1. Academic Validation
  2. 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

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

  • Eur J Heart Fail. 2020 Sep;22(9):1649-1658. doi: 10.1002/ejhf.1933.
Adriaan A Voors 1 Jean-François Tamby 2 John G Cleland 3 Michael Koren 4 Leslie B Forgosh 5 Dinesh Gupta 6 Lars H Lund 7 8 Albert Camacho 9 Ravi Karra 10 Henk P Swart 11 Pierpaolo Pellicori 3 Frank Wagner 12 Ray E Hershberger 13 Narayana Prasad 14 Robert Anderson 2 Anu Anto 2 Kaylyn Bell 2 Jay M Edelberg 2 Liang Fang 2 Marcus Henze 2 Cynthia Kelly 2 Gregory Kurio 2 Wanying Li 2 Kate Wells 2 Chun Yang 2 Sam L Teichman 15 Carlos L Del Rio 2 Scott D Solomon 16
Affiliations

Affiliations

  • 1 University of Groningen, Groningen, The Netherlands.
  • 2 MyoKardia, Brisbane, CA, USA.
  • 3 Robertson Centre for Biostatistics and Clinical Trials Unit, University of Glasgow, Glasgow, UK.
  • 4 Jacksonville Center for Clinical Research, Jacksonville, FL, USA.
  • 5 HealthEast Heart Care, Saint Paul, MN, USA.
  • 6 Tennova Healthcare-Harton, Tullahoma, TN, USA.
  • 7 Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
  • 8 Karolinska University Hospital, Heart and Vascular Theme, Stockholm, Sweden.
  • 9 Oregon Health & Science University, Portland, OR, USA.
  • 10 Department of Medicine, Duke University Medical Center, Durham, NC, USA.
  • 11 Antonius Ziekenhuis Sneek, Sneek, The Netherlands.
  • 12 Charité Research Organization, Berlin, Germany.
  • 13 Divisions of Human Genetics and Cardiovascular Medicine, The Ohio State University, Columbus, OH, USA.
  • 14 Cardiovascular Imaging Core Laboratory, Brigham and Women's Hospital, Boston, MA, USA.
  • 15 Teichman Drug Development Consulting, Oakland, CA, USA.
  • 16 Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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.

Keywords

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

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-109128
    99.12%, Cardiac Myosin Activator