Heart failure – omecamtiv mecarbil

Published: 9-Sep-2010

Up to half of all patients with acute heart failure are likely to be readmitted to hospital within the year; half are also likely to die within five years

Heart failure is caused by any of a number of problems with the heart’s structure and function interfering with the ventricle’s capability to fill with and pump out blood. Up to half of all patients with acute heart failure are likely to be readmitted to hospital within the year; half are also likely to die within five years.

A collection of drugs is usually given to treat the symptoms, such as diuretics to preserve renal function, and inotropic agents like dobutamine and milrinone to increase cardiac contractility. However, they are also associated with an increase in mortality, so safer inotropic agents are much needed.

Omecamtiv mecarbil1 is being developed by Cytokinetics in collaboration with Amgen. It is a cardiac myosin activator that increases the systolic ejection time without affecting myo-cardial oxygen, and several clinical trials have been carried out. In one double blind, randomised, placebo-controlled, dose escalating Phase IIa trial to evaluate safety and tolerability, the drug was given by intravenous infusion to a total of 45 patients with heart failure who were already receiving a stable regimen of drug treatment.2

During four treatment periods, they were given three escalating infusions of active doses plus a placebo infusion randomised into the escalation sequence. These were given as a loading dose to achieve the desired plasma concentration, the highest of which was 650ng/ml, then slower infusions to maintain that concentration.

The drug gave a dose dependent significant increase in systolic ejection time, cardiac output, fractional shortening and left ventricular ejection fraction. There was also a statistically significant correlation between the increase in plasma concentration and increase in systolic function.

In another double blind, randomised placebo-controlled trial in 90 patients, the drug’s effect on symptom limited exercise tolerance in heart failure patients with ischaemic cardiomyopathy and angina was evaluated.3 The patients were divided into two cohorts, in each of which two-thirds were given the active.

A loading dose was given by intravenous infusion over 20 hours, up to a plasma concentration of 295ng/ml in one cohort and 550 in the second, followed by seven days of oral dosing to maintain the concentration. Both doses gave a symptomatic improvement, and at concentrations that increase cardiac function there was no negative impact on a broad range of safety assessments. Trials continue.

references

1. H.M. Rodriguez et al. 51st Ann. Meet. Biophys. Soc. (March 3–7, Baltimore) 2007, Abst 2295-Pos

2. R. Senior et al. J. Am. Col. Cardio. 2009, 53 (Suppl. A),

A-160

3. B.H. Greenberg et al. J. Cardiac Failure 2009, 15

(6, Suppl.), S67

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