GlaxoSmithKline (GSK) today disclosed its second setback in six months for its Phase III prospect drug darapladip, acknowledging that the cardio candidate failed to meet its primary endpoint in a second late-stage clinical trial. 

In the study, Stabilisation Of pLaques usIng Darapladib – Thrombolysis In Myocardial Infarction 52 (SOLID-TIMI 52), darapladib did not achieve a reduction of major coronary events versus placebo when added to standard of care.

The primary endpoint measure in the SOLID-TIMI 52 study was time to first occurrence of any event from the composite of coronary heart disease death, heart attack and urgent coronary revascularisation for myocardial ischemia. GSK said full results of the SOLID-TIMI 52 study will be presented at a later scientific meeting, without giving details.

In SOLID-TIMI 52, darapladib was tested as a long-term therapy in patients within 30 days of an acute coronary syndrome. The randomized, placebo-controlled, double-blind, parallel group multi-center study enrolled more than 13,000 patients across 36 countries. The study design of SOLID-TIMI 52 was published in the October 2011 edition of the American Heart Journal.

The overall safety profile for darapladib showed no major safety concerns and was generally consistent with the safety data seen in the previously reported phase III study, STabilisation of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY).

In findings disclosed November 12, STABILITY also saw darapladip fail to meet a different primary endpoint—namely, time to first occurrence of any major adverse cardiovascular event from the composite of heart attack, stroke, and cardiovascular death (relative risk reduction of 6%; p=0.199). The result placed darapladip on GEN’s list of Top 10 Clinical Trial Failures of 2013.

However, GSK reported at the time that the STABILITY trial showed greater reductions in some pre-defined secondary endpoints that according to the company required further analysis. Providing that analysis was the purpose of SOLID-TIMI 52, the second of two event-driven phase III studies with darapladib in coronary heart disease.

Darapladip is an oral inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzyme that is found in blood and in atherosclerotic plaques. Elevated Lp-PLA2 activity has been implicated in the development and progression of atherosclerosis.

“We are disappointed that the outcome of this second phase III study with darapladib does not support a regulatory submission in atherosclerosis,” Patrick Vallance, GSK’s President of Pharmaceuticals R&D, said in a statement.

Vallance added that GSK has not thrown in the towel on darapladip: “We will now work to further analyze the data and better understand the findings.”

The second Phase III failure for darapladip appears to dash hopes of ever fulfilling predictions made as late as two years ago that the drug would crack the billion-dollar sales mark. Darapladip was “a blockbuster in the making,” declared H. Thomas Watkins in 2012 as then-CEO of Human Genome Sciences, whose collaboration with GSK on the drug helped lead to the pharma giant acquiring HGS later that year.

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