TY - JOUR
T1 - Effects of danicamtiv, a novel cardiac myosin activator, in heart failure with reduced ejection fraction
T2 - experimental data and clinical results from a phase 2a trial
AU - Voors, Adriaan A.
AU - Tamby, Jean François
AU - Cleland, John G.
AU - Koren, Michael
AU - Forgosh, Leslie B.
AU - Gupta, Dinesh
AU - Lund, Lars H.
AU - Camacho, Albert
AU - Karra, Ravi
AU - Swart, Henk P.
AU - Pellicori, Pierpaolo
AU - Wagner, Frank
AU - Hershberger, Ray E.
AU - Prasad, Narayana
AU - Anderson, Robert
AU - Anto, Anu
AU - Bell, Kaylyn
AU - Edelberg, Jay M.
AU - Fang, Liang
AU - Henze, Marcus
AU - Kelly, Cynthia
AU - Kurio, Gregory
AU - Li, Wanying
AU - Wells, Kate
AU - Yang, Chun
AU - Teichman, Sam L.
AU - del Rio, Carlos L.
AU - Solomon, Scott D.
N1 - Publisher Copyright:
© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - 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.
AB - 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.
KW - Cardiac myosin activator
KW - Clinical trial
KW - Danicamtiv
KW - Echocardiography
KW - Heart failure with reduced ejection fraction
KW - Myotrope
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U2 - 10.1002/ejhf.1933
DO - 10.1002/ejhf.1933
M3 - Article
C2 - 32558989
AN - SCOPUS:85087550932
SN - 1388-9842
VL - 22
SP - 1649
EP - 1658
JO - European Journal of Heart Failure
JF - European Journal of Heart Failure
IS - 9
ER -