Baseline Characteristics of Patients in SEQUOIA-HCM: A Phase 3 Trial of Aficamten in Obstructive Hypertrophic Cardiomyopathy

Background Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by myocardial hypercontractility with left ventricular outflow tract obstruction (LVOTO), reduced exercise capacity, and heart failure symptoms. Aficamten is a next-in-class cardiac myosin inhibitor with unique physicochemical properties that appear to safely and effectively reduce LVOTO and improve symptoms and cardiac biomarkers (REDWOOD-HCM; NCT04219826). SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction, Impact of Aficamten in HCM; NCT05186818) is the pivotal Phase 3 trial evaluating the safety and efficacy of aficamten in patients with symptomatic oHCM and objective evidence of reduced functional capacity. Herein we present the baseline characteristics of patients enrolled in SEQUOIA-HCM. Methods SEQUOIA-HCM is an international, multicenter, randomized, double-blind, placebo-controlled trial in patients with symptomatic (NYHA class II–III) oHCM (left ventricular ejection fraction [LVEF] ≥60%; left ventricular outflow tract gradient [LVOT-G] ≥30 mmHg at rest and ≥50 mmHg with Valsalva), and peak oxygen uptake (pVO2) ≤80% of age- and sex-predicted maximum. Patients were randomized (1:1) to either oral placebo or aficamten, with site-based echocardiographic guidance to achieve individualized daily doses of 5, 10, 15, or 20 mg. The primary efficacy outcome is change in pVO2 on exercise testing from baseline to Week 24. Results SEQUOIA-HCM has enrolled 282 patients. Available patient characteristics at baseline are shown in Table 1. The mean (SD) age was 59.1 (12.9) years, 40.8% were female, and 22% were non-white. Baseline New York Heart Association functional class was Class II for 203 patients (72%), Class III for 67 patients (23.8%), and Class IV for 1 patient (0.4%). Just over half of the patients (172; 61%) were treated with beta-blockers. The mean baseline pVO2 was 18.5 (SD 4.5) mL/kg/min or 57.2% of predicted maximum, and the mean Kansas City Cardiomyopathy Questionnaire Clinical Summary Score was 74.7 (SD 18.1). Geometric mean (Q1, Q3) high-sensitivity cardiac troponin I was 16.9 (7.7, 27.2) ng/L. At this time, LVEF, LVOT-G, and N-terminal pro–B-type natriuretic peptide remain blinded measures. Conclusion SEQUOIA-HCM has enrolled a diverse and representative oHCM population with baseline characteristics reflecting significant symptom burden. Results will provide guidance on the utility of aficamten, a next-in-class cardiac myosin inhibitor, in patients with symptomatic oHCM. Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by myocardial hypercontractility with left ventricular outflow tract obstruction (LVOTO), reduced exercise capacity, and heart failure symptoms. Aficamten is a next-in-class cardiac myosin inhibitor with unique physicochemical properties that appear to safely and effectively reduce LVOTO and improve symptoms and cardiac biomarkers (REDWOOD-HCM; NCT04219826). SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction, Impact of Aficamten in HCM; NCT05186818) is the pivotal Phase 3 trial evaluating the safety and efficacy of aficamten in patients with symptomatic oHCM and objective evidence of reduced functional capacity. Herein we present the baseline characteristics of patients enrolled in SEQUOIA-HCM. SEQUOIA-HCM is an international, multicenter, randomized, double-blind, placebo-controlled trial in patients with symptomatic (NYHA class II–III) oHCM (left ventricular ejection fraction [LVEF] ≥60%; left ventricular outflow tract gradient [LVOT-G] ≥30 mmHg at rest and ≥50 mmHg with Valsalva), and peak oxygen uptake (pVO2) ≤80% of age- and sex-predicted maximum. Patients were randomized (1:1) to either oral placebo or aficamten, with site-based echocardiographic guidance to achieve individualized daily doses of 5, 10, 15, or 20 mg. The primary efficacy outcome is change in pVO2 on exercise testing from baseline to Week 24. SEQUOIA-HCM has enrolled 282 patients. Available patient characteristics at baseline are shown in Table 1. The mean (SD) age was 59.1 (12.9) years, 40.8% were female, and 22% were non-white. Baseline New York Heart Association functional class was Class II for 203 patients (72%), Class III for 67 patients (23.8%), and Class IV for 1 patient (0.4%). Just over half of the patients (172; 61%) were treated with beta-blockers. The mean baseline pVO2 was 18.5 (SD 4.5) mL/kg/min or 57.2% of predicted maximum, and the mean Kansas City Cardiomyopathy Questionnaire Clinical Summary Score was 74.7 (SD 18.1). Geometric mean (Q1, Q3) high-sensitivity cardiac troponin I was 16.9 (7.7, 27.2) ng/L. At this time, LVEF, LVOT-G, and N-terminal pro–B-type natriuretic peptide remain blinded measures. SEQUOIA-HCM has enrolled a diverse and representative oHCM population with baseline characteristics reflecting significant symptom burden. Results will provide guidance on the utility of aficamten, a next-in-class cardiac myosin inhibitor, in patients with symptomatic oHCM.