Therapy Type: Small Molecule
Target Type: Other
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: GlaxoSmithKline (GSK)
Rilapladib is an inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2). Also known as plasma platelet-activating factor actetyl hydrolyse, this enzyme is released into the blood by monocytes/macrophages. Lp-PLA2 can have pro-inflammatory and oxidative properties; it is associated with LDL cholesterol and linked to the formation of atherosclerotic plaques. Rilapladib was originally developed for atherosclerosis, but GSK discontinued this indication in Phase 2.
Lp-PLA2 drew interest as a target in Alzheimer's disease when research into the brain's lipid metabolism identified it as a potential factor in cerebrovascular oxidative stress and inflammation. Some studies implicated Lp-PLA2 produced locally in vascular plaques with endothelial dysfunction (Lavi et al., 2007; Adibhatla and Hatcher, 2008).
The epidemiological evidence is mixed. Some studies have linked Lp-PLA2 to increased risk for ischemic stroke and developing dementia (Oei et al., 2005; van Oijen et al., 2006; Fitzpatrick et al., 2014). However, the Framingham Heart Study was unable to associate Lp-PLA with risk for dementia, or with microbleeds as indicators of cerebral amyloid angiopathy (van Himbergen et al., 2012; Romero et al., 2012). Genetic association studies of Lp-PLA2 have been largely negative.
A case-control study of cognitively normal and cognitively impaired people reported no association between plasma Lp-PLA2 levels and cognition (Davidson et al., 2012).
In October 2011, GSK started enrolling 124 people with mild to moderate Alzheimer's disease into a Phase 2 study comparing 250 mg of rilapladib taken once daily to placebo. This study primarily evaluated rilapladib's effect on CSF Aβ and tau biomarkers, as well as on a composite score of working memory and executive function. The study ended in February 2013 but results have not been reported yet.
Since then, GSK has not yet initiated a larger Phase 2 or Phase 3 trial. However, the company has listed a small Phase 1 study to start enrolling 30 healthy volunteers in September 2014. This study will look at pharmacokinetics and elimination of rilapladib, and separately at the effect of the antifungal drug itraconazole on rilapladib.
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