BACKGROUND: Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). METHODS AND RESULTS: A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5-20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site-interpreted Valsalva left ventricular outflow tract gradient <30 mm Hg with left ventricular ejection fraction (LVEF) ≥50%. End points were evaluated during titration (day 1 to week 8), maintenance (weeks 8-24), and washout (weeks 24-28), and included major adverse cardiac events, new-onset atrial fibrillation, implantable cardioverter-defibrillator discharges, LVEF <50%, and treatment-emergent adverse events. At week 8, 3.6%, 12.9%, 35%, and 48.6% of patients achieved 5-, 10-, 15-, and 20-mg doses, respectively. Baseline characteristics were similar across groups. Aficamten concentration increased by dose and remained stable during maintenance. During the treatment period, LVEF decreased by -0.9% (95% CI, -1.3 to -0.6) per 100 ng/mL aficamten exposure. Seven (4.9%) patients taking aficamten underwent per-protocol dose reduction for site-interpreted LVEF <50%. There were no treatment interruptions or heart failure worsening for LVEF <50%. No major adverse cardiovascular events were associated with aficamten, and treatment-emergent adverse events were similar between treatment groups, including atrial fibrillation. CONCLUSIONS: A site-based dosing algorithm targeting the lowest effective aficamten dose reduced left ventricular outflow tract gradient with a favorable safety profile throughout SEQUOIA-HCM. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05186818.

Assistance Publique Hôpitaux de Paris Département de Cardiologie Hôpital Européen Georges Pompidou Paris France

Beijing Anzhen Hospital Capital Medical University Beijing China

Cardiovascular Division Brigham and Women's Hospital Harvard Medical School Boston MA

Charité Campus Virchow Klinikum Berlin Germany

Complexo Hospitalario Universitario A Coruña INIBIC CIBERCV ISCIII A Coruña Spain

Cytokinetics Incorporated South San Francisco CA

Department of Cardiology Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

Department of Cardiology Erasmus Medical Center Cardiovascular Institute Thoraxcenter Rotterdam The Netherlands

Division of Cardiology Department of Medicine Massachusetts General Hospital Harvard Medical School Boston MA

Heart Failure and Biomarker Trials Baim Institute for Clinical Research Boston MA

Hospital CUF Descobertas Lisbon Portugal

Hospital Universitario Puerta de Hierro de Majadahonda IDIPHISA CIBERCV and Centro Nacional de Investigaciones Cardiovasculares Madrid Spain

Hypertrophic Cardiomyopathy Patient Author Zwolle The Netherlands

JV Cardiology Prague Czech Republic

Lahey Hospital and Medical Center Burlington MA

Leviev Heart Center Sheba Medical Center Ramat Gan and Tel Aviv University Ramat Gan Israel

Meyer Children's Hospital Istituto di Ricovero e Cura a Carattere Scientifico Florence Italy

National Institute of Cardiololgy Warsaw Poland

Northwestern University Feinberg School of Medicine Chicago IL

Oregon Health and Science University Portland OR

Radcliffe Department of Medicine University of Oxford United Kingdom

School of Cardiovascular and Metabolic Health University of Glasgow United Kingdom

Section of Forensic Genetics Department of Forensic Medicine Faculty of Health and Medical Sciences University of Copenhagen Denmark

University of California San Francisco San Francisco CA

University of Missouri Kansas City Healthcare Institute for Innovations in Quality and Saint Luke's Mid America Heart Institute Kansas City MO

University of Pennsylvania Perelman School of Medicine Philadelphia PA

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NCT05186818