Abstract 4370461: Aficamten is safe and effective in oHCM with comorbidities obesity, hypertension, and diabetes: a SEQUOIA-HCM sub-study

Introduction/Background: Obesity, hypertension, and diabetes commonly coexist with obstructive hypertrophic cardiomyopathy (oHCM), potentially influencing symptom burden and functional limitation. It is not known if aficamten provides similar benefit across comorbidity subgroups. Research Questions/Hypothesis: Efficacy of aficamten in patients with oHCM and comorbidities. Methods/Approach: SEQUOIA-HCM (NCT05186818) randomized 282 adults with symptomatic oHCM to aficamten or placebo for 24 weeks. Participants were grouped by obesity (body mass index [BMI] ≥30 kg/m 2 ), hypertension (history or average screening/baseline systolic blood pressure ≥140 or diastolic blood pressure ≥90 mmHg), and diabetes (type 1, type 2, or unspecified per history). Baseline characteristics and treatment effects on peak oxygen uptake (pVO 2 ) and secondary endpoints were compared across comorbidity groups. Results/Data: At baseline, 32% had obesity, 55% had hypertension, and 8% had diabetes; 24% had 2 comorbidities, and 3% had all 3 comorbidities. At baseline, obesity was associated with lower Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), N-terminal pro-B-type natriuretic peptide (NT-proBNP), pVO 2 , and resting left ventricular outflow tract gradient (LVOT-G), and higher use of beta-blockers and disopyramide ( Table 1 ). At baseline, hypertension was associated with lower NT-proBNP, pVO 2 , and resting LVOT-G; older age; more atrial fibrillation and diabetes; and more use of non-dihydropyridine calcium-channel blockers and renin angiotensin system blockers. At baseline, diabetes was associated with older age, hypertension, higher KCCQ-CSS, lower NT-proBNP, and pVO 2 , and more use of renin angiotensin system blockers. Despite baseline differences, aficamten treatment compared to placebo consistently improved pVO 2 , KCCQ-CSS, Valsalva LVOT-G, and NT-proBNP independent of comorbid status (all interaction p-values >0.05) ( Figure 1; Table 2 ). The incidence of serious adverse events and left ventricular ejection fraction <50% were similar across subgroups, including when grouped by treatment arm. Conclusion(s): Comorbidities, particularly obesity and hypertension, are common in patients with oHCM. Aficamten treatment showed consistent clinical efficacy regardless of comorbidity status, supporting its use across a broad patient population.