Oral deucrictibant for on-demand treatment of hereditary angioedema attacks: a phase 3, multicentre, randomised, double-blind, placebo-controlled crossover trial.

In hereditary angioedema, a rare bradykinin-mediated condition, oral on-demand treatments facilitating prompt administration and providing rapid, sustained relief and attack resolution remain scant. We investigated the efficacy and safety of deucrictibant, an oral bradykinin B2 receptor antagonist, for on-demand treatment of hereditary angioedema attacks. RAPIDe-3 was a phase 3, double-blind, 2 × 2 crossover trial in adolescent and adult participants (aged ≥12 to <18 years and aged ≥18 to ≤75 years, respectively) with hereditary angioedema, at 59 sites across 24 countries on six continents. Eligible participants had hereditary angioedema, including those with normal C1 inhibitor associated with a documented genetic variant, at least two attacks within the last 3 months before screening, and experience with effectively using conventional on-demand therapies for hereditary angioedema attacks. Participants were randomly allocated in a 1:1 ratio to one of two double-blind crossover sequences to treat two attacks with a 20 mg oral deucrictibant immediate-release capsule or placebo as either deucrictibant-placebo or placebo-deucrictibant, stratified by age and use of long-term prophylaxis. The primary endpoint was time to onset of symptom relief, defined as Patient Global Impression of Change rating of at least a little better. Safety was assessed in all participants who received any dose of study drug. RAPIDe-3 is registered with ClinicalTrials.gov (NCT06343779) and is complete. Between April 4, 2024, and Sept 1, 2025, 149 people were assessed for eligibility, and 134 eligible participants (ten [7%] adolescents and 124 [93%] adults) were randomly allocated. 58 (43%) were male and 76 (57%) were female, and the median age was 38·0 years (IQR 27·0-50·0). 113 participants treated 201 attacks. The primary efficacy analysis included 88 participants with paired treated attacks. Of these, 47 (53%) participants were female and 41 (47%) were male, and 60 (68%), 16 (18%), 4 (5%), and 1 (1%) were White, Asian, Black, and American Indian or Alaska Native, respectively. Onset of symptom relief occurred significantly faster with deucrictibant than placebo, with median times of 1·28 h (95% CI 1·05 to 1·52) and more than 12 h (5·82 to >12), respectively (p<0·0001). Fatigue was the only adverse event reported more than once within 3 days post-treatment: a single event was reported by two participants, one of which was deemed unrelated to treatment. Across the study, no treatment-related adverse events were assessed as severe or serious, and no adverse events led to treatment discontinuation. Oral deucrictibant provided faster times to symptom relief than placebo and was generally well tolerated. These results support the use of deucrictibant as potentially the first orally administered bradykinin B2 receptor antagonist for the treatment of attacks of bradykinin-mediated angioedema, including hereditary angioedema, and may address an unmet need for options that are effective and well tolerated, with convenient administration. Pharvaris.