Standard-of-Care Medication Withdrawal in Patients With Obstructive Hypertrophic Cardiomyopathy Receiving Aficamten in FOREST-HCM.

Background: Standard-of-care (SoC) medications for the treatment of obstructive hypertrophic cardiomyopathy (oHCM) are recommended as first-line therapy despite the lack of evidence from controlled clinical trials and well known off-target side effects.
Objectives: We describe the impact of SoC therapy downtitration and withdrawal in patients already receiving aficamten in FOREST-HCM (Follow-Up, Open-Label, Research Evaluation of Sustained Treatment with Aficamten in Hypertrophic Cardiomyopathy; NCT04848506).
Methods: Patients receiving SoC therapy (beta-blocker, nondihydropyridine calcium-channel blocker, and/or disopyramide) were eligible for protocol-guided SoC downtitration and withdrawal at the discretion of the investigator and after achieving a stable dose of aficamten for ≥4 weeks. Successful SoC withdrawal was defined as at least a 50% dose-reduction in ≥1 medication. Adverse events (AEs) were prospectively evaluated 1 to 2 weeks after any SoC withdrawal.
Results: Of 145 patients with oHCM who were followed for at least 24 weeks (mean age 60.5 ± 13.2 years; 44.8% female; 42% NYHA functional class III), 136 (93.8%) were receiving ≥1 SoC therapy; of those, 64 (47%) had an attempt at withdrawal, with 59 (92.2%) successful. Thirty-eight (64.4%) patients completely discontinued ≥1 medication, and 27 (45.8%) achieved aficamten monotherapy with 2 later restarting a SoC medication. There were no significant differences in baseline characteristics on day 1 in FOREST-HCM in those with a SoC-withdrawal vs no-withdrawal attempt. In patients who underwent successful SoC therapy withdrawal, NYHA functional class improved by ≥1 class in 79.2% from baseline, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score improved to 83.0 ± 15.8 points, and resting and Valsalva left ventricular outflow tract gradient improved to 14.3 ± 10.9 and 32.9 ± 21.4 mm Hg, respectively. N-terminal pro-B-type natriuretic peptide levels improved to a median of 220.0 pg/mL (Q1-Q3: 102.0-554.0.0 pg/mL) and high-sensitivity troponin I improved to a median of 6.0 ng/L (Q1-Q3:3.5-10.7 ng/L). Downtitration and withdrawal of SoC therapy did not impact these results (all P values for change were >0.05), and these changes were similar in patients who did not undergo SoC therapy withdrawal. There were no serious AEs attributed to SoC withdrawal and treatment emergent AEs were similar between groups.
Conclusions: In FOREST-HCM, one-half of the patients with oHCM attempted downtitration and withdrawal of SoC medications while receiving aficamten treatment, with infrequent instances of resumption of SoC. Stopping and dose reduction of SoC medications were well tolerated with no adverse consequences in clinical measures of efficacy (Follow-Up, Open-Label, Research Evaluation of Sustained Treatment with Aficamten in Hypertrophic Cardiomyopathy [FOREST-HCM]; NCT04848506).
Competing Interests: Funding Support and Author Disclosures The FOREST-HCM trial is funded by Cytokinetics, Incorporated. Dr Masri has received consulting/advisor fees from Tenaya, Attralus, Cytokinetics, Bristol Myers Squibb, Eidos, Pfizer, Haya, Lexion, BioMarin, Alexion, and Ionis; and has received research grants from Ionis, Pfizer, Cytokinetics, and Attralus. Dr Choudhury has received advisor fees from Cytokinetics. Dr Barriales-Villa has received consulting/advisor fees from MyoKardia/Bristol Myers Squibb. Dr Elliott has received consulting fees from Bristol Myers Squibb, Pfizer, and Cytokinetics; has received speaker fees from Pfizer; and has received an unrestricted grant from Sarepta. Dr Maron has received consulting/advisor fees from Imbria, Edgewise, and Biomarin; and has received steering committee fees for SEQUIOA-HCM from Cytokinetics, Incorporated. Dr Nassif has received research and grant support from AstraZeneca and Cytokinetics; and has received consulting/advisory fees from Vifor and Cytokinetics. Dr Oreziak has received investigator fees from Cytokinetics and MyoKardia/Bristol Myers Squibb. Dr Owens has received consulting/advisor fees from Bristol Myers Squibb; and has received research grants from Bristol Myers Squibb, Cytokinetics, Novartis, and Actelion Pharmaceuticals. Dr Saberi has received consulting fees from Bristol Myers Squibb and Cytokinetics. Dr Tower-Rader has received research grants from Bristol Myers Squibb and Cytokinetics. Dr Rader has received consulting fees/honoraria from Medtronic, Cytokinetics, Bristol Myers Squibb, and Recor. Dr Garcia-Pavia has received Speakers Bureau fees from Bristol Myers Squibb, Pfizer, BridgeBio, Ionis, AstraZeneca, NovoNordisk, Intellia, and Alnylam; has received consulting fees from Bristol Myers Squibb, Cytokinetics, Rocket Pharma, Lexeo Therapeutics, Pfizer, BridgeBio, Daiichi-Sankyo, Neurimmune, Alnylam, AstraZeneca, Novo Nordisk, Attralus, Intellia, Idoven, General Electric, and Alexion; and has received research/educational support to his institution from Pfizer, BridgeBio, NovoNordisk, AstraZeneca, Intellia, and Alnylam. Dr Olivotto has received Speakers Bureau fees from Bristol Myers Squibb, Amicus, and Genzyme; has received consulting/advisor fees from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Tenaya, Rocket Pharma, and Lexeo; and has received research grant funding from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Menarini International, Chiesi, and Boston Scientific. Dr Wang has received Speakers Bureau fees from Bristol Myers Squibb; has received consulting/advisor fees from Bristol Myers Squibb and Cytokinetics; and has received research grants from Bristol Myers Squibb, Cytokinetics, and Abbott Vascular. Drs Heitner, Jacoby, Kupfer, Malik, Melloni, Meng, and Wei are employees of and hold stock in Cytokinetics Incorporated. Dr Sherrid has received consulting fees/honoraria from Pfizer Inc; and has served as a consultant for Cytokinetics Inc without payment. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)