Late-onset or sporadic Alzheimer's disease (AD) constitute 95 percent of all AD and APOE4 is the dominatinggenetic risk factor. While there are three major APOE allelic variants (APOE2, APOE3, and APOE4), APOE4carriers have an increased risk of developing AD, and up to 66% of individuals with AD-type dementia casesand 64% with mild cognitive impairment, also carry the APOE4 allele. There are currently no treatments forAPOE4 driven AD or other dementias. Artery Therapeutics, Inc. (Artery; ATI) has developed a novel chemicalentity 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 asafe, potent, and druggable ABCA1 agonist. ATI's preclinical data in cell systems and two different apoE4transgenic mice models have demonstrated that CS6253 engages ABCA1 as a target, improves apoElipidation, prevents hippocampal amyloid-β (Aβ) pathophysiology, and improves cognition. In IND-enablingstudies, 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 ourefficacy results in mice pharmacology models and are predictive of efficacy in humans. Thus, with this SBIRproposal, we will advance CS6253 into early clinical trials. In Aim 1, ATI will establish qualifying methods forGMP drug product and stability at -20C for CofA and release for Phase 1 Clinical Trial Material. GMP drugproduct will complete the CMC section (GMP drug substance is already produced) which will be added to theclinical 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 onthe August 2020 pre-IND meeting with FDA where consensus was reached regarding key aspects of theprogram including CMC, nonclinical and the initial clinical trials. In Aim 2, we will perform a randomized doubleblind placebo controlled single ascending dose trial in healthy 50-70 y.o. men and women (n=8/cohort, 6active: 2 placebo, total n=32) who will be characterized but not stratified for APOE isoform. Participants willreceive a single intravenous (iv) administration of CS6253 at 4 single ascending doses. Our Aim 2 milestoneis to establish safety and pharmacokinetics (plasma and CSF) in humans and a safe starting dose for themultiple ascending dose (MAD) study. We will also explore transient effects on lipids and AD biomarkers byCS6253 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 preparefor Phase 1 MAD studies of up to 30 days. Overall, CS6253 is an extremely promising ABCA1 targeting noveltherapy with potential to address APOE4 associated dementia including AD.
Public Health Relevance Statement: 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.
Project Terms: Age ; ages ; Albumins ; Alleles ; Allelomorphs ; Alzheimer's Disease ; AD dementia ; Alzheimer ; Alzheimer Type Dementia ; Alzheimer disease ; Alzheimer sclerosis ; Alzheimer syndrome ; Alzheimer's ; Alzheimer's disease dementia ; Alzheimers Dementia ; Alzheimers disease ; Primary Senile Degenerative Dementia ; dementia of the Alzheimer type ; primary degenerative dementia ; senile dementia of the Alzheimer type ; Apolipoproteins ; Apolipoprotein E ; Apo-E ; ApoE ; Arteries ; Blood ; Blood Reticuloendothelial System ; Brain ; Brain Nervous System ; Encephalon ; Cells ; Cell Body ; Cerebrospinal Fluid ; cerebral spinal fluid ; spinal fluid ; Certification ; Chemistry ; Cholesterol ; Clinical Trials ; Cognition ; Creatinine ; Double-Blind Method ; Double-Blind Study ; Double-Blinded ; Double-Masked Method ; Double-Masked Study ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Female ; Hematology ; Hippocampus (Brain) ; Ammon Horn ; Cornu Ammonis ; Hippocampus ; hippocampal ; Human ; Modern Man ; Laboratories ; Lipids ; Lipoproteins ; High Density Lipoproteins ; HDL ; HDL Lipoproteins ; Heavy Lipoproteins ; High density lipoprotein ; alpha-Lipoproteins ; male ; Manuals ; men ; men's ; Methods ; Transgenic Mice ; Mus ; Mice ; Mice Mammals ; Murine ; neurofilament ; Neurology ; Peptides ; Drug Kinetics ; Pharmacokinetics ; Pharmacology ; Phospholipids ; Phosphatides ; Physical Examination ; Medical Inspection ; Placebos ; Sham Treatment ; sham therapy ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Primates ; Primates Mammals ; Risk ; Safety ; Testing ; Time ; Triglycerides ; Triacylglycerol ; Urinalysis ; Urine ; Urine Urinary System ; Woman ; apolipoprotein E-4 ; APOE e4 ; APOE-ε4 ; APOEε4 ; apo E-4 ; apo E4 ; apo epsilon4 ; apoE epsilon 4 ; apoE-4 ; apoE4 ; apolipoprotein E epsilon 4 ; apolipoprotein E4 ; sulfated glycoprotein 2 ; MAC393 antigen ; SGP-2 protein ; SGP2 ; SP 40,40 protein ; TRPM-2 protein ; TRPM2 ; X-ray-inducible protein 8 ; XIP8 protein ; apoJ protein ; apolipoprotein J ; clusterin ; complement lysis inhibitor ; complement-associated protein SP-40,40 protein ; ionizing radiation-induced protein-8 ; testosterone-repressed prostate message-2 protein ; lysosomal proteins ; Amyloid beta-Protein ; Alzheimer beta-Protein ; Alzheimer's Amyloid beta-Protein ; Alzheimer's amyloid ; Amyloid Alzheimer's Dementia Amyloid Protein ; Amyloid Beta-Peptide ; Amyloid Protein A4 ; Amyloid β ; Amyloid β-Peptide ; Amyloid β-Protein ; Aβ ; a beta peptide ; abeta ; amyloid beta ; amyloid-b protein ; beta amyloid fibril ; soluble amyloid precursor protein ; Generations ; Amyloid beta-Protein Precursor ; Amyloid A4 Protein Precursor ; Amyloid Protein Precursor ; Amyloid β-Protein Precursor ; amyloid precursor protein ; Apolipoprotein A-I ; Apo A-1 ; Apo A-I ; Apo A1 ; Apo AI ; ApoA-1 ; ApoA-I ; Apolipoprotein A-1 ; Apolipoprotein A1 ; Apolipoprotein AI ; base ; Vial device ; Vial ; improved ; Clinical ; Penetration ; Phase ; Chemicals ; Serum ; Blood Serum ; Individual ; Agonist ; tau-1 ; p-tau ; p-Ï ; phospho-tau ; phospho-Ï ; phosphorylated tau ; Functional disorder ; Dysfunction ; Physiopathology ; pathophysiology ; Critical Pathways ; Critical Paths ; Therapeutic ; Intravenous ; Consensus ; programs ; Hour ; System ; Amentia ; Dementia ; meetings ; Isoforms ; Protein Isoforms ; cohort ; novel ; Participant ; Reporting ; inherited factor ; genetic risk factor ; Pharmacodynamics ; Modeling ; Property ; response ; Adverse Experience ; Adverse event ; AP-2 Adaptor (Clathrin-Coated Vesicles) ; AP-2 Protein Complex ; Adaptor-Related Protein Complex 2 ; Clathrin Adaptor Protein Complex 2 ; Clathrin Assembly Protein Complex 2 ; HA-2 Adaptors ; Hydroxyapatite 2 Adaptors ; Adaptor Protein Complex 2 ; Documentation ; Early-Stage Clinical Trials ; Phase 1 Clinical Trials ; phase I protocol ; Phase I Clinical Trials ; Molecular Interaction ; Binding ; preventing ; prevent ; Address ; Dose ; Data ; Disease Marker ; Qualifying ; randomisation ; randomization ; randomly assigned ; Randomized ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Monitor ; Intravenous Bolus ; IV bolus ; Development ; developmental ; Image ; imaging ; pre-clinical ; preclinical ; genetic variant ; Gene variant ; allele variant ; allelic variant ; genomic variant ; child bearing ; bear children ; bearing children ; childbearing ; C-terminal ; healthy volunteer ; mouse model ; murine model ; new therapeutic target ; new drug target ; new druggable target ; new pharmacotherapy target ; new therapy target ; novel drug target ; novel druggable target ; novel pharmacotherapy target ; novel therapeutic target ; novel therapy target ; Biological Markers ; bio-markers ; biologic marker ; biomarker ; phase 1 study ; Phase I Study ; screening ; mild cognitive impairment ; mild cognitive disorder ; phase I trial ; phase 1 trial ; study population ; overtreatment ; over-treatment ; Alzheimer's disease biomarker ; Alzheimer's biomarker ; Alzheimer's disease biological marker ; Alzheimer's biological marker ; Amyloid beta-42 ; A β-42 ; A β42 ; A-beta 42 ; A-beta42 ; Abeta-42 ; Abeta42 ; Amyloid beta42 ; Amyloid β-42 ; Amyloid β42 ; Amyloidβ-42 ; Amyloidβ42 ; Aβ-42 ; Aβ42 ; Alzheimer's disease therapy ; Alzheimer's therapy ; early phase clinical trial ; early clinical trial ;
