Study of the mechanism of action of Blarcamesine (ANAVEX®2‐73): Whole blood transcriptomics analysis identifies treatment impact on compensatory pathways by restoring key neurodegenerative pathways functionality, including Alzheimer’s disease pathway

Abstract

Background Blarcamesine (ANAVEX®2‐73), a novel oral selective sigma‐1 receptor (SIGMAR1) agonist was investigated in a clinical Phase 2a study in Alzheimer’s disease in which blarcamesine resulted in a lower rate of cognitive (MMSE) and functional (ADCS‐ADL) decline. Following the positive results of this study, a translational approach led to investigating blarcamesine in an international, double‐blind, multicenter, placebo‐controlled Phase 2 clinical study of 14‐week duration in 132 patients with Parkinson’s disease dementia (PDD). Whole blood transcriptomics analysis (RNAseq) was performed for the PDD study at two timepoints: baseline and Week 14. After quality control filtering, 14,150 genes were retained for analysis. Methods Weighted gene correlation network analysis (WGCNA) was used to identify clusters of genes that show a correlated expression change across patients and timepoints. Thus, a data‐driven gene network was generated. Associations between the identified clusters and treatment arms were explored in order to select clusters for which gene expression is significantly associated with the high blarcamesine dose. These associations were assessed using linear mixed effect models with three covariates: dose, patient and timepoint. Significance was assessed with Dunett’s test. Results Blarcamesine significantly restores functionality in key pathways of Alzheimer’s disease, Parkinson’s disease and Prion diseases. The analysis identified two clusters of genes that are significantly differentially expressed in treated patients and represent compensatory pathways to genes dysregulations induced by neurodegenerative diseases. In both clusters, majority of genes were confirmed to interact (STRING database). Amongst interacting genes, neurodegenerative pathways were identified as overrepresented (p < 0.01). Down‐regulation of genes involved with neurodegeneration was observed in the placebo arm, however, was compensated in the blarcamesine arm. Conclusions This analysis identified a gene network that is differentially expressed in patients treated with blarcamesine after 14 weeks of treatment, compared to placebo. The biological relevance of this gene network was assessed. Pathway analysis confirmed the impact of the treatment on pathways involved in neurodegenerative diseases The identification of a gene network as the blarcamesine response pathway lays the foundation to better understand the mechanism of action at the molecular level of blarcamesine, thus unlocking characterization of responders based on molecular profiling, as well as identification of new indications in the area of neurodegenerative and other disorders.