%0 Journal Article
%T Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM.
%A Coats CJ
%A Masri A
%A Nassif ME
%A Barriales-Villa R
%A Arad M
%A Cardim N
%A Choudhury L
%A Claggett B
%A Düngen HD
%A Garcia-Pavia P
%A Hagège AA
%A Januzzi JL
%A Lee MMY
%A Lewis GD
%A Ma CS
%A Maron MS
%A Miao ZM
%A Michels M
%A Olivotto I
%A Oreziak A
%A Owens AT
%A Spertus JA
%A Solomon SD
%A Tfelt-Hansen J
%A van Sinttruije M
%A Veselka J
%A Watkins H
%A Jacoby DL
%A German P
%A Heitner SB
%A Kupfer S
%A Lutz JD
%A Malik FI
%A Meng L
%A Wohltman A
%A Abraham TP
%A  
%J J Am Heart Assoc
%V 13
%N 15
%D 2024 Aug 6
%M 39056349
%F 6.106
%R 10.1161/JAHA.124.035993
%X <B>BACKGROUND: </B>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).<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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.<BR><B>BACKGROUND: </B>URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05186818.