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 2020 Sep

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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. 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. 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. © 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Citation

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 Henze, Cynthia Kelly, Gregory Kurio, Wanying Li, Kate Wells, Chun Yang, Sam L Teichman, Carlos L Del Rio, Scott D Solomon. 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. 2020 Sep;22(9):1649-1658