9 research outputs found
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
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 nonâclinical studies (ex vivo : skinned muscle fibres and myofibrils; in vivo : dogs with heart failure) and in a randomized, doubleâblind, singleâ and multipleâdose phase 2a trial in patients with stable HFrEF (placebo, n =â10; danicamtiv, n =â30; 50â100âmg twice daily for 7âdays). 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 <â0.05) and LA emptying fraction (+10.7%, P <â0.05). In patients with HFrEF (mean age 60âyears, 25% women, ischaemic heart disease 48%, mean LV ejection fraction 32%), treatmentâemergent adverse events, mostly mild, were reported in 17 patients (57%) receiving danicamtiv and 4 patients (40%) receiving placebo. Danicamtiv (at plasma concentrations â„2000âng/mL) increased stroke volume (up to +7.8 mL, P <â0.01), improved global longitudinal (up to â1.0%, P <â0.05) and circumferential strain (up to â3.3%, P <â0.01), decreased LA minimal volume index (up to â2.4 mL/m2, P <â0.01) and increased LA function index (up to 6.1, P <â0.01), 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 preâclinical findings of direct activation of LA contractility