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

About This Grant

PROJECT SUMMARY 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.