Variant Pharmaceuticals Has a New Name - ZyVersa Therapeutics, Inc.
VAR 200, 2-Hydroxypropyl-Beta Cyclodextrin (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.
2HPβCD is not orally bioavailable due to its high molecular weight and resistance to digestive enzymes, and therefore must be administered intravenously or subcutaneously. Once administered, 2HPβCD is distributed to various tissues, with most accumulating in the kidney for excretion into the urine.
In the kidney, as well as in other tissues, 2HPβCD interacts with 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 proteinuria.
Passive cholesterol efflux occurs with formation of 2HPβCD dimers, which bind to the cell membrane surface and incorporate cholesterol 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 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 has strong pre-clinical support in three different animal models of kidney disease as summarized below:
Following is a summary of data from the Adriamycin-induced FSGS mouse model.