant vigilance often find it impossible to avoid their disease triggers and are impacted by severe itching and burning hives that dramatically impact all aspects of their lives," said Diane C. Young, MD, Senior Vice President and Chief Medical Officer of Celldex Therapeutics. "Barzolvolimab is the first drug to achieve success in a large, randomized, placebo-controlled study in chronic inducible urticaria and we are excited to report that all primary and secondary endpoints across the study were highly statistically significant and clinically meaningful."
About Chronic Inducible Urticaria
Chronic inducible urticaria (CIndU) is characterized by the occurrence of hives or wheals that have an attributable trigger associated with them. Cold urticaria (ColdU) symptoms include itching, burning wheals/hives, and angioedema when the skin is exposed to cold temperatures. Symptomatic dermographism (SD) symptoms include the development of wheals in response to stroking, scratching, or rubbing of the skin. Approximately 0.5% of the total population suffers from chronic inducible urticarias. Mast cell activation leading to the release of soluble mediators is thought to be the driving mechanism leading to the wheals and other symptoms. Current treatments are limited to antihistamines and trigger avoidance.
Future Directions
Celldex is actively working towards bringing barzolvolimab to patients and plans to initiate Phase 3 development in inducible urticaria in 2025. Barzolvolimab is also being studied in chronic spontaneous urticaria (CSU), prurigo nodularis (PN), and eosinophilic esophagitis (EOE), with additional indications planned, including atopic dermatitis (AD).
