A small molecule inhibitor being developed for hereditary angioedema (HAE) treatment, called PHA121, was as effective as Firazyr (icatibant acetate) — an approved therapy with a similar mechanism of action — at reversing bradykinin-induced changes in blood pressure in monkeys, results of a preclinical study show.
Pharvaris‘s oral investigative treatment also exerted an effect on blood pressure faster than Firazyr in this proof-of-concept animal study, supporting further development.
These findings were to be presented at the American Academy of Allergy, Asthma & Immunology (AAAAI) annual meeting, in the poster titled “PHA-022121, a First in Class Oral Bradykinin B2 Receptor Antagonist in Clinical Development: Proof of Concept Study in a Translational Monkey Bradykinin Challenge Model.” The meeting was scheduled to take place in Philadelphia in March, but was canceled due to the ongoing COVID-19 outbreak.
HAE is a rare disorder in which the inflammatory molecule bradykinin is produced in excess. This molecule causes blood vessels to dilate and fluid to accumulate in soft tissues, triggering the sudden and recurrent bouts of swelling that characterize the disease.
Firazyr is an on-demand therapy taken to ease such painful and potentially serious swelling attacks. Developed by Shire, now part of Takeda, it works by blocking the receptors that bradykinin normally binds to, so it can no longer cause swelling.
While patients are trained to give themselves a Firazyr injection when first symptoms of an attack appear, subcutaneous (under-the-skin) injections can be limiting to some.
Pharvaris is developing PHA121 as an oral treatment as an option to Firazyr.
The company has now established a proof-of-concept, non-human primate model for HAE, in which animals receive bradykinin infusions to mimic the changes in blood pressure that cause attacks in patients. The clinical effects of PHA121 were assessed in this animal model.
Results showed that HAE monkeys experienced a transient drop in their arterial blood pressure when infused with bradykinin. Treatment with either PHA121 or Firazyr potently blocked these bradykinin-induced changes.
Notably, while all doses of PHA121 tested — 0.1, 0.3, 1, 3, and 10 mg/kg — inhibited the blood pressure changes, researchers found that the higher the dose, the greater the benefits. And regardless of dose used, PHA121 reached maximum inhibition faster than Firazyr, suggesting it may ease swelling attacks more rapidly than the approved therapy.
An ongoing Phase 1 trial in healthy volunteers is currently investigating PHA121’s safety and tolerability, given in single ascending doses, and how the therapy behaves in the body — in terms of absorption, distribution, metabolism, and excretion.
The doses studied to date in this randomized, double-blind, placebo-controlled trial have been deemed safe and well tolerated, the company reported. Data also confirmed that PHA121 taken orally rapidly reaches effective concentrations in the blood.
“These results provide confidence in PHA121’s clinical profile for the treatment of hereditary angioedema,” Berndt Modig, CEO and co-founder of Pharvaris, said in a press release.
“Combined with preliminary findings from our ongoing Phase 1 study, these data demonstrate that PHA121 is a potent, orally available bradykinin B2 receptor antagonist,” Modig added.
Pharvaris is planning to develop PHA121 both as an on-demand treatment for acute swelling attacks, and to prevent such attacks. A clinical trial testing multiple ascending doses is expected to be launched in the future.
“These human data will help the dose selection for phase 2 clinical studies,” the researchers wrote.
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