Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy: SEQUOIA-HCM

Published Congress: ESC Heart Failure 2024

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa2401424

Dr. İrem Türkmen

Background:
Hypertrophic cardiomyopathy is an inherited disease that affects the heart muscles. Patients with obstructive hypertrophic cardiomyopathy (oHCM), the most common form of the disease, have a resting or provocable left ventricular outflow tract gradient (LVOT-G) that causes heart failure symptoms. Patients with oHCM face a higher likelihood of experiencing arrhythmias, strokes, heart failure, and sudden death. While current treatments have reduced hospitalizations and mortality rates, individuals with oHCM often experience a decrease in their quality of life due to limitations in physical activity and ongoing symptoms. The LVOT gradient is the main cause of exertional dyspnea, chest pain, fatigue, and exercise intolerance, which affect functional capacity in oHCM patients. Peak oxygen uptake (pVO2), measured by cardiopulmonary exercise testing (CPET), can be used to assess functional capacity. SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of the Obstruction Effect of Aficamten in HCM) is a study evaluating the peak oxygen uptake of aficamten, one of the cardiac myosin inhibitors, in oHCM.

Objective:
The purpose of this study to evaluate the efficacy and safety of aficamten versus placebo in adults with symptomatic obstructive HCM.

Methods:
SEQUOIA-HCM is a global, multicenter, randomized, placebo-controlled, double- blind, phase 3 trial in patients with symptomatic oHCM. SEQUOIA-HCM trial evaluated the efficacy and safety of aficamten (starting dose, 5 mg; maximum dose, 20 mg) versus placebo in adults with symptomatic obstructive HCM. The primary endpoint was the change in pVO2, assessed using cardiopulmonary exercise testing, from baseline to week 24. Secondary endpoints at 24 weeks included the change in KCCQ score; the proportion of patients with ?1 class improvement in New York Heart Association (NYHA); change in Valsalva LVOT gradient; the proportion of patients with Valsalva LVOT gradient <30 mmHg; and eligibility for invasive septal reduction.

Results:
SEQUOIA-HCM included 282 patients from 101 sites in 14 countries in North America, Asia, and Europe, making it the largest-ever obstructive HCM trial. All participants had reduced exercise capacity due to obstructive HCM. Patients were randomised 1:1 to aficamten or placebo on top of their background medical therapy. The starting dose of aficamten was 5 mg once daily with opportunities at weeks 2, 4, and 6 to increase the dose in 5 mg increments to a maximum dose of 20 mg. Dose adjustments were made according to left ventricular ejection fraction and LVOT gradients assessed using echocardiography.
The mean increase in pVO2 from baseline to 24 weeks was 1.8 ml/kg/min with aficamten compared to 0.0 ml/kg/min with placebo (least-squares mean difference between groups, 1.7 ml/kg/min; 95% confidence interval [CI] 1.0, 2.4; p<0.001). Regarding secondary endpoints at 24 weeks, aficamten resulted in a least-squares mean difference of 7 points in KCCQ score relative to placebo (95% CI 5, 10; p<0.0001). A ?1 NYHA class improvement was observed in 58.5% of patients on aficamten and 24.3% of patients on placebo (p<0.0001). Aficamten led to a 50 mmHg greater reduction in Valsalva LVOT gradient versus placebo (95% CI -57, -44; p<0.0001). Some 49.3% of patients on aficamten achieved a Valsalva LVOT gradient <30 mmHg versus 3.6% of patients on placebo (p<0.0001). In the Aficamten group, the need for septal reduction treatment was delayed by 78 days compared to the placebo group (p<0.0001).

Conclusion:
This study demonstrated that aficamten enhanced HCM patients’ exercise capacity with significant improvement in peak oxygen uptake (pVO2), improvement in limiting symptoms, and decreases in LVOT pressure gradients. 

Interpretations:
Aficamten is a promising cardiac myosin inhibitor that has been shown to improve functional capacity in patients with obstructive hypertrophic cardiomyopathy whose quality of life is adversely affected.