At the 12th C1 Inhibitor Deficiency and Angioedema Workshop (held virtually 3-6 June 2021), Anne Lesage, Ph.D., Chief Early Development Officer at Pharvaris, presents bradykinin challenge data supporting the pharmacokinetic and pharmacodynamic profile of PHA121 (PHA-022121) for the treatment of HAE.
“Findings presented here from pre-clinical and clinical studies, particularly from in vivo bradykinin challenge studies, show that PHA121 demonstrates faster onset than icatibant in head-to-head preclinical studies and, compared to published data, is consistently more potent showing longer duration bradykinin-BR2-antagonist activity than icatibant in human pharmacodynamic studies. These data position PHA121 as a potentially valuable treatment option for both on-demand and prophylactic treatment of HAE”, says Dr. Lesage.
Berndt Modig, CEO and co-founder of Pharvaris says: “Our data demonstrate a favorable pharmacokinetic 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 we continues progressing our clinical programs using the PHVS416 and PHVS719 product formulations.”
Pharvaris established a proof-of-concept model for HAE in non-human primates using bradykinin, an endogenous peptide known to mediate signs and symptoms of HAE. The model was validated utilizing icatibant, a marketed injectable B2 receptor antagonist, providing back-translation from human clinical experience with icatibant. The objective of the study was to investigate the ability of PHA121 to attenuate blood-pressure changes induced by bradykinin injection. In this model, PHA121 inhibited bradykinin-induced changes in blood pressure at all doses tested with a faster onset of action than icatibant and the duration of the effect was dose dependent.
PHA121 was also orally administered in two double-blind, placebo-controlled single-ascending-dose studies up to 50 mg, with pharmacokinetics (PK) and safety observed for 72 hours, in healthy volunteers. Pharmacodynamic (PD) effects were evaluated with a nonlinear mixed-effect PK/PD model using 12 mg and 22 mg doses and compared to historical icatibant data. PK/PD analysis showed significant inhibition of bradykinin-induced hemodynamic changes with an average composite EC50 of 2.4 ng/mL and EC85 of 13.8 ng/mL. Single-dose treatment of PHA121 demonstrated effective bradykinin inhibition. Quantitative modeling indicates that single oral doses of PHA121 will maintain pharmacologically active drug levels for a substantially longer time than 30 mg of subcutaneous icatibant.(Source: Pharvaris)