A 24‐week study to evaluate the effect of rilapladib on cognition and cerebrospinal fluid biomarkers of Alzheimer's disease

Alzheimer's and Dementia: Translational Research and Clinical Interventions - Tập 1 - Trang 131-140 - 2015
Gareth Maher-Edwards1, Jeni De'Ath1, Carly Barnett1, Arseniy Lavrov1, Andrew Lockhart2
1Neurosciences, GlaxoSmithKline, Uxbridge, Middlesex, UK
2Neurosciences, GlaxoSmithKline, Clinical Unit Cambridge, Addenbrooke's Hospital, Cambridge, UK

Tóm tắt

AbstractBackgroundThe lipoprotein‐associated phospholipase A2 inhibitor (Lp‐PLA2), rilapladib (SB659032), is being evaluated as a potential treatment to slow the progression of Alzheimer's disease (AD).MethodsOne hundred twenty‐four subjects with possible mild AD and with neuroimaging evidence of cerebrovascular disease were randomized to placebo or 250‐mg rilapladib once daily, for 24 weeks, in addition to stable background acetylcholinesterase inhibitor and/or memantine. The study assessed the safety and tolerability of rilapladib and its effects on cognition, mechanistic, and disease‐related biomarkers. Although the overall intent behind the study was to take a broad exploratory view of the data, two primary end points of interest (cerebrospinal fluid [CSF] amyloid beta peptide 1–42 [Aβ1–42] and CogState executive function/working memory [EF/WM] composite score at week 24) were prespecified in the analysis plan for inferential statistical analysis.ResultsRilapladib was well tolerated with no significant safety concerns. A significant difference from placebo was observed for rilapladib on change from baseline in EF/WM (effect size, 0.45; P = .026). There was no significant difference between groups on the change from baseline in CSF Aβ1–42 (P = .133). Preliminary evidence of effects was detected on other mechanistic (albumin quotient) and disease‐related biomarkers (tau/P‐tau and neurofilament light chain).ConclusionThese data provide initial evidence supporting Lp‐PLA2 inhibition as a novel treatment for dementia.Clinical Trial RegistrationClinicaltrials.gov identifier: NCT01428453.

Tài liệu tham khảo

10.1097/MOL.0b013e3283307c16 Zhang H., 2013, Amelioration of atherosclerosis in apolipoprotein E‐deficient mice by inhibition of lipoprotein‐associated phospholipase A2, Clin Invest Med, 36, E32, 10.25011/cim.v36i1.19403 Johnson J.L., 2014, Effect of darapladib treatment on endarterectomy carotid plaque lipoprotein‐associated phospholipase A2 activity: A randomized, controlled trial, PLoS One, 9, e89034, 10.1371/journal.pone.0089034 10.1016/j.jacc.2007.11.079 10.1016/j.ahj.2011.01.017 10.1016/j.jacc.2013.07.050 Lum H., 2013, Inflammatory stress increases receptor for lysophosphatidylcholine in human microvascular endothelial cells, Am J Physiol Heart Circ Physiol, 285, H1786, 10.1152/ajpheart.00359.2003 10.1152/ajplung.00003.2005 10.1016/S0002-9440(10)63205-1 10.3233/JAD-122254 10.1016/j.neuron.2008.01.003 10.2174/187152709787601867 10.1016/j.neuron.2013.01.002 10.1007/s11910-013-0415-7 10.1007/s00401-010-0718-6 10.1016/S0140-6736(00)03589-3 10.1097/WAD.0b013e31829b72f1 10.2174/156720512801322654 10.1007/s00401-010-0652-7 Licandro A., 1983, Alzheimer's disease and senile brains: An immunofluorescence study, Riv Patol Nerv Ment, 104, 75 10.1016/0022-510X(83)90157-0 10.1016/j.brainres.2007.01.070 10.1111/j.1749-6632.1982.tb26848.x 10.1212/WNL.34.7.939 Cogstate. Cognitive Tasks. Available at:http://cogstate.com/computerized‐tests/cognitive‐tasks/. Accessed June 30 2015. Weintraub S., 2012, The neuropsychological profile of Alzheimer disease, Cold Spring Harb Perspect Med, 2, a006171, 10.1101/cshperspect.a006171 10.1016/j.exger.2009.10.010 10.3233/JAD-2011-110566 10.1002/ana.22247 10.1016/j.neurobiolaging.2007.07.015 10.1016/j.ophtha.2014.12.014
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Alzheimer's and Dementia: Translational Research and Clinical Interventions

Tập 1

131-140

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