Effects of danicamtiv, a novel cardiac myosin activator, in heart failure with reduced ejection fraction: experimental data and clinical results from a phase 2a trial

Voors, A. A. et al. (2020) Effects of danicamtiv, a novel cardiac myosin activator, in heart failure with reduced ejection fraction: experimental data and clinical results from a phase 2a trial. European Journal of Heart Failure, 22(9), pp. 1649-1658. (doi: 10.1002/ejhf.1933) (PMID:32558989) (PMCID:PMC7689751)

Abstract

Aims: Both left ventricular (LV) and left atrial (LA) dysfunction and remodelling contribute to adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Danicamtiv is a novel, cardiac myosin activator that enhances cardiomyocyte contraction. Methods and results: We studied the effects of danicamtiv on LV and LA function in non‐clinical studies (ex vivo : skinned muscle fibres and myofibrils; in vivo : dogs with heart failure) and in a randomized, double‐blind, single‐ and multiple‐dose phase 2a trial in patients with stable HFrEF (placebo, n = 10; danicamtiv, n = 30; 50–100 mg twice daily for 7 days). Danicamtiv increased ATPase activity and calcium sensitivity in LV and LA myofibrils/muscle fibres. In dogs with heart failure, danicamtiv improved LV stroke volume (+10.6 mL, P < 0.05) and LA emptying fraction (+10.7%, P < 0.05). In patients with HFrEF (mean age 60 years, 25% women, ischaemic heart disease 48%, mean LV ejection fraction 32%), treatment‐emergent adverse events, mostly mild, were reported in 17 patients (57%) receiving danicamtiv and 4 patients (40%) receiving placebo. Danicamtiv (at plasma concentrations ≥2000 ng/mL) increased stroke volume (up to +7.8 mL, P < 0.01), improved global longitudinal (up to −1.0%, P < 0.05) and circumferential strain (up to −3.3%, P < 0.01), decreased LA minimal volume index (up to −2.4 mL/m2, P < 0.01) and increased LA function index (up to 6.1, P < 0.01), when compared with placebo. Conclusions: Danicamtiv was well tolerated and improved LV systolic function in patients with HFrEF. A marked improvement in LA volume and function was also observed in patients with HFrEF, consistent with pre‐clinical findings of direct activation of LA contractility.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cleland, Professor John and Pellicori, Dr Pierpaolo
• Authors: Voors, A. A., Tamby, J.‐F., Cleland, J. G.F., Koren, M., Forgosh, L. B., Gupta, D., Lund, L. H., Camacho, A., Karra, R., Swart, H. P., Pellicori, P., Wagner, F., Hershberger, R. E., Prasad, N., Anderson, R., Anto, A., Bell, K., Edelberg, J. M., Fang, L., Henze, M., Kelly, C., Kurio, G., Li, W., Wells, K., Yang, C., Teichman, S. L., Rio, C. L., and Solomon, S. D.
• Subjects: R Medicine > R Medicine (General)
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Robertson Centre
• Journal Name: European Journal of Heart Failure
• Publisher: Wiley
• ISSN: 1388-9842
• ISSN (Online): 1879-0844
• Published Online: 19 June 2020
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in European Journal of Heart Failure 22(9): 1649-1658
• Publisher Policy: Reproduced under a Creative Commons License