Efficacy of Aficamten in Hypertrophic Cardiomyopathy Patients With Very-High Left Ventricular Outflow Tract Gradients

ABSTRACT This sub-analysis of SEQUOIA-HCM (NCT05186818) evaluated the efficacy and safety of aficamten in obstructive hypertrophic cardiomyopathy (oHCM) and very-high Valsalva left ventricular outflow tract gradients (LVOT-G). Patients with oHCM and Valsalva LVOT-G ≥100 mmHg (N = 73) were randomized to aficamten (n = 33) or placebo (n = 40) for 24 weeks. The primary endpoint was proportional change in Valsalva LVOT-G from baseline to Week 24. Secondary endpoints included the proportion of patients achieving Valsalva LVOT-G <30 mmHg, absolute change in Valsalva LVOT-G, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CCS), New York Heart Association (NYHA) functional class, NT-proBNP, and exercise capacity (peak oxygen uptake [pVO₂], workload), and time eligible for septal reduction therapy (SRT). Over 24 weeks, aficamten significantly reduced Valsalva LVOT-G by 66% from 123 ± 28 mmHg to 41 ± 30 mmHg (p = 0.001), including to <30 mmHg in 42% of aficamten patients (p < 0.001). Aficamten was also associated with symptom relief: 16 patients (48%) had ≥1 improvement in NYHA class, including 9 with both class I and ≥5-point increase in KCCQ-CSS. Compared with placebo, aficamten substantially decreased NT-proBNP concentration (‒85%; p = 0.001) and increased pVO₂ (+1.8 mL/kg/min; p = 0.003). Aficamten also reduced time eligible for SRT (p = 0.002) without any clinically relevant decrease in systolic function (ejection fraction <50%). Aficamten effectively reduced gradients in patients with oHCM and very-high Valsalva LVOT-G. Hemodynamic changes were associated with enhanced exercise capacity and symptom relief, underscoring aficamten treatment benefit across the spectrum of LVOT-G.