Drug Development.

Background: ABCA1-mediated cholesterol transport is a central feature in many lipid- dependent diseases including APOE4-associated Alzheimer's disease and atherosclerosis-CVD. ABCA1 upregulation of RNA transcription by nuclear factors (LXR, RXR) have been associated with liver side-effects because of the common promotor element for ABCA1 and Fatty Acid Synthase. The ABCA1 agonist CS6253, derived from the C-terminal of apoE was designed to stabilize and enhance ABCA1 function, thereby providing a safe alternative to transcriptional upregulation. CS6253 has in various mice models shown favorable neuroprotective and vascular-metabolic effects suggesting potential for APOE4 MCI/AD and mixed MCI/AD. IND enabling studies in Wistar rats and Cynomolgus monkeys(cynos) were performed, and a Phase 1 SAD-MAD study initiated, to explore the safety, PK and biomarker effects of CS6253.

Method: Conventional IND enabling toxicology studies, including 30-day GLP studies in male and female rats and cynos were performed, in which CS6253 was injected as IV bolus injection every other day. Following clearing the IND a Phase 1 SAD-MAD double-blind, placebo-controlled study was initiated, including elderly with and without APOE4 genotype, the SAD part ending in March 2024.

Result: Toxicology studies showed that cynos was the more sensitive species with the No Observable Adverse Effect Level (NOAEL) being 75 mg/kg. In plasma exposure/AUC in cynos was linear up to 25 mg/kg and showed already from 10 mg/kg transient increases in preb1-HDL, small HDL and triglycerides which was associated with a significant increase in amyloidb42/40-ratio.

Conclusion: Enhancing ABCA1 functions by CS6253 to form small HDL appears to be a promising approach with neuroprotective properties as indicated by pharmacology, IND-enabling toxicology, and Phase 1 studies. The development of a safe and efficient ABCA1 agonist addresses several indications with unmet medical, notably for Alzheimer's and brain vascular diseases.