Oral PHA121 May Lead to Faster, More Durable Effects Than Firazyr

PHA121 (PHA-022121), Pharvaris’ experimental oral therapy for hereditary angioedema (HAE), results in faster, more potent, and more durable suppression of bradykinin-induced changes in blood pressure than injectable Firazyr (icatibant), according to studies in monkeys and healthy volunteers.

These findings, along with evidence of PHA121’s favorable pharmacological profile, were recently shared by Anne Lesage, PhD, Pharvaris’ chief early development officer, in an oral presentation at the 12th C1-inhibitor Deficiency and Angioedema Workshop, held virtually, June 3–6.

The presentation was titled “PHA-022121: Efficacy in a Monkey Bradykinin Challenge Model Translated to Human.”

“PHA121 demonstrates faster onset than [Firazyr] in head-to-head preclinical studies and, compared to published data, is consistently more potent showing longer … activity than [Firazyr] in human pharmacodynamic studies,” Lesage said in a press release. Pharmacodynamics refers to a therapy’s effects on the body.

“These data position PHA121 as a potentially valuable treatment option for both on-demand and prophylactic [preventive] treatment of HAE,” she added.

Both Takeda’s Firazyr, the leading on-demand therapy for HAE, and PHA121 work by blocking bradykinin B2 receptors. This is meant to suppress the effects of bradykinin, an inflammatory molecule that’s overly produced in HAE patients, resulting in sudden swelling and pain attacks.

However, Firazyr’s under-the-skin injections (30 mg each) can be limiting for some patients, making the orally available PHA121 a potentially more convenient alternative. In addition, Firazyr has been reported to last six to seven hours in some HAE patients, with 6% of them requiring a second injection after six hours.

The preclinical data presented showed a comparison between PHA121 and Firazyr in an established proof-of-concept, non-human primate model of HAE, in which animals received bradykinin infusions to mimic blood pressure changes that cause attacks in patients.

Five doses of oral PHA121 — 0.1, 0.3, 1, 3, and 10 mg/kg — and a Firazyr dose equivalent to that approved in humans (0.6 mg/kg) were tested in the monkeys.

Results showed dose-dependent effects for PHA121, which potently blocked these bradykinin-induced changes in monkeys faster and for longer periods than Firazyr.

PHA121 “elicits an immediate inhibition of the bradykinin-mediated effect, with maximal inhibition at one hour after dosing, [which is] a faster onset of activity than [Firazyr], where the maximum inhibition occurs at two hours after dosing,” Lesage said in the presentation.

These proof-of-concept data provided the foundation for similar results in healthy volunteers, Lesage noted. A similar study design, using 12 or 22 mg of PHA121, was applied to healthy volunteers in a Phase 1 study.

The effective duration of PHA121’s effects was estimated to be six to 12 hours for the lower dose and nine to 15 hours for the higher dose, suggesting that either dose may be as effective or superior to Firazyr, with the higher 22 mg dose being “able to cover two injections of [Firazyr],” Lesage said.

In addition, previous published data indicated PHA121 was approximately four times more potent than Firazyr, based on the therapy’s blood levels needed to achieve 50% of the maximum effect. Additional analyses, which adjusted these findings to take into account other key pharmacological parameters, estimated PHA121 was around 24 times more potent than Firazyr.

To date, the oral therapy was generally well-tolerated at doses up to 50 mg in healthy volunteers.

“We believe that PHA121 is not only bringing convenience to HAE patients, but also potentially can provide great efficacy for on-demand and prophylactic treatment of HAE attacks,” Lesage said.

These positive results “not only provide strong proof-of-mechanism in human, but also sets up a solid foundation for the dose regimens to be further evaluated in both on-demand and prophylactic HAE studies,” she added.

Pharvaris is planning to develop PHA121 as an on-demand and a preventive treatment for acute swelling attacks.

As a potential on-demand treatment, PHA121 is delivered in a softgel capsule formulation, called PHVS416, which is currently being tested in a placebo-controlled Phase 2 trial, called RAPIDe-1 (NCT04618211).

The trial, expected to finish in September 2022, is enrolling up to 54 adults with HAE, who will be assigned randomly to receive either a low, medium, or high dose of PHVS416, or a matched placebo, for their acute HAE attacks.

PHVS719, Pharvaris’ extended-release tablet formulation of PHA121, is also being evaluated in preclinical studies as a potential preventive treatment for HAE attacks.

“Our data demonstrate a favorable pharmacokinetic [which refers to the movement of a drug into, through, and out of the body] and pharmacodynamic profile of PHA121 — providing strong proof of mechanism for PHA121 and a foundation for the dose regimens to be further evaluated for HAE as Pharvaris continues progressing our clinical programs,” said Berndt Modig, company CEO and co-founder.