Effects of the Acetylcholine Release Agent ST101 with Donepezil in Alzheimer's Disease: A Randomized Phase 2 Study.

BACKGROUND AND OBJECTIVE: ST101, an acetylcholine release agent with efficacy in rodent memory and cognition models, was assessed for clinical safety and efficacy. METHODS: A phase 2 double blind, placebo-controlled study enrolled 210 AD patients (MMSE 10-20) on 10 mg donepezil QD. Patients received ST101 (10, 60, or 120 mg QD) or placebo for 12 weeks. The primary endpoint was change in cognitive function measured by ADAS-cog in the modified Intent To Treat (MITT) population and the Per Protocol (PP) population. RESULTS: Mean ADAS-cog change favored ST101 over placebo in the MITT population (p = 0.0957, one-sided) and in the PP population (p = 0.0434, one-sided, ∼1.5 point drug-placebo difference) comparing all ST101 dose groups combined to placebo. Among secondary and exploratory outcome measures the ADCS-CGIC also showed a beneficial trend (p = 0.0294, one-sided). In a post-hoc analysis, the subgroup with more severe disease (MMSE 10-17) showed a dose response in the ADAS-cog with the greatest efficacy at 120 mg (p = 0.0067, one sided). No significant ST101-related safety concerns were identified. CONCLUSION: The study supports the possibility that ST101, in patients receiving a stable dose of donepezil, may provide additional symptomatic benefit in moderate AD.