CS6253 Sequential Subcutaneous Pharmacokinetic Study followed by Phase 2A Placebo-Controlled Trial with Three Fixed Doses in APOE4 MCI and AD Patients to assess Safety, PK, and Biomarker Effects

Artery Therapeutics, Inc. (ATI) is developing CS6253, a highly differentiated, cholesterol-transport focused treatment for the indication of hereditary APOE4-associated dementia including MCI-AD, targeting the ATP- Binding-Cassette-Transporter A1 (ABCA1). We now propose two sequential CS6253 studies to delineate mechanism and show Proof of Concept (PoC) in homozygous APOE4 early AD patients. In the recently performed Phase 1 SAD-MAD study in healthy men and women CS6253 showed favorable safety/tolerability and pharmacokinetics (PK), apoE target engagement and an amyloid-clearance signal consistent with previous mouse model (Boehm, 2016) and primate (Noveir, 2022) studies. In the Phase 1 study we also performed an exploratory IV-SC bioequivalence sub-study showing that a single CS6253 SC bolus injection of 1 mg/kg was safe with a 79% bioavailability (compared to IV injection) and within the exposure range of the successful targeted replacement mice studies (Boehm, 2016). We now need to show that multiple-fold higher exposure levels can be reached by SC route of administration prior to commencing Phase 2A mechanism/Proof of Concept (PoC) studies, covering a wider exposure range, to evaluate safety, PK, and pharmacodynamics (PD) effects. Thus, our objectives are to perform a subcutaneous (SC) injection PK feasibility study with the ABCA1 agonist CS6253, and provided prespecified drug exposure success criteria are met, then perform a 28-day Phase 2A mechanism/PoC study in 48 APOE4-carriers with Mild Cognitive Impairment (MCI), of which half are homozygous, to assess safety, tolerance, PK, plasma and CSF biomarker effects. We will assess; 1) CS6253’s ABCA1 target engagement by following change in CSF and plasma apoE (total and isomer specific protein and glycosylation levels) and lipidation (primary effect); 2) Test amyloid-clearance hypothesis by following CSF and plasma Aβ42, Aβ40, Aβ42/40-ratio (secondary); 3) ABCA1 cholesterol-transport salutary effects by following plasma and CSF changes in P-tau 181, 217, 231, GFAP, NfL, and TREM2 (tertiary); 4) Explore direct vs indirect CS6253 effect by assessing upregulation of natural ABCA1 agonists as apoE and small apoA-I particles in plasma and CSF (exploratory); 5) Inform on optimal dosing-regimen, patient population (homozygous vs heterozygous) and power for subsequent Phase 2-3 studies (trial preparatory). With a positive outcome from these important studies in the APOE4 carrier patient population the next regulatory- clinical development steps are to propose breakthrough designation with the FDA and assess CS6253 effects on cognition in a Phase 2-3, 9 month randomized controlled trial (RCT) in homozygous APOE4 carriers with AD/ADRD. Project Number: 1UG3AG098023-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Jan Johansson | Institution: ARTERY THERAPEUTICS, INC., SAN RAMON, CA | Award Amount: $2,644,490 | Activity Code: UG3 | Study Section: Special Emphasis Panel[ZRG1 NV-F (51)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11291191