Aficamten

Aficamten (CK-3773274, trade name MYQORZO) is a selective, allosteric, reversible small-molecule inhibitor of cardiac myosin motor activity developed by Cytokinetics, Inc. for the treatment of hypertrophic cardiomyopathy (HCM). The compound reduces myocardial contractility by stabilizing a weak actin-binding, pre-power-stroke state of the beta-cardiac myosin head, thereby decreasing the number of functional myosin cross-bridges available during each cardiac cycle and attenuating the left ventricular outflow tract (LVOT) obstruction that drives symptoms in obstructive HCM. Aficamten binds to an allosteric site between the upper 50 kDa and lower 50 kDa subdomains of the myosin catalytic domain, overlapping with the blebbistatin binding pocket but distinct from the mavacamten binding site, and dramatically slows phosphate release from the myosin ATPase cycle to a rate slower than the conventional super-relaxed state.

The compound was engineered to address pharmacokinetic limitations of mavacamten, the first-in-class cardiac myosin inhibitor. Aficamten achieves a plasma elimination half-life of approximately 75 to 100 hours (compared to 7 to 9 days for mavacamten), reaches steady-state plasma concentrations within approximately 2 weeks of daily dosing (compared to approximately 6 weeks for mavacamten), demonstrates reversibility of pharmacodynamic effects within 24 to 48 hours, exhibits a shallow exposure-response relationship that widens the therapeutic window, and is metabolized by multiple cytochrome P450 enzymes (CYP2C9, CYP3A4, CYP2D6, CYP2C19) rather than predominantly by the polymorphic CYP2C19, thereby reducing the drug-drug interaction burden and eliminating the requirement for CYP metabolizer genotyping.

Clinical development of aficamten has proceeded through a comprehensive program. The Phase 1 dose-escalation study in 102 healthy participants demonstrated dose-proportional pharmacokinetics, dose-dependent reductions in left ventricular ejection fraction (LVEF), and favorable tolerability with no serious adverse events. The Phase 2 REDWOOD-HCM trial in patients with symptomatic obstructive HCM demonstrated statistically significant reductions in resting and post-Valsalva LVOT gradients, with 78.6 to 92.9 percent of patients achieving target gradient reduction at 10 weeks. The pivotal Phase 3 SEQUOIA-HCM trial randomized 282 patients with symptomatic obstructive HCM to aficamten or placebo for 24 weeks and met its primary endpoint of improved peak oxygen uptake (pVO2), with a least-squares mean difference of 1.74 mL/kg/min (p = 0.000002), along with statistically significant improvements in all 10 prespecified secondary endpoints including NYHA functional class, Kansas City Cardiomyopathy Questionnaire scores, and LVOT gradient reduction. The Phase 3 MAPLE-HCM trial demonstrated superiority of aficamten monotherapy over metoprolol monotherapy, with a pVO2 least-squares mean difference of 2.3 mL/kg/min (p < 0.0001). The Phase 3 ACACIA-HCM trial in 516 patients with non-obstructive HCM met both dual primary endpoints for symptom burden and exercise capacity improvement.

The United States Food and Drug Administration approved aficamten on December 19, 2025, for the treatment of adults with symptomatic obstructive HCM to improve functional capacity and symptoms, marketed as MYQORZO. The approval includes a boxed warning regarding the risk of heart failure due to systolic dysfunction and a Risk Evaluation and Mitigation Strategy (REMS) requiring echocardiographic monitoring. The principal adverse reaction observed at greater than 5 percent incidence above placebo was hypertension (8 percent versus 2 percent). LVEF reduction below 50 percent occurred in 3.5 percent of aficamten-treated patients in SEQUOIA-HCM compared to 0.7 percent on placebo; all instances were mild, reversible, and not associated with clinical heart failure events. This monograph reviews the chemistry, mechanism, pharmacokinetics, preclinical and clinical evidence, safety profile, handling considerations, and comparative assessment of aficamten against five alternative agents for the management of hypertrophic cardiomyopathy.