Neurogene Announces Expansion and Plans for More Rapid Patient Enrollment of Rett Syndrome Gene Therapy Clinical Trial

Neurogene Inc. (NASDAQ: NGNE) (“Neurogene” or “the Company”), a clinical-stage company founded to bring life-changing genetic medicines to patients and families affected by rare neurological diseases, today 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.

“We are excited to share that we have met our first 2024 program milestones, including dosing the third patient in the NGN-401 Phase 1/2 trial for Rett syndrome and expansion of the trial to include more patients in the current dosing cohort and the addition of a high dose cohort,” said Founder and Chief Executive Officer, Rachel McMinn, Ph.D. “Our clinical development strategy has been to build flexibility and optionality early in the program with two concurrent dose cohorts designed to generate a more complete data package, which we expect will inform future registration discussions with global health authorities. We expect that expansion of the clinical trial and the removal of staggered dosing in Cohort 1 will enable us to treat more patients in a shorter period of time. Based on this update, we expect to complete enrollment of Cohort 1 in the second half of 2024.”

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.