A novel drug that activates a protein that increases the contraction of heart muscle could lead to a new approach to treating systolic heart failure (SHF), a condition characterised by the inability of the heart to contract strongly enough. The results of the first two clinical studies involving the drug omecamtiv mecarbil, published in a special European Society of Cardiology issue of The Lancet, suggest that it could be a promising treatment for SHF, which currently affects about 20 million people in the USA and Europe and leads to at least 4 million admissions to hospital each year.
Omecamtiv mecarbil was designed by a team lead by Fady Malik from Cytokinetics Inc, South San Francisco, USA, to activate cardiac myosin, a motor protein in heart muscle cells that generates the force required for heart muscle to contract. In preclinical studies, omecamtiv mecarbil improved the strength of each heart muscle contraction, increasing the duration of the contraction and the volume of blood moved, without increasing oxygen consumption. But until now, whether this unique mechanism could be translated into humans was not known.
Currently used inotropic drugs (that alter the force of muscular contractions) improve contractility by increasing the concentration of calcium inside cells, which accelerates the speed of contraction but shortens systolic ejection time and can cause potentially life-threatening side effects such as abnormal heart rhythms and myocardial ischemia (restricted oxygen-rich blood flow to the heart muscle).
John Teerlink from San Francisco Veterans Affairs Medical Center, San Francisco, USA and colleagues report the first trial of omecamtiv mecarbil in humans which was designed to establish the maximum tolerated dose and demonstrate an effect in people. Omecamtiv mecarbil or placebo was given once a week as a 6-hour intravenous infusion to 34 healthy men for 4 weeks. Each sequence consisted of three ascending omecamtiv mecarbil doses (ranging from 0.005 to 1.0 mg/kg per hour) and a placebo infusion.
The maximum tolerated dose was 0.5 mg/kg per hour. Omecamtiv mecarbil increased stroke volume (the volume of blood pumped by the heart with each beat), ejection fraction (measurement of the strength the heart has on contraction) and fractional shortening (measurement of the left ventricle's overall effectiveness during contractions) compared with placebo. Increases in systolic ejection time and systolic function were directly proportional to escalating doses in omecamtiv mecarbil, with no significant adverse effects reported in doses up to 0.625 mg/kg per hour.
The authors say: "This study provides the first clinical evidence for the translation into human beings of a novel mechanism to directly improve cardiac function, namely cardiac myosin activation…and supports potential clinical use of the drug in patients with heart failure."
In the first study of omecamtiv mecarbil in heart failure patients, a team led by John Cleland from University of Hull, East Yorkshire, UK conducted a phase 2 trial to investigate the effects of omecamtiv mecarbil given intravenously over 2, 24, or 72 hours to 45 patients with stable heart failure who were already receiving standard treatment.
Omecamtiv mecarbil gave a significant dose-dependent increase in several measures of the heart's pumping function including increasing the duration of systole, stroke volume, and ejection fraction. A significant association between improving systolic function and increasing plasma concentration was also noted.
The authors say: "Omecamtiv mecarbil has dose-dependent and concentration-dependent effects on cardiac function that appear in plasma concentrations that are well tolerated by patients with stable chronic heart failure."
They conclude: "Further studies are needed to establish whether the observed effects on cardiac function translate into benefits on symptoms, quality of life, exercise capacity, morbidity, or mortality."
In a Comment, Kenneth Dickstein from the University of Bergen, Stavanger University Hospital, Stavanger, Norway says: "The data presented in these two papers supports further investigation of omecamtiv mecarbil's therapeutic role in appropriate patients." But, he adds: "Very few new agents have survived the most rigorous test, the randomised clinical trial assessing clinical outcomes…Let's find out how this theory performs in practice."
Professor John Teerlink, San Francisco Veterans Affairs Medical Center, San Francisco, USA. T) +1 415 221 4810 Ext 4160 E) john.teerlink@ucsf.edu
Professor John Cleland, University of Hull, East Yorkshire, UK. T) +44 (0) 1482 46 1780 or +44(0)7968837047 (mobile) E) j.g.cleland@hull.ac.uk
Professor Kenneth Dickstein, University of Bergen, Stavanger University Hospital, Stavanger Norway. E) Kenneth.dickstein@med.uib.no
Journal
The Lancet