To evaluate the efficacy and safety of masupirdine in combination with donepezil and memantine for the symptomatic treatment of moderate AD.

Masupirdine (SUVN-502) is a selective 5-hydroxytryptamine-6 (5-HT6) receptor antagonist being investigated for the symptomatic treatment of moderate Alzheimer’s disease (AD). Animal data show that masupirdine has potential to improve cognitive performance. Masupirdine added to background treatment with donepezil and memantine was evaluated in moderate AD subjects in a double-blind placebo controlled, randomized, 26-week treatment phase-2 study.

Total of 564 moderate AD patients with MMSE scores between 12–20 receiving stable doses of donepezil and memantine were randomized (1:1:1) to receive either 50 mg or 100 mg of masupirdine, or placebo once daily for 26 weeks. The primary efficacy endpoint was change from baseline in the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog 11). Secondary efficacy endpoints included CDR-SB, ADCS-ADL, NPI, C-SDD and MMSE.

Patient baseline characteristics were consistent with moderate AD with MMSE scores ranging from 12-20. The mean (SD) age of patients was 73.6 (7.46) years and the mean (SD) duration of AD diagnosis was 3.73 (2.7) years. Two-thirds of the patients were ApoE-4 carriers. Masupirdine was well-tolerated in patients with moderate AD. Triple therapy of Masupirdine + Donepezil + Memantine resulted in unique and unconventional datasets.  Masupirdine is the first and the only 5-HT6 receptor antagonist which was evaluated as triple therapy.  Post-hoc and hypothesis-generating observations of interest emerged from the detailed data analyses. In the exploratory subgroup analysis, masupirdine treatment arms showed significant improvement in cognitive functions in subjects stratified by memantine regimen, memantine plasma concentrations and memantine treatment duration.

Masupirdine is safe and well tolerated.  Post-hoc and hypothesis-generating observations of interest emerged from the detailed data analyses.  These findings support further exploration of the potential of Masupirdine.