PROJECT SUMMARY Late-onset or sporadic Alzheimer's disease (AD) constitute 95 percent of all AD and APOE4 is the dominating genetic risk factor. While there are three major APOE allelic variants (APOE2, APOE3, and APOE4), APOE4 carriers have an increased risk of developing AD, and up to 66% of individuals with AD-type dementia cases and 64% with mild cognitive impairment, also carry the APOE4 allele. There are currently no treatments for APOE4 driven AD or other dementias. Artery Therapeutics, Inc. (Artery; ATI) has developed a novel chemical entity for the treatment of APOE4 driven dementias, including AD. CS6253 is a 2nd-generation selective ATP- Binding-Cassette A1 (ABCA1) transporter agonist peptide derived from the C-terminal of apoE. CS6253 is a safe, potent, and druggable ABCA1 agonist. ATI's preclinical data in cell systems and two different apoE4 transgenic mice models have demonstrated that CS6253 engages ABCA1 as a target, improves apoE lipidation, prevents hippocampal amyloid-β (Aβ) pathophysiology, and improves cognition. In IND-enabling studies, which showed excellent safety and pharmacokinetics properties, it was demonstrated that in primates, CS6253 treatment over 9 days showed pronounced dose-response reductions in cerebrospinal fluid (CSF) concentrations of Aβ42, Aβ40, and APP, and other markers. These data strongly support and extend our efficacy results in mice pharmacology models and are predictive of efficacy in humans. Thus, with this SBIR proposal, we will advance CS6253 into early clinical trials. In Aim 1, ATI will establish qualifying methods for GMP drug product and stability at -20C for CofA and release for Phase 1 Clinical Trial Material. GMP drug product will complete the CMC section (GMP drug substance is already produced) which will be added to the clinical and nonclinical sections of the IND, for submitting the IND. The aim 1 milestone is to open the IND, i.e. receive FDA buy-in for initiating the CS6253 Phase 1 trial. We are confident of a successful IND based on the August 2020 pre-IND meeting with FDA where consensus was reached regarding key aspects of the program including CMC, nonclinical and the initial clinical trials. In Aim 2, we will perform a randomized double blind placebo controlled single ascending dose trial in healthy 50-70 y.o. men and women (n=8/cohort, 6 active: 2 placebo, total n=32) who will be characterized but not stratified for APOE isoform. Participants will receive a single intravenous (iv) administration of CS6253 at 4 single ascending doses. Our Aim 2 milestone is to establish safety and pharmacokinetics (plasma and CSF) in humans and a safe starting dose for the multiple ascending dose (MAD) study. We will also explore transient effects on lipids and AD biomarkers by CS6253 including temporal plasma – CSF dynamics of apolipoproteins and AD markers. This project will determine CS6253's pharmacokinetics (plasma and CSF) and single dose safety, and prepare for Phase 1 MAD studies of up to 30 days. Overall, CS6253 is an extremely promising ABCA1 targeting novel therapy with potential to address APOE4 associated dementia including AD.

PROJECT NARRATIVE Artery Therapeutics is advancing its ABCA1 stabilizing peptide CS6253 that targets a critical pathway in APOE driven Alzheimer's disease (AD) into an early Phase 1 clinical trial. Artery's therapy has promising target engagement markers, favorable safety profile, and pharmacodynamics effects on AD biomarker expression in primate studies. With this proposal, Artery Therapeutics will take its novel AD therapy through a randomized double blind placebo controlled Phase 1 SAD study to evaluate pharmacokinetics, tolerance, safety, and transient biomarker efficacy (no cognition or imaging) in 50-70 y.o. healthy subjects with and without APOE4.