Cognition Therapeutics (CGTX) Study Update summary

Study design and objectives

• SHINE was a double-blind, randomized, placebo-controlled phase 2 trial in mild-to-moderate Alzheimer's disease, enrolling 153 participants across multiple countries, randomized to 100 mg, 300 mg CT1812, or placebo daily for six months.

• All participants had confirmed amyloid pathology and were stratified by baseline plasma p-tau217 above or below the median (1.0 pg/mL); subgroups were well balanced in demographics and ApoE4 status.

• Key objectives included assessing safety, tolerability, cognitive and functional endpoints, and biomarker analysis, with pre-specified subgroup analyses based on plasma p-tau217 levels.

• Efficacy was measured using cognitive and functional scales, including ADAS-Cog 11/13, MMSE, ADCS-ADL, and CGIC.

• The study was supported by approximately $30 million in NIH grants.

Mechanism of action and rationale

• CT1812 is an orally delivered small molecule that antagonizes the sigma-2 receptor complex, displacing toxic Aβ oligomers from synapses and facilitating their clearance in CSF.

• The mechanism is distinct from anti-amyloid immunotherapies and aims to protect synapses and slow neuronal injury.

• Prior data suggest individuals with lower plasma p-tau217 respond better to amyloid-based therapies.

Key results and subgroup findings

• In the subgroup with baseline p-tau217 below 1.0 pg/mL, CT1812 treatment resulted in 95% slowing of cognitive decline on ADAS-Cog 11 (p=0.04) and 108% slowing on MMSE (p=0.02) versus placebo, with participants maintaining cognitive function over six months.

• Functional endpoints (ADCS-ADL, CGIC) also favored CT1812 in the below-median p-tau217 group, with observed differences of 1.24 and 0.51 points, respectively.

• The treatment effect size appeared to widen over time, suggesting potential for durable benefit.

• Participants above the median p-tau217 declined similarly on drug and placebo, indicating efficacy is concentrated in the lower tau subgroup.