Phase 2 study of aficamten in patients with obstructive hypertrophic cardiomyopathy

Maron, M. S. et al. (2023) Phase 2 study of aficamten in patients with obstructive hypertrophic cardiomyopathy. Journal of the American College of Cardiology, 81(1), pp. 34-45. (doi: 10.1016/j.jacc.2022.10.020) (PMID:36599608)

Abstract

Background: Left ventricular outflow tract (LVOT) obstruction is a major determinant of heart failure symptoms in obstructive hypertrophic cardiomyopathy (oHCM). Aficamten, a next-in-class cardiac myosin inhibitor, may lower gradients and improve symptoms in these patients. Objectives: This study aims to evaluate the safety and efficacy of aficamten in patients with oHCM. Methods: Patients with oHCM and LVOT gradients ≥30 mm Hg at rest or ≥50 mm Hg with Valsalva were randomized 2:1 to receive aficamten (n = 28) or placebo (n = 13) in 2 dose-finding cohorts. Doses were titrated based on gradients and ejection fraction (EF). Safety and changes in gradient, EF, New York Heart Association functional class, and cardiac biomarkers were assessed over a 10-week treatment period and after a 2-week washout. Results: From baseline to 10 weeks, aficamten reduced gradients at rest (mean difference: −40 ± 27 mm Hg, and −43 ± 37 mm Hg in Cohorts 1 and 2, P = 0.0003 and P = 0.0004 vs placebo, respectively) and with Valsalva (−36 ± 27 mm Hg and −53 ± 44 mm Hg, P = 0.001 and <0.0001 vs placebo, respectively). There were modest reductions in EF (−6% ± 7.5% and −12% ± 5.9%, P = 0.007 and P < 0.0001 vs placebo, respectively). Symptomatic improvement in ≥1 New York Heart Association functional class was observed in 31% on placebo, and 43% and 64% on aficamten in Cohorts 1 and 2, respectively (nonsignificant). With aficamten, N-terminal pro–B-type natriuretic peptide was reduced (62% relative to placebo, P = 0.0002). There were no treatment interruptions and adverse events were similar between treatment arms. Conclusions: Aficamten resulted in substantial reductions in LVOT gradients with most patients experiencing improvement in biomarkers and symptoms. These results highlight the potential of sarcomere-targeted therapy for treatment of oHCM.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Coats, Dr Caroline
• Authors: Maron, M. S., Masri, A., Choudhury, L., Olivotto, I., Saberi, S., Wang, A., Garcia-Pavia, P., Lakdawala, N. K., Nagueh, S. F., Rader, F., Tower-Rader, A., Turer, A. T., Coats, C., Fifer, M. A., Owens, A., Solomon, S. D., Watkins, H., Barriales-Villa, R., Kramer, C. M., Wong, T. C., Paige, S. L., Heitner, S. B., Kupfer, S., Malik, F. I., Meng, L., Wohltman, A., and Abraham, T.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Journal of the American College of Cardiology
• Publisher: Elsevier
• ISSN: 0735-1097
• ISSN (Online): 1558-3597
• Published Online: 02 January 2023
• Copyright Holders: Copyright © 2022 Elsevier on behalf of the American College of Cardiology Foundation
• First Published: First published in Journal of the American College of Cardiology 81(1): 34-45
• Publisher Policy: Reproduced under a Creative Commons License