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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-109128

Danicamtiv

99.12%, Cardiac Myosin Activator

Myosin

Cancer

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