Primary trial results at a glance
- The phase 3 CHAPTER-3 trial randomized 85 adolescents and adults across 21 countries to evaluate once-daily oral deucrictibant extended-release.
- Participants receiving deucrictibant XR 40 mg once daily experienced an 83% reduction in mean monthly hereditary angioedema attacks compared to placebo over 24 weeks.
- Among the 80 study participants diagnosed with type 1 or type 2 hereditary angioedema, attack rates fell by approximately 87%.
- Preventive protection against attacks began during the first week of treatment and persisted throughout the full 24-week evaluation window.
- No treatment-related serious adverse events occurred, and exactly one participant in each arm discontinued treatment due to an adverse event.
- Biotechnology company Pharvaris reported plans to submit a New Drug Application to the U.S. Food and Drug Administration during the first half of 2027.
| Finding | Plain-English meaning |
|---|---|
| Deucrictibant XR 40 mg reduced mean monthly attack rates by 83% compared with placebo (P < .0001). | Patients taking the daily oral pill experienced far fewer swelling attacks over 24 weeks than those taking a placebo pill. |
| Attack rates decreased by approximately 87% in participants with type 1 or type 2 disease. | People with the two most common forms of hereditary angioedema had nearly nine out of ten swelling episodes prevented. |
| Symptom protection began in week 1 and held through week 24 of continuous treatment. | The medicine began shielding patients against dangerous swelling during the first seven days and kept working for six months. |
| Zero treatment-related serious adverse events occurred, with one dropout per group due to side effects. | The experimental drug was well tolerated in the trial, showing a safety profile similar to the dummy pill. |
How deucrictibant addresses hereditary angioedema
Hereditary angioedema, abbreviated as HAE, is a rare genetic disease that causes unpredictable, painful swelling attacks. These episodes affect the skin, the gastrointestinal tract, and the upper respiratory airway. Gastrointestinal swelling causes acute, severe abdominal pain due to fluid accumulation in the intestinal wall. Swelling in the throat or larynx can restrict airflow and become life-threatening.
Unlike allergic swelling, hereditary angioedema is not driven by histamine. Standard allergy treatments such as antihistamines, corticosteroids, and epinephrine do not stop an active attack. Instead, the disorder stems from excessive activity of a peptide called bradykinin. Bradykinin acts like a valve that opens blood vessels, forcing fluid to leak into surrounding body tissues. In many patients, this happens because of mutations in the SERPING1 gene, which causes a deficiency or malfunction in C1 inhibitor protein.
Deucrictibant is an investigational small-molecule drug that targets this pathway directly. It acts as a selective antagonist for the bradykinin B2 receptor. By binding to these specific receptors, the drug blocks bradykinin from signaling blood vessels to open. The extended-release formulation, termed deucrictibant XR, is engineered for once-daily oral administration to maintain consistent blood levels. A separate immediate-release oral version is also undergoing evaluation for on-demand rescue treatment during sudden flare-ups.
Results from the phase 3 CHAPTER-3 study
The phase 3 CHAPTER-3 trial (NCT06669754) was a randomized, double-blind, placebo-controlled clinical study conducted across 21 countries. Investigators enrolled 85 participants, including both adolescents and adults. The study design allocated participants in a 2:1 ratio: 55 received deucrictibant XR 40 mg once daily, while 30 received a matching placebo for 24 weeks.
CHAPTER-3 included patients with type 1 HAE, type 2 HAE, and HAE with normal C1 inhibitor levels. According to drug developer Pharvaris, this was the first phase 3 prophylaxis trial in hereditary angioedema to enroll participants across all three disease categories.
Across the overall study population of 85 participants, oral deucrictibant reduced the mean monthly attack rate by 83% compared to placebo, reaching statistical significance (P < .0001). In the subgroup of 80 participants with type 1 or type 2 disease, treatment produced an attack reduction of approximately 87%.
All secondary efficacy endpoints achieved statistical significance under a multiplicity-controlled analysis framework. Protection from attacks appeared during the first week of dosing and remained consistent through the entire 24-week period. The active drug group also demonstrated higher proportions of completely attack-free participants and substantial reductions in attack frequency relative to baseline measurements.
Core statistics from the CHAPTER-3 clinical trial
| Trial Parameter | Stated Outcome or Value |
|---|---|
| Enrolled Study Population | 85 adolescents and adults across 21 countries |
| Treatment Allocation Ratio | 2:1 (55 active deucrictibant XR 40 mg, 30 placebo) |
| Primary Endpoint Result | 83% mean monthly attack rate reduction vs placebo (P < .0001) |
| Type 1 and Type 2 Subgroup Effect | Approximately 87% attack rate reduction (n=80) |
| Treatment Duration | 24 weeks of continuous daily administration |
| Treatment-Related Serious Adverse Events | 0 reported events |
| Discontinuations Due to Adverse Events | 1 participant in active group, 1 participant in placebo group |
Tolerability profile and competitive outlook
Safety data from CHAPTER-3 indicated that most treatment-emergent adverse events were mild or moderate. No treatment-related serious adverse events were reported in either group. Tolerability appeared consistent across arms, evidenced by equal numbers of study dropouts: one participant taking deucrictibant XR and one taking placebo discontinued treatment due to an adverse event.
Long-term safety and durability are currently under evaluation in CHAPTER-4 (NCT06679881), an open-label extension trial. Because preventive therapy for hereditary angioedema can last indefinitely, multi-year follow-up will be necessary to observe long-term safety, potential drug interactions, and real-world medication adherence.
The clinical landscape for long-term HAE prevention includes both injectable monoclonal antibodies, such as lanadelumab, and oral therapies like berotralstat. Current international clinical guidelines recommend an individualized approach to preventive care, balancing attack burden against treatment administration burden. If approved, deucrictibant XR would offer a daily oral alternative for individuals who prefer to avoid routine subcutaneous or intravenous injections.
Pharvaris announced plans to use the CHAPTER-3 trial findings to support global marketing applications. The company intends to submit a New Drug Application to the FDA in the first half of 2027 for the prevention of bradykinin-mediated angioedema attacks. Deucrictibant remains an investigational agent and is not currently approved by regulatory authorities.
Assessing trial limits and open regulatory questions
The topline results from CHAPTER-3 demonstrate substantial efficacy, but several reporting limits warrant consideration. Full numerical breakdowns for secondary endpoints, exact baseline attack frequencies, and detailed patient-reported quality-of-life scores have not yet been published in complete peer-reviewed form.
While an 83% attack reduction represents a large relative change, the small total trial size of 85 participants reflects the rare nature of hereditary angioedema. Clinical trials in rare genetic diseases inherently study smaller cohorts than trials for common conditions like hypertension or diabetes.
Clinical guidelines also emphasize that effective preventive treatment does not eliminate the need for acute rescue medication. Patients receiving oral prophylaxis must still retain access to fast-acting acute therapies in the event of a breakthrough swelling episode, particularly when attacks involve the throat or upper airway.
Sources:
- Pharmacy Times, “Phase 3 Trial Shows Oral Deucrictibant Reduces Hereditary Angioedema Attacks by 83%” (https://www.pharmacytimes.com/view/phase-3-trial-shows-oral-deucrictibant-reduces-hereditary-angioedema-attacks-by-83-)
- Pharvaris N.V., “Pharvaris Announces Positive Topline Data from CHAPTER-3 Pivotal Study of Deucrictibant XR for Prophylaxis of HAE Attacks” (https://www.globenewswire.com/news-release/2026/09/08/3357455/0/en/pharvaris-announces-positive-topline-data-from-chapter-3-pivotal-study-of-deucrictibant-xr-for-prophylaxis-of-hae-attacks.html)
- ClinicalTrials.gov, “CHAPTER-3: Phase 3 Study of Deucrictibant Extended-Release Tablet for Prophylaxis Against Angioedema Attacks in HAE (NCT06669754)” (https://clinicaltrials.gov/study/NCT06669754)
Disclaimer: This article is for general information only and does not constitute medical advice, diagnosis, or treatment. Always consult a qualified healthcare provider about any medical condition or before making health decisions.