UPREGULATING ABCA1‐MEDIATED CHOLESTEROL TRANSPORTATION BY CS6253 – OPPORTUNITY FOR CONVENIENT SC ROUTE OF ADMINISTRATION

Abstract

AbstractBackgroundThe ATP‐binding cassette transporter A1 (ABCA1) is a validated target for AD and upregulation has therapeutic potential in APOE4‐associated AD. The apoE4 protein compared to E2/E3 has impaired interaction with the ABCA1 transporter protein, affecting cholesterol homeostasis in the brain, causing dementia and hemorrhage. CS6253 is an ABCA1‐agonist that in monkey’s has shown safety and increase in Ab42/40‐ratio. A phase 1 SAD‐MAD with CS6253 administered IV was initiated. Here we describe translational efforts for transitioning from IV to SC route‐of‐administration.MethodThe Phase 1 is initiated with SAD:In 4‐6 cohorts of 8 subjects (6 active: 2 placebo) CS6253 starting with 1 mg/kg will be administered IV and plasma and CSF collected simultaneously over 24 hours to assess PK and response markers, and, MAD: In 3‐4 cohorts of 8 subjects (6 active: 2 placebo) CS6253 will be administered to elderly stratified for sex and APOE4 status.Using the identical CS6253 drug product, a GLP local‐tolerance study in rats was conducted to support up to 30 days SC administration in humans. Rat groups of n = 12 received PBS‐control and 7.5, 25 and 75 mg/kg CS6253 SC every other day, 7 times. PK is analyzed by LC‐MS following first and 7th/last dose.ResultBodyweight: Treated animals gained weight throughout the study at a comparable rate to control; no Test Article(TA)‐related variations identified.Clinical Signs: No TA‐related observations were noted, all animals remained in good condition until the end of dosing and end of recovery.Food consumption: No TA‐related effects on food consumption, all means were comparable to controls.Gross Pathology: No gross lesions were observed for terminal and recovery animals.Human Phase 1 SAD results are expected late summer of 2023 and human MAD data late fall of 2023 and with clearing local‐tolerance toxicology the CS6253 program can transition from IV to SC route‐of‐administration.ConclusionThe ABCA1 agonist CS6253 has therapeutic potential for APOE4‐associated AD. Safety, PK and biomarker efficacy is being assessed in a Phase 1 study. The SC local tolerance study opens up the potential to self‐administer CS6253 SC for optimal convenience and compliance.