Cogpep (CS6253) / Artery Therap, University of California Berkeley - LARVOL DELTA

CS6253 MULTIPLE ASCENDING DOSES INCREASE PLASMA APOE AND AΒ42/40 RATIO IN ADULTS ≥50 YEARS; RATIO INCREASE DRIVEN BY ELEVATED AΒ42 (ADPD 2026) - "It was previously reported that CS6253 in the Phase 1 SAD-MAD study demonstrated excellent safety, tolerability, and PK in healthy volunteers, the majority being 50 years and older. Here we show that CS6253 administered in 3 doses over 8 days in older men and women increases plasma apoE and Aβ42/40 ratio significantly. The findings are encouraging as they suggest that PK-PD modelling in ensuing Phase 2 studies can rely on plasma apoE, Aβ42, Aβ40, and Aβ42/40 ratio assessments."

Clinical • Alzheimer's Disease • CNS Disorders • ABCA1 • APOE • Aβ42 • CSF Aβ42

Developing Topics. (PubMed, Alzheimers Dement) - "The CS6253 Phase 1 MAD study showed excellent safety, tolerance and PK. Furthermore, consistent with previous findings in mice and monkey models CS6253 increased plasma small HDL and apoE, and showed signs of amyloid clearance. CS6253 may have utility in ABCA1-related diseases, including APOE4 AD, by correcting cholesterol homeostasis."

Biomarker • Clinical • Journal • Alzheimer's Disease • CNS Disorders • Dementia • ABCA1 • APOE

ABCA1-agonist treatment by CS6253 and effects on plasma total and isoform-specific apolipoprotein E in elderly men and women. (CTAD 2025) - No abstract available

Clinical • ABCA1 • APOE

The ATP Binding Cassette A1 (ABCA1) agonist CS6253 developed for APOE4-associated dementia shows favorable profiles in humans (Neuroscience 2025) - "APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease, yet very few therapies have been directed at APOE4 to date. This session will present progress on ApoE genetics, lipids, and inflammatory pathways from drug targets to clinical trials."

Alzheimer's Disease • CNS Disorders • Dementia • ABCA1 • APOE

Safety and Pharmacokinetics of Single Ascending Doses and Multiple Ascending Doses of CS6253 in Healthy Volunteers (clinicaltrials.gov) - P1 | N=66 | Completed | Sponsor: Artery Therapeutics, Inc. | Active, not recruiting ➔ Completed

Trial completion • Alzheimer's Disease • CNS Disorders

The potential of ARL4C and its-mediated genes in atherosclerosis and agent development. (PubMed, Front Pharmacol) - "Many agents, including ABCA1 agonists (CS-6253, IMM-H007, RG7273, and R3R-01), FLNA antagonist sumifilam, LRP6 inhibitor BI-905677 and agonist SZN-1326, and SOX2 inhibitor STEMVAC, were investigated in clinical trials. Thus, ARL4C and its regulated genes may be a potential target for drug development. Thus, we focus on the role of ARL4C and its-mediated genes in atherosclerosis and agent development, which provide insights for the identification, research, and drug development of novel targets."

Journal • Review • Atherosclerosis • Cardiovascular • Colorectal Cancer • Hepatology • Liver Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ABCA1 • ALDH1A3 • SNAI2 • SOX2

RESULTS FROM THE PHASE 1 SAD-MAD STUDY OF THE ATP BINDING CASSETTE A1 AGONIST CS6253, DEVELOPED FOR THE INDICATION OF APOE4-ASSOCIATED DEMENTIA INCLUDING MCI-AD (ADPD 2025) - P1 | "A single CS6253 (n=18) vs. placebo (n=6) dose increased CSF Aβ42 (active 53.68% vs. placebo -24.59%) and Aβ40 (active 62.45% vs. placebo -8.07%) with p-values of 0.16 and 0.02, respectively, with the Aβ42/40 ratio nominally increased. Conclusions The CS6253 Phase 1 SAD-MAD trial in HV, including elderly showed excellent safety, tolerance, PK and trends for brain amyloid-clearance to CSF pointing to CS6253 as a safe and efficient ABCA1-agonist with potential in addressing unmet medical need including Alzheimer's disease."

P1 data • Alzheimer's Disease • CNS Disorders • Dementia • ABCA1 • Aβ42 • CSF Aβ42

Drug Development. (PubMed, Alzheimers Dement) - "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."

Journal • Alzheimer's Disease • Atherosclerosis • Cardiovascular • CNS Disorders • ABCA1 • APOE • FASN

A Phase 1 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Pharmacokinetics of Single Ascending Doses of CS6253 in Healthy Volunteers (CTAD 2024) - No abstract available

Clinical • P1 data • PK/PD data

Safety and Pharmacokinetics of Single Ascending Doses and Multiple Ascending Doses of CS6253 in Healthy Volunteers (clinicaltrials.gov) - P1 | N=66 | Active, not recruiting | Sponsor: Artery Therapeutics, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Alzheimer's Disease • CNS Disorders

The ABCA1 agonist CS6253 shows favorable safety and pharmacokinetics in IND-enabling toxicology and Phase 1 human studies aimed at the indication of Alzheimer’s disease. (AAIC 2024) - "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."

Clinical • P1 data • PK/PD data • Alzheimer's Disease • Atherosclerosis • Cardiovascular • CNS Disorders • Dyslipidemia • ABCA1 • APOE • FASN

A novel apoE-mimetic increases brain apoE levels, reduces Aβ pathology and improves memory when treated before onset of pathology in male mice that express APOE3. (PubMed, Alzheimers Res Ther) - "CS treatment reduced Aβ pathology and improved memory only in young male E3FAD, the cohort with the least AD pathology. Therefore, the degree of Aβ pathology or Aβ overproduction may impact the ability of targeting ABCA1 to be an effective AD therapeutic. This suggests that ABCA1-stabilizing treatment by CS-6253 works best in conditions of modest Aβ levels."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • ABCA1 • APOE

Safety and Pharmacokinetics of Single Ascending Doses and Multiple Ascending Doses of CS6253 in Healthy Volunteers (clinicaltrials.gov) - P1 | N=64 | Recruiting | Sponsor: Artery Therapeutics, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Alzheimer's Disease • CNS Disorders

Mechanisms of reduced Apolipoprotein E4 lipidation in iPSC-derived astrocytes (AAIC 2023) - "The protein levels of ABCA1, which mediates cholesterol and phospholipid efflux to the nascent apolipoprotein particles, were lower in APOE4/4 iPSC-derived astrocytes compared to astrocytes derived from isogenic APOE3/3 iPSCs. Advanced image analysis revealed lower ABCA1 protein levels in Rab11 + recycling endosomes and less colocalization between ABCA1 and Rab7, a late endosome marker, in APOE4/4 astrocytes than APOE3/3 astrocytes. Consequently, less ABCA1 was detected at the cell membrane."

Alzheimer's Disease • CNS Disorders • Metabolic Disorders • ABCA1 • APOE

Mechanisms of reduced Apolipoprotein E4 lipidation in iPSC-derived astrocytes (AAIC 2023) - "The protein levels of ABCA1, which mediates cholesterol and phospholipid efflux to the nascent apolipoprotein particles, were lower in APOE4/4 iPSC-derived astrocytes compared to astrocytes derived from isogenic APOE3/3 iPSCs. Advanced image analysis revealed lower ABCA1 protein levels in Rab11 + recycling endosomes and less colocalization between ABCA1 and Rab7, a late endosome marker, in APOE4/4 astrocytes than APOE3/3 astrocytes. Consequently, less ABCA1 was detected at the cell membrane."

Alzheimer's Disease • CNS Disorders • Metabolic Disorders • ABCA1 • APOE

UPREGULATING ABCA1-MEDIATED CHOLESTEROL TRANSPORTATION BY CS6253 – OPPORTUNITY FOR CONVENIENT SC ROUTE OF ADMINISTRATION (AAIC 2023) - "The ABCA1 agonist CS6253 has therapeutic potential for APOE4-associated AD. Safety, PK and biomarker efficacy is being assessed in a Phase 1 study. The SC local tolerance study opens up the potential to self-administer CS6253 SC for optimal convenience and compliance."

Alzheimer's Disease • CNS Disorders • Dementia • Hematological Disorders • ABCA1

Mechanisms of reduced Apolipoprotein E4 lipidation in iPSC-derived astrocytes (AAIC 2023) - "The protein levels of ABCA1, which mediates cholesterol and phospholipid efflux to the nascent apolipoprotein particles, were lower in APOE4/4 iPSC-derived astrocytes compared to astrocytes derived from isogenic APOE3/3 iPSCs. Advanced image analysis revealed lower ABCA1 protein levels in Rab11 + recycling endosomes and less colocalization between ABCA1 and Rab7, a late endosome marker, in APOE4/4 astrocytes than APOE3/3 astrocytes. Consequently, less ABCA1 was detected at the cell membrane."

Alzheimer's Disease • CNS Disorders • Metabolic Disorders • ABCA1 • APOE

Mechanisms of reduced Apolipoprotein E4 lipidation in iPSC-derived astrocytes (AAIC 2023) - "The protein levels of ABCA1, which mediates cholesterol and phospholipid efflux to the nascent apolipoprotein particles, were lower in APOE4/4 iPSC-derived astrocytes compared to astrocytes derived from isogenic APOE3/3 iPSCs. Advanced image analysis revealed lower ABCA1 protein levels in Rab11 + recycling endosomes and less colocalization between ABCA1 and Rab7, a late endosome marker, in APOE4/4 astrocytes than APOE3/3 astrocytes. Consequently, less ABCA1 was detected at the cell membrane."

Alzheimer's Disease • CNS Disorders • Metabolic Disorders • ABCA1 • APOE

Design of the ABCA1 agonist CS6253 Phase 1 SAD and MAD study in male and female, APOE4 and non-APOE4 carriers to assess safety, PK and biomarker efficacy (CTAD 2022) - "The Phase 1 SAD and MAD study of the ABCA1 agonist CS6253 treatment will evaluate safety, PK and biomarker efficacy in male and female subjects with and w/o APOE4. Simultaneous collection and analysis in plasma and CSF of PK and of PD markers including apoE and Ab42/40- ratio will assess clinical potential for this cholesterol-targeting treatment of hereditary APO4-associated AD."

Biomarker • Clinical • P1 data • Alzheimer's Disease • CNS Disorders • ABCA1 • APOE

Strong effects of the ABCA1 agonist CS6253 on Amyloidβ42/40 ratio and lipoproteins in cynomolgus monkeys (AAIC 2022) - No abstract available

ABCA1

Effect of the ABCA1 agonist CS-6253 on amyloid-β and lipoprotein metabolism in cynomolgus monkeys. (PubMed, Alzheimers Res Ther) - "Treatment with the ABCA1 agonist CS-6253 appears to favor Aβ clearance from the brain."

Journal • Alzheimer's Disease • CNS Disorders • Dyslipidemia • ABCA1 • APOE • CSF Aβ42

TREATMENT WITH THE ABCA1 AGONIST CS6253 IN CYNOMOLGUS MONKEYS INCREASES PLASMA APOLIPOPROTEIN E AND A42/40-RATIO (ADPD 2022) - "The findings suggests that CS6253 treatment effects in primates can be assessed by monitoring plasma apoE and Ab42/40-ratio levels, to be confirmed in ensuing human studies."

Alzheimer's Disease • CNS Disorders • APOE

[VIRTUAL] CS6253 ABCA1 AGONIST IN CYNOMOLGUS MONKEYS INCREASE APOA-I SUBSPECIES PREβ-HDL AND LOWERS Aβ42 AND Aβ40 IN CEREBRO SPINAL FLUID (AAIC 2021) - "The CS6253 ABCA1 agonist transiently increases plasma preβ-HDL and reduces CSF concentrations of Aβ42 and Aβ40. The Aβ reduction is consistent with apoE targeted replacement mice models studies where CS6253 reduced Aβ42, prevented AD brain pathology and improved cognition. Studies in human APOE ε4 carriers with and without AD are needed to corroborate these findings and to investigate the therapeutic potential of CS6253 or similar compounds."

Alzheimer's Disease • CNS Disorders • APOE

CS6253 ABCA1 AGONIST IN CYNOMOLGUS MONKEYS INCREASE APOA-I SUBSPECIES PREβ-HDL AND LOWERS Aβ42 AND Aβ40 IN CEREBRO SPINAL FLUID (AAIC 2021) - "The CS6253 ABCA1 agonist transiently increases plasma preβ-HDL and reduces CSF concentrations of Aβ42 and Aβ40. The Aβ reduction is consistent with apoE targeted replacement mice models studies where CS6253 reduced Aβ42, prevented AD brain pathology and improved cognition. Studies in human APOE ε4 carriers with and without AD are needed to corroborate these findings and to investigate the therapeutic potential of CS6253 or similar compounds."

Alzheimer's Disease • CNS Disorders • APOE

[VIRTUAL] CS6253 ABCA1 AGONIST TREATMENT IN JUVENILE CYNOMOLGUS MONKEYS REDUCES CSF AΒ42 AND INCREASES PLASMA AΒ42 IN DOSE-RESPONSE MANNER (ADPD 2021) - "CSF and plasma Aβ42 and Aβ40 were analyzed by SIMOA, CSF APP and amyloid protein complex2B1 (AP2B1) by mass spectrometry.  Results CS6253 treatment decreased CSF levels of Aβ42, Aβ40, APP and AP2B1 and increased plasma Aβ42, Aβ40, both following dose-response pattern, see Figures.  Conclusions The CS6253 ABCA1 agonist reductions of Aβ42, Aβ40, APP and AP2B1 in CSF of juvenile cynos are consistent with previous finding in apoE4 mice models where brain Aβ42 (and P-tau) was reduced, AD pathology was prevented, and cognition improved. Studies in human APOE ε4 carriers are needed to corroborate these findings."

APOE • CSF Aβ42 • Plasma Aβ40 • Plasma Aβ42