Updates Delayed on Regenxbio’s CLN2 Gene Therapy Programs

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by Forest Ray PhD |

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Regenxbio updates

Regenxbio plans to provide updates on its RGX-181 and RGX-381 gene therapy candidates for late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease, one of the most common forms of Batten disease, in the second half of this year.

The company is currently reviewing information requests from the U.S. Food and Drug Administration (FDA), related to a clinical hold the agency placed on a proposed trial of RGX-181, after the company submitted an investigational new drug (IND) application.

In an open letter to the Batten disease community, Regenxbio stated the FDA had requested more information regarding “the initial dose selection and certain study drug administration procedures.”

The delay involved in attending to the FDA request also has pushed updates on the RGX-381 program to the second half of the year. Regenxbio intended to submit an IND application for RGX-381 to the FDA or to foreign drug regulators this year.

RGX-181 is an investigational one-time gene therapy designed to deliver a functional copy of the TPP1 gene to cells of the central nervous system (CNS,  the brain and spinal cord).

Mutations in TPP1 cause CLN2. The enzyme produced by this gene is critical to breaking down fat and protein molecules called lipofuscins, which then accumulate to toxic amounts, eventually killing the cells in which they are found. Nerve cells are especially sensitive to damage by lipofuscins, leading to the neurological symptoms seen in CLN2.

Preclinical data from studies involving animal models of CLN2 showed that a single injection of RGX-181 significantly improved animals’ neurological symptoms and survival times by increasing the amount of TPP1 enzyme throughout the CNS.

The FDA has granted the investigational therapy both rare pediatric disease and orphan disease designations, both meant to ease a potential medicine’s path to market.

RGX-381 is meant to deliver the TPP1 gene directly to the retina — the layer of the eye containing light-sensitive cells — to correct for symptoms of CLN2 in the eyes (ocular manifestations). Ocular manifestations typically first appear around age 4. They involve rapid vision loss, progressing to blindness over several years. No treatment currently exists for CLN2-related vision loss.

Both therapies use an adeno-associated virus to deliver their copies of TPP1. These non-replicating viruses are a common gene therapy tool, used because they cannot cause disease and rarely trigger immune responses.