For People with Alzheimer Disease, Treatment with an Experimental, Oral Small Molecule was Linked to Significant Slowing in Cognitive Decline

Participants with mild-to-moderate Alzheimer disease (AD) treated with CT1812 (Cognition Therapeutics, Purchase, NY) experienced a significant slowing of cognitive decline compared with those who received placebo. Additionally, greater slowing in cognitive decline was linked to lower baseline plasma phosphorylated tau217 (p-tau217) levels at baseline. CT1812 is an experimental, orally delivered small molecule oligomer agonist that penetrates the blood–brain barrier to selectively bind to the sigma-2 (σ-2) receptor complex. These data from the phase 2 SHINE clinical trial (NCT03507790) were presented at the 17th annual Clinical Trials on Alzheimer’s Disease (CTAD) conference.

SHINE was a double-blind, placebo-controlled signal-finding trial that included 153 adult participants with mild-to-moderate AD who were randomized to receive placebo, CT1812 at 100 mg, or CT1812 at 300 mg by oral administration daily for 6 months. The primary endpoint was safety and tolerability, with key secondary and exploratory endpoints assessing change in cognitive outcomes. A prespecified subgroup analysis compared cognitive changes in participants with baseline plasma p-tau217 levels above and below the median.

At week 26:

• Participants who received CT1812 (n=45) demonstrated a 95% slowing in cognitive decline as assessed by Alzheimer’s Disease Assessment Scale–Cognitive Subscale 11 (ADAS-Cog11) vs placebo (n=24).
• In the subgroup of participants with baseline plasma p-tau217 levels below the median, those who received CT1812 showed a 108% slowing in cognitive decline as assessed by Mini-Mental State Examination (MMSE).

“Participants with lower levels of p-tau217 who were treated with CT1812 performed extremely well in the SHINE study. These findings are consistent with the clinical experience of the anti-amyloid immunotherapeutics, which have been reported to be more effective in people with low p-tau,” said Study Author Michael Woodward, MD, Associate Professor and Head of Dementia Research at Austin Health in Melbourne, Australia. “The degree of cognitive preservation in the CT1812-treated patients is impressive and could point to plasma p-tau217 as a predictive biomarker of robust treatment effect.”