Deucrictibant works quickly on HAE attacks, may help prevent them
Peer-reviewed articles point to treatment’s benefits
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Deucrictibant, an experimental oral small molecule from Pharvaris, delivers rapid relief when used on demand for acute attacks of hereditary angioedema (HAE) and can, over time, also reduce the frequency of the swelling that causes the attacks, a pair of scientific articles suggested.
The two peer-reviewed articles “add to the scientific evidence to further advance understanding of bradykinin-mediated angioedema and eventually inform clinical decisions about management in real-world clinical practice,” Peng Lu, MD, PhD, chief medical officer of Pharvaris, said in a company press release.
The articles, “Oral deucrictibant for prophylaxis of hereditary angioedema attacks (CHAPTER-1): primary analysis of a randomised, double-blind, placebo-controlled, phase 2 trial,” and “Oral deucrictibant for on-demand treatment of hereditary angioedema attacks (RAPIDe-1): a randomised, double-blind, placebo-controlled, phase 2 trial,” were published in The Lancet Haematology.
Angioedema occurs when fluid builds up under the skin or mucous membranes, leading to repeated episodes of swelling that can occur anywhere in the body. In HAE, this is caused by genetic mutations that lead to excess bradykinin production. Too much of this protein widens blood vessels and causes fluid to leak from blood vessels into tissues.
Deucrictibant blocks the bradykinin B2 receptor, preventing bradykinin from causing blood vessels to leak. It is being developed in two forms: as an immediate-release capsule that aims to stop acute attacks, and as an extended-release tablet that slowly releases deucrictibant over 24 hours to prevent swelling and reduce how often it occurs.
Mechanism aims for both prevention and management
“Since HAE is a bradykinin-mediated disease, regulation of bradykinin signaling through B2 receptor antagonism could both prevent HAE attacks and manage angioedema symptoms when they occur,” said Marc A. Riedl, MD, professor of medicine and clinical director of the U.S. Hereditary Angioedema Association Angioedema Center at the University of California San Diego.
RAPIDe-1 (NCT04618211), a Phase 2 clinical study, tested the immediate-release capsule as an on-demand treatment in 74 adults with HAE type 1 or 2, ages 18 to 75. All had experienced three or more attacks in the previous four months or two or more attacks in the two months prior to screening. In its first part, patients received a single dose of 10, 20, or 30 mg of deucrictibant when they were not having an attack. In its second part, patients were randomly assigned to receive either deucrictibant or a placebo and use it as an at-home, on-demand treatment for three attacks.
The main goal was to watch for changes in angioedema symptoms from before treatment to four hours after treatment, measured by a composite visual analogue scale that combines skin swelling, skin pain, and abdominal pain. Data from 147 attacks in 62 patients showed that the average score was 16.72 points lower with the lowest dose of deucrictibant than with the placebo, indicating greater symptom relief. For the other doses, the difference was similar.
The company said it plans to submit a new drug application to the U.S. Food and Drug Administration (FDA) in the first half of this year seeking approval of immediate-release deucrictibant as an on-demand treatment for acute HAE attacks.
To test long-term prophylaxis (preventive treatment), the Phase 2 clinical study CHAPTER-1 (NCT05047185) enrolled 34 adults with HAE type 1 or 2. They were randomly assigned to receive 20 or 40 mg of deucrictibant immediate-release tablets twice daily or a placebo for three months. Thirty patients completed this part and joined an open-label extension, during which all received 40 mg of deucrictibant daily for up to three years.
Patients treated with deucrictibant had fewer attacks per month than those who received a placebo. With the 20 mg dose, there were an average of 0.4 attacks per month, and with 40 mg, 0.3 attacks per month, significantly fewer than the 1.9 attacks per month with the placebo. This corresponds to a reduction of 79.2% with 20 mg and 84.5% with 40 mg.
This study served as a proof of concept, demonstrating that maintaining a steady drug level in the bloodstream could effectively prevent HAE attacks. By administering the immediate-release capsule twice daily, the researchers used the results as a bridge to develop the extended-release tablet formulation, intended for once-daily use. This extended-release version of deucrictibant is being tested in two Phase 3 trials: CHAPTER-3 (NCT06669754) and the open-label extension study CHAPTER-4 (NCT06679881), which is recruiting at several locations worldwide.
“Deucrictibant is emerging as a potentially unique oral therapy for HAE, providing on-demand and preventative treatment effects through the availability of both the immediate-release capsule and extended-release tablet,” said Riedl, an investigator in both trials. “This complementary approach may further improve HAE management for patients and prescribers alike.”
