title: Blood transcriptomic biomarkers of Alzheimer's disease patients treated with EHT 0202.
abstract: Monitoring the genomic expression of patients in clinical trials for Alzheimer's disease (AD) can assist trial design and treatment response analysis. Here, we report on the identification in AD patients of blood-based transcriptomic signatures associated with treatment response of EHT 0202, a new compound with potential disease-modifying and symptomatic properties, in a 3-month, placebo-controlled, Phase IIA study aimed at determining the clinical safety, tolerability, and exploratory efficacy of EHT 0202 (40 and 80 mg bid) as adjunctive therapy to one cholinesterase inhibitor in mild to moderate AD patients. Genome-wide transcriptomic profiling was performed on blood samples taken prior to treatment and at study completion in a subpopulation of 60 AD patients selected as either the 10 worst disease decliners or the 10 best improvers of each treatment group, using ADAS-Cog scores as measure of disease severity. In the patients responding to EHT 0202, a pre-treatment (baseline) transcriptomic signature showed activation of pathways related to AD, CNS disorders, diabetes, inflammation, and autoimmunity, while a post-treatment signature indicated reduced activation of these pathways with induced metabolic and transcription stimulation. This pilot study demonstrates the utility of blood transcriptomic signatures used as biomarkers for predicting patient response or monitoring efficacy, for an administered therapeutic drug in a complex disease such as AD. For EHT 0202 or other AD drugs, such biomarkers may help to improve strategies to better identify appropriate patient populations for treatment, understand the drug mechanism of efficacy, and/or clarify the inherent subjectivity in most clinical endpoints used in this disease.
authors.affiliation: Exonhit SA, Paris, France. laurent.desire@exonhit.com
authors.forename: Laurent
authors.initials: L
authors.lastname: Désiré
authors.forename: Elodie
authors.initials: E
authors.lastname: Blondiaux
authors.forename: Jennifer
authors.initials: J
authors.lastname: Carrière
authors.forename: Raphael
authors.initials: R
authors.lastname: Haddad
authors.forename: Olivier
authors.initials: O
authors.lastname: Sol
authors.forename: Pascale
authors.initials: P
authors.lastname: Fehlbaum-Beurdeley
authors.forename: Rich
authors.initials: R
authors.lastname: Einstein
authors.forename: Weiyin
authors.initials: W
authors.lastname: Zhou
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Pando
mesh_terms: D000544:Alzheimer Disease / Q000097:blood* / Q000188:drug therapy / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage*; D015331:Cohort Studies; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D006801:Humans; D010865:Pilot Projects; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D002800:Cholinesterase Inhibitors