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 - Funding Information:
The study was designed and conducted by the authors in collaboration with MyoKardia, who sponsored the trial. Data collection was performed by Medpace (Cincinnati, OH, USA) under the supervision of the sponsor. The analysis was performed by the sponsor. Interpretation of the study results was conducted in cooperation between the authors and the trial sponsor. The corresponding author had access to the final data and wrote the first and subsequent drafts of the report, which were critically edited by the co-authors and representatives of MyoKardia. Authors who were not employed by the sponsor had the ultimate editorial authority. Conflict of interest: Personal fees may include but are not limited to consulting fees, lecture fees, research funding, honoraria for steering committee activities, speaker fees or travel support. A.A.V. received personal fees from Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim, Cytokinetics, Merck, MyoKardia, Novartis and Roche. S.L.T. received personal fees from MyoKardia. J.G.C. received personal fees from MyoKardia. L.H.L. received personal fees from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Merck, Mundipharma, MyoKardia, Novartis, Relypsa, Sanofi, ViforPharma. S.D.S. received personal fees from Akros, Alnylam, Amgen, AoBiome, Arena, AstraZeneca, Bayer, Bellerophon, BMS, Cardiac Dimensions, Cardior, Cardurion, Corvia, Celladon, Cytokinetics, Daiichi-Sankyo, Dinaqor, Eidos, Gilead, GSK, Ionis, Ironwood, Janssen, Lone Star Heart, Merck, Mesoblast, MyoKardia, NIH/NHLBI, Novartis, Quantum Genetics, Roche, Sanofi Pasteur, Takeda, Tenaya, Theracos and Tremeau. J.F.T., R.A., A.A., K.B., J.M.E., L.F., M.H., C.K., G.K., W.L., K.W., C.Y. and C.L.R. are employees of MyoKardia. All other authors have no conflict of interest. Medical writing support was provided by Dr Nicolas Bertheleme of Oxford Pharma Genesis, Oxford, UK, with funding from MyoKardia. The study was designed and conducted by the authors in collaboration with MyoKardia, who sponsored the trial. Data collection was performed by Medpace (Cincinnati, OH, USA) under the supervision of the sponsor. The analysis was performed by the sponsor. Interpretation of the study results was conducted in cooperation between the authors and the trial sponsor. The corresponding author had access to the final data and wrote the first and subsequent drafts of the report, which were critically edited by the co-authors and representatives of MyoKardia. Authors who were not employed by the sponsor had the ultimate editorial authority. Conflict of interest: Personal fees may include but are not limited to consulting fees, lecture fees, research funding, honoraria for steering committee activities, speaker fees or travel support. A.A.V. received personal fees from Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim, Cytokinetics, Merck, MyoKardia, Novartis and Roche. S.L.T. received personal fees from MyoKardia. J.G.C. received personal fees from MyoKardia. L.H.L. received personal fees from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Merck, Mundipharma, MyoKardia, Novartis, Relypsa, Sanofi, ViforPharma. S.D.S. received personal fees from Akros, Alnylam, Amgen, AoBiome, Arena, AstraZeneca, Bayer, Bellerophon, BMS, Cardiac Dimensions, Cardior, Cardurion, Corvia, Celladon, Cytokinetics, Daiichi-Sankyo, Dinaqor, Eidos, Gilead, GSK, Ionis, Ironwood, Janssen, Lone Star Heart, Merck, Mesoblast, MyoKardia, NIH/NHLBI, Novartis, Quantum Genetics, Roche, Sanofi Pasteur, Takeda, Tenaya, Theracos and Tremeau. J.F.T., R.A., A.A., K.B., J.M.E., L.F., M.H., C.K., G.K., W.L., K.W., C.Y. and C.L.R. are employees of MyoKardia. All other authors have no conflict of interest.
Funding Information:
Medical writing support was provided by Dr Nicolas Bertheleme of Oxford Pharma Genesis, Oxford, UK, with funding from MyoKardia.
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
UR - http://www.scopus.com/inward/record.url?scp=85087550932&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85087550932&partnerID=8YFLogxK
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 -