PHA121, Oral Therapy for HAE Attacks, Safe at All Doses in Phase 1 Trial

PHA121, an investigational oral therapy for hereditary angioedema attacks, was well tolerated across multiple doses in a group of healthy volunteers in a Phase 1 trial.

Study data also indicates that PHA121 reached therapeutic levels in the first day of a 10-day treatment period, and stable levels within the first three days.

“We are encouraged by these results to continue development of PHA121 as an oral treatment for hereditary angioedema,” Berndt Modig, CEO and co-founder of Pharvaris, its developer, said in a press release.

People with HAE produce excessive amounts of the inflammatory molecule bradykinin, which causes blood vessels to dilate and fluid to leak into surrounding tissues, resulting in bouts of swelling.

PHA121 is a small molecule that binds the bradykinin B2 receptor, and prevents bradykinin from activating it. It works in ways similar to Firazyr (icatibant acetate), an approved under-the-skin HAE treatment marketed by Takeda (a generic is also available). But data suggest it may be more potent and long lasting than Firazyr.

Pharvaris is planning to develop three formulations of PHA121. In addition to an oral solution, the company will also develop a soft oral capsule formulation (PHVS416) for preventing HAE attacks in the long-term and for treating them when they occur, and a tablet formulation (PHVS719) for preventive use only.

The Phase 1 trial enrolled 38 healthy volunteers, randomly assigned to one of four doses of PHA121 (ranging from 12 to 50 mg) or to a placebo. Participants were dosed two times a day for 10 days.

The trial assessed the therapy’s safety, tolerability, and pharmacokinetics, which refers to the movement of a medicine into, through, and out of the body.

According to Pharvaris, PHA121 was well tolerated, even at the highest dose tested. All treatment-related adverse events were considered mild, and occurred at similar rates in the PHA121 and placebo-treated groups. All were also completely resolved.

Participants vital signs, lab tests, and heart rate (measured by an electrocardiogram) all remained within normal limits.

The company recently launched a Phase 2 clinical trial (NCT04618211) to investigate the soft capsule formulation (PHVS416), at one of three escalating doses, as an on-demand treatment for acute attacks in HAE patients.

A total of 54 adult participants are to be recruited at five clinical sites in Canada. To be eligible, patients must have HAE type 1 or 2 and have experienced at least three attacks in the last four months, or at least two in the last two months. Contact and site information is available here.

In study’s first part, participants will be given PHVS416 at their assigned dose, or a matching placebo, in the absence of an attack to determine the treatment’s safety and pharmacokinetics. Then, while at home, patients take PHA121 or a placebo during three attacks.

This study is due to conclude in September 2022.

“In 2021, we will explore the therapeutic potential of PHA121 for both acute and prophylactic treatment of HAE. Our upcoming Phase 2 studies will utilize PHVS416, a soft capsule formulation containing PHA121,” Modig said.