O4–03–08: Efficacy and safety of MPC–7869 (R–flurbiprofen), a selective Aβ42–lowering agent, in Alzheimer's disease (AD): Results of a 12–month phase 2 trial and 1–year follow–on study

MPC–7869 (R–flurbiprofen) is a Selective Aβ42–Lowering Agent (SALA). In a mouse model of AD (Tg2576), MPC–7869 lowers brain levels of Aβ42 and chronic dosing in this model reduces brain amyloid pathology and prevents defects in learning and memory. These data suggest a potential for MPC–7869 to have disease–modifying properties. This study evaluated the efficacy and safety of treatment with MPC–7869 for 12 months in subjects with mild–to–moderate AD, and includes data from a 1–year follow–on study. This was a placebo–controlled, double–blind, 1–year trial evaluating 400 mg BID and 800 mg BID of MPC–7869 in 207 patients with mild–to–moderate AD (MMSE 15–26, with an average MMSE score of 21). The mean age of the subjects at baseline was 75 years and 94% of subjects were on stable acetylcholinesterase inhibitor therapy. Primary outcomes included measures of cognition (ADAS–cog), activities of daily living (ADCS–ADL), and global function (CDR–sb). A population pharmacokinetic analysis was also performed. At the end of this study, over 80% of eligible patients were enrolled into a 1–year follow–on treatment study in which placebo patients were randomized into one of the two treatment groups and treated patients continued their stable dose. Treatment groups remained blinded to patient/investigator. A prespecified interaction analysis revealed that mild and moderate AD patients responded differently to MPC–7869 (P= 0.03). In mild AD patients (MMSE 20–26) taking the 800–mg BID dose, statistically significant benefit was observed at 12 months in activities of daily living with a treatment effect size of d=0.44 (P= 0.033) and global function with a treatment effect size of d=0.42 (P= 0.042) with a positive trend observed in cognition. In addition, there was a significant plasma drug concentration to response relationship (ADCS–ADL, P= 0.037 and CDR–sb, P= 0.019). No benefit was observed in moderate AD patients. MPC–7869 was well tolerated and patients taking the 800–mg BID dose continued to show benefit in the 1–year follow–on study. MPC–7869 has an attractive therapeutic and safety profile in patients with mild AD. This study justifies larger–scale confirmatory trials of MPC–7869 as an amyloid–based intervention strategy for AD treatment.

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