A Phase 1 Randomized, Double-Blind, Placebo Controlled Study to Evaluate the Safety and Pharmacokinetics of Single Ascending Doses and Multiple Ascending Doses of CS6253 in Healthy Volunteers and in APOE4 Carriers

* Phase 1A SAD: Five or more cohorts of 8 healthy volunteers (HVs) will receive a single IV bolus injection of study drug or placebo. The first 4 cohorts will be male only. The last cohort will be repeated with the max safe dose of the previous cohorts in healthy elderly subjects (male and female of non childbearing potential, > 50years)
* Phase 1B MAD: Two or more cohorts of 8 male and female HVs will receive multiple (4) IV bolus injections of study drug or placebo every 72 hours.
* Phase 1 Subcutaneous SC Cohort: One cohort of 6 male and 6 female HVs will receive one SC injection of study drug.

Start Date23 Oct 2023

Sponsor / Collaborator

Artery Therapeutics, Inc.

[+1]

100 Clinical Results associated with Artery Therapeutics, Inc.

0 Patents (Medical) associated with Artery Therapeutics, Inc.

Literatures (Medical) associated with Artery Therapeutics, Inc.

01 Dec 2024·Alzheimer's & Dementia

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

Author: Winblad, Bengt ; Johansson, Jan O. ; Zetterberg, Henrik ; Yassine, Hussein N ; Cummings, Jeffrey L. ; Michaelson, Daniel M

AbstractBackgroundABCA1‐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.MethodConventional 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.ResultToxicology 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.ConclusionEnhancing 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.

01 Dec 2023·Alzheimer's & Dementia

UPREGULATING ABCA1‐MEDIATED CHOLESTEROL TRANSPORTATION BY CS6253 – OPPORTUNITY FOR CONVENIENT SC ROUTE OF ADMINISTRATION

Author: Cummings, Jeffrey L. ; Winblad, Bengt ; Johansson, Jan O. ; Zetterberg, Henrik ; Michaelson, Daniel M ; Yassine, Hussein N.

AbstractBackgroundThe ATP‐binding cassette transporter A1 (ABCA1) is a validated target for AD and upregulation has therapeutic potential in APOE4‐associated AD. The apoE4 protein compared to E2/E3 has impaired interaction with the ABCA1 transporter protein, affecting cholesterol homeostasis in the brain, causing dementia and hemorrhage. CS6253 is an ABCA1‐agonist that in monkey’s has shown safety and increase in Ab42/40‐ratio. A phase 1 SAD‐MAD with CS6253 administered IV was initiated. Here we describe translational efforts for transitioning from IV to SC route‐of‐administration.MethodThe Phase 1 is initiated with SAD:In 4‐6 cohorts of 8 subjects (6 active: 2 placebo) CS6253 starting with 1 mg/kg will be administered IV and plasma and CSF collected simultaneously over 24 hours to assess PK and response markers, and, MAD: In 3‐4 cohorts of 8 subjects (6 active: 2 placebo) CS6253 will be administered to elderly stratified for sex and APOE4 status.Using the identical CS6253 drug product, a GLP local‐tolerance study in rats was conducted to support up to 30 days SC administration in humans. Rat groups of n = 12 received PBS‐control and 7.5, 25 and 75 mg/kg CS6253 SC every other day, 7 times. PK is analyzed by LC‐MS following first and 7th/last dose.ResultBodyweight: Treated animals gained weight throughout the study at a comparable rate to control; no Test Article(TA)‐related variations identified.Clinical Signs: No TA‐related observations were noted, all animals remained in good condition until the end of dosing and end of recovery.Food consumption: No TA‐related effects on food consumption, all means were comparable to controls.Gross Pathology: No gross lesions were observed for terminal and recovery animals.Human Phase 1 SAD results are expected late summer of 2023 and human MAD data late fall of 2023 and with clearing local‐tolerance toxicology the CS6253 program can transition from IV to SC route‐of‐administration.ConclusionThe 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.

01 Dec 2022·Alzheimer's Research & Therapy

Effect of the ABCA1 agonist CS-6253 on amyloid-β and lipoprotein metabolism in cynomolgus monkeys

Article

Author: Yassine, Hussein N ; Parks, Bryan A ; Meuret, Cristiana ; Johansson, Johannes ; Smadi, Sabrina ; Johansson, Jan O ; Xian, Haotian ; Noveir, Sasan D ; Martinez, Ashley E ; Kerman, Bilal E ; Kuklenyik, Zsuzsanna ; Zetterberg, Henrik ; Mack, Wendy J

Abstract Background Inducing brain ATP-binding cassette 1 (ABCA1) activity in Alzheimer’s disease (AD) mouse models is associated with improvement in AD pathology. The purpose of this study was to investigate the effects of the ABCA1 agonist peptide CS-6253 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.MethodsCS-6253 peptide was injected intravenously into cynomolgus monkeys at various doses in three different studies. 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.ResultsFollowing CS-6253 intravenous injection, within minutes, small plasma high-density lipoprotein (HDL) particles were increased. In two independent experiments, plasma TG, apolipoprotein E (apoE), and Aβ42/40 ratio were transiently increased following CS-6253 intravenous injection. This change was associated with a non-significant decrease in CSF Aβ42. Both plasma total cholesterol and HDL-cholesterol levels were reduced following treatment. AF4 fractionation revealed that CS-6253 treatment displaced apoE from HDL to intermediate-density- and low density-lipoprotein (IDL/LDL)-sized particles in plasma. In contrast to plasma, CS-6253 had no effect on the assessed CSF apolipoproteins or lipids.ConclusionsTreatment with the ABCA1 agonist CS-6253 appears to favor Aβ clearance from the brain.

100 Deals associated with Artery Therapeutics, Inc.

100 Translational Medicine associated with Artery Therapeutics, Inc.

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Drug(Targets)	Indications	Global Highest Phase

CS-6253 ( ABCA1 )	Alzheimer Disease More	Phase 1 Clinical
ATI-5261 ( APOA1 x APOE )	Atherosclerosis More	Preclinical
Dipep (Artery Therapeutics)	-	Preclinical

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