Neurogene Inc. (Nasdaq: NGNE) has announced positive interim clinical data from the Phase 1/2 open-label trial of NGN-401, a gene therapy for female pediatric patients with Rett syndrome. The low-dose cohort demonstrated a favorable safety profile and showed clinically meaningful improvements in developmental skills. This marks a significant step forward in addressing the underlying cause of this challenging neurodevelopmental disorder, for which there are currently no curative treatments.
Interim Efficacy Data
The interim data, with a cut-off date of October 17, 2024, highlighted the consistent and durable improvements observed in the first four participants in the low-dose Cohort 1 (age range 4-7 years). Assessments were conducted at 15, 12, 9, and 3 months post-dosing. Key findings include:
- All participants achieved a rating of "much improved" (score of 2) on the Clinical Global Impression Scale of Improvement (CGI-I) from baseline, where a score < 3 is considered clinically meaningful.
- All participants showed improvement in the caregiver-completed Rett Syndrome Behavior Questionnaire (RSBQ), with improvements ranging from 28% to 52% from baseline.
- Participants acquired new skills and/or developmental milestones in core clinical domains, including hand function/fine motor skills, language/communication, and ambulation/gross motor skills.
These improvements included the acquisition of complex skills rarely learned in this population, and skills that are rarely relearned after developmental regression, when compared to the NIH-sponsored Rett syndrome natural history study. The new skills and milestones have increased and deepened over time.
Safety Profile
NGN-401 has been well-tolerated in the first seven pediatric participants (N=5 low-dose; N=2 high-dose). The safety data revealed:
- No treatment-related serious adverse events (SAEs) were reported in the low-dose cohort.
- No signs or symptoms indicative of MeCP2 overexpression toxicity were observed.
- Most treatment-related adverse events (AEs) were consistent with known potential risks of adeno-associated virus (AAV) vectors, responsive to steroid treatment, and resolved or resolving.
- No intracerebroventricular (ICV)-related AEs were reported.
- No seizures were reported for any participants following NGN-401 treatment.
It was noted that an emerging treatment-related SAE consistent with known risks of AAV gene therapy was observed in the third high-dose participant who was recently dosed.
Expansion to Adolescent/Adult Cohort
Neurogene has initiated an adolescent/adult Cohort 3 to assess the potential of NGN-401 in a broader patient population. This cohort will enroll three participants ages 16 and above at the high dose.
Regulatory Alignment and Manufacturing
Neurogene has gained alignment with the FDA on its potency assay strategy for NGN-401, a critical step before initiating a registrational trial. The FDA is also aligned with Neurogene’s manufacturing scale-up plans, which are essential for supporting a future commercial product launch.
Future Milestones
Neurogene anticipates completing enrollment in the low-dose pediatric Cohort 1 (N=8) in the fourth quarter of 2024. The company plans to provide an update on the registrational trial design in the first half of 2025 and announce additional interim Phase 1/2 clinical data in the second half of 2025.
About NGN-401
NGN-401 is an investigational AAV9 gene therapy designed as a one-time treatment for Rett syndrome. It delivers the full-length human MECP2 gene under the control of Neurogene’s EXACT™ transgene regulation technology. This technology is designed to enable targeted levels of MECP2 transgene expression, avoiding overexpression-related toxic effects associated with conventional gene therapy.
NGN-401 has received multiple designations from the FDA, including selection for the START Pilot Program, Regenerative Medicine Advanced Therapy (RMAT) designation, orphan drug designation, Fast Track designation, and rare pediatric disease designation. It has also received orphan designation and advanced therapy medicinal product designation from the European Medicines Agency (EMA) and Innovative Licensing and Application Pathway (ILAP) designation from the United Kingdom (UK) Medicines and Healthcare products Regulatory Agency (MHRA).
