Single-dose PHA121 Shows Promise in Trial as Treatment for HAE

Phase 1 data support development of PHA121 tablets as preventive therapy

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A single dose of the extended-release formulation of PHA121 — an investigational molecule under development for the prevention and treatment of swelling attacks associated with hereditary angioedema (HAE) — led to sustained, therapeutic levels of the medication in the bloodstream of participants.

That’s according to promising data from a Phase 1 trial that evaluated the extended-release formulation — called PHVS719 — against PHVS416, a faster-release version, in healthy adult males. The study was testing the formulation’s pharmacokinetics, or how a treatment moves into, through, and out of the body.

The results also showed that PHA121, the formulation’s active ingredient, was thoroughly absorbed in the digestive tract, and wasn’t quickly excreted, or eliminated, from the body.

Altogether, according to researchers, the data support the development of PHVS719 as a preventive treatment for swelling attacks in patients with HAE.

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New trial data presented at ACAAI

PHA121 is being developed by Pharvaris, based in the Netherlands. Researchers presented the new data in two posters at the American College of Allergy, Asthma & Immunology (ACAAI) Annual Scientific Meeting, held recently in Louisville, Kentucky.

“The data presented at ACAAI demonstrate the optimized pharmacokinetic and tolerability profiles of Pharvaris’ drug candidates that are in clinical development for the treatment of HAE,” Peng Lu, MD, PhD, chief medical officer of Pharvaris, said in a company press release.

Lu added that the data also “support the dosing regimen in CHAPTER-1, a Phase 2 study evaluating PHVS416 as a proof of concept of PHVS719 for the prophylactic [preventive] treatment of HAE.”

The placebo-controlled HAE CHAPTER-1 study (NCT05047185), as well as all other trials in the PHA121 clinical program, have been placed on hold by the U.S. Food and Drug Administration (FDA) based on a recent review of non-clinical data.

That means that clinical testing of PHVS719 and PHVS416 are paused in the U.S. However, recruiting for CHAPTER-1 is ongoing outside the U.S., with enrollment at sites in Bulgaria, Canada, Germany, Israel, Poland, Spain, and the U.K.

Eligible participants must be ages 18–75 and have HAE type 1 or 2. Each must also have a documented history of at least three HAE attacks occurring in the three months before screening, or at least two HAE attacks taking place during the study’s screening period.

The trial is funded by Pharvaris.

HAE swelling attacks are caused by an excess in the body of a signaling molecule called bradykinin. Pharvaris designed PHA121 to interfere with bradykinin signaling by preventing the molecule from binding to its receptor, called bradykinin B2 receptor.

The company believes the potential benefits of PHA121 to be twofold, with an ability to both treat and prevent HAE attacks.

PHVS416, a soft-capsule, faster-release formulation of PHA121, is being developed as an on-demand treatment for active attacks in HAE. PHVS719, intended instead as a preventive therapy, is an extended-release tablet. This means the active ingredient is released more slowly and is expected to last longer in the body.

To support the feasibility of an extended-release formulation for preventing HAE attacks, researchers investigated the pharmacokinetic properties of the active ingredient, PHA121.

Anne Lesage, PhD, co-founder and chief early development officer at Pharvaris, presented these data in a poster titled “Development of PHVS719: an Oral Extended-Release Bradykinin B2 Receptor Antagonist to Prevent Hereditary Angioedema Attacks.”

According to Pharvaris, good absorption of PHA121 in the digestive tract — specifically the colon — is important for an extended-release formulation therapy. That is because high absorption of the medication in the colon means less of it will be eliminated from the body. This in turn also means that the medication will remain in the body for a longer period of time.

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Developing a preventive treatment for HAE

Preclinical experiments in rats demonstrated that the treatment was absorbed in the colon. In humans, oral PHA121 was excreted in low amounts in feces, suggesting that most of the medication was absorbed in the gastrointestinal tract.

A Phase 1 pharmacokinetic study was subsequently conducted to evaluate these properties in the extended-release formulation, PHVS719. The trial involved 10 healthy adult men, ages 18–65.

Participants received each of a total five treatments in a random order, separated by a one-week washout period to ensure the medication from the previous dose was fully out of the body. Treatments consisted of 20 mg of PHVS719 with or without food, 40 mg of PHVS719 with or without food, or 20 mg PHVS416 without food.

When taken under fed conditions, treatment was administered 30 minutes after a high-fat, high-calorie breakfast.

Findings from the Phase 1 study were presented by Kees Groen, PhD, a Pharvaris consultant and co-founder and CEO of DGr Pharma, in a poster titled “Pharmacokinetics of PHVS719, Extended-Release Tablet Formulation of PHA121, a First-in-Class Oral Human Bradykinin B2-Receptor Antagonist.”

Results showed that the administration of PHVS416 rapidly led to therapeutic levels of PHA121 in the bloodstream within 30 minutes, consistent with its intended on-demand action.

In contrast, PHVS719 reached its peak in the bloodstream after about two hours, but remained at therapeutic levels for up to at least 30 hours, regardless of whether it was taken with or without food.

Both formulations were well-tolerated, with 10 adverse events reported in five patients, none of which were deemed serious, and all of which were temporary.

Pharvaris believes the data further backs clinical development of PHA121 as a preventive HAE treatment. When or if the clinical trial hold in the U.S. will be removed has not been announced.