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

作者：Caroline Coats, Ahmad Masri, Michael E. Nassif, Roberto Barriales‐Villa, Michael Arad, Nuno Cardim, Lubna Choudhury, Brian Claggett, Hans‐Dirk Düngen, Pablo García‐Pavía, Albert Hagège, James L. Januzzi, Matthew M.Y. Lee, Gregory D. Lewis, Changsheng Ma, Martin S. Maron, Zi Michael Miao, Michelle Michels, Iacopo Olivotto, Artur Oręziak, Anjali Owens, John A. Spertus, Scott D. Solomon, Jacob Tfelt‐Hansen, Marion van Sinttruije, Josef Veselka, Hugh Watkins, Daniel Jacoby, Polina German, Stephen B. Heitner, Stuart Kupfer, Justin D. Lutz, Fady I. Malik, Lisa Meng, Amy Wohltman, Theodore P. Abraham, Yuhui Zhang, Haibo Yang, Chunli Shao, Zuyi Yuan, Qingchun Zeng, Xiaodong Li, Yushi Wang, Yan Shu, Mulei Chen, Ling Tao, Xinli Li, Jingfeng Wang, Zaixin Yu, Xiang Cheng, Kui Hong, David Zemánek, Henning Bundgaard, Jens Jakob Thune, Morten K. Jensen, Jens Mogensen, Gilbert Habib, Philippe Charron, Thibault Lhermusier, Jean‐Noël Trochu, Patricia Réant, Damien Logeart, Veselin Mitrović, Tarek Bekfani, Frank Edelmann, Tim Seidler, Benjamin Meder, P. Christian Schulze, S. Stoerk, Tienush Rassaf, Béla Merkely, Donna Zfat‐Zwas, Majdi Halabi, Offir Paz, Xavier Piltz, Marco Metra, Marco Canepa, Beatrice Musumeci, Michele Emdin, Ahmad S. Amin, Christian Knackstedt, Wojciech Wojakowski, Dariusz Dudek, Alexandra Toste, José Mesquita Bastos, Juan R. Gimeno, Rafael Jesus Hidalgo Urbano, Ana García Álvarez, Luis Miguel Rincón Diaz, Tomás Vicente Vera, Perry Elliott, NHS Greater Glasgow, Robert Cooper, Liverpool Heart, Masliza Mahmod, Antonis Pantazis, Maite Tome, Oregon Health, Ali J. Marian, David S. Owens, Frank McGrew, Richard G. Bach, Omar Wever‐Pinzon, Elias Collado, Aslan T. Turer, Bashar Hannawi, Jeffrey B. Geske, Penn Heart, John D. Symanski, Sanger Heart, Christopher M. Kramer, Nitasha Sarswat, Ferhaan Ahmad, Jeremy Markowitz, Neal K. Lakdawala, Sandeep M. Jani, Marshall Brinkley, Ozlem Bilen, Craig R. Asher, Sitaramesh Emani, Abhinav Sharma, David Fermin, Melissa Lyle, David Raymer, Andrew Darlington, Christopher Sivert Nielsen, Andrew Wang, Sherif F. Nagueh, Matthew W. Martinez, Milind Y. Desai, Albree Tower‐Rader, Jacob P. Kelly, Alaska Heart, Florian Rader, Sounok Sen, Patrick Bering, Mathew Maurer, Sumeet S. Mitter, Mark V. Sherrid, Timothy C. Wong, Zainal Hussain, Sara Saberi, Srihari S. Naidu, Jorge Silva Enciso · 发表于：Journal of the American Heart Association · 年份：2024 · DOI：10.1161/jaha.124.035993 · 被引用次数：19 · 研究领域：Cardiomyopathy and Myosin Studies、Cardiac Structural Anomalies and Repair、Cardiovascular Function and Risk Factors

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%. Ther...