Cytokinetics Reveals SEQUOIA-HCM Results at ESC Heart Failure 2024 and in NEJM

Cytokinetics, Incorporated has revealed the primary results from its SEQUOIA-HCM clinical trial, a pivotal Phase 3 study evaluating the efficacy and safety of aficamten in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM). Presented by Dr. Martin Maron, Director of the Hypertrophic Cardiomyopathy Center at Lahey Hospital and Medical Center, the findings were showcased at the European Society of Cardiology's Heart Failure 2024 conference and published in the New England Journal of Medicine.

SEQUOIA-HCM enrolled 282 patients with obstructive HCM, characterized by high resting and post-Valsalva gradients, indicative of significant disease burden. The trial demonstrated that, over a 24-week period, aficamten significantly enhanced exercise capacity. Specifically, patients treated with aficamten showed a notable increase in peak oxygen uptake (pVO2), by 1.8 ml/kg/min compared to baseline, in contrast to no change in patients receiving a placebo.

Improvements with aficamten were consistent across all patient subgroups, regardless of age, sex, or baseline characteristics, and whether patients were on beta-blocker therapy. Importantly, all ten prespecified secondary endpoints exhibited statistically significant improvements. Functional and symptomatic enhancements were evident within two weeks and continued throughout the treatment period.

Notably, aficamten led to a substantial reduction in the left ventricular outflow tract gradient (LVOT-G), a key measure in HCM management, with a mean difference of -50 mmHg compared to placebo. It also significantly alleviated symptom burden, as evidenced by a 7-point improvement in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and a 34% shift to a higher New York Heart Association (NYHA) Functional Class.

Aficamten also decreased the necessity for septal reduction therapy (SRT). Patients on aficamten spent significantly fewer days eligible for SRT over the 24-week period compared to those on placebo. Additionally, aficamten treatment resulted in an 80% reduction in NT-proBNP levels, a biomarker of cardiac stress.

The responder analysis within SEQUOIA-HCM indicated that aficamten notably improved both exercise capacity and symptoms. A substantial portion of patients treated with aficamten achieved the composite responder endpoint, demonstrating a considerable improvement over those on placebo.

Dr. Fady I. Malik, Cytokinetics' Executive Vice President of Research & Development, highlighted that these results affirm the potential of aficamten as a treatment for obstructive HCM, showing it to be well-tolerated with no treatment interruptions due to low left ventricular ejection fraction (LVEF). Cytokinetics plans to submit regulatory filings in the U.S. and Europe based on these positive outcomes.

Dr. Martin Maron emphasized the remarkable consistency and magnitude of aficamten’s effects across various patient subgroups, including those on beta-blockers, which mirrors real-world clinical practice. He suggested that aficamten has the potential to significantly improve quality of life by relieving symptoms and enhancing exercise capacity in patients with obstructive HCM.

Safety data from SEQUOIA-HCM indicated that aficamten was well-tolerated, with a serious adverse event rate lower than that of the placebo group. Core echocardiographic assessments showed a small percentage of patients with reduced LVEF, but no cases of worsening heart failure or treatment disruptions were attributed to low LVEF.

Cytokinetics plans to further explore aficamten’s clinical applications in several ongoing Phase 3 trials, including MAPLE-HCM, ACACIA-HCM, CEDAR-HCM, and FOREST-HCM. These trials aim to validate aficamten's efficacy in varied patient populations and its long-term impact on cardiac structure and function.

Hypertrophic cardiomyopathy (HCM) is a common genetic cardiovascular disorder characterized by thickened heart muscle, leading to reduced heart function and symptoms like chest pain and shortness of breath. Two-thirds of HCM cases involve obstructive HCM, which causes outflow tract obstruction. HCM patients are also at risk for severe complications such as atrial fibrillation, stroke, and sudden cardiac death, particularly among younger individuals and athletes.