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Nov 12, 2013

GSK Heart Disease Compound Disappoints in Phase III

  • GlaxoSmithKline (GSK) said today its investigational lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor darapladib failed to meet its primary endpoint in the Phase III STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial, which assessed the drug candidate’s efficacy in adults with chronic coronary artery disease.

    Darapladib failed to meet its primary endpoint, namely time to first occurrence of any major adverse cardiovascular event (MACE) from the composite of myocardial infarction, stroke, and cardiovascular death.

    The drug candidate delivered a relative risk reduction of 6%—but yielded greater reductions in some secondary endpoints that GSK said will require further study. STABILITY’s key secondary endpoints included major coronary events, total coronary events, individual components of MACE, and all-cause mortality.

    According to GSK, darapladib’s overall safety profile showed no major imbalance in serious adverse events between treatment and placebo patients. Frequently reported adverse events included diarrhea and odor, both occurring at similar frequencies to that seen in Phase II. The company said further analysis of the adverse-effects data is ongoing.

    “Given the level of patient need in this area, we continue to investigate the role of Lp-PLA2 inhibition in coronary heart disease and other diseases,” Patrick Vallance, GSK’s president of pharmaceuticals R&D, said in a statement. “We will now work to better understand the data, including evaluation of the patient subgroups, and await the outcome of a second Phase III study of darapladib in acute coronary syndrome, called SOLID-TIMI 52, to determine our next steps.”

    Full results of the STABILITY study will be submitted for presentation at a scientific meeting in 2014, while additional data from SOLID-TIMI 52 “will be forthcoming,” according to GSK.

    In the STABILITY trial, patients were randomized to receive either 160 mg darapladib or placebo in addition to “standard of care” that could include a statin, aspirin, and blood pressure medications. The study enrolled more than 15,000 patients across 39 countries, and continued until 1,500 major adverse cardiovascular events had occurred.

    SOLID-TIMI 52—which is ongoing and expected to finish in 2014—has enrolled over 13,000 patients in 36 countries in a study designed to assess the efficacy of darapladib in patients with acute coronary syndrome.

    Darapladib is designed to work by inhibiting the enzyme Lp-PLA2 found in blood and in atherosclerotic plaques, since elevated Lp-PLA2 activity has been linked with the development and progression of atherosclerosis.

    Darapladib is one of three GSK in-house or partnered compounds to disappoint in late-stage trials over recent weeks. In September, the company said its in-house cancer vaccine MAGE-A3 failed its first co-primary endpoint in the Phase III DERMAi trial of 1,345 melanoma patients by showing no statistically significant extension of disease-free survival compared with placebo.

    Also that month, GSK and Prosensa said their partnered investigational drug drisapersen for Duchenne muscular dystrophy missed its Phase III primary endpoint of statistically significant improvement in the six-minute walking distance test compared to placebo.



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