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.

Abstract

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.

• Authors: John G F Cleland, John R Teerlink, Roxy Senior, Evgeny M Nifontov, John J V Mc Murray, Chim C Lang, Vitaly A Tsyrlin, Barry H Greenberg, Jamil Mayet, Darrel P Francis, Tamaz Shaburishvili, Mark Monaghan, Mitchell Saltzberg, Ludwig Neyses, Scott M Wasserman, Jacqueline H Lee, Khalil G Saikali, Cyril P Clarke, Jonathan H Goldman, Andrew A Wolff, Fady I Malik
• Journal: Lancet (London, England) (Lancet) Vol. 378 Issue 9792 Pg. 676-83 (Aug 20 2011) ISSN: 1474-547X [Electronic] England
• PMID: 21856481 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• omecamtiv mecarbil
• Urea
• Cardiac Myosins

Topics

• Blood Pressure (drug effects)
• Cardiac Myosins (metabolism)
• Cross-Over Studies
• Double-Blind Method
• Echocardiography
• Female
• Heart Failure, Systolic (diagnostic imaging, drug therapy, physiopathology)
• Humans
• Infusions, Intravenous
• Male
• Stroke Volume (drug effects)
• Systole (drug effects)
• Urea (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics, therapeutic use)
• Ventricular Dysfunction, Left (complications, physiopathology)