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BACKGROUND: Hereditary angioedema is a bradykinin-mediated disorder characterised by recurrent painful swelling attacks. Treatment relies on medications to prevent attacks and on-demand therapies for attack manifestations. Parenteral administration associated with most available on-demand therapies often leads to treatment being delayed or forgone. Deucrictibant is an orally bioavailable bradykinin B2 receptor antagonist under development for prophylaxis and on-demand treatment of hereditary angioedema attacks. We aimed to investigate the efficacy and safety of deucrictibant for the on-demand treatment of hereditary angioedema attacks. METHODS: RAPIDe-1 was a double-blind, randomised, placebo-controlled, crossover, dose-ranging, phase 2 trial that recruited adults aged 18-75 years with hereditary angioedema type 1 or 2 from 38 sites (eg, university hospitals and accredited angioedema centres) across North America, Europe, and Israel. Participants were required to have experienced two or more attacks within the past 2 months or three or more attacks within the past 4 months before screening. An interactive response technology system randomly assigned eligible patients (1:1:1) to receive a blinded dose of oral deucrictibant (immediate-release capsule) 10 mg, 20 mg, or 30 mg during an attack-free period to assess pharmacokinetics and safety in the part 1 of the study; and, subsequently, to receive a crossover treatment sequence of two administrations of the same deucrictibant dose (10 mg, 20 mg, or 30 mg) and one of placebo to treat three investigator-confirmed angioedema attacks in the part 2. Randomisation was stratified by whether the participant was willing to participate in full pharmacokinetic sampling. Participants, investigators, site personnel, and the sponsor were masked to treatment assignment and capsules of deucrictibant and placebo were identical. For each attack, patients self-administered the oral study drug within 3 h after at least one symptom (skin pain, skin swelling, or abdominal pain) reached a visual analog scale (VAS) individual score of 30 or more out of 100 and within 6 h from symptom onset. The primary endpoint was change in the patient-reported composite VAS-3 score measuring severity of attack manifestations from before treatment to 4 h post-treatment and assessed in the modified intention-to-treat and per-protocol populations. Safety was assessed in all patients who received any dose of study drug. RAPIDe-1 is registered with ClinicalTrials.gov (NCT04618211) and is completed. FINDINGS: Between Feb 3, 2021, and June 23, 2022, 89 patients were screened, of whom 74 were randomly assigned between Feb 23, 2021, and July 26, 2022. For the primary analysis set, the median follow-up was 130·0 (IQR 92·5 to 212·5) days for the deucrictibant 10 mg group, 166·5 (80·0 to 275·0) days for the deucrictibant 20 mg group, and 172·0 (65·0 to 242·0) days for the deucrictibant 30 mg group. The primary efficacy analysis included 147 attacks in 62 patients, of whom 42 (68%) were female and 60 (97%) were White. Least squares mean differences of change in VAS-3 score between deucrictibant and placebo was -16·75 (95% CI -21·52 to -11·97) for 10 mg, -15·02 (-20·22 to -9·81; p<0·0001) for 20 mg, and -16·28 (-21·27 to -11·29; p<0·0001) for 30 mg. In part 1, all treatment-emergent adverse events were grades 1-2, with the most common in two or more patients being headache (two 8% of 25) and nasopharyngitis (two 8% of 25) in the deucrictibant 30 mg group. In part 2, no single treatment-emergent adverse event was reported by two or more patients in any treatment group. Most adverse events were considered unrelated to the study drug and there were no grade 3 or worse adverse events. INTERPRETATION: Deucrictibant significantly reduced the severity of hereditary angioedema attacks compared with placebo; these results support continued investigation of antagonism of the bradykinin B2 receptor with an orally available agent as a potentially effective approach, with a safety profile similar to placebo, for on-demand treatment. FUNDING: Pharvaris.
Maurer et al. (Fri,) studied this question.