PLX-100 is an investigational therapy being developed by Polaryx Therapeutics to treat Batten disease, the most common form of neuronal ceroid lipofuscinoses (NCLs), a group of neurodegenerative disorders caused by mutations in one of 14 genes. These mutations result in the accumulation of abnormal deposits in lysosomes — cell compartments where unwanted biomolecules are broken down or digested — causing nerve cells in the brain and the retina to deteriorate.

PLX-100 was recently designated an orphan drug by the U.S. Food and Drug Administration (FDA) as a potential treatment for Batten disease.

How PLX-100 works

PLX-100 contains a combination of PLX-200 and all-trans retinoic acid (ATRA), both reported to be safe in treating other conditions (PLX-200 has been studied to lower cholesterol and ATRA has been used to treat acute promyelocytic leukemia). In PLX-100 the two components are combined and repurposed to possibly treat Batten disease.

PLX-200, also developed by Polaryx, works by binding to a receptor found in the nucleus of brain cells called retinoid X receptor-α (RXRα). RXRα functions as an activator of gene expression when bound to its ligand, PPARα. The binding of PLX-200 to RXRα allows the formation of a  PPARα/RXRα heterodimer, which increases the expression of a gene called tripeptidyl peptidase 1 (TPP1), whose deficiency causes Batten disease. TPP1 encodes for an enzyme that digests protein fragments within lysosomes.

PLX-200 also enhances the production of transcription factor EB (TFEB) in brain cells via the PPARα/RXRα pathway. TFEB then activates the genes involved in the production of new lysosomes (biogenesis).

Like PLX-200, ATRA also enhances the production of TFEB and promotes lysosome biogenesis in brain cells (biogenesis being the synthesis of substances by living organisms that leads to new organisms). This may help lysosomes function more effectively in Batten patients.

PLX-100 is intended to combine the activities of both PLX-200 and ATRA so as to provide a synergistic effect, which may allow for lower doses to be effective and bring a clinical benefit. As such, PLX-100 may be a safer option when treating young children with Batten disease.

PLX-100 in preclinical studies

The company reports that PLX-100 in preclinical studies in TPP1-deficient animals showed neuroprotective effects, reduced inflammation, prevented cell death, delayed the loss of mobility, and prolonged treated animals’ lifespan.

Based on these positive results and the orphan drug designation, Polaryx is now planning a clinical trial program that will test PLX-100 for safety and efficacy in people.

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