Pharvaris Brings Injectable-Grade Attack Prevention to an Oral Hereditary Angioedema Pill
Pharvaris reported Phase 3 CHAPTER-3 data for deucrictibant extended-release 40 mg, delivering an 83% attack reduction in hereditary angioedema and matching the efficacy of injectable biologics.
Pharvaris N.V. (NASDAQ: PHVS) has placed an oral hereditary angioedema pill in the same efficacy band as an injectable monoclonal antibody. In the Phase 3 CHAPTER-3 trial, once-daily deucrictibant extended-release 40 mg cut investigator-confirmed attacks by 83% versus placebo over 24 weeks (95% CI: 72% to 90%, p < 0.0001). The Leiden, Netherlands, company reported the topline data on September 8, 2026, in a Form 6-K.
Deucrictibant is a selective small-molecule antagonist of the bradykinin B2 receptor. That terminal-pathway target is the core clinical and commercial argument. Injectable plasma kallikrein blockade has defined high-efficacy prophylaxis for years, while oral kallikrein inhibition has fallen short. CHAPTER-3 now asks whether a daily pill matching Takeda's Takhzyro on attack reduction can reshape routine HAE prevention.
An 83% attack cut in a broader HAE population
CHAPTER-3 was a multicenter, randomized, double-blind, placebo-controlled study evaluating deucrictibant XR 40 mg once daily versus placebo (2:1 randomization) in 85 participants aged 12 and older across 56 sites in 24 countries. Baseline attack rates were substantial: 3.76 attacks per month on active drug and 3.47 on placebo. The primary endpoint was the time-normalized number of investigator-confirmed HAE attacks over 24 weeks.
The trial is the first pivotal HAE prophylaxis study to enroll all forms of the condition. Eighty participants had Type 1 or Type 2 HAE from C1 inhibitor deficiency or dysfunction (52 on deucrictibant XR, 28 on placebo). Five had normal C1 inhibitor disease, known as Type 3 (3 active, 2 placebo). In the Type 1/2 subgroup of 80 patients, deucrictibant XR achieved an 87% attack reduction versus placebo, matching the 87% reduction Takeda's lanadelumab posted in the JAMA HELP study at 300 mg subcutaneously every two weeks.
Onset was rapid. Statistically significant attack reduction appeared within week 1 and held through week 24. Patient-reported outcomes tracked the clinical data. The Angioedema Quality of Life total score improved by a least-squares mean of -32.23 points on deucrictibant XR versus -8.70 on placebo at Week 24, a difference of -23.53 points (95% CI: -32.15 to -14.92, p < 0.0001). That improvement is nearly four times the 6-point minimal clinically important difference.
Bradykinin at the receptor, not upstream
HAE is an unpredictable, debilitating, and potentially fatal rare genetic disorder of recurrent subcutaneous and submucosal swelling. Attacks can cause facial disfigurement, severe abdominal pain, or fatal asphyxiation via laryngeal edema. In pathophysiology, the contact system generates bradykinin, which opens endothelial junctions. Plasma kallikrein inhibitors, including lanadelumab, BioCryst's oral berotralstat, and investigational RNAi agents such as donidalorsen, act upstream to prevent cleavage of high-molecular-weight kininogen. Deucrictibant acts at the terminal step. By directly blocking B2 receptors on endothelial cells, it halts vascular hyperpermeability regardless of upstream contact-system activity.
That positioning provides a mechanistic hedge against residual contact activation. It also explains why CHAPTER-3's inclusion of five Type 3 patients matters beyond their small count. Normal-C1-inhibitor disease involves diverse genetic drivers, but all converge on bradykinin signaling at the B2 receptor.
The comparison with the only approved oral prophylactic is stark. Orladeyo (berotralstat) gained approval in December 2020. In its pivotal JACI APeX-2 publication, 150 mg berotralstat reduced attacks by 44% versus placebo (rate ratio 0.56), missed statistical significance on AE-QoL change versus placebo (-4.90 points, p=0.188), and caused gastrointestinal adverse events in roughly 50% of patients during month 1. CHAPTER-3's 83% overall reduction and -23.53-point AE-QoL benefit present a much stronger clinical profile.
Safety and tolerability profile
Treatment-emergent adverse events occurred in 76.4% (42 of 55) of deucrictibant XR patients versus 56.7% (17 of 30) on placebo. Most events were mild to moderate: Grade 1 in 27.3% and Grade 2 in 41.8% of the active cohort. Grade 3 events occurred in 3 patients (5.5%) and Grade 4 in 1 patient (1.8%). Study-drug-related TEAEs occurred in 20.0% (11 of 55) on deucrictibant XR versus 10.0% (3 of 30) on placebo. One serious adverse event (1.8%) on active drug was deemed unrelated to treatment. Discontinuations due to adverse events were 1.8% (1 patient) on deucrictibant XR versus 3.3% (1 patient) on placebo.
While TEAE rates exceeded placebo, the safety findings showed no dose-limiting toxicities or severe GI clustering that would compromise an 83% attack reduction.
Two filings on a single receptor
Pharvaris is advancing a dual-product B2 franchise. Deucrictibant immediate-release 20 mg, an oral on-demand capsule, met its endpoints in Phase 3 RAPIDe-3. The U.S. NDA and EU MAA have been accepted, with an FDA PDUFA target date of April 23, 2027. For long-term prophylaxis, Pharvaris plans to submit a U.S. NDA for the 40 mg XR tablet in the first half of 2027.
If both gain approval, HAE management could center on an integrated oral regimen: an acute capsule for breakthrough swelling and a daily tablet for ongoing prevention. Cross-trial comparisons with lanadelumab are not head-to-head proof, and long-term durability past 24 weeks requires ongoing open-label confirmation. Even so, CHAPTER-3 demonstrates that terminal B2 receptor blockade can deliver injectable-level efficacy in a daily pill.