薬物開発

Participants with Alzheimer's disease (AD) treated with sigma-2 receptor (S2R) modulator zervimesine (CT1812) exhibited slowing (39% in mITT, 95% in a pre-specified plasma-pTau217 subgroup (below-median at baseline)) of cognitive decline (ADAS-Cog11) compared to placebo in the SHINE trial (NCT03507790, COG0201). Given favorable clinical outcomes in the below-median pTau217 subgroup, correlation analysis of the CSF proteome with ADAS-Cog11 was performed to elucidate mechanisms of zervimesine-mediated preservation of cognition.

SHINE was a Phase 2 randomized, double-blind, placebo-controlled study. Participants (N=152) received a daily oral dose of zervimesine (100 or 300 mg) or placebo for 6-months (end-of-study). The median baseline plasma-pTau217 concentration (ALZpath, SIMOA) designated participants into subgroups below median (<1 pg/mL, N=69) or above/equal median (≥1 pg/mL, N=69). A proteomics sub-study of 45 participants was performed (tandem-mass tag mass spectrometry, TMT-MS) of baseline and 6-month CSF. CSF from treatment-compliant participants (N=43 mITT, N=17 below-median) were used for further analyses. Pearson correlation analysis was performed with protein change-from-baseline (CFB) to ADAS-Cog11 CFB. Pathway analyses (STRING, Metacore) were performed on correlated proteins (p≤0.01).

The previously-reported mITT CSF cognitive correlates were compared to those in the below-median pTau217 subgroup that demonstrated greater cognitive benefit with zervimesine versus placebo. In this subgroup, 106 proteins correlated with ADAS-Cog11 (p≤0.01), exhibiting enrichment in amyloid biology and immune response pathways (p≤0.05). To elucidate the biological underpinnings of robust pharmacodynamic correlates of cognitive improvement, pathway analysis was performed on 62 proteins that correlated with ADAS-Cog11 (p≤0.01) in both mITT and below-median pTau217 subgroup (excluding correlates (p≤0.01) in the subgroup that did not exhibit cognitive benefit with zervimesine). These 62 proteins were enriched in immune response, complement, and synapse biology pathways (FDR≤0.05).

In a pre-specified subgroup exhibiting 95% slowing of cognitive impairment with zervimesine, we identified protein correlates of cognition related to amyloid biology, supporting zervimesine mechanism of action. Enriching the mITT analysis with correlates from this biomarker-defined patient population reinforced observations of immune response and synaptic pathways that correlate with cognition in both mITT and below-median pTau217 subgroup. These biomarker findings paired with positive clinical outcomes support the further clinical development of zervimesine for AD.