Concomitant Aficamten and Disopyramide in Symptomatic Obstructive Hypertrophic Cardiomyopathy
- PMID: 40285763
- DOI: 10.1016/j.jchf.2025.03.008
Concomitant Aficamten and Disopyramide in Symptomatic Obstructive Hypertrophic Cardiomyopathy
Abstract
Background: Disopyramide, used in obstructive hypertrophic cardiomyopathy (oHCM) for its negative inotropic properties mediated by its reduction in cytosolic calcium, has been recommended for decades as an option to relieve resistant obstruction. Aficamten is a selective cardiac myosin inhibitor that reduces hypercontractility directly by reducing myosin-actin interaction.
Objectives: This study aims to investigate the safety and efficacy of concomitant use and withdrawal of disopyramide in patients with symptomatic oHCM receiving aficamten.
Methods: Patients with oHCM enrolled in REDWOOD-HCM Cohort 3 (open-label), SEQUOIA-HCM (placebo-controlled), and FOREST-HCM (open-label) were analyzed. The authors identified 4 groups, each with patients symptomatic despite background therapy with disopyramide who received: 1) disopyramide plus aficamten and subsequent aficamten withdrawal per protocol (Diso-Afi Withdrawal); 2) disopyramide plus placebo (Diso-Pbo); 3) aficamten plus disopyramide with subsequent disopyramide withdrawal (Afi-Diso Withdrawal); and 4) continued both disopyramide and aficamten (Diso+Afi Continuous). Assessments were performed at baseline, after aficamten or placebo add-on therapy, and after washout (except at week 24 for Diso+Afi Continuous group).
Results: Overall, 50 unique patients from 3 trials enrolled, resulting in 93 subjects (segments) across 4 groups: Diso-Afi Withdrawal (n = 29), Diso-Pbo (n = 20), Afi-Diso Withdrawal (n = 17), and Diso+Afi Continuous (n = 27); mean disopyramide dose was 331 ± 146 mg/d. The addition of aficamten to disopyramide alleviated left ventricular outflow tract (LVOT) obstruction (resting: change [Δ] in least squares mean -27.0 ± 3.6, Valsalva: Δ least squares mean -39.2 ± 5.0, both P < 0.0001), symptoms (≥1 NYHA functional class improvement: 77.8% [95% CI: 61.0-94.5]; P < 0.0001; Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score: 12.3 ± 3.3 [P < 0.001]), and reduced N-terminal pro-B-type natriuretic peptide ratio: 0.35 [95% CI: 0.26-0.48]; P < 0.0001, and there was no significant change with placebo. Withdrawal of aficamten while on disopyramide resulted in return of LVOT obstruction, worsening of symptoms, and increase in NT-proBNP to baseline values. Conversely, withdrawal of disopyramide while on aficamten did not impact efficacy. There were no safety events associated with aficamten or disopyramide withdrawal, and no episodes of atrial fibrillation after disopyramide withdrawal.
Conclusions: In this cohort of patients with symptomatic oHCM with persistent LVOT obstruction, combination therapy with aficamten and disopyramide was safe and well tolerated but did not enhance clinical efficacy vs aficamten alone. For such oHCM patients, aficamten treatment may be considered with an option to discontinue disopyramide. (Dose-finding Study to Evaluate the Safety, Tolerability, PK, and PD of CK-3773274 in Adults With HCM [REDWOOD-HCM]; NCT04219826) (Aficamten vs Placebo in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy [SEQUOIA-HCM]; NCT05186818) (Open-label Extension Study to Evaluate the Long-term Safety and Tolerability of Aficamten in Adults With HCM [FOREST-HCM]; NCT04848506).
Keywords: aficamten; disopyramide; left ventricular outflow tract gradient; obstructive hypertrophic cardiomyopathy.
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Funding Support and Author Disclosures Funding was provided by Cytokinetics, Incorporated, South San Francisco, California, USA. Dr Masri has received research grants from Pfizer, Ionis, Attralus, Cytokinetics Inc, and Janssen and consulting fees from BridgeBio, Pfizer, Ionis, Lexicon, Attralus, Cytokinetics Inc, Bristol Myers Squibb, Alnylam, Haya, Edgewise, Alexion, Akros, Prothena, BioMarin, Lexeo, AstraZeneca, Rocket, and Tenaya. Dr Maron has received consulting/advisor fees from Imbria, Edgewise, and BioMarin; and has received steering committee fees for SEQUIOA-HCM from Cytokinetics Inc. Dr Nassif has received research and grant support to his institution from Cytokinetics Inc and Bristol Myers Squibb, and consulting/advisory fees from Vifor and Cytokinetics Inc. Dr Barriales-Villa has received consultant/advisor fees from MyoKardia/Bristol Myers Squibb, Pfizer, Sanofi, Alnylam, and Cytokinetics Inc. Dr Garcia-Pavia has received speaker fees from BMS, and consulting fees from BioMarin, BMS, Cytokinetics Inc, Edgewise, Rocket Pharmaceuticals, and Lexeo. Dr Bilen has received consulting fees from Bristol Myers Squibb and Cytokinetics Inc. Dr Coats has received consultant/advisor fees from Alnylam, Cytokinetics Inc, and Roche Diagnostics and speaker fees from Pfizer. Dr Elliott has received consulting fees from Bristol Myers Squibb, Pfizer, and Cytokinetics Inc; speaker fees from Pfizer; and an unrestricted grant from Sarepta. Dr Massera has received consulting fees from Sanofi, Tenaya Therapeutics, Chiesi Pharmaceuticals, and Cytokinetics Inc. Dr Olivotto has received speakers’ bureau fees from Bristol Myers Squibb, Amicus, and Genzyme; consultant/advisor fees from Bristol Myers Squibb, Cytokinetics Inc, Sanofi Genzyme, Amicus, Bayer, Tenaya, Rocket Pharma, and Lexeo; and research grant funding from Bristol Myers Squibb, Cytokinetics Inc, Sanofi Genzyme, Amicus, Bayer, Menarini International, Chiesi, and Boston Scientific. Dr Oreziak has received investigator fees from Cytokinetics Inc and MyoKardia/Bristol Myers Squibb. Dr Owens has received consultant/advisor fees from Alexion, Bayer, BioMarin, Bristol Myers Squibb, Cytokinetics Inc, Corvista, Edgewise, Imbria, Lexeo, Stealth, and Tenaya and a research grant from Bristol Myers Squibb. Dr Saberi has received consulting fees from Bristol Myers Squibb and Cytokinetics Inc. Dr Solomon has received consultant/advisor fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics Inc, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, MyoKardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Puretech Health; and research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics Inc, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi-Pasteur, Theracos, and Us2.ai. Dr Tower-Rader has received research grants from Bristol Myers Squibb and Cytokinetics Inc. Drs Heitner, Jacoby, Melloni, and Wei are employees and shareholders of Cytokinetics Inc. Dr Sherrid has received consultant fees/honoraria from Pfizer and has served as a consultant for Cytokinetics Inc, without payment. Dr Abraham has reported that he has no relationships relevant to the contents of this paper to disclose.
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