Deucrictibant for hereditary angioedema

Last updated April 11, 2024, by Margarida Maia, PhD
Fact-checked by Joana Carvalho, PhD

What is deucrictibant for hereditary angioedema?

Deucrictibant, formerly known as 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 oral suspension, an immediate-release capsule (called PHVS416), or an extended-release tablet (called PHVS719).

Pharvaris recently initiated a Phase 3 clinical trial into its immediate-release capsule formulation of deucrictibant as an on-demand treatment for HAE. Preparations also are underway for a global Phase 3 clinical trial aiming to test the extended-release tablet form of deucrictibant as a prophylactic treatment for HAE attacks.

Deucrictibant was designated an orphan drug by the U.S. Food and Drug Administration (FDA) in 2022.

Therapy snapshot

How does deucrictibant work in hereditary angioedema?

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

Deucrictibant is a small molecule designed to block the B2 receptor for bradykinin. It effectively prevents bradykinin from interacting with its receptor and triggering blood vessel leakage, which is expected to 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 works by targeting and blocking 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 is being tested as an on-demand treatment to control swelling attacks as they occur. PHVS719, an extended-release tablet, is designed to release deucrictibant slowly over the course of 24 hours, allowing for once-daily dosing for prophylaxis. This is expected to reduce how often swelling attacks occur.

How will deucrictibant be administered in hereditary angioedema?

In clinical trials, deucrictibant has been given to healthy adults as an oral solution at doses ranging from 12 to 50 milligrams (mg) twice daily after meals. PHVS416 has been given to people with HAE as soft capsules at doses ranging from 10 to 40 mg per day.

Deucrictibant in hereditary angioedema clinical trials

Deucrictibant has been tested across a range of clinical trials involving both healthy volunteers and HAE patients. The therapy is currently in Phase 2 and Phase 3 clinical testing.

Phase 1 trial

A Phase 1 clinical trial tested the safety, tolerability, and pharmacokinetics (movement into, through, and out of the body) of an oral solution of deucrictibant against a placebo in 38 healthy adults. Deucrictibant was given twice daily after meals at doses of 12, 22, 33, or 50 mg for 10 days.

Deucrictibant was well tolerated up to the highest, 50 mg dose. Side effects were mild and comparable to those in the placebo group. Deucrictibant was rapidly taken into the bloodstream and achieved peak blood concentrations at a median of one to 1.75 hours after dosing. It reached steady state within three days, meaning that the amount of deucrictibant taken into the bloodstream equaled the amount eliminated from the body within that period of time. Blood concentrations remained above the anticipated threshold for clinical efficacy.

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 to 75. All enrolled patients had experienced three or more attacks in the previous four months, or two or more attacks in the two months prior to trial screening.

In its first part, study participants received a single 10, 20, or 30 mg dose of deucrictibant when they were not having an attack to evaluate its pharmacokinetics. In its second part, these patients randomly were 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 they were maintained for eight hours when PHVS416 was given at a dose of 10 or 20 mg, and for more than 10 hours when given at the 30 mg dose.

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.

Ongoing trials

Patients who received at least one dose of PHVS416 in RAPIDe-1 were eligible to enter an extension study, called RAPIDe-2 (NCT05396105), evaluating the long-term safety and efficacy of on-demand treatment with PHVS416. The study is expected to conclude by the end of this year.

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 to 75. Its main goal is to provide proof of concept for once-daily dosing with PHVS719, deucrictibant’s intended formulation as a preventative 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, where all are being treated with PHVS416 at a daily dose of 40 mg for up to 30 months (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 therapy dose saw their mean monthly attack rate drop by more than 80% compared with a placebo. The rate of moderate or severe attacks, as well as 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. CHAPTER-1 is expected to conclude in 2026.

Pharvaris recently opened a Phase 3 trial, called RAPIDe-3 (NCT06343779) to evaluate the safety and efficacy of PHVS416 as an on-demand treatment for HAE attacks. The trial is expected to enroll up to 120 adolescents and adults with HAE types 1 or 2, ages 12-75, and study sites are starting to recruit eligible patients.

RAPIDe-3 participants will self-administer either PHVS416 at a 20 mg dose or a placebo capsule, given in random order, at the onset of one of two swelling attacks. The study’s main goal is to assess whether PHVS416 outperforms the placebo in perceptions of symptom relief starting within 12 hours of taking a capsule, as measured using the seven-point Patient Global Impression of Change (PGI-C) scale.

Secondary trial goals include the proportion of attacks in which symptom relief started within four hours of treatment, also assessed using the PGI-C scale, as well as the proportion of attacks requiring the use of rescue medications and those that resolve within 24 hours. The RAPIDe-3 trial is expected to conclude in 2026.

Common side effects of deucrictibant

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

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