Our understanding of the role that inflammation plays in the formation, progression and rupture of atherosclerotic plaques has increased considerably in recent years. Indeed, drug therapies that specifically modulate oxidation, inflammation and other pathways underlying atherosclerosis prior to plaque rupture are key targets for drug developers. Key inflammation-related targets under investigation include: the proinflammatory enzymes lipoprotein-associated phospholipase A2 (Lp-PLA2) and secretory phospholipase A2 (sPLA2); the proinflammatory cytokine interleukin-1 (IL-1); and components of the leukotriene biosynthesis pathway.

On November 12, 2013, GSK announced top-line results from its Phase III STABILITY trial (NCT00799903), evaluating its investigational Lp-PLA2 inhibitor, darapladib, in more than 15,000 chronic coronary heart disease (CHD) patients. The study failed to meet the primary end point: time to first occurrence of any major adverse cardiovascular event (MACE) from the composite of myocardial infarction, stroke and cardiovascular death (relative risk reduction of 6%; p=0.199). The drug showed no major imbalance in terms of serious adverse events compared with placebo. Full results are expected next year.

The failure of darapladib in STABILITY has not come as a shock to some thought leaders interviewed by Decision Resources who question Lp-PLA2 as a viable target. Some also call into question the targeting of these proinflammatory enzymes, pointing to the failure of Anthera Pharmaceutical's sPLA2 inhibitor varespladib in its VISTA-16 Phase III trial in acute coronary syndrome (ACS) patients, which was discontinued in March 2012. However, most interviewed thought leaders do not believe that the termination of VISTA-16 is indicative of darapladib's prospects, stating that the duration of therapy (16 weeks) and the patient population size (5,000 patients) in varespladib's trial were too limited to show any effect. They also believe the targets to be sufficiently different for darapladib to avoid the reported elevated risk of MACE in patients treated with varespladib (recently reported at the AHA conference in Dallas, TX). Furthermore, the results from STABILITY demonstrate the difficulty in proving efficacy in the chronic CHD population, where event rates are low and large patient numbers and long trials are needed to reveal significant differences between treatment groups.

Along with the full findings of STABILITY, we are keen to explore which sub-populations demonstrated the greatest reduction in primary and secondary end points, data which should be revealed next year. In 2014, we should also see the reporting of results for the second Phase III study of darapladib in 13,000 ACS patients, called SOLID-TIMI 52 (NCT01000727), as well as the integrated analysis of both Phase III trials (NCT01636271). With a higher risk population (ACS patients) providing for a greater number of events, we expect the small benefits seen in STABILITY to be more pronounced in SOLID-TIMI 52. Thus, as previously forecast by Decision Resources, combined data from STABILITY and SOLID-TIMI 52 should provide GSK with a platform to file for approval of darapladib in secondary prevention in the post-ACS population.

Senior Analyst Graeme Green and Senior Director Conor Walsh are part of the Cardiovascular, Metabolic and Renal Disorders team at Decision Resources Group.

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