Neurogene Inc. announced the expansion of its ongoing Phase 1/2 gene therapy clinical trial for NGN-401 for female pediatric patients with Rett syndrome and updates to enable more rapid enrollment in the trial. Rett Syndrome Program Update: The U.S. Phase 1/2 clinical protocol for NGN-401 has been amended as follows: Cohort 1, which specifies a total dose of 1×1015 total vector genomes delivered via intracerebroventricular (ICV) administration, was expanded from five patients to eight patients. The dosing stagger has been removed from Cohort 1, enabling the remaining patients to be dosed in parallel.

Cohort 2, which specifies a total dose of 3×1015 total vector genomes delivered via ICV administration, was added and is expected to include a total of eight patients. The first three patients in Cohort 2 will be dosed in a staggered manner, with first patient dosing expected in the second quarter of 2024; pending Data and Safety Monitoring Board review of the safety data for the first three patients, the protocol will allow parallel enrollment for the remaining patients in Cohort 2. In addition, the protocol includes a targeted immunosuppression regimen for Cohort 2, designed as a preventative measure to aid in avoiding potential adeno-associated virus (AAV)-related immune responses that have been observed with other AAV-based products in this dose range. The immunosuppression regimen includes the use of rituximab and sirolimus, along with a shortened course of corticosteroids.

Cohort 1 immunosuppression remains unchanged with corticosteroids alone. A similar protocol amendment was submitted to the UK regulatory authorities. These changes are consistent with the Company?s guidance issued in January 2024.

Importantly, in comprehensive nonclinical studies, the EXACT transgene regulation technology embedded in NGN-401 was shown to mechanistically constrain MECP2 transgene expression levels, allowing for the potential to dose escalate and enhance biodistribution to the brain, without the commensurate increase in MECP2 transgene expression observed with conventional gene therapy. Both doses in the updated protocol are below the ?no observed adverse effect? level established in rodent and nonhuman primate models.

A third patient was dosed in the trial early in the first quarter. NGN-401 has been generally well-tolerated and there have been no treatment-emergent or procedure-related serious adverse events, or signs of overexpression-related toxicity observed in any patient. Neurogene remains on track to report interim clinical data from Cohort 1 in the fourth quarter of 2024 and additional data, including from Cohort 2, in the second half of 2025.