A participant in Neurogene's clinical trial for NGN-401, an experimental gene therapy for Rett syndrome, has died after experiencing severe complications following administration of the high dose. The company disclosed the death in a regulatory filing, noting that the FDA is permitting the Phase 1/2 study to continue with the low dose of the therapy.
Trial Details and FDA Response
The patient, a girl aged 4 to 10, received 3E15 vector genomes (vg) of NGN-401 on November 5th as part of the high-dose group in an ongoing open-label clinical trial. Following signs of a systemic immune reaction, the FDA reviewed safety data from the low-dose group (1E15 vg) and allowed Neurogene to proceed with the trial at the lower dose. Neurogene is updating the trial protocol to remove the 3E15 vg dose and will not enroll further participants in the high-dose group.
NGN-401 Mechanism and AAV Delivery
NGN-401 delivers a functioning version of the MECP2 gene to cells, aiming to restore expression of the protein critical for brain function. Rett syndrome is a neurodevelopmental disorder caused by mutations in the MECP2 gene. The therapy uses an adeno-associated virus serotype 9 (AAV9) vector to deliver the gene directly to the cerebrospinal fluid in the ventricles of the brain via an implanted port.
Expert Commentary on Safety and Dosing
Kyle Fink, associate professor of neurology at the University of California, Davis, noted the FDA's decision to allow the trial to continue suggests sufficient data on the safety and efficacy of the low dose to outweigh the risks. Eric Marsh, professor of neurology and pediatrics at the University of Pennsylvania, stated that this event provides insight into the upper limit of safe dosing for AAV9 vectors.
Previous Interim Data and Future Plans
Neurogene previously reported that the first four participants in the low-dose group demonstrated improvements in language and communication, hand function, and gross motor skills, with no serious adverse events. The company expects to resume dosing in the low-dose cohort after completing protocol revisions. An update on the design of NGN-401’s registrational study is expected in the first half of next year, with additional interim Phase 1/2 data anticipated in the second half of 2025.
Broader Context of Rett Syndrome Therapies
NGN-401 is one of several Rett syndrome therapies under development. Taysha Gene Therapies is also testing a gene therapy, TSHA-102, in clinical trials. In March 2023, the FDA approved the first drug for Rett syndrome, trofinetide.
Considerations for Brain-Directed Gene Therapy
Walter E. Kaufmann, adjunct professor of human genetics at Emory University School of Medicine, noted that while direct CNS administration typically causes milder reactions, the reported immune reaction shows that inflammatory responses can still occur. Data suggest that AAV vectors can leak into the periphery even with direct cerebrospinal fluid delivery, raising questions about the dose at which systemic responses are elicited.
