Impact of Aficamten on Echocardiographic Cardiac Structure and Function in Symptomatic Obstructive Hypertrophic Cardiomyopathy

Background: Aficamten, a next-in-class cardiac myosin inhibitor, improved peak oxygen uptake (pVO₂) and lowered resting and Valsalva left ventricular outflow (LVOT) gradients in adults with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in SEQUOIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM), a phase 3, multicenter, randomized, double-blinded, placebo-controlled study. Objectives: The authors sought to evaluate the effect of aficamten on echocardiographic measures of cardiac structure and function in SEQUOIA-HCM. Methods: Serial echocardiograms were performed over 28 weeks in patients randomized to receive placebo or aficamten in up to 4 individually titrated escalating doses (5-20 mg daily) over 24 weeks based on Valsalva LVOT gradients and left ventricular ejection fraction (LVEF). Results: Among 282 patients (mean age 59 ± 13 years; 41% female, 79% White, 19% Asian), mean LVEF was 75% ± 6% with resting and Valsalva LVOT gradients of 55 ± 30 mm Hg and 83 ± 32 mm Hg, respectively. Over 24 weeks, aficamten significantly lowered resting and Valsalva LVOT gradients, and improved left atrial volume index, lateral and septal eʹ velocities, and lateral and septal E/eʹ (all P ≤ 0.001). LV end-systolic volume increased and wall thickness decreased (all P ≤ 0.003). Aficamten resulted in a mild reversible decrease in LVEF (−4.8% [95% CI: −6.4% to −3.3%]; P < 0.001) and absolute LV global circumferential strain (−3.7% [95% CI: 1.8%-5.6%]; P < 0.0010), whereas LV global longitudinal strain was unchanged. Several measures, including LVEF, LVOT gradients, and E/eʹ returned to baseline following washout. Among those treated with aficamten, improved pVO₂ and reduction in N-terminal pro–B-type natriuretic peptide (NT-proBNP) were associated with improvement in lateral eʹ velocity and septal and lateral E/eʹ (all P < 0.03), whereas improvement in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores (KCCQ-CSS) was associated with a decrease in both LVOT gradients (all P < 0.001). Conclusions: Compared with placebo, patients receiving aficamten demonstrated significant improvement in LVOT gradients and measures of LV diastolic function, and several of these measures were associated with improvements in pVO₂, KCCQ-CSS, and NT-proBNP. A modest decrease in LVEF occurred yet remained within normal range. These findings suggest aficamten improved multiple structural and physiological parameters in oHCM without significant adverse changes in LV systolic function.