PII-111 - DRUG-DRUG INTERACTION STUDY TO EVALUATE THE EFFECT OF STRONG CYP3A INHIBITION AND P450 INDUCTION ON THE PHARMACOKINETICS OF AFICAMTEN, AND THE EFFECT OF AFICAMTEN ON P-GLYCOPROTEIN, IN HEALTHY PARTICIPANTS.

D. Xu¹, J. Lutz², P. Divanji², K. Cheplo², J. Li², S. Kupfer², P. German²; ¹Cytokinetics, Incorporated, South San Francisco, CA, ²Cytokinetics, Incorporated.

Background: Aficamten is a next-in-class small molecule, selective cardiac myosin inhibitor in phase 3 development for potential treatment of hypertrophic cardiomyopathy. In vitro studies suggest aficamten is metabolized by CYP2D6, CYP3A4 and CYP2C9/19, and may inhibit P-glycoprotein (P-gp) in vivo. A CYP2D6 genetic polymorphism study showed minimal involvement of CYP2D6 in aficamten elimination. The study objective was to evaluate the effect of strong CYP3A4 inhibition (itraconazole, ITR) and P450 induction (carbamazepine, CAR) on the pharmacokinetics (PK) of aficamten, and the impact of aficamten on the PK of a sensitive P-gp substrate (dabigatran [DAB] etexilate, DE).

Methods: This was a phase 1, open-label, fixed sequence study in healthy participants. The change in aficamten PK was evaluated for single dose 10 mg aficamten alone and after multiple-dose 200-mg QD doses of ITR (3 days [d]) or single dose 20 mg aficamten alone and after multiple-dose 100 mg (3 d), 200 mg (4 d), and 300 mg (11 d) BID CAR coadministration (n=17/cohort). The change in single dose DAB (total [t] and free) PK was evaluated for single dose 75 mg DE alone and combined with single dose 20 mg aficamten (n=25). All treatments were administered ≤1 h of consuming a standardized meal. Safety was assessed throughout the study.

Results: Weak CYP3A inhibition on aficamten (↑26% in aficamten AUC) was observed with ITR. Weak to moderate P450 induction (↓51% in aficamten AUC) was observed with CAR. Aficamten weakly inhibited P-gp (↑26% in total DAB AUC). Study treatments were generally well-tolerated. Two participants discontinued the study due to apparent transaminitis, likely secondary to CAR administration. There were no serious adverse events and no trends in the mean or individual participant clinical laboratory evaluations, vital signs, or ECG data across all 3 cohorts.

Conclusion: Aficamten dose adjustments are not required with CYP3A inhibitors. Coadministration of aficamten with strong P450 inducers may lower aficamten exposure. Aficamten can be co-administered with sensitive P-gp substrates. Further in vivo study of CYP2C9/19 inhibition of aficamten elimination is on-going.