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NEWS & ANALYSIS
Anthony Lynn/Alamy
GSKs darapladib failures dim hopes for anti-inflammatory heart drugs
New approaches to target inflammation in atherosclerosis remain elusive, as a potential firstinclass drug fails in two mega trials.
AsherMullard
The recent failures of two PhaseIII trials of GlaxoSmithKline (GSK)s darapladib an oral inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2) are bad news for anti-inflammatory atherosclerosis drug research.
In March, the treatment missed its primary end point a reduction in the risk of cardiovascular death, heart attack or stroke in the STABILITY trial, in over 15,000 patients with chronic coronary heart disease (http://www.nejm.org/doi/full/10.1056/NEJMoa1315878
Web End =N. Engl. J. Med. 370, 17021711; http://www.nejm.org/doi/full/10.1056/NEJMoa1315878
Web End =2014 ). In May, top-line results showed that the drug also missed its primary end point reduction in coronary heart disease death, heart attack or urgent coronary revascularization in the 13,000-patient SOLID-TIMI52 trial in acute coronary syndrome.
I wasnt that surprised by these failures, says Robert Rosenson,a cardiologist at the Mount Sinai Hospital in New York, who was not
involved in either trial. Preclinical, clinical and genetic data suggested that the writing was on the wall, he explains. I dont think the lid is completely closed on the coffin, but it is most of the way down and falling quickly, headds.
STABILITY investigator Lars Wallentin, a cardiologist at Uppsala University in Sweden, holds out more hope, based largely on a nominally significant lower rate of major coronary events, a secondary end point in the STABILITY trial. Our speculation is that maybe we didnt focus enough on the coronary events, he says. Biomarker data and a paired companion diagnostic could still save the drug, he says. But it is likely that another trial would be needed to verify any retrospective findings, headds.
Caveats included
Although agents that lower low-density lipoprotein (LDL) cholesterol in particular statins have transformed the management
of atherosclerosis, this therapeutic avenue is nearly tapped out. Drug developers consequently started turning their attention years ago to the inflammatory component of atherosclerosis, an aspect of the disease that has not been directly targeted asyet.
Lp-PLA2, a pro-inflammatory lipid-modifying enzyme that researchers first cloned and characterized in 1994 (http://www.nature.com/nature/journal/v374/n6522/abs/374549a0.html
Web End =Nature 374, http://www.nature.com/nature/journal/v374/n6522/abs/374549a0.html
Web End =549553; 1994 ), was one of the lead anti-inflammatory atherosclerosis drug targets....