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

Abstract

Background: The 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).

Methods: One 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 [Aβ_1-42] and CogState executive function/working memory [EF/WM] composite score at week 24) were prespecified in the analysis plan for inferential statistical analysis.

Results: Rilapladib 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 Aβ_1-42 (P = .133). Preliminary evidence of effects was detected on other mechanistic (albumin quotient) and disease-related biomarkers (tau/P-tau and neurofilament light chain).

Conclusion: These data provide initial evidence supporting Lp-PLA₂ inhibition as a novel treatment for dementia.

Clinical trial registration: Clinicaltrials.gov identifier: NCT01428453.

Keywords: Albumin quotient; Alzheimer's disease; Amyloid-beta peptide; Biomarkers; Cerebrospinal fluid; Cerebrovascular disease; Cognition; Lp-PLA2; Neurofilament light chain; Rilapladib; SB659032; Small vessel disease; Tau.

Fig. 1

Subject disposition (safety population). *One subject was randomized in error and did not receive any study treatment. Two further subjects (one in each treatment group) were randomized and received treatment but withdrew before any postbaseline measurements and are therefore excluded from the ITT population. Abbreviations: AE, adverse event; ITT, intent-to-treat.

Fig. 2

Time profile of executive function/working memory composite score (adjusted mean change from baseline in Z score ± 95% confidence intervals [MMRM analysis]). Abbreviation: MMRM, mixed model repeated measures.