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

Adriaan A. Voors, Jean François Tamby, John G. Cleland, Michael Koren, Leslie B. Forgosh, Dinesh Gupta, Lars H. Lund, Albert Camacho, Ravi Karra, Henk P. Swart, Pierpaolo Pellicori, Frank Wagner, Ray E. Hershberger, Narayana Prasad, Robert Anderson, Anu Anto, Kaylyn Bell, Jay M. Edelberg, Liang Fang, Marcus HenzeCynthia Kelly, Gregory Kurio, Wanying Li, Kate Wells, Chun Yang, Sam L. Teichman, Carlos L. del Rio, Scott D. Solomon

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1649-1658
Number of pages10
JournalEuropean Journal of Heart Failure
Volume22
Issue number9
DOIs
StatePublished - Sep 1 2020

Keywords

  • Cardiac myosin activator
  • Clinical trial
  • Danicamtiv
  • Echocardiography
  • Heart failure with reduced ejection fraction
  • Myotrope

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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