The Lancet presents the results of two small studies investigating a novel cardiac myosin activator, omecamtiv mecarbil (formerly CK-1827452). The agent has inotropic action and is being investigated as a potential therapeutic alternative to present treatments for patients with heart failure and systolic dysfunction.
The first study is a first-in-man dose-ranging study of omecamtiv mecarbil in 34 healthy volunteers. The primary aim of the study was to establish a maximum tolerated dose and plasma concentrations of omecamtiv mecarbil. Secondary aims were evaluation of pharmacodynamic and pharmacokinetic characteristics, safety, and tolerability. The maximum tolerated dose of omecamtiv mecarbil was found to be 0.5 mg/kg per hour. The study found a highly dose-dependent augmentation of left ventricular systolic function in response to omecamtiv mecarbil and the researchers conclude that their data support potential clinical use of the drug in patients with heart failure.
The second study was designed as a phase 2, double-blind, placebo-controlled, crossover, dose-escalation study which aimed to assess the drug's safety and tolerability. It also aimed to define a range of pharmacodynamically active, well tolerated target plasma concentrations for later trials. Overall, 45 patients, with stable heart failure and left ventricular systolic dysfunction, received 151 infusions of active drug or placebo. The drug was given intravenously for 2, 24, or 72 h. Clinical assessment (including vital signs, echocardiograms, and electrocardiographs) and testing of plasma drug concentrations took place during and after completion of each infusion. The study found that omecamtiv mecarbil has dose-dependent and concentration-dependent effects on cardiac function that appear at plasma concentrations that are well tolerated by patients with stable chronic systolic heart failure. The drug improved cardiac function in patients enrolled and the researchers suggest that it could be the first in class of a new therapeutic agent. They note, “Further studies are needed to establish whether the observed effects on cardiac function translate into benefits related to symptoms, quality of life, exercise capacity, morbidity, or mortality.”
A related Comment article discusses the results of these papers and putting theory into practice. The author concludes, “So, in view of the attractive mechanistic theory, omecamtiv mecarbil's safety and tolerability profile, and these encouraging results, what would Einstein have suggested? Probably a controlled, randomised clinical trial assessing the effect on clinical outcomes. Let's find out how this theory performs in practice.”