Clinical Evaluation of Drug–Drug Interactions With Aficamten

Aficamten is a next-in-class small molecule cardiac myosin inhibitor that was recently approved by the United States Food and Drug Administration (FDA) for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (oHCM). A comprehensive drug-drug interaction (DDI) evaluation of aficamten was achieved through two phase 1 studies in healthy participants. Aficamten as a victim of DDIs was studied using a moderate-to-strong P450 inducer (carbamazepine) and CYP inhibitors-itraconazole (strong CYP3A), paroxetine (strong CYP2D6), fluconazole (strong CYP2C19 and moderate 2C9 and 3A), and fluoxetine (strong CYP2D6 and 2C19). Aficamten's potential for P-glycoprotein (P-gp) inhibition was assessed using dabigatran etexilate (sensitive P-gp substrate). Minor increases in aficamten exposure (area under the curve) were observed following treatment with itraconazole (26%), paroxetine (27%), and fluoxetine (32%) compared with aficamten alone. Treatment with carbamazepine decreased aficamten exposure by 50%. Concomitant administration of aficamten with fluconazole, a multi-P450 inhibitor, resulted in a 278% increase in aficamten exposure. Taken together, results from these studies indicate that aficamten is primarily eliminated via CYP2C9-mediated metabolism (fraction metabolized [fm] = 54%) with contributions from CYP2D6 (fm = 21%), CYP3A (fm = 21%), and minimal metabolism via CYP2C19 (fm = 3%). A small increase (26%-27%) in dabigatran exposure was observed in the presence of aficamten; indicative of weak inhibition of P-gp. Aficamten was well tolerated, and adverse events were generally mild. In conclusion, aficamten is metabolized by multiple P450 enzymes, limiting its DDI liability. Only weak DDIs (< 2-fold) are likely from strong inhibition of any one pathway, and only moderate (< 5-fold) impact on aficamten exposure is expected with strong multi-pathway inhibitors or inducers.