Lancet: Cardiac myosin activator holds promise for HF
A novel drug that is a cardiac myosin activator showed promising results in two clinical trials, according to studies published in the Aug. 20 issue of The Lancet. The drug, omecamtiv mecarbil, could provide a new treatment for certain heart failure (HF) patients, but an accompanying editorial emphasized that like any new agent, omecamtiv mecarbil needs to be rigorously tested in a randomized controlled clinical trial.
Omecamtiv mecarbil (Cytokinetics) is a compound that increases contraction ability in heart muscle without affecting the calcium transient in cardiac myocytes. It is considered an attractive option to other agents that raise cardiac myocyte intracellular calcium, which has been associated with myocardial ischemia as well as atrial and ventricular arrhythmias. Results from preclinical studies showed that omecamtiv mecarbil increased the extent of myocardial contraction without increasing contraction rate or oxygen consumption, making it an attractive candidate as an HF therapeutic.
In a double-blind, placebo-controlled, crossover, dose-escalating trial, John R. Teerlink, MD, of the San Francisco Veterans Affairs Medical Center and colleagues assessed dose ranges of omecamtiv mecarbil in 34 healthy men. In a second study, John G.F. Cleland, MD, of the Hull York Medical School at the University of Hull in Hull, England, conducted a double-blind, placebo-controlled, crossover, dose-ranging Phase II trial by giving omecamtiv mecarbil to 45 patients with stable heart failure and left ventricular systolic dysfunction. The goal of the second study was to test for safety and efficacy in the patient population.
Teerlink and colleagues infused omecamtiv mecarbil or a placebo once a week for four weeks in four cohorts. Each participant received three active ascending-dose treatments (0.005 to 1 mg/kg per hour) with the placebo dose randomized. Researchers obtained vital signs, blood samples, electrocardiographs (ECGs) and echocardiograms before, during and after each six-hour treatment.
They found that the highest tolerated dose was 0.5 mg/kg per hour. The researchers reported no clinically significant dose-related adverse effects in dosages of 0.625 mg/kg per hour, and noted an increase in stroke volume (13 percent increase above baseline), ejection fraction (8 to 10 percentage point increase) and fractional shortening compared to placebo. Increase in dosage led to a proportional increase in systolic ejection time and systolic function.
“The physiological actions of omecamtiv mecarbil evident in this study support its clinical efficacy as an agent to increase systolic function,” they wrote. “The absence of increases in heart rate supports the mechanism of action and the concept that there is no increase in myocardial oxygen consumption.”
In the second study, Cleland and colleagues assigned 45 patients with a clinical diagnosis of heart failure and a left ventricular ejection fraction of 40 percent or less into five cohorts. The patients were infused with omecamtiv mecarbil or a placebo for two, 24 and then 72 hours and were tested for plasma drug concentrations after each treatment. They also underwent testing for vital signs, ECGs and echocardiograms.
Cleland et al reported concentration-dependent increases in left ventricular ejection time, stroke volume and fractional shortening as well as a slight reduction in heart rate. They also noted that higher plasma concentrations were associated with reductions in end-systolic and end-systolic volumes. They reported three serious adverse effects: septicemia, pneumonia and non-ST elevation MI in a patient who received an overdose. They found no consistent adverse effects in patients who tolerated the dosage.
“Although omecamtiv mecarbil increased the duration of left ventricular systole, possibly as a consequence of the increase in stroke volume and cardiac output, heart rate also slowed and therefore the duration of diastole was only slightly reduced,” they wrote. “Conversely, the duration of left atrial systole increased, possibly because of an increase in atrial contractility, emptying of the left ventricle improved and ventricular end-systolic and end-systolic volumes decreased. … Clearly, the effects of omecamtiv mecarbil on cardiac function are likely to be complex and can vary depending on the underlying pathophysiology and disease stage.”
Kenneth Dickstein, MD, PhD, of the Stavanger University Hospital in Stavanger, Norway, wrote in an accompanying editorial that a randomized clinical trial was warranted, but warned that many promising therapeutics fail at that stage. “Cardiac myosin activation should first be assessed in the large population with chronic systolic dysfunction, signs of heart failure and New York Hospital Association functional Class III and IV symptoms,” Dickstein recommended. “Subsequently, the potential role of patients managed in critical care, especially after cardiovascular surgery, should be explored.”
Omecamtiv mecarbil (Cytokinetics) is a compound that increases contraction ability in heart muscle without affecting the calcium transient in cardiac myocytes. It is considered an attractive option to other agents that raise cardiac myocyte intracellular calcium, which has been associated with myocardial ischemia as well as atrial and ventricular arrhythmias. Results from preclinical studies showed that omecamtiv mecarbil increased the extent of myocardial contraction without increasing contraction rate or oxygen consumption, making it an attractive candidate as an HF therapeutic.
In a double-blind, placebo-controlled, crossover, dose-escalating trial, John R. Teerlink, MD, of the San Francisco Veterans Affairs Medical Center and colleagues assessed dose ranges of omecamtiv mecarbil in 34 healthy men. In a second study, John G.F. Cleland, MD, of the Hull York Medical School at the University of Hull in Hull, England, conducted a double-blind, placebo-controlled, crossover, dose-ranging Phase II trial by giving omecamtiv mecarbil to 45 patients with stable heart failure and left ventricular systolic dysfunction. The goal of the second study was to test for safety and efficacy in the patient population.
Teerlink and colleagues infused omecamtiv mecarbil or a placebo once a week for four weeks in four cohorts. Each participant received three active ascending-dose treatments (0.005 to 1 mg/kg per hour) with the placebo dose randomized. Researchers obtained vital signs, blood samples, electrocardiographs (ECGs) and echocardiograms before, during and after each six-hour treatment.
They found that the highest tolerated dose was 0.5 mg/kg per hour. The researchers reported no clinically significant dose-related adverse effects in dosages of 0.625 mg/kg per hour, and noted an increase in stroke volume (13 percent increase above baseline), ejection fraction (8 to 10 percentage point increase) and fractional shortening compared to placebo. Increase in dosage led to a proportional increase in systolic ejection time and systolic function.
“The physiological actions of omecamtiv mecarbil evident in this study support its clinical efficacy as an agent to increase systolic function,” they wrote. “The absence of increases in heart rate supports the mechanism of action and the concept that there is no increase in myocardial oxygen consumption.”
In the second study, Cleland and colleagues assigned 45 patients with a clinical diagnosis of heart failure and a left ventricular ejection fraction of 40 percent or less into five cohorts. The patients were infused with omecamtiv mecarbil or a placebo for two, 24 and then 72 hours and were tested for plasma drug concentrations after each treatment. They also underwent testing for vital signs, ECGs and echocardiograms.
Cleland et al reported concentration-dependent increases in left ventricular ejection time, stroke volume and fractional shortening as well as a slight reduction in heart rate. They also noted that higher plasma concentrations were associated with reductions in end-systolic and end-systolic volumes. They reported three serious adverse effects: septicemia, pneumonia and non-ST elevation MI in a patient who received an overdose. They found no consistent adverse effects in patients who tolerated the dosage.
“Although omecamtiv mecarbil increased the duration of left ventricular systole, possibly as a consequence of the increase in stroke volume and cardiac output, heart rate also slowed and therefore the duration of diastole was only slightly reduced,” they wrote. “Conversely, the duration of left atrial systole increased, possibly because of an increase in atrial contractility, emptying of the left ventricle improved and ventricular end-systolic and end-systolic volumes decreased. … Clearly, the effects of omecamtiv mecarbil on cardiac function are likely to be complex and can vary depending on the underlying pathophysiology and disease stage.”
Kenneth Dickstein, MD, PhD, of the Stavanger University Hospital in Stavanger, Norway, wrote in an accompanying editorial that a randomized clinical trial was warranted, but warned that many promising therapeutics fail at that stage. “Cardiac myosin activation should first be assessed in the large population with chronic systolic dysfunction, signs of heart failure and New York Hospital Association functional Class III and IV symptoms,” Dickstein recommended. “Subsequently, the potential role of patients managed in critical care, especially after cardiovascular surgery, should be explored.”