Phase 2 Study of Aficamten in Patients With Obstructive Hypertrophic Cardiomyopathy.

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.

Informations de copyright

Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Funding Support and Author Disclosures The REDWOOD-HCM study was funded by Cytokinetics, Incorporated. Dr Maron has received consultant/advisor fees from Imbria and Takeda; and has received steering committee fees for REDWOOD-HCM from Cytokinetics, Incorporated. Dr Masri has received consultant/advisor fees from Tenaya, Attralus, Cytokinetics, Bristol Myers Squibb, and Ionis; and has received research grants from Ionis, Akcea, Pfizer, Ultromics, and Wheeler Foundation. Dr Olivotto has received Speakers Bureau fees from Boston Scientific, Amicus, and Novartis; has received consultant/advisor fees from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, and Tenaya; and has received research grant funding from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Menarini International, and Boston Scientific. Dr Saberi has received consultant/advisor fees from Bristol Myers Squibb; and has received research grants from Bristol Myers Squibb, Cytokinetics, Novartis, and Actelion Pharmaceuticals. Dr Wang has received Speakers Bureau fees from Bristol Myers Squibb; has received consultant/advisor fees from Bristol Myers Squibb and Cytokinetics; and has received research grants from Bristol Myers Squibb, Cytokinetics, and Abbott Vascular. Dr Garcia-Pavia has received Speakers Bureau fees from Pfizer and Alnylam; has received consultant/advisor fees from Pfizer, Alnylam, MyoKardia/Bristol Myers Squibb, Cytokinetics, Neuroimmune, BridgeBio, Attralus, and AstraZeneca; and has received research/educational grants to his institution from Pfizer, BridgeBio, and Alnylam. Dr Lakdawala has received consultant/advisor fees from Tenaya, Pfizer, Bristol Myers Squibb, Cytokinetics, and Sarepta; and has received a research grant from Pfizer. Dr Rader has received Speakers Bureau fees from Bristol Myers Squibb and Medtronic; and has received consultant/advisor fees from Bristol Myers Squibb, Cytokinetics, ReCor, and Medtronic. Dr Turer has received consultant/advisor fees from Cytokinetics. Dr Coats has received consultant/advisor fees from Cytokinetics. Dr Fifer has received consultant/advisor fees from Cytokinetics; and has received research grants from Bristol Myers Squibb and Novartis. Dr Owens has received consultant/advisor fees from Cytokinetics, Bristol Myers Squibb/MyoKardia, and Pfizer. 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, Daiichi-Sankyo, GSK, 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 has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI. Dr Watkins has received consultant/advisor fees from Cytokinetics, BioMarin, and BridgeBio. Dr Barriales-Villa has received consultant/advisor fees from MyoKardia/Bristol Myers Squibb. Dr Kramer has received consultant/advisor fees from Cytokinetics, and Bristol Myers Squibb; and has received research grants from Cytokinetics and Bristol Myers Squibb. Dr Wong has received Speakers Bureau fees from Projects in Knowledge, PCM Scientific; and has served as an unpaid consultant/advisor for Bristol Myers Squibb and Cytokinetics. Drs Heitner, Kupfer, Malik, Meng, and Wohltman are employees of Cytokinetics Incorporated; and holds stock in Cytokinetics Incorporated. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.