Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM.

Autor: Coats CJ; School of Cardiovascular and Metabolic Health University of Glasgow United Kingdom., Masri A; Oregon Health and Science University Portland OR., Nassif ME; University of Missouri Kansas City Healthcare Institute for Innovations in Quality and Saint Luke's Mid America Heart Institute Kansas City MO., Barriales-Villa R; Complexo Hospitalario Universitario A Coruña, INIBIC, CIBERCV-ISCIII A Coruña Spain., Arad M; Leviev Heart Center, Sheba Medical Center Ramat-Gan and Tel Aviv University Ramat-Gan Israel., Cardim N; Hospital CUF Descobertas Lisbon Portugal., Choudhury L; Northwestern University Feinberg School of Medicine Chicago IL., Claggett B; Cardiovascular Division Brigham and Women's Hospital, Harvard Medical School Boston MA., Düngen HD; Charité Campus Virchow-Klinikum Berlin Germany., Garcia-Pavia P; Hospital Universitario Puerta de Hierro de Majadahonda, IDIPHISA, CIBERCV, and Centro Nacional de Investigaciones Cardiovasculares (CNIC) Madrid Spain., Hagège AA; Assistance Publique Hôpitaux de Paris, Département de Cardiologie, Hôpital Européen Georges-Pompidou Paris France., Januzzi JL; 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., Lee MMY; School of Cardiovascular and Metabolic Health University of Glasgow United Kingdom., Lewis GD; Division of Cardiology, Department of Medicine Massachusetts General Hospital, Harvard Medical School Boston MA., Ma CS; Beijing Anzhen Hospital, Capital Medical University Beijing China., Maron MS; Lahey Hospital and Medical Center Burlington MA., Miao ZM; Cardiovascular Division Brigham and Women's Hospital, Harvard Medical School Boston MA., Michels M; Department of Cardiology Erasmus Medical Center, Cardiovascular Institute, Thoraxcenter Rotterdam The Netherlands., Olivotto I; Meyer Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Florence Italy., Oreziak A; National Institute of Cardiololgy Warsaw Poland., Owens AT; University of Pennsylvania Perelman School of Medicine Philadelphia PA., Spertus JA; University of Missouri Kansas City Healthcare Institute for Innovations in Quality and Saint Luke's Mid America Heart Institute Kansas City MO., Solomon SD; Cardiovascular Division Brigham and Women's Hospital, Harvard Medical School Boston MA., Tfelt-Hansen J; Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health and Medical Sciences University of Copenhagen Denmark.; Department of Cardiology Copenhagen University Hospital Rigshospitalet Copenhagen Denmark., van Sinttruije M; Hypertrophic Cardiomyopathy Patient Author Zwolle The Netherlands., Veselka J; JV Cardiology Prague Czech Republic., Watkins H; Radcliffe Department of Medicine University of Oxford United Kingdom., Jacoby DL; Cytokinetics, Incorporated South San Francisco CA., German P; Cytokinetics, Incorporated South San Francisco CA., Heitner SB; Cytokinetics, Incorporated South San Francisco CA., Kupfer S; Cytokinetics, Incorporated South San Francisco CA., Lutz JD; Cytokinetics, Incorporated South San Francisco CA., Malik FI; Cytokinetics, Incorporated South San Francisco CA., Meng L; Cytokinetics, Incorporated South San Francisco CA., Wohltman A; Cytokinetics, Incorporated South San Francisco CA., Abraham TP; University of California San Francisco San Francisco CA.
Jazyk: angličtina
Zdroj: Journal of the American Heart Association [J Am Heart Assoc] 2024 Aug 06; Vol. 13 (15), pp. e035993. Date of Electronic Publication: 2024 Jul 26.
DOI: 10.1161/JAHA.124.035993
Abstrakt: 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.
Databáze: MEDLINE
Externí odkaz: