Cytokinetics Launches CEDAR-HCM Trial of Aficamten for Pediatric Obstructive Hypertrophic Cardiomyopathy

Cytokinetics, Incorporated has announced the commencement of the CEDAR-HCM clinical trial, aimed at evaluating aficamten in pediatric patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM). Aficamten is a prospective cardiac myosin inhibitor intended for treating HCM. Fady I. Malik, M.D., Ph.D., Executive Vice President of Research & Development at Cytokinetics, emphasized the importance of this trial in potentially providing new treatment options for families affected by HCM, including adolescents and children who face high risks of heart failure and serious arrhythmias.

The CEDAR-HCM clinical trial is designed as a multi-center, randomized, double-blind, placebo-controlled study with an open-label extension. The trial will assess the efficacy, pharmacokinetics, and safety of aficamten in children with obstructive HCM. The primary endpoint focuses on the change in Valsalva left ventricular outflow tract gradient (LVOT-G) from the baseline over 12 weeks. Secondary endpoints include changes in resting LVOT-G, New York Heart Association (NYHA) Functional Class, pharmacokinetics, and cardiac biomarkers like NT-proBNP and hs-cTnI.

The trial plans to enroll two cohorts. The first cohort will consist of around 40 adolescent patients aged 12 to 17 who meet specific criteria, including a left ventricular ejection fraction (LVEF) of at least 60%, a Valsalva LVOT-G of 50 mmHg or more, and a NYHA Functional Class of II or higher. Participants will be randomly assigned in a 2:1 ratio to receive either aficamten or a placebo. Those receiving aficamten will start with a daily dose of 5 mg, which could be increased based on echocardiogram results taken at weeks 2, 4, and 6. Dose escalation is conditional on a Valsalva LVOT-G of at least 30 mmHg and an LVEF of at least 55%. Safety, efficacy, and pharmacokinetic data from at least 20 adolescents completing 12 weeks of treatment will determine the initiation of the second cohort, which will enroll 8 to 10 younger patients aged 6 to 11. The protocol will be updated to include eligibility and dosing criteria for this younger group. After the 12-week double-blind treatment, eligible patients can continue into the trial's open-label extension phase.

Aficamten, a selective small molecule inhibitor targeting cardiac myosin, was developed with a focus on therapeutic index and pharmacokinetic properties. The drug aims to reduce myocardial hypercontractility by decreasing the number of active actin-myosin cross bridges during cardiac cycles. Preclinical studies demonstrated that aficamten binds directly to cardiac myosin at a selective allosteric site, preventing myosin from entering a force-producing state.

The comprehensive Phase 3 clinical trials program for aficamten includes several studies beyond CEDAR-HCM. SEQUOIA-HCM was a pivotal Phase 3 trial that showed significant improvements in exercise capacity with aficamten in patients with obstructive HCM. The trial reported significant enhancements in peak oxygen uptake and secondary endpoints, with a tolerable safety profile comparable to placebo.

Aficamten is also under evaluation in MAPLE-HCM, a trial comparing it as monotherapy to metoprolol in obstructive HCM patients; ACACIA-HCM, a study in non-obstructive HCM patients; and FOREST-HCM, an open-label extension study. The FDA and China's National Medical Products Administration granted aficamten Breakthrough Therapy Designation for treating symptomatic obstructive HCM.

Hypertrophic cardiomyopathy (HCM) is a condition characterized by the thickening of the heart muscle, which can lead to reduced pumping efficiency and various symptoms such as chest pain, shortness of breath, and dizziness. HCM is a common inherited cardiovascular disorder, with a significant number of patients remaining undiagnosed. The disorder can lead to severe complications, including atrial fibrillation, stroke, and sudden cardiac death, particularly among younger individuals and athletes.

Cytokinetics is dedicated to developing innovative treatments for cardiovascular diseases, focusing on muscle activators and inhibitors. The company is preparing regulatory submissions for aficamten following promising Phase 3 trial results and continues to explore its potential in various patient populations and conditions.