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. (10th July 2020)

• Record Type: Journal Article
• Authors: Voors, Adriaan A.; Tamby, Jean‐François; Cleland, John G.; Koren, Michael; Forgosh, Leslie B.; Gupta, Dinesh; Lund, Lars H.; Camacho, Albert; Karra, Ravi; Swart, Henk P.; Pellicori, Pierpaolo; Wagner, Frank; Hershberger, Ray E.; Prasad, Narayana; Anderson, Robert; Anto, Anu; Bell, Kaylyn; Edelberg, Jay M.; Fang, Liang; Henze, Marcus; Kelly, Cynthia; Kurio, Gregory; Li, Wanying; Wells, Kate; Yang, Chun; Teichman, Sam L.; del Rio, Carlos L.; Solomon, Scott D.
• Is Part Of: European journal of heart failure. Volume 22:Number 9(2020)
• Page Start: 1649
• Page End: 1658
• Publication Date: 2020-07-10
• Subjects: Danicamtiv -- Cardiac myosin activator -- Heart failure with reduced ejection fraction -- Echocardiography -- Clinical trial -- Myotrope; Heart failure -- Periodicals; Heart Failure -- Periodicals; Insuffisance cardiaque -- Périodiques; Heart failure; Periodicals; 616.129005
• DOI: 10.1002/ejhf.1933
• Languages: English
• ISSNs: 1388-9842

Abstract

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/m 2, 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.