Efficacy and Safety of Aficamten in Children and Adolescents With Obstructive Hypertrophic Cardiomyopathy: Study Design and Rationale of CEDAR-HCM

Background: Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality in children, but treatment options are limited. Aficamten, a next-in-class cardiac myosin inhibitor, directly targets the hypercontractility underlying HCM. Aficamten improved exercise capacity, health status, and symptoms in adults with obstructive HCM in the pivotal, phase 3 SEQUOIA-HCM trial (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM; NCT05186818). Methods: CEDAR-HCM (Clinical Evaluation of dosing With Aficamten to Reduce Obstruction in Pediatric Population With HCM) is an international, multicenter, randomized, double-blind, placebo-controlled trial followed by an open-label extension to evaluate the efficacy, safety, and pharmacokinetics of aficamten in pediatric participants with symptomatic obstructive HCM. The trial will enroll ≈55 adolescents (12 to <18 years) and subsequently expand to include at least 10 children (6 to <12 years) with nonsyndromic obstructive HCM, left ventricular ejection fraction ≥60%, Valsalva left ventricular outflow tract gradient ≥50 mm Hg, and New York Heart Association functional class ≥II. Participants will be randomized 2:1 to aficamten or placebo in addition to standard of care therapy or as monotherapy, with echocardiogram-guided dose adjustments targeting a Valsalva left ventricular outflow tract gradient <30 mm Hg while maintaining left ventricular ejection fraction ≥50%. The primary end point is the change in Valsalva left ventricular outflow tract gradient from baseline to week 12. Secondary end points include change in resting left ventricular outflow tract gradient, cardiac biomarkers, New York Heart Association functional class, and assessment of pharmacokinetics. After completing the 12-week randomized period, eligible participants will continue into a long-term open-label extension. Results: The trial is currently enrolling. Conclusions: Results of CEDAR-HCM will provide insight into the safety and efficacy of aficamten in adolescents and in children as young as 6 years of age. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT06412666.