Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
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.
- Lavi S, McConnell JP, Rihal CS, Prasad A, Mathew V, Lerman LO, Lerman A. Local production of lipoprotein-associated phospholipase A2 and lysophosphatidylcholine in the coronary circulation: association with early coronary atherosclerosis and endothelial dysfunction in humans. Circulation. 2007 May 29;115(21):2715-21. Epub 2007 May 14 PubMed.
- Adibhatla RM, Hatcher JF. Altered lipid metabolism in brain injury and disorders. Subcell Biochem. 2008;49:241-68. PubMed.
- Oei HH, van der Meer IM, Hofman A, Koudstaal PJ, Stijnen T, Breteler MM, Witteman JC. Lipoprotein-associated phospholipase A2 activity is associated with risk of coronary heart disease and ischemic stroke: the Rotterdam Study. Circulation. 2005 Feb 8;111(5):570-5. PubMed.
- van Oijen M, van der Meer IM, Hofman A, Witteman JC, Koudstaal PJ, Breteler MM. Lipoprotein-associated phospholipase A2 is associated with risk of dementia. Ann Neurol. 2006 Jan;59(1):139-44. PubMed.
- Fitzpatrick AL, Irizarry MC, Cushman M, Jenny NS, Chi GC, Koro C. Lipoprotein-associated phospholipase A2 and risk of dementia in the Cardiovascular Health Study. Atherosclerosis. 2014 Aug;235(2):384-91. Epub 2014 May 22 PubMed.
- van Himbergen TM, Beiser AS, Ai M, Seshadri S, Otokozawa S, Au R, Thongtang N, Wolf PA, Schaefer EJ. Biomarkers for Insulin Resistance and Inflammation and the Risk for All-Cause Dementia and Alzheimer Disease: Results From the Framingham Heart Study. Arch Neurol. 2012 May 1;69(5):594-600. PubMed.
- Romero JR, Preis SR, Beiser AS, DeCarli C, Lee DY, Viswanathan A, Benjamin EJ, Fontes J, Au R, Pikula A, Wang J, Kase CS, Wolf PA, Irrizary MC, Seshadri S. Lipoprotein phospholipase A2 and cerebral microbleeds in the Framingham Heart Study. Stroke. 2012 Nov;43(11):3091-4. Epub 2012 Sep 6 PubMed.
- Davidson JE, Lockhart A, Amos L, Stirnadel-Farrant HA, Mooser V, Sollberger M, Regeniter A, Monsch AU, Irizarry MC. Plasma lipoprotein-associated phospholipase A2 activity in Alzheimer's disease, amnestic mild cognitive impairment, and cognitively healthy elderly subjects: a cross-sectional study. Alzheimers Res Ther. 2012 Dec 7;4(6):51. PubMed.
- Shaddinger BC, Xu Y, Roger JH, Macphee CH, Handel M, Baidoo CA, Magee M, Lepore JJ, Sprecher DL. Platelet aggregation unchanged by lipoprotein-associated phospholipase A₂ inhibition: results from an in vitro study and two randomized phase I trials. PLoS One. 2014;9(1):e83094. Epub 2014 Jan 27 PubMed.
- Tawakol A, Singh P, Rudd JH, Soffer J, Cai G, Vucic E, Brannan SP, Tarka EA, Shaddinger BC, Sarov-Blat L, Matthews P, Subramanian S, Farkouh M, Fayad ZA. Effect of treatment for 12 weeks with rilapladib, a lipoprotein-associated phospholipase A2 inhibitor, on arterial inflammation as assessed with 18F-fluorodeoxyglucose-positron emission tomography imaging. J Am Coll Cardiol. 2014 Jan 7-14;63(1):86-8. Epub 2013 Aug 21 PubMed.
- Magrioti V, Kokotos G. Phospholipase A2 inhibitors for the treatment of inflammatory diseases: a patent review (2010--present). Expert Opin Ther Pat. 2013 Mar;23(3):333-44. Epub 2013 Jan 8 PubMed.
- Moutzouri E, Tsimihodimos V, Tselepis AD. Inflammatory biomarkers and cardiovascular risk assessment. Current knowledge and future perspectives. Curr Pharm Des. 2013;19(21):3827-40. PubMed.
- Gattaz WF, Talib LL, Schaeffer EL, Diniz BS, Forlenza OV. Low platelet iPLA2 activity predicts conversion from mild cognitive impairment to Alzheimer's disease: a 4-year follow-up study. J Neural Transm. 2013 Sep 15; PubMed.