Mixed results from Phase II trial of the anti-inflammatory drug candidate losmapimod prompt pivotal study in heart attack patients.

The lowdown: GlaxoSmithKline (GSK) is moving a small-molecule inhibitor of the p38 mitogen-activated protein kinase (MAPK) α- and β-isoforms forward for the short-term treatment of acute coronary syndrome on the basis of mixed results from a Phase II trial (Lancet; 13 Jun 2014). In the trial in 526 patients with non-ST-segment elevation myocardial infarction, losmapimod missed the primary end points of inflammation (assessed by concentrations of C-reactive protein (CRP) at 12 weeks) and infarct size. “In retrospect ... we might have expected that serum concentrations of [CRP] ... would normalise by week 12 and that this timepoint would provide an insensitive signal of biological activity,” the authors write. Efficacy signals on CRP at 72 hours, B-type natriuretic peptide (BNP) at 12 weeks, and imaging measures of left ventricular function and end-diastolic and end-systolic volumes led the authors to conclude that treatment “might improve outcomes after acute coronary syndromes”. They add that losmapimod and related compounds have also been associated with reduced circulating markers of inflammation and vascular inflammation in trials in other cardiovascular indications.

Many other drug developers have been stumped on the p38 MAPK front because of intolerable liver, skin and neurological adverse events (Nature Rev. Drug Discov. 8, 480–499; 2009). GSK's latest results do not show any major liver or other safety signals, although there were numerical yet statistically insignificant increases in alanine aminotransferase (ALT) concentrations that were three or more times the upper limit of normal (ULN), serum creatinine concentrations at 12 weeks and adverse events leading to study drug termination with losmapimod treatment.

A Phase III trial will now randomize 25,500 patients who have presented with acute coronary syndrome (specifically, a heart attack) to twice-daily oral treatment with losmapimod or placebo for 3 months. The primary end point is the composite measure of time to first occurrence of cardiovascular death, myocardial infarction or severe recurrent ischaemia requiring urgent coronary artery revascularization. The study should be completed in December 2018.

Losmapimod is the only p38 MAPK inhibitor in development for acute coronary syndrome. Array's ARRY-797 is in Phase II development for congestive heart failure.

The news came less than a month after GSK reported that its anti-inflammatory candidate darapladib — an inhibitor of lipoprotein-associated phospholipase A2 — had failed in a Phase III acute coronary syndrome trial (see page 481).