Neurogene Pauses High-Dose Rett Syndrome Gene Therapy Trial After Serious Adverse Event

• Neurogene's Phase 1/2 trial of NGN-401 for Rett syndrome faced a setback with a participant experiencing a serious hyperinflammatory syndrome after receiving the high dose.
• The FDA allowed Neurogene to proceed with the trial using the lower dose (1E15 vg) after reviewing safety data, while further use of the high dose (3E15 vg) is paused.
• No other treatment-related serious adverse events have been reported in the low-dose cohort or the initial high-dose participants, with mild adverse events resolving with steroids.
• Neurogene is updating the trial protocol to reflect the discontinuation of the high dose and no longer anticipates completing enrollment in the low-dose cohort in Q4 2024.

Neurogene Inc. has announced a pause in the high-dose arm of its Phase 1/2 clinical trial evaluating NGN-401, a gene therapy for Rett syndrome, following a serious adverse event (SAE). The trial participant, who received NGN-401 at a dose of 3E15 vg, experienced a systemic hyperinflammatory syndrome, a rare and life-threatening immune response associated with high doses of adeno-associated virus (AAV) vectors.

The company proactively engaged with the FDA under the START program after the notification of the SAE. The FDA has completed a review of the safety data for NGN-401 and allowed Neurogene to proceed with the Phase 1/2 trial using the 1E15 vg dose. Neurogene has paused further use of the 3E15 vg dose upon initial notification of the SAE and does not plan to enroll any further participants at the 3E15 vg dose level.

Safety Data and Trial Modifications

To date, there have been no other treatment-related SAEs in the clinical trial, including in the five participants who received the 1E15 vg dose and in the first two participants who received the 3E15 vg dose of NGN-401. All treatment-related AEs in the 1E15 vg cohort have been Grade 1 (mild). Most treatment-related AEs are known potential risks of AAV, have been responsive to steroids, and have resolved or are resolving. There have been no signs or symptoms indicative of MeCP2 overexpression toxicity. In addition, there have been no intracerebroventricular (ICV) procedure-related AEs.

Neurogene no longer anticipates completing enrollment in the 1E15 vg cohort of NGN-401 in the fourth quarter of 2024 as the Company updates the protocol to reflect the discontinuation of the 3E15 vg dose.

Rett Syndrome and NGN-401

Rett syndrome is a rare genetic neurological disorder that primarily affects girls, leading to severe impairments in cognitive, motor, and communicative functions. NGN-401 is an investigational gene therapy designed to deliver a functional copy of the MECP2 gene to address the underlying genetic cause of Rett syndrome.

Neurogene is developing novel approaches and treatments to address the limitations of conventional gene therapy in central nervous system disorders. This includes selecting a delivery approach to maximize distribution to target tissues and designing products to maximize potency and purity for an optimized efficacy and safety profile. The Company’s novel and proprietary EXACT™ transgene regulation platform technology allows for the delivery of therapeutic levels while limiting transgene toxicity associated with conventional gene therapy.