A 24‐week Study to Evaluate the Effect of Rilapladib on Cognition and CSF Markers of Alzheimer's Disease

Rilapladib (SB659032) is a selective orally available inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2)being developed as a potential treatment for Alzheimer's disease (AD). Nonclinical findings with LpPLA2 inhibitors demonstrated effects on CNS A b and BBB function supporting a potential role for LpPLA2 inhibitors in the treatment of AD. 124 subjects with a clinical diagnosis of possible AD (MMSE score 20-26) and with radiological evidence of cerebrovascular disease were randomised to receive placebo or 250 mg rilapladib once daily, for 24 weeks, in addition to stable background acetylcholinesterase inhibitor and/or memantine. The study investigated effects on cognition using the CogState battery and cerebrospinal fluid (CSF) biomarkers as detailed in the results table below. Primary comparisons of interest were differences between rilapladib and placebo on the change from baseline in CSF Aβ 1-42 and working memory executive function (WM/EF) composite score at week 24. Inferential testing was only performed on these endpoints. Treatment comparisons are presented as point estimates and 95% confidence intervals alongside Bayesian posterior probabilities using a non€‘informative prior. Safety and tolerability of rilapladib were also assessed. Rilapladib was well tolerated with no significant safety findings of concern observed in the study. 90% of subjects in the placebo group and 85% in the rilapladib group completed the study. Cognition was maintained around baseline for rilapladib compared to a decline with placebo after 24 weeks. Effects sizes were 0.45 (p=0.026) for EF/WM, 0.43 for overall composite score and 0.27 for episodic memory. All three analyses yielded a posterior probability (PP) of a treatment difference in favour of rilapladib of > 90%. CSF Aβ 1-42 was increased with rilapladib and decreased with placebo, but differences between groups were not significant. Changes in plasma Aβ were small with no differences between groups. The study provided preliminary evidence of reductions in T-tau, P-tau, neurofilament Light Chain (NF-L) and Albumin Quotient (AlbQ) with rilapladib compared to placebo. A summary of the findings is provided Table 1. The data from this clinical study provides preliminary evidence that inhibition of Lp-PLA2 has potential as a novel treatment for dementia.