CSF proteomics analysis to investigate the pharmacodynamic response of the S2R modulator CT1812 in Alzheimer’s disease patients from the SPARC clinical trial

Abstract

AbstractBackgroundCT1812 is an investigational therapeutic that can displace toxic amyloid‐beta oligomers from neuronal receptors and is currently in development for Alzheimer’s disease (AD). SPARC (COG0105; NCT03493282), was a randomized double‐blinded placebo‐controlled clinical trial designed to test the impact of the small molecule sigma‐2 receptor (S2R) modulator CT1812 on safety and synaptic density. Exploratory analyses included discovery proteomics for pharmacodynamic biomarker identification and to understand the impact of CT1812 on CSF proteins detected in mild to moderate AD patients.MethodUnbiased quantification, using tandem‐mass tag mass spectrometry (TMT‐MS), of proteomes from AD patients given the S2R modulator CT1812 or placebo (N=18) was performed on baseline and end of study CSF to test two doses (100 mg, 300 mg) of CT1812 given once daily for 6 months in participants with mild‐moderate AD. Individual CSF proteomes were compared to within‐study pooled AD and non‐demented control CSF reference standards from the Emory ADRC to benchmark protein levels in SPARC participant CSF at baseline and to assess treatment effects, via differential expression analysis (one‐way ANOVA; p<0.05) and pathway analyses.ResultA total of 2,760 CSF proteins were detected across all CSF samples. Strong correlations (r>|0.70|) between TMT‐MS values and clinically validated ELISAs for canonical AD biomarker levels (Tau, NFL) were observed across participants and timepoints, confirming previous findings of TMT‐MS as a quantitative method. Differential expression analyses identified 327 proteins altered (one‐way ANOVA; p<0.05) in CT1812 vs placebo CSF. From a curated list of previously published AD biomarkers representing distinct pathways, a subset of proteins were found to be significantly altered by treatment with CT1812 compared to placebo (p<0.05), and included some proteins known to be genetically linked to AD. Pathway analysis identified statistically significant pathways (p<0.05) altered by CT1812, including that tied to inflammation, amyloid biology, and synaptic function.ConclusionThis study enabled the identification of candidate pharmacodynamic biomarkers that may reflect target/pathway engagement or disease modification, and extends proteomics CSF learnings from previous clinical trials with CT1812. Overall, this data suggest CT1812 may impact key proteins and pathways in AD and provides additional support for CT1812 to be further evaluated as a promising therapy for AD.