The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial

Summary

Background

Many patients with heart failure remain symptomatic and have a poor prognosis despite existing treatments. Decreases in myocardial contractility and shortening of ventricular systole are characteristic of systolic heart failure and might be improved by a new therapeutic class, cardiac myosin activators. We report the first study of the cardiac myosin activator, omecamtiv mecarbil, in patients with systolic heart failure.

Methods

We undertook a double-blind, placebo-controlled, crossover, dose-ranging, phase 2 trial investigating the effects of omecamtiv mecarbil (formerly CK-1827452), given intravenously for 2, 24, or 72 h to patients with stable heart failure and left ventricular systolic dysfunction receiving guideline-indicated treatment. Clinical assessment (including vital signs, echocardiograms, and electrocardiographs) and testing of plasma drug concentrations took place during and after completion of each infusion. The primary aim was to assess safety and tolerability of omecamtiv mecarbil. This study is registered at ClinicalTrials.gov, NCT00624442.

Findings

45 patients received 151 infusions of active drug or placebo. Placebo-corrected, concentration-dependent increases in left ventricular ejection time (up to an 80 ms increase from baseline) and stroke volume (up to 9·7 mL) were recorded, associated with a small reduction in heart rate (up to 2·7 beats per min; p<0·0001 for all three measures). Higher plasma concentrations were also associated with reductions in end-systolic (decrease of 15 mL at >500 ng/mL, p=0·0026) and end-diastolic volumes (16 mL, p=0·0096) that might have been more pronounced with increased duration of infusion. Cardiac ischaemia emerged at high plasma concentrations (two patients, plasma concentrations roughly 1750 ng/mL and 1350 ng/mL). For patients tolerant of all study drug infusions, no consistent pattern of adverse events with either dose or duration emerged.

Interpretation

Omecamtiv mecarbil improved cardiac function in patients with heart failure caused by left ventricular dysfunction and could be the first in class of a new therapeutic agent.

Funding

Cytokinetics Inc.

Introduction

For many patients, treatment of heart failure remains unsatisfactory. Available treatments that are aimed at diverse targets including sodium retention, arterial and venous constriction, neuroendocrine activation, increased heart rate, cardiac dyssynchrony, and arrhythmias often fail to control symptoms or restore quality of life.¹ Moreover, morbidity and mortality remains high in this population. Another target for treatment of heart failure due to reduced left ventricular systolic function is to improve myocardial contractility, although realisation of this goal remains elusive. Inotropic agents increase the velocity and force of contraction but do not increase, and in fact usually shorten, the duration of systole.² Cardiac myosin activators are a new mechanistic class designed specifically to increase myocardial contractility; by contrast with existing inotropic drugs, they instead increase the duration of systole (systolic ejection time) without changing the rate of left ventricular pressure development, thereby increasing stroke volume and cardiac output.3, 4

In systolic heart failure, the reasons for reduced myocardial contractility are complex and include the loss of cardiac myocytes, changes in the extracellular matrix, reduced availability of high energy substrates such as ATP and creatinine phosphate,⁵ impaired calcium recycling,⁶ and myofilament abnormalities.⁷ Within the myofilament, cardiac myosin is central to myocardial contractility. During myocardial contraction, myosin forms cross-bridges with actin. Initially weakly bound to the actin filament, transition to a strongly bound cross-bridge state is needed for myosin to undergo a force-generating power stroke. As described in the companion paper,⁸ cardiac myosin activators increase the transition rate from the weakly bound to the strongly bound force-generating state,³ increasing myocardial contraction. In preclinical studies, cardiac myosin activators increased myocardial contraction and stroke volume without increasing oxygen consumption, thereby increasing myocardial efficiency.⁴

The cardiac myosin activator omecamtiv mecarbil has been studied in healthy volunteers in whom it produced dose-dependent and concentration-dependent increases in systolic ejection time, fractional shortening, and ejection fraction.⁸ We report the first study of omecamtiv mecarbil given intravenously to patients with systolic heart failure. We aimed to assess the drug's safety and tolerability and define a range of pharmacodynamically active, well tolerated target plasma concentrations for later trials.