FDA Approved NDA for Aficamten to Treat Patients With Obstructive Hypertrophic Cardiomyopathy

In December 2024, the FDA approved the new drug application for aficamten (CK-3773274; Cytokinetics, Incorporated), a next-in-class cardiac myosin inhibitor, for the treatment of obstructive hypertrophic cardiomyopathy (HCM), based on data from the phase 3 SEQUOIA-HCM trial (NCT05186818).¹

Visualization of glowing chest anatomy showing heart complications | Image Credit: © Thipphaphone - stock.adobe.com

HCM is the most common inherited cardiovascular disease, with about 280,000 diagnosed cases in the US, although up to 800,000 may remain undiagnosed. It is a genetic condition in which the heart muscle thickens abnormally, reducing the size and flexibility of the left ventricle and impairing its ability to fill and pump blood. This can lead to chest pain, shortness of breath, dizziness, or fainting during exertion. HCM increases the risk of atrial fibrillation, stroke, mitral valve disease, and life-threatening arrhythmias. It is a leading cause of sudden cardiac death in young people. Some patients may progress to heart failure or require heart transplantation.²

Aficamten is an investigational, selective cardiac myosin inhibitor designed to optimize therapeutic index and pharmacokinetics. It works by reducing actin-myosin cross-bridge formation during each heartbeat, suppressing the hypercontractility seen in HCM. In preclinical studies, aficamten was observed to decrease myocardial contractility by binding to a specific allosteric site on cardiac myosin, preventing it from generating force.²

SEQUOIA-HCM is a phase 3, multi-center, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of aficamten in adults with symptomatic HCM and left ventricular outflow tract obstruction. The study results showed that 24 weeks of aficamten significantly improved exercise capacity compared to placebo, increasing peak oxygen uptake (pVO₂) by 1.8 mL/kg/min versus no change with placebo (LSM difference: 1.74 mL/kg/min; 95% CI: 1.04–2.44; P = .000002).^1,2

All 10 prespecified secondary end points also showed statistically significant improvement, including Valsalva LVOT gradient, NYHA class, KCCQ-CSS, proportion of patients with LVOT gradient less than 30 mmHg (at weeks 12 and 24), duration of guideline-based SRT eligibility, and CPET workload at week 24. Serious adverse events occurred in 5.6% of aficamten-treated patients and 9.3% of those on placebo. LVEF less than 50% was seen in 3.5% of patients on aficamten compared with 0.7% on placebo, with no cases of worsening heart failure or treatment interruptions due to low LVEF.²

“The NDA acceptance for aficamten by FDA is a significant milestone that moves our company another step closer to hopefully translating our pioneering science to the potential benefit of patients suffering from obstructive HCM,” Robert I. Blum, president and CEO of Cytokinetics, said in a news release. “The results from SEQUOIA-HCM, the pivotal phase 3 clinical trial, which form the foundation of the NDA, demonstrated that aficamten has a positive impact on exercise capacity, clinical outcomes, symptom burden, and cardiac biomarkers in patients with HCM, with a consistent effect across all prespecified subgroups and a favorable safety and tolerability profile.”²

REFERENCES

1. Aficamten vs placebo in adults with symptomatic obstructive hypertrophic cardiomyopathy (SEQUOIA-HCM) (SEQUOIA-HCM). Updated February 27, 2025. Accessed May 16, 2025. https://clinicaltrials.gov/study/NCT05186818

2. Cytokinetics announces FDA acceptance of new drug application for aficamten for the treatment of obstructive hypertrophic cardiomyopathy. Globe Newswire. December 2, 2024. Accessed May 16, 2025. https://ir.cytokinetics.com/news-releases/news-release-details/cytokinetics-announces-fda-acceptance-new-drug-application-0