Rett gene therapy NGN-401 safe in first patients dosed in trial

Neurogene also plans UK trial of experimental treatment

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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NGN-401, Neurogene’s gene therapy candidate for Rett syndrome, was well tolerated in the first three patients dosed in a Phase 1/2 clinical trial.

The Phase 1/2 trial (NCT05898620) is enrolling girls with Rett, ages 4-10, at three sites in the U.S. The company also plans to establish the first clinical trial for the treatment in the U.K., following recent regulatory approval.

Trial results were presented during the American Society of Gene and Cell Therapy (ASGCT) annual meeting, held May 7-11 in Baltimore. The company expects to share interim efficacy data from the first group of patients later this year, and additional results, including data from a second group of participants, in 2025.

“The NGN-401 data presented at ASGCT demonstrate a favorable tolerability profile in the first three pediatric patients … with no signs or symptoms of overexpression-related toxicity reported in any patient,” Rachel McMinn, PhD, Neurogene’s founder and CEO, said in a company press release.

In most cases, Rett syndrome is caused by mutations in the MECP2 gene that impair the function of MeCP2, a protein that regulates the activity of other genes. The loss of MeCP2 impairs the growth and connectivity of neurons (nerve cells), leading to disease symptoms.

NGN-401 provides a full-length version of the gene, packaged in a harmless adeno-associated virus (AAV). The therapy is delivered directly into the fluid-filled cavities of the brain, a process known as intracerebroventricular infusion, in a one-time treatment.

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Technology designed to deliver controlled, consistent therapy without toxic effects

The gene therapy was developed using Neurogene’s EXACT gene regulation technology, for the delivery of highly controlled and consistent levels of the lab-made MECP2 gene without the toxic effects associated with high levels of the MeCP2 protein, or overexpression, associated with conventional gene therapy.

“We designed NGN-401 to overcome the limitations of conventional gene therapy for Rett syndrome by incorporating our EXACT transgene regulation technology, which we believe provides tolerable and therapeutic levels of protein expression to the key areas of the brain and nervous system that drive disease,” McMinn said.

Preclinical studies showed NGN-401 extended survival and eased the disease burden in a mouse model of Rett syndrome, without signs of toxicity associated with MeCP2. Data presented at ASGCT showed that the therapy was well tolerated in non-human primates, without overexpression concerns.

The ongoing clinical trial is assessing NGN-401’s safety, tolerability, and preliminary efficacy in girls with Rett syndrome, following them for several years after treatment. The first group of patients consists of eight girls, receiving a low NGN-401 dose (1x1E 15 vector genomes).

The first two girls were dosed in 2023, and the third received the treatment this year. So far, the therapy has been well tolerated, with no treatment- or procedure-related serious adverse events, after a follow-up between three and nine months.

All reported adverse events were mild, and were mainly known potential risks of AAV, including increased blood levels of liver enzymes and decreased levels of certain immune proteins.

There were no signs of overexpression toxicity, even in a girl with a milder form of Rett, predicted to result in residual MECP2 gene activity.

A second group of eight girls will receive a high dose of NGN-401 (3 x 10^15 vector genomes). As with the first group, the first three patients will be dosed in a staggered manner, and if the gene therapy is considered safe, the other five will be dosed in parallel.

Efficacy measures will include clinician-rated assessments of symptom severity and patient improvement, as well the Rett Syndrome Behavior Questionnaire that evaluates behavioral challenges.

“Gene therapy has the potential to address the underlying cause of Rett syndrome with a one-time treatment, and these interim safety data from the NGN-401 trial provide an important milestone on the path to realizing its potential for patients,” said Bernhard Suter, MD, medical director of the Blue Bird Circle Rett Center at Texas Children’s Hospital and principal investigator in the clinical trial.