A unique drug that activates a protein to increase the contraction of heart muscle could lead to a new approach for the treatment of systolic heart failure (SHF), a condition characterized by the inability of the heart to contract strongly enough.
According to a publication in a special European Society issue of The Lancet, results of the first two clinical studies of the drug omecamtiv mecarbil, suggest that it could be a promising treatment for SHF, a condition currently affecting about 20 million people in the USA and Europe, which leads to at least 4 million hospital admissions each year.
A team led by Fady Malik from Cytokinetics Inc. in South San Francisco, USA, developed omecamtiv mecarbil, a drug that activates cardiac myosin, a motor protein in heart muscle cells that generates the force required for heart muscle to contract. Pre-clinical studies confirmed that 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. Until today it wasn’t known if this unique mechanism could be applied to humans.
Inotropic drugs (that alter the force of muscular contractions) used at present, improve contractility, by increasing the concentration of calcium inside cells, accelerating the speed of contraction but shortening 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 in San Francisco, USA and his colleagues conducted the first trial of omecamtiv mecarbil in humans, which was designed to establish the maximum tolerated dose and demonstrate an effect in people.
The trial was conducted on 34 healthy men, who received omecamtiv mecarbil or placebo once a week as a 6-hour intravenous infusion for a 4-week duration. 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 determined maximum tolerated dose was 0.5 mg/kg per hour. Research showed, that 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 a rising dosage of omecamtiv mecarbil, with no significant adverse effects noted in doses up to 0.625 mg/kg per hour.
The authors comment:
“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, team-leader John Cleland from the University of Hull in East Yorkshire, UK carried out a phase 2 trial to evaluate the effects of omecamtiv mecarbil given intravenously. The study involved 45 patients with stable heart failure, already in standard treatment, receiving omecamtiv mecarbil intravenously over 2, 24, or 72 hours.
Results showed that 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. Researchers also noted an important link between improving systolic function and increasing plasma concentration.
The authors’ comment:
“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.”
Their concluding statement said that further studies are required to establish whether the observed effects on cardiac function translate into benefits on symptoms, quality of life, exercise capacity, morbidity, or mortality.
Kenneth Dickstein, from the University of Bergen at the Stavanger University Hospital in Stavanger, Norway says in a comment: “The data presented in these two papers supports further investigation of omecamtiv mecarbil’s therapeutic role in appropriate patients.” He continued to add, “Very few new agents have survived the most rigorous test, the randomized clinical trial assessing clinical outcomes…Let’s find out how this theory performs in practice.”
Written by Petra Rattue