Impact of zervimesine on the neuroinflammatory biomarker GFAP and related proteomic molecular correlates in plasma of participants from a phase 2 clinical trial in Alzheimer's disease.

BACKGROUND: Zervimesine (CT1812) is an investigational brain-penetrant small molecule modulator of the sigma-2 receptor (S2R/TMEM97), currently in clinical development for the treatment of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) that selectively prevents and displaces the binding of amyloid beta (Aβ) and α-synuclein oligomers from neuronal synapses. Given the mechanism of action, it was hypothesized that zervimesine might be more effective in patients with lower levels of AD pathology. Indeed, in the SHINE trial, a completed Phase 2, randomized, double-blind, clinical trial conducted in participants with AD, a robust, 95%, slowing of cognitive decline, as assessed via ADAS-Cog11, was observed in a pre-specified subgroup of participants with lesser AD pathology (i.e., low p-tau217 subgroup) compared to a 38% slowing in the overall modified intent-to-treat (mITT)) population. METHODS: In SHINE, exploratory plasma biomarkers were assessed using both a targeted and an unbiased, proteomics discovery approach in plasma from participants at baseline and end of study. Treatment effects of zervimesine relative to placebo were assessed in both the mITT population and in a low p-tau217 subgroup, who entered the study with lower (< 1pg/ml) plasma p-tau217 concentrations. Plasma biomarkers Aβ40, Aβ42, GFAP, NfL and BD-tau were assessed using clinically validated targeted assays, along with untargeted TMT-mass spectrometry (MS)-based discovery proteomics followed by bioinformatic, pathway and correlation analyses. RESULTS: Collectively, plasma biomarker findings in the low p-tau217 subgroup were more robust than in the mITT population. Levels of GFAP were significantly decreased and NfL, Aβ42 and Aβ40 levels trended towards a decrease with zervimesine compared to placebo. Proteomics analyses identified candidate pharmacodynamic biomarkers of zervimesine, and gene ontology and pathway analyses pointed to an impact on amyloid biology, trafficking, lipid metabolism, and immune response. Bioinformatics and correlation analyses with GFAP identified biomarkers that may reflect pathway engagement of S2R and/or decreased neuroinflammation. CONCLUSIONS: Exploratory plasma biomarker findings align with the degree of clinical benefit in SHINE mITT and low p-tau217 populations, and support future trial enrichment with patients with lower levels of pathology as defined by lower baseline plasma levels of p-tau217. TRIAL REGISTRATION: July 20th, 2018 ClinicalTrials.gov Identifier NCT03507790 https://clinicaltrials.gov/study/NCT03507790. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02025-4.