TY - JOUR
T1 - Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy
T2 - Results From SEQUOIA-HCM
AU - on behalf of the SEQUOIA-HCM Investigators
AU - Coats, Caroline J.
AU - Masri, Ahmad
AU - Nassif, Michael E.
AU - Barriales-Villa, Roberto
AU - Arad, Michael
AU - Cardim, Nuno
AU - Choudhury, Lubna
AU - Claggett, Brian
AU - Düngen, Hans Dirk
AU - Garcia-Pavia, Pablo
AU - Hagège, Albert A.
AU - Januzzi, James L.
AU - Lee, Matthew M.Y.
AU - Lewis, Gregory D.
AU - Ma, Chang Sheng
AU - Maron, Martin S.
AU - Miao, Zi Michael
AU - Michels, Michelle
AU - Olivotto, Iacopo
AU - Oreziak, Artur
AU - Owens, Anjali T.
AU - Spertus, John A.
AU - Solomon, Scott D.
AU - Tfelt-Hansen, Jacob
AU - van Sinttruije, Marion
AU - Veselka, Josef
AU - Watkins, Hugh
AU - Jacoby, Daniel L.
AU - German, Polina
AU - Heitner, Stephen B.
AU - Kupfer, Stuart
AU - Lutz, Justin D.
AU - Malik, Fady I.
AU - Meng, Lisa
AU - Wohltman, Amy
AU - Abraham, Theodore P.
N1 - Publisher Copyright:
© 2024 The Authors and Cytokinetics.
PY - 2024/8/6
Y1 - 2024/8/6
N2 - 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.
AB - 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.
KW - aficamten
KW - cardiac myosin inhibitor
KW - hypertrophic cardiomyopathy
UR - http://www.scopus.com/inward/record.url?scp=85200827341&partnerID=8YFLogxK
U2 - 10.1161/JAHA.124.035993
DO - 10.1161/JAHA.124.035993
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C2 - 39056349
AN - SCOPUS:85200827341
SN - 2047-9980
VL - 13
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 15
M1 - e035993
ER -