P1‐047: A Phase 2 Clinical Trial of PF‐05212377 (SAM‐760) in Subjects with Mild to Moderate Alzheimer's Disease with Existing Neuropsychiatric Symptoms on a Stable Daily Dose of Donepezil

Symptomatic benefits have been reported for 5-HT6 receptor antagonists (RA) in Alzheimer’s disease (AD) trials. PF-05212377 is a selective 5-HT6 RA with good tolerability in Phase 1, and demonstrated central 5-HT6 receptor saturation in humans at a dose of 30 mg. This was a randomized, placebo-controlled (PC), parallel-group, multi-center trial of 12-weeks double-blind (DB) treatment evaluating the efficacy and safety of PF-05212377 30 mg QD when added to a stable regimen of 5 to 10 mg donepezil QD. Up to 342 subjects with AD (MMSE 10 − 24) and neuropsychiatric symptoms (NPI total score ≥ 10) were to be enrolled. Subjects who maintained an NPI total score ≥ 5 and a change in MMSE of no greater ± 3 at the end of a 4-week, single-blind, placebo run-in period, entered the 12-week DB period and were randomized to either PF-05212377 or Placebo. The primary efficacy variable was the ADAScog13 Week 12 change from baseline (CFB), and the key secondary variable was the week 12 NPI CFB. Secondary efficacy assessments included ADCS-ADL, CSDD, MMSE, COWAT, and CFT. Up to 2 interim analyses (IA) were planned for determination of futility or early efficacy. Mixed effects repeated measures models were used to analyze the data. The study was stopped for meeting futility criteria after the first IA of 185 completers. The Week 12 mean treatment difference for ADAScog13 (0.7 points; p=0.43) and NPI (2.2 points; p =0.2) numerically favored placebo. Other secondary endpoints did not demonstrate any significant benefit for PF-05212377. A total of 46.2% of subjects on PF-05212377 reported adverse events (AE) vs. 44.7% on placebo, and there were 5 (5.5%) serious AE on PF-05212377 vs. 3 (3.2%) on placebo. There were 2 deaths unrelated to treatment (one prior to randomization and one due to traffic accident during washout of active treatment). There was no benefit of PF-05212377 on measures of cognition, neuropsychiatric symptoms, or daily function in this study. PF-05212377 was safe and well tolerated. Differences in trial design, study population, region, and/or pharmacological profile may explain differences in outcome compared to other 5-HT6 RA.