Therapy Type: Small Molecule (timeline)
Target Type: Cholesterol
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: GlaxoSmithKline (GSK)
GSK2647544 is an inhibitor of lipoprotein-associated phospholipase A2. Lp-PLA2 is a circulating enzyme secreted by monocytes and linked primarily to low-density lipoprotein in atherosclerotic plaques. Lp-PLA2 generates proinflammatory and oxidative mediators such as lysophosphatidylcholine and oxidized fatty acids, which promote development of atherosclerotic lesions. Lp-PLA2 is considered a risk factor for cardiovascular disease and for vascular inflammation. Dysregulated lipid metabolism has been implicated in stroke and dementia. Some studies have linked Lp-PLA2 to risk for dementia, but other studies show no correlation between Lp-PLA2 plasma concentrations and clinical dementia status (Davidson et al., 2012, Adibhatla and Thatcher, 2008).
GSK began three Phase 1 studies with GSK2647544. Between October 2012 and April 2013, an initial safety study evaluated low doses of between 0.5 and 50 mg in 27 healthy volunteers. In August 2013, a small PET study began to assess brain penetrance of the compound, and in November 2013 another Phase 1 study began to evaluate escalating doses starting at 80 mg twice daily in young and elderly volunteers. GSK terminated both studies because low doses of GSK2647544 were found to inhibit the detoxifying liver enzyme cytochrome P450. GSK's February 2014 product pipeline still lists GSK2647544 as being in Phase 1 development for Alzheimer' disease. For all clinicial trials with GSK2647544 see clinicaltrials.gov.
GSK has another LP-PLA2 inhibitor, rilapladib, in Phase 2 development for Alzheimer's disease.
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- 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.