Single PHA121 Dose Can Block Bradykinin Effects in Healthy Volunteers

A single dose of PHA121 (PHA-022121), Pharvaris’ investigational therapy for hereditary angioedema (HAE), is safe and can rapidly and sustainably block bradykinin-induced changes in blood parameters, according to two studies in healthy volunteers.

According to the company, these findings indicate PHA121 may be well suited for use as a single oral treatment to prevent acute HAE attacks in people with the chronic swelling disorder.

The results also support the launch of future clinical trials exploring PHA121’s therapeutic potential in patients, researchers said.

“The data from PHA121 continue to support our development plans to initiate studies in HAE patients this year,” Berndt Modig, co-founder and CEO of Pharvaris, said in a press release.

The studies’ findings were presented by Pharvaris at the 2021 American Academy of Allergy Asthma & Immunology (AAAAI) Virtual Annual Meeting, in a poster titled “PHA-022121, a Novel and Potent Bradykinin B2 Receptor Antagonist for Oral Treatment of Hereditary Angioedema” (L23). The AAAAI meeting is being held online Feb. 26 to March 1.

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

PHA121 is a small molecule that binds to the bradykinin B2 receptor, effectively preventing the compound from activating the signaling cascade that would prompt an HAE attack. This mechanism of action is similar to that of Firazyr (icatibant acetate), an approved HAE treatment marketed by Takeda. Earlier research has indicated that PHA121 may be more potent than Firzayr.

Previous data from PHA121 studies in healthy volunteers indicated that the potential treatment was safe and well-tolerated when given in a range of different doses. It also was shown to possibly more long-lasting and potent than Firazyr.

Consistent with these findings, Pharvaris now presented data from two double-blind, placebo-controlled studies, which demonstrated that a single oral dose of PHA121 can safely, rapidly, and sustainably inhibit bradykinin-induced effects in healthy volunteers. 

Both studies assessed the safety, tolerability, and pharmacological properties of single increasing doses (1–50 mg) of PHA121 in healthy volunteers. These participants were monitored for up to 72 hours (three days) following treatment administration.

Analyses indicated that PHA121 was rapidly absorbed when given with or without food, reaching concentrations that were able to effectively block the activity of bradykinin within a period of 15 minutes.

Compared with Firazyr, which lasts approximately six hours in circulation after being administered (30 mg given by via under-the-skin injection), PHA121 remained above the levels needed to block the activity of bradykinin for at least 12 hours.

“Orally dosed PHA121 was rapidly absorbed and exceeded projected efficacious therapeutic thresholds within 15 minutes with or without food,” said Peng Lu, MD, PhD, chief medical officer of Pharvaris.

“Pharmacodynamic [the effects of a drug on the body] results suggest that PHA121 may provide longer pharmacological effect with a single oral dose than icatibant,” Lu added.

“We look forward to exploring the therapeutic potential of this compound in multiple clinical studies this year,” Lu said.

Additional analyses showed that PHA121 was generally safe and well-tolerated. The incidence of side effects was similar in participants who received PHA121 and in those given a placebo (25% in both groups). All reported side effects were either mild or moderate in severity and rapidly subsided and resolved.

“There remains an unmet medical need for highly effective oral therapies with favorable safety profiles,” Modig said. “We will continue to evaluate PHA121 for both on-demand and prophylactic (preventive) treatment of HAE through our soft-capsule formulation, PHVS416, and tablet formulation, PHVS719.”

Pharvaris recently launched a Phase 2 trial (NCT04618211) in Canada that will assess three escalating doses of PHVS416 — the therapy’s soft oral capsule formulation — as an on-demand treatment for HAE attacks. The trial aims to enroll around 54 adults with HAE type 1 or 2; more information on contacts and locations can be found here.

In addition to the oral solution and soft oral capsule, the company will  develop a tablet formulation (PHVS719) for the prevention of HAE attacks.