FDA Places Hold on US Clinical Trials of PHA121 Therapy for HAE
Regulatory agency cites 'nonclinical data' in notification to developer Pharvaris
According to Pharvaris, the FDA plans to formally notify the company of its decision in approximately 30 days via a clinical hold letter. The initial notification was done verbally.
The FDA’s hold applies to U.S. trials covered under two investigational new drug (IND) applications — formal requests made by therapy developers that ask regulators for permission to initiate clinical testing.
“We are fully committed to working closely with the FDA to address the agency’s concerns,” said Berndt Modig, Pharvaris’ CEO.
“Pharvaris remains dedicated to providing new therapeutic choices for the treatment of HAE and is working diligently to bring PHA121 to people living with HAE,” Modig added.
In HAE, patients produce excessive amounts of an inflammatory molecule, called bradykinin, in the deep layers of the skin. High levels of bradykinin cause blood vessels to widen and fluid to leak into nearby tissues, resulting in swelling attacks.
PHA121 is a small molecule that binds to the bradykinin B2 receptor, preventing bradykinin from activating it. By doing so, PHA121 has the potential to stop HAE attacks and to prevent future attacks. Its mechanism of action is similar to that of Firazyr (icatibant), the leading on-demand therapy for HAE.
Preclinical studies in animal models of HAE have shown that treatment with PHA121 rapidly prevented bradykinin’s action by effectively binding to the B2 receptor.
Clinical trials of PHA121
In clinical trials in healthy volunteers, PHA121 was safe and well-tolerated when given in a range of multiple doses. It also was shown that the potential treatment led to faster and more durable effects than Firazyr.
Now, the company will suspend ongoing clinical trials of PHA121 involving patients with HAE in the U.S. One of them is HAE CHAPTER-1 (NCT05047185), a Phase 2 trial that aimed to enroll about 30 adults with regular swelling attacks. The targeted recruitment was for patients ages 18–75.
Participants in the study were to be randomly assigned to receive a low or high dose of PHA121’s soft capsule formulation (called PHVS416), or a placebo, for three months. The study’s primary goal is to determine the effect of treatment on the number of swelling attacks.
Anther on-hold trial is RAPIDe-1 (NCT04618211), a Phase 2 trial that was testing PHVS416 as an on-demand treatment for swelling attacks. Participants were first given a dose of the treatment when they were not having a swelling attack, to monitor safety and pharmacological properties. They then received PHVS416 or a placebo to treat swelling attacks at home.
Patients who participated and received at least one dose of the experimental therapy in RAPIDe-1 might enroll in a Phase 2/3 extension study, called RAPIDe-2 (NCT05396105), which is designed to assess the safety and efficacy of long-term on-demand treatment with PHA121.
Pharvaris also is developing an extended-release tablet form of PHA121, called PHVS719, as a potential prophylactic, or preventive, therapy for HAE. This extended-release formulation has already been tested in a Phase 1 trial enrolling healthy volunteers, and shown to be suitable for once-daily dosing.