Barzolvolimab achieves complete responses in chronic inducible urticaria
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Key takeaways:
- Barzolvolimab binds receptor tyrosine kinase KIT to inhibit its activity, which mast cells need for survival.
- Mast cell activation drives cold urticaria and symptomatic dermographism.
Patients with cold urticaria and symptomatic dermographism experienced clinically meaningful and statistically significant complete responses with barzolvolimab, according to a webinar by Celldex Therapeutics.
These results come from the first large, randomized placebo-controlled study to demonstrate success in treating these common forms of chronic inducible urticaria with barzolvolimab, the company reported.
The need for treatment
“Inducible urticaria is a miserable disease,” Diane C. Young, MD, senior vice president and chief medical officer at Celldex, said during the webinar.
“Patients go to great lengths to avoid disease triggers, but many find it impossible to do so and are impacted by severe itching and burning hives or wheals that impair all parts of their lives, their work, their concentration, their sleep and their social behavior,” she continued.
For example, Young said, patients with cold urticaria can be triggered by temperatures as high as 80°F.
“Navigating your day-to-day activities, trying to stay above these thresholds, to avoid the onset of symptoms is daunting,” Young said.
When mast cells activate, Young continued, soluble mediators are released, which drives hives, wheals, itch and other symptoms in these diseases. But aside from antihistamines, she added, no other therapies have been approved for chronic inducible urticaria.
“Unfortunately for patients, very little forward progress has been made over the years,” Young said. “To achieve the best outcome in chronic urticarias, we believe you need to target the root driver of the disease — the mast cell.”
Barzolvolimab binds the receptor tyrosine kinase KIT to inhibit its activity. Mast cells, which express KIT, mediate inflammatory responses and play a central role in the onset and progression of chronic urticaria. KIT signaling controls their differentiation, tissue recruitment, survival and activity.
“Barzolvolimab’s unique mast cell depleting mechanism and long half-life position the candidate as best in class,” Young said. “The consistent positive results we have reported to date across our phase 1 and phase 2 studies in early career support this.”
Study design, results
The double-blind, parallel-group phase 2 study comprised 196 patients across 78 sites in 11 countries with chronic inducible urticaria who remained symptomatic even with antihistamine treatment.
Patients were grouped by cold urticaria or symptomatic dermographism subtype and randomly assigned 1:1:1 to one of three arms for 20-week treatment: 150 mg of barzolvolimab every 4 weeks, 300 mg of barzolvolimab every 8 weeks or placebo every 4 weeks.
The primary endpoint of the study was the percentage of patients that achieved complete disease control based on negative provocation tests, Young said.
“All patients have now crossed the 12-week time point, allowing for analysis of the primary endpoint by provocation test,” she said.
The cold urticaria patients had a mean baseline critical temperature threshold of 66°F (19°C) on the TempTest, and the symptomatic dermographism patients had an average baseline FricTest threshold of 3.6 out of four pins, both in initial provocation testing.
“Clearly in both settings, these are challenging dynamics for patients to navigate in their daily lives,” Young said. “I am excited to share that we met our primary endpoint in both diseases across both doses. These results are unprecedented.”
Percentages of patients in the cold urticaria group with a negative provocation test at 12 weeks included 46.9% of the 150 mg barzolvolimab group (P = .0023), 53.1% of the 300 mg group (P = .0011) and 12.5% of the placebo group.
Similarly, percentages of patients in the symptomatic dermographism group with a negative provocation test at 12 weeks included 57.6% of the 150 mg barzolvolimab group (P < .0001), 42.4% of the 300 mg group (P = .0003) and 3.2% of the placebo group.
“The results of both diseases are highly positive and, most importantly, very clinically meaningful for patients,” Young said.
Barzolvolimab also was well tolerated and had a favorable safety profile, Young said, which she also called very consistent with previous data. Most of the adverse events were mild to moderate, she said, most commonly hair color changes (13%) and neutropenia (11%).
The treatment and placebo groups had similar rates of infections as well, Young continued, with no associations between them and neutropenia.
“The adjudication committee further determined that there has only been a single case of confirmed anaphylaxis in the entire barzolvolimab program to date, which includes approximately 500 treated patients across our phase 1 studies and our ongoing phase 2 studies,” Young said.
The patient with anaphylaxis had multiple comorbidities, which Young said likely meaningfully contributed to the severity of the event.
“The growing body of clinical data continue to consistently position barzolvolimab as a well-tolerated, potentially lifechanging drug for patients whose lives have been controlled for far too long by these diseases of misery,” Young said.
Next steps
Young said that these findings support further registrational studies.
“As a physician, I am very excited about the potential opportunity that lies ahead for patients who need much better treatment options,” she said.
Young and her colleagues expect to present the full results of the study at a medical meeting later this year and work with health authorities to design a successful registration program.
Celldex also is now actively enrolling patients in a pair of phase 3 studies in chronic spontaneous urticaria.
“With these studies, our knowledge base grows and supports ongoing efforts to explore and prioritize additional opportunities for indication expansion,” Anthony S. Marucci, MBA, MHL, founder, president, CEO and director of Celldex, said during the presentation.
Celldex also is conducting phase 2 studies of barzolvolimab’s use in prurigo nodularis and eosinophilic esophagitis, in addition to working toward initiating a phase 2 trial of its use in atopic dermatitis before the end of 2024.
“Barzolvolimab is actively delivering on its significant potential to be a pipeline and a product,” Marucci said. “Barzolvolimab has incredible potential to transform the lives of patients with mast cell-mediated disease.”
Reference:
- Celldex Therapeutics presents positive topline results from barzolvolimab phase 2 study in chronic inducible urticaria. https://ir.celldex.com/news-releases/news-release-details/celldex-therapeutics-presents-positive-topline-results. Published July 29, 2024. Accessed July 30, 2024.