Positive Top-Line Results With Omecamtiv Mecarbil in HF, But Losmapimod Falters in ACS

October 27, 2015

THOUSAND OAKS, CA and LONDON, UK — Omecamtiv mecarbil (Amgen/Cytokinetics), an investigational cardiac myosin activator, significantly improved several markers of cardiac function in patients with heart failure, according to top-line results announced today[1].

In a study of 448 individuals with chronic heart failure with reduced ejection fraction, those treated with omecamtiv mecarbil 25 mg twice daily (or 50 mg twice daily) for 20 weeks had significant improvements in systolic ejection time, stroke volume, and N-terminal pro-brain natriuretic peptide (NT-proBNP), all of which were prespecified secondary end points.

The positive results are based on patients participating in the expansion phase of Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF), a study that included several secondary end points assessing cardiac function, such as changes in systolic ejection time, left ventricular end-diastolic diameter, left ventricular end-systolic diameter, heart rate, stroke volume, and NT-proBNP.

COSMIC-HF is primarily a phase 2 safety and tolerability study designed to assess the pharmacokinetics and pharmacodynamics of omecamtiv mecarbil. The dose-escalation phase of the trial was completed in 2013. The primary end point of the expansion study was an assessment of the maximum and predose plasma concentration of omecamtiv mecarbil.

Regarding adverse events, including serious adverse events, no safety signal was seen among patients treated with omecamtiv mecarbil when compared with patients treated with placebo. As in previous studies, there was a "small increase in troponin" among the omecamtiv mecarbil–treated patients. In the Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure (ATOMIC-AHF) study, reported by heartwire from Medscape, there was a numerical increase in MIs in the active-treatment arm vs the control arm, which investigators believed were mainly small, subclinical elevations in troponin. In this latest trial, an independent adjudication of the troponin elevations determined none of these to be MIs, according to Amgen and Cytokinetics.

Omecamtiv mecarbil is designed to increase contractility and is not currently approved for use. The full results of COSMIC-HF will be submitted for presentation at a medical meeting and for publication, according to the company.

Losmapimod Falters in Latitude

In other clinical-trial news, a study investigating the use of losmapimod (GlaxoSmithKline), an anti-inflammatory agent that inhibits p38, a mitogen-activated protein kinase associated with acute inflammation and cellular injury after acute coronary syndrome (ACS), appears to have run aground[2].

The LATITUDE-TIMI 60 study was designed as a trial in two parts. In reviewing part A of the study, which included 3503 ACS patients randomized to 3 months of losmapimod or placebo on top of standard care, investigators report the drug did not reduce the primary composite measure of cardiovascular death, MI, or recurrent ischemia requiring revascularization. As a result, the negative data do "not support investment in the larger part B of the study as currently designed," according to GlaxoSmithKline.

The company has not made a final decision on the drug's development, noting there was a statistically nonsignificant hint of benefit in STEMI patients, and plans to evaluate its options over the coming months. Part A of the LATITUDE trial will be submitted for publication and presentation.


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