Deucrictibant for hereditary angioedema

Last updated Feb. 17, 2025, by Margarida Maia, PhD
Fact-checked by Joana Carvalho, PhD

What is deucrictibant for HAE?

Deucrictibant, formerly PHA121, is an investigational small molecule being developed by Pharvaris as an on-demand and prophylactic (preventive) treatment for attacks of hereditary angioedema (HAE). It comes in the form of an immediate-release capsule called PHVS416 or an extended-release tablet called PHVS719.

Both formulations are being tested in Phase 3 clinical trials to treat or prevent attacks of HAE and the company plans to expand clinical testing of deucrictibant to acquired angioedema this year.

Deucrictibant has been designated an orphan drug by the U.S. Food and Drug Administration (FDA) in 2022 for treating bradykinin-mediated angioedema.

Therapy snapshot

How does deucrictibant work in HAE?

Angioedema occurs when fluid builds up beneath the skin or mucous membranes, resulting in repeated attacks of swelling that can arise anywhere in the body. In HAE, this is generally due to genetic mutations that lead to the excessive production and release of bradykinin. Too much bradykinin causes blood vessels to widen and become permeable, leaking fluid into surrounding tissues.

Unlike HAE, acquired angioedema doesn’t have a genetic cause. Instead, it usually occurs as a result of an underlying disorder, such as certain cancers or autoimmune diseases, that increase the consumption or impair the function of C1-inhibitor (C1-INH), a protein that regulates bradykinin production. Without sufficient C1-INH, bradykinin levels rise, triggering swelling.

Deucrictibant is a small molecule that’s designed to block the B2 receptor for bradykinin. It effectively prevents bradykinin from interacting with its receptor and triggering blood vessel leakage, which should bring swelling under control. Studies in lab-grown cells showed that deucrictibant is about 20 times more potent than icatibant, the active ingredient in Firazyr, an approved injectable on-demand treatment for HAE that also targets and blocks the B2 receptor for bradykinin.

PHVS416, an immediate-release capsule formulation of deucrictibant, is expected to take less than 30 minutes to reach a therapeutic level in the blood. It’s being tested as an on-demand treatment to control swelling attacks as they occur. PHVS719, an extended-release tablet formulation, is designed to release deucrictibant slowly over 24 hours, allowing for once-daily dosing for prophylaxis. This should reduce how often swelling attacks occur.

How will deucrictibant be administered in HAE?

In clinical trials involving HAE patients, deucrictibant has been given as immediate-release capsules at doses ranging from 10 to 40 milligrams (mg) per day, and as extended-release tablets at 40 mg a day.

Deucrictibant in HAE clinical trials

Deucrictibant has been tested across a range of clinical trials involving both healthy volunteers and people with HAE. It’s currently in Phase 3 clinical testing.

RAPIDe-1 Phase 2 trial

A two-part Phase 2 clinical trial, called RAPIDe-1 (NCT04618211), tested how well PHVS416 worked at easing symptoms associated with swelling attacks in 74 adults with HAE type 1 or 2, ages 18-75. All enrolled patients had had three or more attacks in the previous four months, or two or more attacks in the two months before trial screening.

In its first part, the participants received a single 10, 20, or 30 mg dose of deucrictibant when they were not having an attack to evaluate its pharmacokinetics, that is, movement into, through, and out of the body. In its second part, the patients were randomly assigned to either deucrictibant or a placebo for at-home, on-demand treatment of three swelling attacks.

Consistent with data from healthy adults, PHVS416 was rapidly absorbed into the bloodstream. Mean concentrations of 13.8 nanograms per milliliter were reached within 30 minutes and were maintained for eight hours at a dose of 10 or 20 mg, and for more than 10 hours when given at 30 mg.

The trial met its main goal of easing skin pain, skin swelling, and abdominal pain within four hours of dosing with PHVS416 versus a placebo. A composite visual analogue scale (VAS-3) score covering 147 swelling attacks in 62 patients was an average of 16 points lower for PHVS416 versus a placebo, indicating greater symptom relief. PHVS416 was effective at all tested doses, and the median time for patients to report the start of a swelling attack coming under control was less than 30 minutes.

PHVS416 reduced by almost six times the median time for the VAS-3 score to drop by half (50%) compared with a placebo (3.9 vs. 22.8 hours). Likewise, fewer patients treated with PHVS416 required rescue medication for symptom relief (up to 18.9% vs. 60.8%). PHVS416 was well tolerated, with three mild side effects (nausea, vomiting, and fatigue) reported with on-demand treatment at the highest dose of 30 mg.

RAPIDe-2 Phase 2/3 trial

Patients who received at least one dose of PHVS416 in RAPIDe-1 were eligible to enter an open-label extension, called RAPIDe-2 (NCT05396105), that is evaluating the long-term safety and efficacy of on-demand treatment with PHVS416.

Early data from 265 treated swelling attacks showed it took patients a median of 1.1 hours to start seeing symptom relief. The majority (85.8%) of swelling attacks were fully under control within a day, with as many as 90.2% achieving complete resolution with a single dose of PHVS416.

This open-label extension is underway and expected to conclude by mid-2027.

CHAPTER-1 Phase 2 trial

A fully enrolled two-part Phase 2 clinical trial called CHAPTER-1 (NCT05047185) is testing the safety and efficacy of PHVS416 as a prophylactic treatment in 34 adults with HAE type 1 or 2, ages 18-75. Its main goal is to provide proof of concept for once-daily dosing with PHVS719, deucrictibant’s intended formulation as a preventive HAE treatment.

In the first part of CHAPTER-1, patients either were treated with PHVS416, at a daily dose of 20 or 40 mg, or given a placebo, for about three months. Those who completed this first part could roll into an open-label extension part, where all are being treated with PHVS416 at a daily dose of 40 mg for up to 30 months, or about 2.5 years.

Top-line CHAPTER-1 data showed the study met its main goal, with deucrictibant significantly outperforming the placebo in reducing monthly HAE attack rates. Patients given the higher dose saw their mean monthly attack rate drop by more than 80% over a placebo. The rate of moderate or severe attacks, along with the rate of attacks requiring on-demand treatment, also dropped by more than 90% among patients given the higher dose of deucrictibant compared with a placebo. The therapy was generally well tolerated, with no serious side effects reported. 

Early data from 30 patients who entered the open-label extension and had received deucrictibant for a mean of 12.8 months showed the monthly rate of swelling attacks was reduced by 93% compared with the start of CHAPTER-1, suggesting the benefits of the therapy were sustained in the long term. On average, patients had fewer than one yearly swelling attack that required on-demand treatment.

CHAPTER-1 is expected to conclude later this year.

RAPIDe-3 Phase 3 trial

Pharvaris recently opened a Phase 3 clinical trial called RAPIDe-3 (NCT06343779) to assess the safety and efficacy of PHVS416 as an on-demand treatment for swelling attacks in up to 120 adults and adolescents with HAE type 1 or 2, ages 12-75.

Patients who enter RAPIDe-3 will self-administer either 20 mg of PHVS416 or a placebo, given in random order, at the onset of one of two swelling attacks. The main goal is to measure the time to symptom relief, defined as a Patient Global Impression of Change (PGI-C) rating of “a little better” or higher at two consecutive times within 12 hours of taking PHVS416 or a placebo.

Secondary goals include assessing the proportion of swelling attacks in which symptom relief started within four hours of treatment, also measured using the PGI-C scale, as well as the proportion of swelling attacks requiring rescue medication and those that completely resolved within a day.

Top-line data are expected in 2026. Patients who complete RAPIDe-3 are eligible to enter the RAPIDe-2 extension study.

CHAPTER-3 Phase 3 trial

A separate Phase 3 trial called CHAPTER-3 (NCT06669754) is also underway to assess the safety and efficacy of PHVS719, deucrictibant’s extended-release tablet formulation, as a preventive treatment for HAE attacks.

The study is planning to enroll up to 81 adults and adolescents with HAE, ages 12 and older, who experienced at least three swelling attacks in the three months before screening. They will be randomly assigned to receive either PHVS719 at a daily dose of 40 mg, or a placebo, for 24 weeks (about six months).

The trial’s main goal is to check how well PHVS719 prevents swelling attacks compared with a placebo by tracking their frequency over the 24 weeks. Other goals include assessing the therapy’s safety and pharmacokinetic profile.

Data are expected in the second half of 2026.

CHAPTER-4 Phase 3 trial

A long-term open-label Phase 3 clinical trial called CHAPTER-4 (NCT06679881) is also set to start evaluating the safety and efficacy of deucrictibant’s extended-release tablet formulation as a preventive treatment for swelling attacks.

The study will enroll up to 130 adults and adolescents with HAE, ages 12 and older, who will receive PHVS719 at a daily dose of 40 mg for 130 weeks, or about 2.5 years. Eligible patients may roll over from the CHAPTER-3 trial, transition from Phase 2 clinical testing of twice-daily immediate-release capsules in CHAPTER-1, or qualify after a screening period.

CHAPTER-4 is expected to be completed in 2028.

Common side effects of deucrictibant

Side effects reported with deucrictibant during clinical testing were mild, and included headache, nausea, vomiting, and fatigue.

Angioedema News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.