Strong effects of the ABCA1 agonist CS6253 on Amyloidβ42/40 ratio and lipoproteins in cynomolgus monkeys

Abstract

AbstractBackgroundATI has discovered a novel molecule, CS6253, for hereditary Apolipoprotein E4 (ApoE4) associated Alzheimer’s disease (AD), which is highly differentiated from other molecules in development by its focus on cholesterol transport. CS6253 is a 26mer peptide optimized for ATP binding cassette transporter A1 (ABCA1) mediated cholesterol efflux, in the brain a rate‐limiting step in cholesterol transport from cells to ApoE. ABCA1 activity, as well as CS6253 in AD mouse models, is associated with improvement in AD pathology.In preparation for human studies, we investigated the effects of the ABCA1 agonist peptide CS6253 on amyloid‐β peptides (Aβ) and lipoproteins in plasma and cerebrospinal fluid (CSF) of cynomolgus monkeys, a species with amyloid and lipoprotein metabolism similar to humans.MethodsCS6253 peptide was injected intravenously to cynomolgus monkeys at various doses in three different studies, 1) a pharmacokinetics (PK) study, 2) a dose‐range finding (DRF) study, and 3) a 30‐day Good Laboratory Practice (GLP) toxicology study. Plasma and CSF samples were collected at several time points before and after treatment. Levels of cholesterol, triglyceride (TG), lipoprotein particles, apolipoproteins, and Aβ were measured using ELISA, ion‐mobility analysis, and asymmetric flow field flow fractionation (AF4). The relationship between the change in levels of these biomarkers was analyzed using multiple linear regression models and linear mixed‐effects models.ResultsCS6253 intravenous injection, within minutes, induced an increase in small, plasma high‐density lipoprotein (HDL) particles. Plasma TG, ApoE, and Aβ42/40 ratio were transiently increased following CS‐6253 intravenous injection, and a non‐significant decrease in CSF APP and Aβ42 was observed. CS‐6253 in plasma displaced ApoE from HDL to intermediate‐density‐ and low density‐lipoprotein (IDL/LDL) sized particles paralleled by transient reductions in total cholesterol and HDL‐cholesterol. In contrast to plasma, CS6253 had no effect on the assessed CSF apolipoproteins or lipids.ConclusionsIn cynomolgus monkeys administration of the ABCA1 agonist CS6253 transiently increased plasma ApoE and TGs which was paralleled by plasma Aβ42/40 ratio increase, providing a strong rationale for following these markers in ensuing human studies.