Pharvaris gearing up to launch Phase 3 trial of PHVS416 in 2024

Planning follows FDA meeting on next steps for on-demand HAE treatment

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Pharvaris is now gearing up startup activities with clinical site investigators and staff to launch a Phase 3 trial next year of PHVS416 — an immediate-release capsule formulation of deucrictibant — as an on-demand treatment for hereditary angioedema (HAE).

The Switzerland-based clinical-stage company recently met with the U.S. Food and Drug Administration (FDA), in an end-of-Phase 2 meeting, to align on the next steps for continued testing of PHVS416.

This took place following an earlier Phase 2 clinical trial, called RAPIDe-1 (NCT04618211), that showed that PHVS416 outperformed a placebo in relieving symptoms of swelling in people with HAE type 1 or 2, while being generally safe and well tolerated.

The purpose of an end-of-Phase 2 meeting is to further communication between a company and the FDA, and ensure that both sides are in tandem prior to a therapy candidate moving forward in clinical development. Based on the feedback received from the regulatory agency, Pharvaris expects to start the Phase 3 trial, which will be called RAPIDe-3, by the end of the second quarter of 2024.

“We appreciate the FDA’s ongoing communication and collaboration, including our recent productive end-of-Phase 2 meeting, and anticipate initiating RAPIDe-3, our global Phase 3 on-demand study of PHVS416, within the first half of 2024,” Berndt Modig, Pharvaris’ CEO, said in a company business update.

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Clinical hold of deucrictibant for on-demand treatment lifted by FDA

Phase 3 trial of immediate-release capsule expected by June

Meanwhile, top-line data from another Phase 2 trial, called CHAPTER-1 (NCT05047185), is expected to be announced in the coming months. That trial, which completed enrollment in August, is testing PHVS416 as a long-term prophylactic treatment for HAE attacks in 34 patients with HAE type 1 or 2.

The use of deucrictibant as a preventive treatment remains on hold in the U.S., but the company is planning to submit data from a rodent toxicology study to the FDA still this year. That submission is expected to provide data to address the remaining issues of the hold.

Interim data from that animal study provided the basis for lifting a hold for the on-demand use of deucrictibant.

“Pharvaris remains committed to resolving the U.S. clinical hold on deucrictibant for the prophylactic treatment of HAE, and we are on track to submit the non-clinical rodent data to the FDA by the end of the year,” Modig said.

HAE is a type of angioedema that occurs due to mutations that lead to excess levels of bradykinin in the blood. Too much bradykinin, a small protein that controls blood vessel dilation, makes blood vessels widen and become leaky, resulting in swelling attacks — the hallmark symptom of HAE.

Deucrictibant, formerly known as PHA121, is an oral small molecule that blocks the receptors for bradykinin, preventing the small protein from triggering a cascade of events leading to swelling.

The immediate-release capsule formulation of deucrictibant, known as PHVS416, is now being investigated both as an on-demand and a preventive treatment for HAE swelling attacks.

The RAPIDe-1 trial, now completed, tested PHVS416 as an on-demand treatment in 74 adults with HAE. Participants were randomly assigned to receive either PHVS416 — at a 10, 20, or 30 mg dose — or a placebo, as soon as they experienced an attack.

A total of 62 patients experienced 147 attacks that qualified for the study’s efficacy analysis. The results showed that treatment significantly eased symptoms within four hours, and that it acted much faster than the placebo. There also were fewer patients requiring additional medications to ease their swelling.

For its part, the ongoing CHAPTER-1 trial, still on hold in the U.S., is testing if PHVS416 can prevent swelling attacks and reduce their severity when they occur. The participants received either a low or high dose of PHVS416 or a placebo, given once daily for 12 weeks, or about three months.

In addition to testing as its primary goal whether PHVS416 can reduce the number of HAE attacks versus a placebo, secondary measures include the number of moderate or severe attacks, and the number of attacks requiring acute treatment. It’s also assess the number of attack-free patients and the number of days spent with angioedema symptoms.

“Top-line data from CHAPTER-1, a Phase 2 proof-of-concept study of deucrictibant, potentially the first B2-receptor antagonist for long-term prophylaxis in HAE, is anticipated to be announced by the end of the year,” Modig said.

Certain clinical data have shared at multiple recent medical and patient meetings. Pharvaris also plans to present two ePosters at this year’s American College of Allergy, Asthma & Immunology (ACAAI) annual scientific meeting, to be held Nov. 9-13 in Anaheim, California.