FDA gives NGN-401, potential Rett gene therapy, RMAT status
Supportive designation follows early safety findings in ongoing Phase 1/2 trial
NGN-401, Neurogene‘s experimental gene therapy for Rett syndrome, was designated a regenerative medicine advanced therapy (RMAT) by the U.S. Food and Drug Administration (FDA).
Based on preliminary data from an ongoing Phase 1/2 trial (NCT05898620), which is testing the gene therapy in girls with Rett, the designation intends to speed the development and review of potential treatments for unmet medical needs. RMAT benefits include early and frequent interactions with the FDA, which provides guidance on a therapy’s development and its eligibility for accelerated review.
Regenerative medicine refers to therapies based on cells or tissues, products from human cells or tissues, or any combination of these therapies or products.
“We are pleased that NGN-401 gene therapy for Rett syndrome received RMAT designation,” Rachel McMinn, PhD, founder and CEO of Neurogene, said in a company press release.
A first Rett patient given the gene therapy at high dose in trial
A first patient in the high-dose group of the Phase 1/2 trial has been treated, and NGN-401 at that dose was well tolerated while showing favorable safety, the company stated. The trial remains on track to complete enrollment in the low-dose group and report on efficacy by the end of this year, with interim high-dose group data expected in the second half of 2025.
“We continued to advance the NGN-401 program with the first patient dosed in Cohort 2 in May, marking an important program milestone and demonstrating an early favorable safety profile with high-dose NGN-401,” McMinn said.
In June, the FDA selected NGN-401Â for its Support for Clinical Trials Advancing Rare Disease Therapeutics (START) pilot program. This program provides opportunities for frequent advice and ad hoc conversations with the agency to address specific development issues.
“We appreciate the FDA’s ongoing commitment to expedite development of our NGN-401 gene therapy for Rett syndrome, with RMAT designation following NGN-401’s selection for the FDA’s START Pilot Program, two synergistic initiatives designed to more rapidly advance promising treatments for patients with unmet medical needs,” McMinn said in a separate release.
“RMAT and START designations underscore the therapeutic potential of NGN-401 for Rett syndrome,” she added.
NGN-401 provides a full-length version of the MECP2 gene, whose mutations are the most frequent cause of Rett. Such mutations impair the function of MeCP2, a protein that controls the activity of other genes. This disrupts the growth and connectivity of nerve cells and leads to disease symptoms.
NGN-401 designed to deliver gene at controlled levels to prevent side effects
The one-time treatment, packaged in an adeno-associated virus (AAV) engineered to be safe, is infused directly into the fluid-filled cavities of the brain, where it’s expected to restore the production of a healthy MeCP2 protein and ease symptoms.
Neurogene reported using its EXACT gene regulation technology to ensure NGN-401 provides highly controlled and consistent levels of the lab-made MECP2 gene. Too much MeCP2 can lead to toxic side effects.
In a Rett mouse model, NGN-401 extended survival and eased the disease severity, while it was well tolerated in nonhuman primates.
The Phase 1/2 trial is enrolling up to 16 girls with Rett, ages 4-10, at three sites in the U.S. and one in Australia. In May, the company reported that the gene therapy was well tolerated in the first three patients treated with a low dose — two in 2023 and one earlier this year. There were no signs of toxicity due to excess MeCP2 protein, with most side effects considered mild and related to the use of the AAV.
Treatment safety and tolerability at five years are the trial’s primary goals. Clinicians will determine NGN-401’s efficacy in easing symptom severity and improving patient outcomes, and changes in behavior will be assessed using the Rett Syndrome Behavior Questionnaire.
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