Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study.

Abstract

BACKGROUND:

Decreased systolic function is central to the pathogenesis of heart failure in millions of patients worldwide, but mechanism-related adverse effects restrict existing inotropic treatments. This study tested the hypothesis that omecamtiv mecarbil, a selective cardiac myosin activator, will augment cardiac function in human beings.

METHODS:

In this dose-escalating, crossover study, 34 healthy men received a 6-h double-blind intravenous infusion of omecamtiv mecarbil or placebo once a week for 4 weeks. Each sequence consisted of three ascending omecamtiv mecarbil doses (ranging from 0·005 to 1·0 mg/kg per h) with a placebo infusion randomised into the sequence. Vital signs, blood samples, electrocardiographs (ECGs), and echocardiograms were obtained before, during, and after each infusion. The primary aim was to establish maximum tolerated dose (the highest infusion rate tolerated by at least eight participants) and plasma concentrations of omecamtiv mecarbil; secondary aims were evaluation of pharmacodynamic and pharmacokinetic characteristics, safety, and tolerability. This study is registered at ClinicalTrials.gov, number NCT01380223.

FINDINGS:

The maximum tolerated dose of omecamtiv mecarbil was 0·5 mg/kg per h. Omecamtiv mecarbil infusion resulted in dose-related and concentration-related increases in systolic ejection time (mean increase from baseline at maximum tolerated dose, 85 [SD 5] ms), the most sensitive indicator of drug effect (r(2)=0·99 by dose), associated with increases in stroke volume (15 [2] mL), fractional shortening (8% [1]), and ejection fraction (7% [1]; all p<0·0001). Omecamtiv mecarbil increased atrial contractile function, and there were no clinically relevant changes in diastolic function. There were no clinically significant dose-related adverse effects on vital signs, serum chemistries, ECGs, or adverse events up to a dose of 0·625 mg/kg per h. The dose-limiting toxic effect was myocardial ischaemia due to excessive prolongation of systolic ejection time.

INTERPRETATION:

These first-in-man data show highly dose-dependent augmentation of left ventricular systolic function in response to omecamtiv mecarbil and support potential clinical use of the drug in patients with heart failure.

FUNDING:

Cytokinetics Inc.

• Authors: John R Teerlink, Cyril P Clarke, Khalil G Saikali, Jacqueline H Lee, Michael M Chen, Rafael D Escandon, Lyndsey Elliott, Rachel Bee, Mohammad Reza Habibzadeh, Jonathan H Goldman, Nelson B Schiller, Fady I Malik, Andrew A Wolff
• Journal: Lancet (London, England) (Lancet) Vol. 378 Issue 9792 Pg. 667-75 (Aug 20 2011) ISSN: 1474-547X [Electronic] England
• PMID: 21856480 (Publication Type: Journal Article, 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

• Adult
• Cardiac Myosins (metabolism)
• Cross-Over Studies
• Dose-Response Relationship, Drug
• Double-Blind Method
• Humans
• Infusions, Intravenous
• Male
• Maximum Tolerated Dose
• Middle Aged
• Myocardial Contraction (drug effects)
• Stroke Volume (drug effects)
• Systole (drug effects)
• Urea (administration & dosage, analogs & derivatives, pharmacokinetics, pharmacology)
• Ventricular Function, Left (drug effects)
• Young Adult