Neurogene (NGNE) Study Update summary

Program Overview and Study Design

• NGN-401 is a gene therapy for Rett syndrome using intracerebroventricular delivery of full-length human MECP2 with EXACT technology to fine-tune expression and avoid toxicity, targeting pediatric (4–10 years) and adolescent/adult (16+ years) female cohorts with classic Rett syndrome and confirmed MECP2 mutation.

• The Phase 1/2 open-label trial enrolled participants with moderate to severe disease, with efficacy assessments at 3–15 months post-dosing and a new adolescent/adult high-dose cohort initiated to support a broader label.

• Key efficacy assessments include CGI-I, CGI-S, RSBQ, and autonomic function measures, with trial design and endpoints informed by natural history data from a 1,000-patient NIH study.

• Prophylactic immunosuppression regimens differ between cohorts, with corticosteroids in cohort 1 and a targeted regimen in high-dose cohorts.

• NGN-401 received FDA RMAT, orphan drug, Fast Track, and rare pediatric designations, and is in the FDA START program, supporting accelerated development and regulatory engagement.

Efficacy Results

• All low-dose pediatric participants showed a two-point improvement in CGI-I, with durable, clinically meaningful gains across hand function, gross motor, communication, and autonomic domains, deepening over time.

• RSBQ scores improved by 28–52% from baseline, with objective improvements in sleep, constipation, and dysphagia, and some participants reaching ideal sleep metrics and improved stool consistency.

• Participants acquired or reacquired complex skills rarely seen in natural history, such as using utensils, climbing stairs, purposeful speech, and overcoming severe dysphagia.

• Multi-domain improvements were observed regardless of mutation severity, with baseline clinical presentation more predictive of response.

• Improvements were not expected based on natural history data, with consistent gains in developmental milestones.

Safety Results

• Low-dose NGN-401 maintained a favorable safety profile, with only mild (Grade 1) adverse events, all resolving or resolved, and no serious adverse events, seizures, or MeCP2 overexpression toxicity observed.

• Most adverse events were known risks of AAV therapy, responsive to steroids, and resolved or resolving.

• High-dose cohort experienced two Grade 3 ALT/AST elevations and one emerging SAE consistent with AAV-related inflammatory response, not impacting the low-dose cohort.

• Prophylactic regimens for high-dose included corticosteroids, rituximab, and sirolimus, with further interventions as needed.

• No safety concerns were identified with the low-dose, which remains the focus for pivotal development.