Early Phase 1 Data Support PHA121 as Oral HAE Prophylactic

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by Marta Figueiredo PhD |

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Multiple doses of PHA121 (PHA-022121), an investigational oral therapy for hereditary angioedema (HAE), were well-tolerated and rapidly reached therapeutic levels in healthy volunteers, according to data from a Phase 1 clinical trial.

The therapy’s pharmacological profile “suggests that the therapeutic effect of PHA121 can be achieved as early as the first day of dosing, with steady-state plasma levels achieved within three days,” Peng Lu, MD, PhD, chief medical officer of Pharvaris, which is developing the therapy, said in a press release.

These findings, together with previous preclinical and clinical data highlighting that PHA121 may lead to faster and more durable effects than standard, on-demand Firazyr (icatibant), support the therapy’s further development as a preventive oral treatment for HAE.

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Phase 1 data were presented in a poster at the European Academy of Allergy and Clinical Immunology Hybrid Congress 2021, held in-person and virtually, July 10–12. The poster was titled “Multiple dose administration of PHA-022121, an orally available, bradykinin B2 receptor antagonist is well tolerated and shows a favorable pharmacokinetic profile for prophylactic treatment of HAE.”

PHA121 is a small molecule that works by preventing the activation of bradykinin B2 receptors by bradykinin — an inflammatory molecule overly produced in HAE patients, leading to sudden swelling and pain attacks.

Its mechanism of action is similar to that of Takeda’s injectable Firazyr, the leading on-demand therapy for HAE. However, PHA121 is administered orally and was previously shown to lead to faster, stronger, and more durable suppression of bradykinin-induced changes in blood pressure in monkeys and healthy volunteers.

Bradykinin B2 receptor suppression “has been demonstrated to be effective in treating acute HAE attacks but is currently not available as oral treatment,” Berndt Modig, Pharvaris’ CEO and co-founder, said.

“Pharvaris remains committed to providing patients with oral alternatives both for on-demand and prophylactic [preventive] treatment in HAE via our softgel capsule formulation, PHVS416, and extended-release tablet formulation, PHVS719,” he added.

PHVS416 is being developed for HAE attacks, and is currently being tested in the placebo-controlled Phase 2 RAPIDe-1 trial (NCT04618211), which is enrolling up to 54 adults with HAE at sites in Canada, Israel, and several European countries. The study is expected to end in September 2022.

In turn, PHVS719 is being evaluated in preclinical studies as a potential preventive treatment for acute swelling attacks.

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Newly presented data concerned results of a placebo-controlled, multiple ascending dose Phase 1 study that evaluated PHA121’s safety, tolerability, and pharmacokinetics (referring to its movement into, through, and out of the body) in 38 male and female healthy volunteers.

Participants were randomly assigned to receive one of four oral liquid doses of PHA121 (12, 22, 33, or 50 mg) or a placebo after standard meals, twice a day for nine days, and a morning dose on day 10.

In the first three dose groups, eight patients were given the therapy, while two received a placebo. Eight participants were enrolled in the last dose group (50 mg) due to COVID-19-related constraints. Six of these were assigned to PHA121 and two to placebo.

Results showed that PHA121 was well-tolerated across all doses, with adverse events being mild in intensity, resolving completely, and occurring at similar rates as those in the placebo groups. The most commonly reported treatment-related adverse events were related to the gastrointestinal, nervous, and respiratory systems.

Laboratory findings, vital signs, and heart rates (as measured by an electrocardiogram) remained within normal limits in all participants.

In addition, the therapy was rapidly well-absorbed, reaching its highest levels in the bloodstream between one and two hours after dosing. It also showed dose-proportional exposures, with higher doses resulting in higher and more durable treatment exposures, with a mean average half-life ranging from 4.8 to 7.3 hours after day 10. Half-life is the time needed for a therapy’s initial concentration to drop to half.

All PHA121 doses reached therapeutic levels in the first day of treatment and stable levels within the first three days. After that, therapy levels remained within a therapeutic range up to day 10.

Moreover, 10 days of treatment with PHA121 did not affect the activity of a key therapy-metabolizing enzyme, suggesting that the PHA121 would not interfere with the body’s ability to metabolize, or process, other therapies.

“PHA121 was well-tolerated in healthy volunteers up to 50 mg dosed twice a day for 10 days,” Lu said.

Coupled with previous data showing PHA121’s potential to suppress bradykinin-induced blood-related effects, these results in healthy volunteers support “future development to assess the efficacy and safety of prophylactic use of PHA121 in HAE patients,” Lu added.