PRECLINICAL PHARMACOLOGICAL DATA FOR SMALL MOLECULE PHA121
Pharvaris publishes pharmacological data for the novel small molecule bradykinin B2-receptor antagonist PHA121 and its active metabolite PHA-022484 in an article in International Immunopharmacology.
The preclinical data demonstrate PHA121 specificity and potency for both recombinant and endogenous B2 receptor, including 20-fold higher potency than icatibant, an approved injectable B2-receptor antagonist. Relative to icatibant, PHA121 exhibited improved intrinsic clearance, which predicted the improved in vivo half-life and oral bioavailability seen in clinical studies to date. This novel small molecule bradykinin B2 receptor antagonist is in clinical development for the treatment and prevention of hereditary angioedema attacks. Early clinical data in healthy participants indicate that PHA121 is orally bioavailable, with rapid absorption, favorable pharmacokinetics, and good tolerance.
“To our knowledge, PHA121 is the most potent, and the only oral, small-molecule human bradykinin B2 receptor antagonist that has ever been reported,” says Anne Lesage, Ph.D., Chief Early Development Officer of Pharvaris and lead author on the publication. “PHA121 acts as a selective and competitive antagonist of the bradykinin B2 receptor, blocking the effect of elevated bradykinin levels that lead to angioedema. This specificity is shown through large margins of inhibition at other targets. Its high potency allows for oral administration with a small dose, and supports Pharvaris’ development of this compound for on-demand and prophylactic treatment of HAE.”
The dataset in this publication demonstrates the in vitro pharmacological characteristics of PHA121 and its active metabolite, PHA-022484. Both compounds show high affinity for the recombinant human bradykinin B2 receptor. In contractility assays, both PHA121 and PHA-022484 demonstrate potent and reversible B2 antagonist activity. The data support a high degree of selectivity over a wide range of molecular targets, including the bradykinin B1 receptor.
(Source: Pharvaris)