PLX-200 is an investigational oral small molecule that was originally developed to lower cholesterol. Polaryx Therapeutics is repurposing it to potentially treat juvenile Batten disease (also known as CLN3 disease) and late infantile Batten disease (also known as CLN2 disease).

The U.S. Food and Drug Administration (FDA) designated PLX-200 an orphan drug in August 2017.

How does PLX-200 work?

Late infantile Batten disease is caused by mutations in the TPP1 gene. This gene encodes for an enzyme called tripeptidyl peptidase 1 (TPP1). The role of this enzyme is to digest protein fragments within lysosomes (or cell compartments involved in waste removal). Poorly functional TPP1 due to the mutation results in the accumulation of protein fragments within lysosomes. This causes damage to cells and, particularly, to neurons (nerve cells).

PLX-200 is designed to bind to retinoid X receptor-α (RXRα), which is a receptor found in the nucleus of brain cells. RXRα is a transcription factor, or a protein that activates gene expression when bound by its ligand, called PPARα. The binding of PLX-200 to RXRα enhances the binding of the receptor with its ligand, and the formation of a PPARα/RXRα heterodimer. This heterodimer can then bind to the TPP1 gene and increase its expression in neurons.

PLX-200 can also enhance the production of transcription factor EB in brain cells. This protein binds and activates the expression of genes involved in lysosome function and biogenesis (the production of new lysosomes) — thereby potentially reversing the defective functioning of lysosomes, which may benefit patients with Batten disease.

PLX-200 in clinical trials

Polaryx reported that PLX-200 demonstrated neuroprotective activity in TPP1-deficient animals and prolonged their lifespan, delaying loss of mobility and reducing inflammation and cell death.

The company plans to test the efficacy of PLX-200 in clinical trials. The FDA has approved the company’s investigational new drug applications permitting the start of trials in both CLN2 disease and CLN3 disease.

Last updated: April 13, 2020

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