Novel Drug for Chronic Inducible Urticaria Delivers in Mid-Stage Trial

BOSTON — Treatment with an investigational anti-KIT monoclonal antibody induced clinically meaningful responses in the two most common forms of chronic inducible urticaria, a dose-ranging phase II trial showed.

In patients with inadequately controlled disease despite antihistamines, up to 53% of those with cold urticaria and up to 58% of those with symptomatic dermographism achieved a complete response (CR) after 12 weeks of treatment with barzolvolimab, rates significantly higher than with placebo (up to 13%), Jonathan Bernstein, MD, of the University of Cincinnati Medical Center, reported here.

“This is the first randomized placebo-controlled study to demonstrate clinical benefit in patients with chronic inducible urticaria,” he said at the American College of Allergy, Asthma & Immunology annual meeting, noting that there are currently no approved therapies for the condition beyond antihistamines.

Chronic inducible urticaria is a mast cell-driven disease characterized by the development of wheals and itch, Bernstein explained. The condition is triggered by cold temperatures in the case of cold urticaria and by pressure on the skin in symptomatic dermographism. Symptoms can last for as long as 6 weeks and can take a substantial physical and psychological toll on patients, he said.

Barzolvolimab inhibits the activation of KIT by stem cell factors, which control the survival and activity of mast cells. The drug has also demonstrated efficacy in chronic spontaneous urticaria, where phase III trials are underway.

The current phase II study was a double-blind randomized trial involving 96 patients with cold urticaria and 97 patients with symptomatic dermographism. Eligible patients had their diagnosis for more than 3 months, recurrent wheals despite a stable antihistamine regimen, and a positive provocation test at screening and randomization.

Patients were randomized 1:1 to receive either barzolvolimab (150 mg every 4 weeks or 300 mg every 8 weeks) or placebo subcutaneously during a 20-week placebo-controlled period with a 24-week follow-up.

The primary endpoint was the percentage of patients with a CR at 12 weeks, as determined by a negative provocation test at the 10-minute mark. In cold urticaria, this involved no reaction to 4°C on the TempTest. For symptomatic dermographism, a CR involved no wheal response to any of the four pins on the FricTest (applied to the forearm).

Enrolled patients had an average age of about 40 years, a majority were female, and over 80% were white. Average disease duration ranged from a mean of 7 to 11 years in the cold urticaria group and 5 to 7 years in the symptomatic dermographism group. Mean baseline provocation thresholds ranged from 18.6°C to 20.7°C for the TempTest and 3.55 to 3.64 pins for the FricTest.

In the cold urticaria group, CR rates reached 46.9% with the 150-mg barzolvolimab dose and 53.1% with the 300-mg dose, as compared with 12.5% with placebo (P=0.0023 and P=0.0011, respectively). Rates of CR plus partial response were 62.5%, 75%, and 31.3%, respectively.

In symptomatic dermographism, CR rates reached 57.6% with the 150-mg dose of barzolvolimab and 42.4% with the 300-mg dose, versus 3.2% with placebo (PP=0.0003). Including partial responses increased the response rates to 66.6%, 57.5%, and 12.9%, respectively.

Marked improvements were observed at week 12 in critical temperature thresholds for the cold urticaria patients (-8.82°C in the 150-mg group, -9.61°C in the 300-mg group) and in friction thresholds in symptomatic dermographism (-2.46 and -2.27 pins in the two groups, respectively). “Improvements were seen as early as 2 weeks after the first dose,” Bernstein noted.

Regarding safety, 98% of treatment-emergent adverse events (AEs) were grade 1 or 2, and there were no differences in discontinuation rates between the barzolvolimab groups and the placebo group. Common AEs with barzolvolimab included neutropenia (10% vs none with placebo) and hair color changes (13% vs none).

The phase II study has an estimated completion date of September 2025.

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