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

Autor:	Cynthia Kelly, Robert E. Anderson, Pierpaolo Pellicori, Jean François Tamby, Scott D. Solomon, Chun Yang, Frank Wagner, Albert Camacho, Michael J. Koren, Gregory Kurio, Henk P. Swart, Narayana Prasad, Carlos L. del Rio, Wanying Li, Kate Wells, Leslie B. Forgosh, Dinesh Gupta, Ray E. Hershberger, Marcus Henze, Lars H. Lund, Anu R. Anto, Fang Liang, Kaylyn M Bell, Sam L. Teichman, Ravi Karra, Adriaan A. Voors, John G.F. Cleland, Jay M. Edelberg
Přispěvatelé:	Cardiovascular Centre (CVC)
Rok vydání:	2020
Předmět:	Male medicine.medical_specialty Contraction (grammar) Danicamtiv Angiotensin-Converting Enzyme Inhibitors 030204 cardiovascular system & hematology Placebo Ventricular Function Left Contractility Angiotensin Receptor Antagonists 03 medical and health sciences Dogs 0302 clinical medicine Myotrope Internal medicine medicine Animals Humans Adverse effect Aged Heart Failure Ejection fraction business.industry Cardiac myosin activator Stroke Volume Stroke volume Middle Aged Heart failure with reduced ejection fraction medicine.disease R1 Clinical trial Echocardiography Heart failure Cardiology Female Cardiology and Cardiovascular Medicine business Myofibril Cardiac Myosins
Zdroj:	European Journal of Heart Failure, 22(9), 1649-1658. Wiley
ISSN:	1879-0844 1388-9842
DOI:	10.1002/ejhf.1933
Popis:	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.
Databáze:	OpenAIRE
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