In the phase 3 RAPIDe-3 trial published in The Lancet, median time to symptom relief was 1.28 hours with deucrictibant vs more than 12 hours with placebo.
Oral deucrictibant produced significantly faster symptom relief than placebo for on-demand treatment of
Most on-demand therapies for HAE attacks require parenteral administration, and the only approved oral option, sebetralstat (Ekterly), inhibits plasma kallikrein upstream of bradykinin formation.¹ Deucrictibant instead blocks the bradykinin B2 receptor directly, regardless of the pathway generating bradykinin, and icatibant, the only approved agent in this class, requires subcutaneous injection.¹
“Bradykinin B2 receptor antagonism is a validated and reliable mechanism currently being widely used for the on-demand treatment of HAE attacks,” said lead investigator, Marc A. Riedl, MD, professor of medicine and clinical director of the US Hereditary Angioedema Association Angioedema Center at the University of California San Diego, in a statement. “If approved, deucrictibant IR will be the first approved oral bradykinin B2 receptor antagonist, with the potential to address unmet needs of people living with HAE.”
RAPIDe-3 was a randomized, double-blind, placebo-controlled, 2 × 2 crossover phase 3 trial conducted at 59 sites across 24 countries on 6 continents.¹ Investigators randomized 134 participants aged 12 to 75 years, including 10 adolescents, to treat 2 qualifying attacks with a single 20-mg deucrictibant immediate-release capsule or placebo in either sequence. Eligible participants included those with HAE with normal C1 inhibitor and a documented genetic variant, and 23% of participants who treated an attack were receiving long-term prophylaxis.¹
The primary efficacy analysis included 88 participants with paired treated attacks. Median time to onset of symptom relief, defined as a Patient Global Impression of Change (PGI-C) rating of at least “a little better” at 2 consecutive timepoints, was 1.28 hours (95% CI, 1.05-1.52) with deucrictibant vs more than 12 hours (95% CI, 5.82 to >12) with placebo (P <.0001).2
At 4 hours post-treatment, 83% of deucrictibant-treated attacks had reached onset of symptom relief vs 28% (24/87) of placebo-treated attacks (P <.0001).¹ Within 12 hours, 83% of deucrictibant-treated attacks required only a single capsule, compared with 33% of placebo-treated attacks.¹
RAPIDe-3 met all 11 secondary endpoints.¹ Median time to end of progression, a prespecified endpoint marking the earliest evidence of treatment effect, was 17.47 minutes with deucrictibant vs 228.67 minutes with placebo. Median time to complete symptom resolution by Patient Global Impression of Severity (PGI-S) was 11.95 hours vs more than 48 hours, respectively (P <.0001 for both).¹
Complete symptom resolution with 1 capsule at 24 hours occurred in 60% of deucrictibant-treated attacks vs 15% of placebo-treated attacks. Conventional on-demand rescue medication was used within 24 hours for 9% and 44% of attacks, respectively (P <.0001 for both).¹ Efficacy was consistent across subgroups defined by age, HAE type, long-term prophylaxis use, and attack location and severity.¹
Treatment-emergent adverse events (TEAEs) within 3 days of dosing occurred in 15% of participants receiving deucrictibant and 2% receiving placebo, all mild or moderate in severity.¹ Fatigue was the only TEAE reported more than once in this window. No treatment-related TEAEs were serious or severe, no TEAEs led to discontinuation, and no participants reported difficulty swallowing the capsule.¹
Pharvaris reported a New Drug Application (NDA) for deucrictibant for on-demand treatment is under FDA review, with a Prescription Drug User Fee Act (PDUFA) target action date of April 23, 2027.² A Marketing Authorization Application is also under review with the European Medicines Agency, and the company is developing an extended-release tablet formulation for prophylaxis.² The ongoing RAPIDe-2 open-label extension is expected to provide further data in these populations.
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