Phase 3 Trial Shows Oral Deucrictibant Reduces Hereditary Angioedema Attacks by 83%

Once-daily oral deucrictibant extended-release (XR) reduced the mean monthly rate of hereditary angioedema (HAE) attacks by 83% compared with placebo in the pivotal phase 3 CHAPTER-3 trial (NCT06669754). The investigational bradykinin B2 receptor antagonist met its primary end point and all secondary efficacy end points, supporting its continued development as an oral prophylactic treatment.^1,2

The trial included adolescents and adults with type 1 HAE, type 2 HAE, or HAE with normal C1 inhibitor. According to Pharvaris, CHAPTER-3 is the first phase 3 prophylaxis study to enroll patients across all 3 disease types.¹

Pharvaris intends to utilize these findings to support marketing authorization applications, including a proposed new drug application to the FDA for prevention of bradykinin-mediated angioedema attacks during the first half of 2027. Deucrictibant remains investigational and is not currently approved for prophylactic treatment.

CHAPTER-3 Demonstrates Early, Sustained Protection

CHAPTER-3 was a global, randomized, double-blind, placebo-controlled study conducted across 21 countries. Investigators enrolled 85 participants who were randomly assigned 2:1 to receive deucrictibant XR 40 mg once daily or placebo for 24 weeks. The active-treatment group included 55 participants, and 30 received placebo.^1,2

Across the complete study population, deucrictibant reduced the mean monthly HAE attack rate by 83% compared with placebo (P < .0001). Among the 80 participants with type 1 or type 2 HAE, treatment produced an approximately 87% reduction in monthly attacks. The primary end point findings were consistent across evaluated subgroups.¹

All secondary efficacy end points were met with statistical significance under a multiplicity-control procedure. Protection was observed during the first week of treatment and remained evident through the 24-week treatment period. Deucrictibant was also associated with reductions in attack frequency from baseline and an increased proportion of attack-free participants.¹

Complete numerical results for the secondary end points have not yet been released. Additional efficacy, safety, and patient-experience data are expected to be presented at upcoming medical meetings, the news release said.¹

Oral Therapy Targets Bradykinin Signaling

HAE is a rare genetic disorder that is characterized by recurrent episodes of swelling that can affect the skin, gastrointestinal tract, and upper airway. Attacks involving the larynx can become life-threatening. Unlike histamine-mediated allergic swelling, HAE attacks are driven primarily by excessive bradykinin activity and generally do not respond to antihistamines, corticosteroids, or epinephrine.³

Deucrictibant is a selective small-molecule antagonist of the bradykinin B2 receptor. By blocking the receptor through which bradykinin produces increased vascular permeability, the therapy is intended to prevent the fluid leakage and localized swelling underlying HAE attacks.

The XR formulation is designed to maintain therapeutic exposure with once-daily administration. A separate immediate-release formulation is being developed for on-demand treatment of active attacks.

Earlier phase 2 findings established the rationale for prophylactic B2 receptor blockade. In the CHAPTER-1 trial (NCT05047185), oral deucrictibant significantly reduced HAE attack rates compared with placebo in adults with type 1 or type 2 disease.⁴ The phase 3 results extend that evidence to a larger multinational study and include patients with HAE with normal C1 inhibitor.

Safety Findings Support Continued Development

Most treatment-emergent adverse events (AEs) in CHAPTER-3 were mild or moderate. No treatment-related serious AEs were reported. One participant in each treatment group discontinued therapy because of an adverse event.¹

The CHAPTER-4 (NCT06679881) open-label extension trial is evaluating the long-term safety and efficacy of deucrictibant XR. Longer follow-up will be important because prophylactic HAE therapy may continue indefinitely. Additional data are also needed to characterize specific adverse events, laboratory abnormalities, drug interactions, and adherence outside a controlled clinical trial.

Implications for Pharmacists

Current long-term prophylactic options include oral and injectable therapies, allowing treatment decisions to incorporate attack burden and patient preference. International HAE guidelines recommend an individualized approach with routine reassessment of disease control and treatment burden.⁵

If approved, once-daily deucrictibant could provide an oral option for patients with HAE who prefer to avoid injections. Pharmacists would have a central role in distinguishing prophylaxis from on-demand rescue therapy and reinforcing that patients should maintain access to an acute treatment even when preventive therapy is effective. Medication counseling would also need to address adherence, missed doses, AE monitoring, and recognition of potentially life-threatening airway attacks. Pharmacists could document changes in attack frequency and rescue-medication use to help clinicians assess whether prophylaxis is providing adequate control.

The 83% reduction observed in CHAPTER-3 positions deucrictibant as a promising oral preventive therapy. Regulatory review and complete phase 3 findings will determine its eventual place among established HAE prophylactic treatments.

REFERENCES

1. Pharvaris. Pharvaris announces positive topline data from CHAPTER-3 pivotal study of deucrictibant XR for prophylaxis of HAE attacks. Pharvaris. News release. September 8, 2026. Accessed September 10, 2026. https://ir.pharvaris.com/news-releases/news-release-details/pharvaris-announces-positive-topline-data-chapter-3-pivotal

2. ClinicalTrials.gov. Study of oral deucrictibant extended-release tablet for prophylaxis against angioedema attacks in adolescents and adults with HAE. ClinicalTrials.gov identifier: NCT06669754. Updated February 13, 2026. Accessed September 10, 2026. https://clinicaltrials.gov/study/NCT06669754

3. Busse PJ, Christiansen SC. Hereditary Angioedema. N Engl J Med. 2020;382(12):1136-1148. doi:10.1056/NEJMra1808012

4. Aygören-Pürsün E, Stobiecki M, Valerieva A, et al. Oral deucrictibant for prophylaxis of hereditary angioedema attacks (CHAPTER-1): primary analysis of a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Haematol. 2026;13(4):e215–e226. doi:10.1016/S2352-3026(26)00004-9

5. Maurer M, Magerl M, Betschel S, et al. The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update. Allergy. 2022;77(7):1961-1990. doi:10.1111/all.15214