Pharvaris's Oral Deucrictibant XR Cuts HAE Attack Rate 83% in Phase III CHAPTER-3
核心洞察
Once-daily deucrictibant extended-release tablets reduced hereditary angioedema (搜索) attack rates by 83% versus placebo in the Phase 3 CHAPTER-3 trial, with a p-value below 0.0001.
The global, double-blind study randomized 85 adolescents and adults across 21 countries to 40 mg deucrictibant XR or placebo for 24 weeks, with all secondary endpoints met.
Pharvaris plans to submit a prophylaxis New Drug Application to the FDA in the first half of 2027, following an accepted NDA for the immediate-release formulation.
Pharvaris N.V. (Nasdaq: PHVS) reported that once-daily deucrictibant extended-release (XR) tablets reduced hereditary angioedema (搜索) (HAE) attack rates by 83% relative to placebo in the pivotal Phase 3 CHAPTER-3 trial, a statistically significant result with a 95% confidence interval of 72% to 90% and a p-value below 0.0001. The readout, reported September 8, clears the path for a prophylaxis New Drug Application submission planned for the first half of 2027.
Trial Design and Endpoints
The global, double-blind, placebo-controlled study randomized 85 adolescents and adults with all three HAE types — including HAE with normal C1 inhibitor, a subtype excluded from most approved agents' labels — across 21 countries in a 2:1 ratio to deucrictibant XR 40 mg once daily or placebo for 24 weeks. Fifty-five participants received deucrictibant and 30 received placebo.
The primary endpoint measured investigator-confirmed attacks per four weeks. All secondary efficacy endpoints achieved statistical significance under a procedure controlling for multiple comparisons, and were met sequentially under a multiplicity-control procedure. Secondary endpoints covered clinically relevant outcomes including attacks requiring on-demand medication, moderate or severe attacks, attack-free status, and disease-specific quality of life.
A descriptive analysis showed attack-rate reductions within the first week that were sustained throughout treatment, with protection evident within the first week and sustained through the full treatment period. The 83% attack-rate reduction was consistent across subgroups.
Subgroup Findings and Limitations
Among the 80 participants with Type 1 or Type 2 HAE, an additional analysis showed an 87% attack-rate reduction, though that analysis was not adjusted for multiple comparisons. Five participants had HAE with normal C1 inhibitor, limiting conclusions for that subgroup.
The CHAPTER-3 population was small, which the company's own analysis acknowledges as a constraint on the strength of the findings.
Safety Profile
Most treatment-emergent adverse events were mild or moderate. No treatment-related serious adverse events were reported, and one participant in each arm discontinued treatment because of an adverse event.
Mechanism and Competitive Positioning
Deucrictibant targets the bradykinin B2 receptor (搜索), aiming to block signaling that drives swelling. The company describes the receptor as the downstream effector of vascular permeability that drives swelling attacks regardless of which upstream pathway generates bradykinin — a mechanistic property that makes it potentially relevant across HAE subtypes and in acquired angioedema due to C1 inhibitor deficiency (搜索) (AAE-C1INH), an indication for which no approved prophylactic currently exists. The XR formulation is designed to sustain exposure with one daily tablet.
The HAE prophylaxis market has become increasingly competitive. BioCryst's Orladeyo (berotralstat), a once-daily oral plasma kallikrein (搜索) inhibitor, has been approved in the US since 2020, while CSL Behring's once-monthly injectable Factor XIIa (搜索) inhibitor Andembry and Ionis Pharmaceuticals' prekallikrein (搜索)-targeting Dawnzera (搜索) expanded the market in 2025. Deucrictibant XR would add a second oral mechanism, differentiating itself by blocking the bradykinin B2 receptor (搜索) downstream of kallikrein.
If approved, the oral option could appeal to patients who want effective prevention while avoiding injections. The commercial opportunity extends to people dissatisfied with their current treatment burden, with an oral option offering sustained disease control potentially encouraging preventive-treatment adoption and continued use. Those benefits remain commercial possibilities; CHAPTER-3 did not establish better real-world adherence than competing therapies.
Dual-Formulation Strategy and Next Steps
CHAPTER-3 completes the prophylaxis arm of a dual-formulation strategy. The FDA accepted the company's NDA for deucrictibant immediate-release (IR) capsule for on-demand HAE treatment in July 2026, with a PDUFA date of April 23, 2027. Data presented at EAACI 2026 supported the combined use of the two formulations — XR for daily prophylaxis, IR for breakthrough attacks — with adequate safety margins. Pharvaris said it plans to submit the prophylaxis NDA in the first half of 2027, targeting potential dual launches from the same B2 receptor antagonist mechanism.
Deucrictibant has the potential to become the first oral HAE therapy spanning both on-demand treatment and long-term prophylaxis. Separately, the CREAATE Phase III study evaluating deucrictibant XR for AAE-C1INH prophylaxis is ongoing, with Part 1 topline data expected in the first quarter of 2027.