PLX-200 is an investigational oral small molecule that was originally developed to lower cholesterol, and is being repurposed by Polaryx Therapeutics to potentially treat a type of Batten disease called late infantile neuronal ceroid lipofuscinosis (LINCL or CLN2 disease). Its compounds have been used safely to treat other indications.

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

How PLX-200 works

Batten disease is caused by mutations in the TPP1 gene, which 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, causing 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 (TFEB) in brain cells. This protein binds and activates the expression of genes involved in lysosome function and biogenesis (the production of new lysosomes). This may reverse the defective functioning of lysosomes, which may benefit patients with Batten disease.

PLX-200 in preclinical studies

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

The company now plans to test the efficacy of PLX-200 in patients, with the goal of getting this potential treatment approved and into clinics where it might help patients with LINCL and other types of NCL diseases. The company intends to submit an investigational new drug (IND) application to the FDA in early 2018, requesting the start of clinical studies of PLX-200.

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