title: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Cytokinetics Inc.
authors.affiliation: Department of Cardiology, Hull York Medical School, University of Hull, Hull, UK. j.g.cleland@hull.ac.uk
authors.forename: John G F
authors.initials: JG
authors.lastname: Cleland
authors.forename: John R
authors.initials: JR
authors.lastname: Teerlink
authors.forename: Roxy
authors.initials: R
authors.lastname: Senior
authors.forename: Evgeny M
authors.initials: EM
authors.lastname: Nifontov
authors.forename: John J V
authors.initials: JJ
authors.lastname: Mc Murray
authors.forename: Chim C
authors.initials: CC
authors.lastname: Lang
authors.forename: Vitaly A
authors.initials: VA
authors.lastname: Tsyrlin
authors.forename: Barry H
authors.initials: BH
authors.lastname: Greenberg
authors.forename: Jamil
authors.initials: J
authors.lastname: Mayet
authors.forename: Darrel P
authors.initials: DP
authors.lastname: Francis
authors.forename: Tamaz
authors.initials: T
authors.lastname: Shaburishvili
authors.forename: Mark
authors.initials: M
authors.lastname: Monaghan
authors.forename: Mitchell
authors.initials: M
authors.lastname: Saltzberg
authors.forename: Ludwig
authors.initials: L
authors.lastname: Neyses
authors.forename: Scott M
authors.initials: SM
authors.lastname: Wasserman
authors.forename: Jacqueline H
authors.initials: JH
authors.lastname: Lee
authors.forename: Khalil G
authors.initials: KG
authors.lastname: Saikali
authors.forename: Cyril P
authors.initials: CP
authors.lastname: Clarke
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Goldman
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Wolff
authors.forename: Fady I
authors.initials: FI
authors.lastname: Malik
mesh_terms: D001794:Blood Pressure / Q000187:drug effects; D024722:Cardiac Myosins / Q000378:metabolism*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004452:Echocardiography; D005260:Female; D054143:Heart Failure, Systolic / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D013318:Stroke Volume / Q000187:drug effects; D013599:Systole / Q000187:drug effects; D014508:Urea / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D018487:Ventricular Dysfunction, Left / Q000150:complications / Q000503:physiopathology
chemical_list: C547293:omecamtiv mecarbil; D014508:Urea; D024722:Cardiac Myosins