PHA121 outperforms icatibant in a bradykinin-challenge study
Zug, Switzerland, Nov. 13, 2020 – Pharvaris, a clinical-stage company focused on the discovery and development of novel oral bradykinin-B2-receptor antagonists for the treatment of hereditary angioedema (HAE) and other bradykinin-B2-receptor-mediated indications, announced the presentation of two posters at the virtual American College of Asthma, Allergy and Immunology (ACAAI) Annual Scientific Meeting. The data in both posters present the pharmacokinetic (PK), pharmacodynamic (PD), and safety profiles of PHA121 in healthy volunteers. Pharvaris expects to advance PHVS416 (PHA121 in soft capsules) to provide a rapid and convenient on-demand HAE treatment using a small oral dosage form.
The first poster, titled “Bradykinin Challenge Provides Surrogate Endpoints For Hereditary Angioedema Treatment Using Bradykinin-B2-Receptor Antagonists,” and its associated prerecorded session can be found online. The effect of PHA121 on cardiovascular changes induced by bradykinin (BK) was evaluated in a proof-of-concept study in healthy volunteers. Two doses (12 and 22 mg) of PHA121 were administered orally to 16 healthy volunteers, followed by bradykinin challenges to induce brief hemodynamic responses. The PHA121-mediated dampening of these BK-induced hemodynamic responses was evaluated using a non-linear mixed-effect PK/PD model. The effective treatment duration from both doses of PHA121 exceeds the published duration of subcutaneous icatibant (30 mg), with the duration of 22 mg PHA121 approximately twice as long as icatibant. The plasma concentration producing 50% of the maximum effect of the study drug (EC50) was found to be approximately four-fold more potent than that observed for icatibant in published data.
“When we scale the observed clinical potencies in this human bradykinin challenge by the molecular weight and plasma protein binding for PHA121 and icatibant, we find that PHA121 is 24-fold more potent than icatibant on a molar basis (IC50 of 170 pM versus 4.1 nM, respectively), consistent with our preclinical in vitro and ex vivo measurements,” observed Jochen Knolle, Ph.D., chief scientific officer and co-founder of Pharvaris. “This agreement between clinical and preclinical studies gives us confidence in the models and approach that Pharvaris has used in developing PHA121.”
