Aficamten: A Game -Changer for Treating Obstructive Hypertrophic Cardiomyopathy
Obstructive hypertrophic cardiomyopathy (oHCM) is defined by excessive contractility and dynamic left ventricular outflow tract (LVOT) obstruction that can markedly restrict functional capacity, causing dyspnoea, fatigue, and an increased risk of arrhythmias.Until recently, treatment options focused on managing symptoms with β-blockers, calcium channel blockers, or disopyramide, but did not target the underlying sarcomeric hyperactivity responsible for LVOT obstruction.
Why Aficamten?
Aficamten is a selective cardiac myosin inhibitor that tackles this hypercontractility at its core. By reducing actin-myosin cross-bridge formation, it eases LVOT obstruction and directly modifies the disease mechanism rather than merely alleviating symptoms. It is the first-in-class therapy to demonstrate rapid, reversible inhibition of sarcomeric hypercontractility with a wide therapeutic window.
The phase 3 SEQUOIA-HCM trial provides compelling evidence for this approach. A total of 282 adults with symptomatic NYHA class II–III oHCM were randomised to receive daily aficamten (5–20 mg, titrated by echocardiography) or placebo for 24 weeks. The primary endpoint was change from baseline to week 24 in peak oxygen uptake (VO₂) as assessed by cardiopulmonary exercise testing. Secondary endpoints included the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), NYHA functional class improvement, LVOT gradient reduction (rest and Valsalva), achievement of a gradient <30 mmHg, duration of eligibility for septal reduction therapy, total workload, and NT-proBNP levels.
Results
A total of 282 patients were randomised (142 aficamten, 140 placebo), with a mean age of 59.1 years, 59.2% men, baseline mean LVOT gradient 55.1 mmHg, and left ventricular ejection fraction (LVEF) of 74.8%. At 24 weeks, peak oxygen uptake increased by 1.8 mL/kg/min in the aficamten group versus 0.0 mL/kg/min with placebo (between-group difference 1.7 mL/kg/min; 95% CI, 1.0–2.4; P<0.001).
All 10 prespecified secondary endpoints favored aficamten: 58.5% improved by ≥1 NYHA class (vs. 24.3% placebo), KCCQ-CSS increased by 7 points (95% CI, 5–10), LVOT gradient after Valsalva decreased by 50 mmHg (95% CI, –57 to –44), and 49.3% achieved a gradient <30 mmHg (vs. 3.6% placebo). Patients spent 78 fewer days eligible for septal reduction therapy, and NT-proBNP declined to 0.20 compared with 1.00 in placebo. Effects were consistent across subgroups. Adverse events were similar between groups. Transient LVEF reductions occurred in 3.5% of aficamten patients. Serious adverse events occurred in 5.6% (aficamten) vs. 9.3% (placebo).
Future implications
Aficamten represents a meaningful advance in oHCM therapy, offering improvements in symptoms, exercise capacity, and LVOT gradients with a favorable safety profile. By targeting the underlying hypercontractility, it may reduce the need for septal reduction therapy and reshape future management strategies.
References :
1. Maron MS, et al. Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy. N Engl J Med. 2024; [doi:10.1056/NEJMoa2401424].
2. Cytokinetics. Positive Results From SEQUOIA-HCM Trial. Globe Newswire. 2024 Dec 27.
3. Masri A, et al. Cardiac MRI Substudy of SEQUOIA-HCM: Structural and Functional Effects of Aficamten. Eur Heart J. 2024;45:xxx–xxx.
4. Sherrod R, et al. Aficamten Improves Exercise Capacity in Obstructive HCM: SEQUOIA-HCM CPET Analysis. JAMA Cardiol. 2024;9(5):xxx–xxx.