Background Hereditary angioedema is a bradykinin-mediated, rare condition characterised by recurrent and potentially life-threatening attacks of subcutaneous and submucosal swelling. Bradykinin B2 receptor antagonism is a proven mechanism for on-demand treatment of attacks, but no evidence exists on its effects when used prophylactically. Deucrictibant is an investigational orally bioavailable bradykinin B2 receptor antagonist. We aimed to evaluate the efficacy, safety, and tolerability of two dose regimens of oral deucrictibant administered as prophylaxis against hereditary angioedema attacks. Methods CHAPTER-1 was a multicentre, double-blind, placebo-controlled, randomised, phase 2 trial conducted in two parts, a double-blind placebo controlled first part and an open-label second part, with only part 1 reported here. Part 1 recruited adults (aged 18–75 years) with hereditary angioedema type 1 or 2 from 37 sites (university hospitals and accredited angioedema centres) across North America, Europe, and Israel. Patients required a documented history of three or more attacks within the last 3 consecutive months before screening or two or more during the screening period (up to 8 weeks) to be eligible. An interactive response technology system randomised eligible patients 1:1:1 to receive oral deucrictibant 20 mg daily, 40 mg daily, or matching placebo for 12 weeks. Randomisation to treatment groups was stratified by the baseline attack rate. Patients, investigators, site personnel, and the sponsor were blinded to treatment assignment. Masking was achieved with identically appearing deucrictibant and placebo capsules. The primary endpoint was the time-normalised number of investigator-confirmed attacks per 4 weeks (monthly attack rate) from weeks 1 to 12 and was assessed using the intention-to-treat set. The endpoint was analysed by comparing each deucrictibant group with the placebo group using a Poisson generalised linear model with a log link function and Pearson's χ 2 scaling of SEs to account for potential dispersion. The safety analysis set included all patients who were randomly assigned and who received one or more doses of study drug (deucrictibant or placebo). CHAPTER-1 is registered with ClinicalTrials.gov (NCT05047185) and is now complete. Findings Between March 9, 2022, and June 19, 2023, 44 patients were screened. Of 34 patients who were randomly assigned, 11 patients received deucrictibant 20 mg, 12 patients received deucrictibant 40 mg, and 11 patients received the placebo, with a median follow-up of 85·0 days (IQR 84·0–86·0). 21 (62%) patients were female, 13 (38%) were male, and 34 (100%) patients were White. The least squares mean monthly attack rate (primary analysis) was 0·40 (95% CI 0·18–0·92) for deucrictibant 20 mg, 0·30 (0·11–0·81) for deucrictibant 40 mg, and 1·93 (1·30–2·88) for placebo; percent reduction in attack rate compared with placebo was 79·2% (95% CI 47·2–91·8) for deucrictibant 20 mg (p=0·0010) and 84·5% (95% CI 53·8–94·8) for deucrictibant 40 mg (p=0·0008). Treatment-related treatment-emergent adverse events were experienced by two (18%) patients receiving deucrictibant 20 mg, one (8%) patient receiving deucrictibant 40 mg, and one (9%) patient receiving the placebo; all were mild in severity (grade 1) and did not require dosing modification of the study drug. There were no serious adverse events or deaths in any treatment group. Interpretation To the best of our knowledge, this trial provides the first clinical evidence and proof-of-concept for bradykinin B2 receptor antagonism as a therapeutic approach for the prevention of hereditary angioedema attacks and supports further investigation of oral deucrictibant for bradykinin-mediated angioedema. Funding Pharvaris.
Percent reduction in attack rate compared with placebo was 79.2% for deucrictibant 20 mg and 84.5% for deucrictibant 40 mg
prespecified blinded primary analysis shows consistent large reductions, with wide intervals and no multiplicity correction across doses
The safety profile of deucrictibant was similar to that of placebo
systematic adverse-event collection found similar short-term rates, but 34 participants cannot establish broader safety
Improvements in patient-reported health-related quality of life and disease control and higher levels of satisfaction were consistent with clinical findings
patient-reported outcomes were descriptive and unadjusted for baseline differences or missing values
Consistent attack rate reductions in the deucrictibant groups compared with placebo were observed independent from baseline attack rates
post-hoc subgroup analysis was not powered to establish independence across baseline-rate strata
Derived from the full evaluation — not a separate score.
Strengths
The Research in context panel identifies no prior prophylaxis trial of bradykinin B2 receptor antagonism and distinguishes this mechanism from available kallikrein, C1-inhibitor, and factor XIIa approaches.
↳ Research in context, pp e216–e217
Allocation used an interactive response system with baseline-rate stratification, matching capsules, and masking of patients, investigators, site personnel, and the sponsor. The primary endpoint was investigator-confirmed and analysed in the intention-to-treat set.
↳ Methods, Randomisation and masking and Statistical analysis, pp e217–e219
The paper links this proof-of-concept study to a named larger and longer phase 3 trial using an extended-release, once-daily formulation and to a parallel on-demand development programme.
↳ Research in context, p e216; Discussion, pp e224–e225
Limitations
Only 34 adults were randomised, all were White, and treatment lasted 12 weeks. These features widen uncertainty and limit conclusions about broader populations and durable safety.
↳ Abstract Findings, p e215; Table 1; Limitations, p e224
Patient-reported outcomes were analysed descriptively without adjustment for baseline differences or missing values, yet they are narrated as corroborating and sustained findings in the Discussion.
↳ Statistical analysis, p e219; Discussion, pp e223–e224
The sponsor participated throughout design, conduct, analysis, interpretation, and drafting. The Data sharing statement also calls the study ongoing despite the Summary and Methods describing it as complete.
↳ Role of the funding source, p e219; Data sharing, pp e225–e226
The prespecified blinded primary analysis in Table 2 provides credible evidence that both deucrictibant doses reduced investigator-confirmed attack rates over 12 weeks. Central randomisation, matching placebo, intention-to-treat analysis, sensitivity models, and systematic harms reporting support a high Methodological Rigour assessment, but the 34-person sample and unadjusted dose comparisons keep it below the airtight band. The paper is appropriately framed as proof of concept and connects its limitations to phase 3, although descriptive patient-reported outcomes receive disproportionate narrative emphasis. Clinical relevance is clear, but transferability and deployment remain constrained by the all-White cohort, short follow-up, and non-final formulation.
Nabu’s assessment, alongside the field’s view.
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Strong4.0
Confidence mediumThe trial supplies a clearly delineated clinical proof of concept for prophylactic bradykinin B2 receptor antagonism, addressing a gap identified through the paper's treatment review. Its contribution remains phase 2 rather than definitive because only 34 participants were followed for 12 weeks.
“the first clinical evidence and proof-of-concept for bradykinin B2 receptor antagonism”
Central randomisation, matching placebo, broad masking, investigator-confirmed attacks, intention-to-treat analysis, sensitivity models, and systematic harms collection support the primary inference. The small sample, four active-arm discontinuations, and absence of multiplicity correction across two dose comparisons prevent an airtight rating.
“a multiplicity correction for the two comparisons was not used”
The paper clearly separates its primary attack-rate analysis from its phase 3 implications and reports absolute rates, intervals, and p values. Patient-reported outcomes receive confident narrative emphasis despite being descriptive and unadjusted, although this status is stated in Methods and Limitations.
“Descriptive analyses were performed for pre-specified patient-reported outcomes”
The Discussion compares relevant oral and parenteral prophylactic options and cautions against direct cross-trial comparisons. It also links the short, homogeneous phase 2 study and immediate-release formulation to a larger, longer phase 3 trial using extended-release dosing.
“these limitations are anticipated to be addressed in a larger and longer global phase 3 trial”
Caveats4 of 4 checks
Participant counts, efficacy estimates, confidence intervals, adverse-event totals, and stated analyses are mutually consistent. The absence of multiplicity adjustment and the descriptive status of secondary outcomes are disclosed methodological limitations rather than internal contradictions.
Ethics approval, consent, registration, funding, and competing interests are declared, but sponsor involvement spans the full research and reporting process. The data-sharing statement also uses completion language that is inconsistent with the Summary and Methods.
Flags: 4 declared / 5 total
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No retraction or expression of concern found in Crossref (includes Retraction Watch).
Sources: Crossref (incl. Retraction Watch) ✓
Where this paper’s evidence sits on the path from initial observation to real-world use.
The intervention has been tested in patients in a multicentre placebo-controlled trial, placing it beyond laboratory proof of concept. Larger and longer phase 3 evidence is still required before clinical deployment.
“support further investigation of the efficacy and safety of deucrictibant in a phase 3 trial”
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