Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM.
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Coats Caroline J, Masri Ahmad, Nassif Michael E, Barriales-Villa Roberto, Arad Michael, Cardim Nuno, Choudhury Lubna, Claggett Brian, Düngen Hans-Dirk, Garcia-Pavia Pablo, Hagège Albert A, Januzzi James L, Lee Matthew M Y, Lewis Gregory D, Ma Chang-Sheng, Maron Martin S, Miao Zi Michael, Michels Michelle, Olivotto Iacopo, Oreziak Artur, Owens Anjali T, Spertus John A, Solomon Scott D, Tfelt-Hansen Jacob, van Sinttruije Marion, Veselka Josef, Watkins Hugh, Jacoby Daniel L, German Polina, Heitner Stephen B, Kupfer Stuart, Lutz Justin D, Malik Fady I, Meng Lisa, Wohltman Amy, Abraham Theodore P, SEQUOIA‐HCM Investigators *
Аннотация
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.