Cholesterol Efflux Mediator™ VAR 200

Overview

Cholesterol Efflux Mediator^TM VAR 200 is in development for treatment of chronic kidney diseases focal segmental glomerulosclerosis (FSGS), Alport syndrome, and diabetic kidney disease, with initial focus on FSGS. Based on preclinical data, VAR 200 is expected to ameliorate damaging lipid accumulation in the kidneys’ filtration system to halt progression of renal injury that may lead to kidney failure.

The active ingredient of Cholesterol Efflux Mediator VAR 200 is 2-hydroxypropyl-beta cyclodextrin (2HPβCD). 2HPβCD is an oligosaccharide of 7 glucose (sugar) molecules bound together in a 3-D cone-shaped ring. The outer structure is hydrophilic (water soluble), and the center cavity is hydrophobic (water insoluble) enabling incorporation of other hydrophobic molecules, such as cholesterol and other lipids, into its cavity as an inclusion complex.

The active ingredient in VAR 200 is not orally bioavailable due to its high molecular weight and resistance to digestive enzymes, and therefore VAR 200 must be administered intravenously or subcutaneously. Once administered, VAR 200 is distributed to various tissues, with most accumulating in the kidney for excretion into the urine.

VAR 200 interacts with kidney cell membranes, where it can passively and actively mediate transport of cholesterol out of the cell (efflux). Removal of excess cholesterol from kidney podocytes protects against structural damage, resulting in reduced protein in the urine (proteinuria).

PASSIVE CHOLESTEROL EFFLUX WITH VAR 200

Passive cholesterol efflux occurs with interaction of HPβCD with the cell membrane surface. Cholesterol is incorporated into its hydrophobic core as an inclusion complex. Release of the 2HPβCD/cholesterol inclusion complex from the cell membrane surface brings the cholesterol into solution for transfer to cholesterol acceptors, such as HDL¹.

ACTIVE CHOLESTEROL EFFLUX WITH VAR 200

Active cholesterol efflux occurs through mediating metabolism of free cholesterol into oxysterols. Oxysterols activate LXR-transcription factors, resulting in induction of cellular cholesterol efflux pathways, including upregulation cholesterol efflux transporters, ABCA1 and ABCG1, which transport free cholesterol outside the cell to cholesterol acceptors, such as HDL².

VAR 200 Scientific Support

VAR 200 has strong preclinical support in animal models of three different kidney diseases as summarized below:

VAR 200 was evaluated in two FSGS mouse models, an experimental nuclear factor of activated T-cells (“NFAT”) model and an Adriamycin (“ADR”)-induced model, which is characterized by a milder, less progressive form of nephropathy than the NFAT model.

FSGS NFAT Model Data³

FSGS mice (DT) demonstrated increased kidney cortex cholesterol and associated damage to the kidney’s filtration system compared to controls (ST).

Cholesterol Efflux Mediator^TM VAR 200 (CD) reduced kidney cortex cholesterol in FSGS mice, which was associated reduced levels of protein in the urine (Alb/Creat).

FSGS ADR Model Data⁴

Following is a summary of data from the Adriamycin-induced FSGS mouse model.