Before study drug infusion, 1 patient in the placebo group and 1 patient in cohort 1 had detectable or elevated troponin I levels at screening, and 1 patient in the placebo group had detectable or elevated troponin I levels before and after ETT1. Two patients taking omecamtiv mecarbil had troponin I results that were just above the ULN after study drug infusion following ETT3: peak troponin I levels were 0.13 μg/l (ULN <0.11 μg/l) for a patient in cohort 1 and 1.1 μg/l
(ULN <1.0 μg/l) for a patient in cohort 2. There were no other clinical signs or symptoms of ischemia in these 2 patients. Mean plasma concentrations of omecamtiv mecarbil at 20 h after IV dosing were 283 ng/ml for cohort 1 and 575 ng/ml for cohort 2, consistent with the predicted values (295 ng/ml and 550 ng/ml for cohorts 1 and 2, respectively) derived by using pharmacokinetic LBH589 parameters from Veliparib cell line healthy volunteers (3). Increases in mean maximum plasma concentration (Cmax) and area under the plasma concentration–time curve from time 0 to the time of last quantifiable plasma concentration values from cohort 1 to cohort 2 were modestly higher than predicted from a strictly dose-proportional increase; mean ± SD Cmax levels were
344 ± 265 ng/ml and 708 ± 268 ng/ml in cohorts 1 and 2, respectively. Time to Cmax was similar between doses (Table 4). Mean plasma concentrations 1 h after the last oral dose were 74 ng/ml for cohort 1 and 208 ng/ml for cohort 2. Increasing cardiac contractility would seem to be a rational approach to treating patients with systolic heart failure. However, inotropic drugs increase the risk of ischemia, Florfenicol arrhythmias, and death, and this risk has limited their utility in treating acute and chronic heart failure 6, 7, 8, 9 and 10. Currently available inotropic drugs increase cardiac contractility indirectly by increasing cardiac myocyte intracellular calcium concentration (11). Another approach to increasing cardiac contractility by directly activating the sarcomere with a cardiac myosin activator may overcome the
limitations of the currently available inotropic drugs (12). Omecamtiv mecarbil is a novel, direct cardiac myosin activator that increases cardiac contractility and may become an important therapy for heart failure patients with systolic dysfunction. The echocardiographic hallmark for the pharmacodynamic activity of omecamtiv mecarbil is an increase in the systolic ejection time that is highly correlated with omecamtiv mecarbil plasma concentration 2 and 3. Because the majority of coronary blood flow occurs during diastole, this effect of omecamtiv mecarbil could reduce the time for myocardial perfusion. Thus, it was critical to evaluate omecamtiv mecarbil in patients with ischemic cardiomyopathy and angina during exercise in a well-controlled and monitored setting.