Neurogene (NGNE) Virtual CNS Forum summary

Program and technology overview

• Lead program NGN-401 targets Rett syndrome, a rare neurodevelopmental disorder with severe impairments and no approved therapies addressing its root cause.

• NGN-401 uses the EXACT platform to control transgene expression at the cellular level, critical for efficacy and safety in Rett syndrome.

• Interim phase 1/2 data from four patients showed clinically meaningful improvements across multiple domains, including hand function, motor skills, and communication.

• Improvements observed were beyond what is expected in the natural history of Rett syndrome, including regaining lost or never-learned developmental milestones.

• Additional clinical data from ongoing trials are expected in the second half of 2025.

Clinical trial design and regulatory strategy

• Future pivotal trial design focuses on control strategy and primary endpoints, with a preference for single-arm studies using natural history data as a comparator.

• Placebo arms are considered impractical due to unblinding risks and ethical concerns; delayed-start designs are an alternative if more data are needed.

• Endpoints under consideration include CGI-I, developmental milestones, and RSBQ, with input from clinicians, caregivers, and payers to ensure clinical relevance.

• Ongoing engagement with the FDA under the START pilot program has been positive, with strong alignment and regulatory flexibility for rare disease therapies.

• Regulatory guidance on the pivotal trial is expected in the first half of 2025.

Safety, dosing, and protocol modifications

• A severe hyperinflammatory reaction (HLH) was observed at the highest dose (3E15), leading to its removal from the protocol.

• The ongoing and future trials use a lower 1E15 dose, which translates to a safer exposure level based on published data.

• Protocol modifications include enhanced monitoring for HLH markers to enable early detection and intervention.

• No HLH cases have been associated with AAV9 doses lower than 1E14 VG/kg.