Omecamtiv Mecarbil in Chronic Heart Failure With Reduced Ejection Fraction

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

“…29,30 The results of GALACTIC-HF, a randomized, placebo-controlled trial of omecamtiv mecarbil conducted in more than 8000 patients with HFrEF should be reported soon, and will determine whether these small increases in serum troponin, observed in the context of cardiac myosin activation, are clinically important. 31 Danicamtiv appears to share some common features with omecamtiv mecarbil, such as leveraging cardiac myosin to activate the sarcomere, increasing SET, improving LV systolic function, with potential impact on diastolic function and relaxation at higher concentrations. Both agents are associated with a small rise in troponin and are generally well tolerated.…”

Human hypertrophic cardiomyopathy mutation R712L suppresses the working stroke of cardiac myosin and can be rescued by omecamtiv mecarbil

“…Crystal structures of myosin [11,12] reveal that R712L is located near the binding pocket for omecamtiv mecarbil (OM), a drug in phase-3 clinical trials that Figure 3C-3D increases cardiac ejection fraction in HCM patients [18]. Addition of OM decreased the in vitro actin filament gliding rate of WT-myosin ( Figure 4A-black points, Table 1, and Movie 1), consistent with earlier measurements [11,[24][25][26] and with our previous report that OM inhibits β-cardiac myosin motility by suppressing its working stroke [13].…”

“…Although OM abrogates the working stroke of myosin, the prolonged attachment increases calcium sensitivity in muscle fibers via cooperative activation of the thin filament regulatory system, which activates the muscle [14]. At submicromolar concentrations, it has been shown to improve cardiac output in both animal models and in human clinical trials [15][16][17][18]. We reasoned that the HCM mutation of R712 to a Leucine (R712L), located adjacent to the drug binding site, might serve as a mechanistically informative target, and might alter the kinetics and step size of β-cardiac myosin in a similar manner to OM.…”

Is myosin activation a new treatment for heart failure?

“…The results of the GALACTIC-HF study on the effects of omecamtiv mecarbil in more than 8000 patients with heart failure and reduced ejection fraction, are thus much anticipated. 6 The study reported on in this issue of the Journal provides important experimental and early clinical information on the new myosin activator, danicamtiv.…”