Rett gene therapy NGN-401 selected for FDA’s START program

NGN-401 is being evaluated in a Phase 1/2 trial, which is enrolling at three sites

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by Steve Bryson, PhD |

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The U.S. Food and Drug Administration (FDA) has selected Neurogene‘s NGN-401, an experimental gene therapy for Rett Syndrome, for its Support for Clinical Trials Advancing Rare Disease Therapeutics (START) pilot program.

As part of START, which the FDA launched in September 2023, Neurogene will have enhanced communications with the agency to accelerate NGN-401’s development. The company will have regular ad hoc conversations with the FDA to address development issues, such as clinical study design and choosing a patient population and control group.

The gene therapy is one of six new drugs selected for START, three by the Center for Biologics Evaluation and Research (CBER), and three by the Center for Drug Evaluation and Research (CDER).

“We are honored that NGN-401 gene therapy for Rett syndrome has been chosen as one of only three CBER programs for FDA’s START pilot program and are grateful that the FDA has committed to investing significant agency resources to accelerate development of NGN-401,” Rachel McMinn, PhD, founder and CEO of Neurogene, said in a company press release.

Most cases of Rett are caused by mutations in the MECP2 gene, which alters the structure or lowers the production of MeCP2, a protein that controls the activity of other genes. Without normal MeCP2 activity, the growth and connectivity of nerve cells are impaired, leading to Rett symptoms

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What does NGN-401 gene therapy do in Rett syndrome?

NGN-401 is a gene therapy, meaning it’s designed to replace the defective gene with a fully functioning one. Packaged in a harmless adeno-associated virus (AAV), the one-time treatment will be infused directly into the brain’s fluid-filled cavities.

Selection in the milestone-driven START program was based on NGN-401’s potential for clinical benefit and the readiness of its developmental program. Along with addressing unmet medical needs for a rare neurodegenerative condition, START applications require clinical and nonclinical development plans and an update on developmental status.

The gene therapy’s development plans must also align with chemistry, manufacturing, and controls (CMC) development timelines, which ensure quality and consistency during a drug’s manufacturing.

“We look forward to participating in this landmark effort with the FDA as we seek to rapidly advance NGN-401 toward a potential registrational study for the patients and families who live with this devastating disease,” McMinn said.

Using Neurogene’s EXACT gene regulation technology, NGN-401 was made to deliver consistent levels of the lab-made MECP2 gene without the harmful effects associated with high levels of MeCP2.

In preclinical studies, NGN-401 extended survival and eased disease severity in a mouse model of Rett syndrome and was well tolerated in nonhuman primates.

NGN-401 is being evaluated in a Phase 1/2 trial (NCT05898620), which is enrolling girls with Rett, ages 4-10, at three U.S. sites. The therapy was well tolerated in the first three girls who received a low dose. So far, there have been no serious adverse events after a follow-up between three and nine months.

All the adverse events were mild and associated with the known risks of AAV, such as elevated blood levels of liver enzymes and a drop in certain immune proteins. There were also no signs of toxicity associated with excess MECP2 production.

A second group of three girls will receive a high dose of NGN-401, and if it’s deemed safe, five more girls will be dosed in parallel.

Clinicians will evaluate the impact of NGN-401 on symptom severity and patient improvement, and the Rett Syndrome Behavior Questionnaire will assess behavior. According to Neurogene, interim efficacy data from the trial will be reported by the end of the year.

“We are pleased our application demonstrated the potential clinical benefits of NGN-401, one of the factors evaluated by the FDA in making its selection,” McMinn added.