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
  • 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.
PMID: 32558989 DOI: 10.1002/ejhf.1933
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.
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