UG3AG098023

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 - 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.

Artery Therapeutics

<P>TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE.</P>

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

San Ramon, California 945832691 United States

Single Zip Code

Seamless Early-Stage Clinical Drug Development (Phase 1 to 2a) for Novel therapeutic Agents for the Spectrum of Alzheimer's Disease (AD) and AD-related Dementias (ADRD) (UG3/UH3 Clinical Trial Required) (PAR-25-226)