Written agreement from FDA to evaluate NGN-401 in females with Rett syndrome ages 3 years and older based on natural history study analysis

Neurogene Inc., a clinical-stage company founded to bring life-changing genetic medicines to patients and families affected by rare neurological diseases, announced details of Embolden, the Company’s registrational clinical trial designed to evaluate NGN-401 gene therapy for the treatment of females with Rett syndrome in participants ages 3 years and older. The Company has written agreement from the U.S. Food and Drug Administration (FDA) on key aspects of the registrational trial’s design.

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“We appreciate the partnership with the FDA as we aligned on the key elements of our NGN-401 registrational trial design, which will allow for rapid conversion of the current Phase 1/2 study to a pivotal trial,” said Rachel McMinn, Ph.D., Founder and Chief Executive Officer of Neurogene. “We believe that the robust endpoint design, which was informed by key opinion leaders, caregiver input and primary market research with payors, will support NGN-401’s best-in-class potential and provide key differentiating data critical to the Rett syndrome community and the future commercial success of NGN-401.”

“I appreciate the multi-domain approach across the clinical manifestations of Rett syndrome, and rigor in which the primary endpoint will be evaluated, including both the clinician perspective of improvement using the CGI-I scale with Rett syndrome anchors and videos to demonstrate gains of skills that are clinically meaningful for girls and women with Rett syndrome and their families,” said Elizabeth M. Berry-Kravis, M.D., Ph.D., Professor of Pediatrics, Neurological Sciences and Biochemistry at Rush University, and principal investigator in the NGN-401 clinical trial. “Participants treated with NGN-401 have demonstrated increased independence, with both fine and gross motor function improvement, and gained the ability to better communicate wants, needs and choices. I have been impressed with the improvements observed in participants after NGN-401 administration, which have included global improvement in signs and symptoms of Rett syndrome and gains of multi-domain developmental milestones that would not be expected to occur spontaneously in the post-regression stage of Rett syndrome. Evaluating treatment effect in participants ages 3 and above in the registrational study will provide important insights on the potential benefits of NGN-401 in younger patients early in the course of this progressive disease.”

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Obtained Written Agreement from FDA on the Following Key Elements of Embolden Registrational Trial Design After Discussions Under the START Program

  • Study Design: Open-label, single arm, baseline control (i.e., participantsserving as their own control); N=18 proposed, subject to feedback from the FDA.
  • Patient Population: Females ages ≥ 3 years with Rett syndrome, which is consistent with Neurogene’s analysis of the NIH-sponsored, International Rett Syndrome Foundation (IRSF) Rett syndrome natural history study that shows patients ages 3 and above rarely learn new skills/reach developmental milestones or relearn skills once lost. The FDA’s written agreement endorsed the Company’s analysis.
  • Dose: 1E15 vector genomes (vg).
  • Primary Endpoint: Responder-based composite endpoint that will assess an improvement in the Clinical Global Impression-Improvement (CGI-I) scale with Rett syndrome anchors and the gain of a developmental milestone/skill, compared to a participant’s own baseline. Responders are defined as participants who:
    • Attain a CGI-I score of ≤ 3 (“minimally improved”); and
    • Gain any one developmental milestone/skill from a list of 28, as captured through standardized video recordings and independently verified by blinded central raters.
      • Developmental milestones/skills were informed by a Rett syndrome caregiver survey, provided to the FDA, demonstrating that the acquisition of any single skill within the selected set is considered clinically meaningful.
    • The primary endpoint will be evaluated at 12 months following NGN-401 administration, with feedback pending from the FDA to consider the addition of a 6-month endpoint.

Neurogene has begun registrational trial initiation activities.

“It has been incredibly rewarding to see how RSRT’s early investments in foundational Rett syndrome science helped lay the groundwork for what’s now a promising gene therapy program approaching a registrational trial,” said Monica Coenraads, Founder and Chief Executive Officer of RSRT. “RSRT has been a long-time champion of addressing the underlying genetic cause of Rett syndrome and Neurogene’s program has the potential to do just that. We appreciate the thoughtful design of the trial that importantly incorporates the caregiver perspective on what meaningful improvement may look like. We congratulate the Neurogene team on reaching alignment with the FDA and thank the Rett community at large for their support in advancing this program. The future is bright!”

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“Our partnership with Neurogene reflects a shared commitment to accelerating meaningful treatments for Rett syndrome,” said Laura Hameed, Chief Executive Officer of the International Rett Syndrome Foundation (IRSF). “The use of IRSF’s Natural History Study data to support the NGN-401 gene therapy registrational trial design is a powerful example of how families accelerate and streamline therapeutic development. We are grateful to the families that contributed to the NHS, and to the families participating in this trial whose time and commitment are essential to evaluating gene therapy for Rett syndrome.”

Phase 1/2 Trial Data Support Registrational Trial Design

Previously disclosed clinical data from the Phase 1/2 study* support the registrational trial design. Data showed improvements in Rett syndrome assessments with an aggregate of 23 developmental milestones/skills acquired in the first four participants. Specifically, the four participants:

  • Each achieved a clinically meaningful rating of 2, or “much improved,” on the CGI-I; and
  • Collectively achieved 23 developmental milestones/skills in the core clinical domains of Rett syndrome – hand function/fine motor, communication/language, and ambulation/gross motor, including:
    • Participant 1 gained 10 skills across multiple domains by 15 months post-dose;
    • Participant 2 gained 8 skills across multiple domains by 12 months post-dose;
    • Participant 3 gained 3 skills across multiple domains by 9 months post-dose; and
    • Participant 4 gained 2 skills by 3 months post-dose.

*Efficacy data from the first four participants; as of data cut-off date of October 17, 2024

Phase 1/2 Trial Enrollment and Update

Neurogene previously shared that five additional participants had been dosed in the Phase 1/2 portion of the NGN-401 clinical trial during the first half of 2025. A total of 10 participants have received the 1E15 vg dose. There has been no evidence of hemophagocytic lymphohistiocytosis (HLH) / hyperinflammatory syndrome in any participant at the 1E15 vg dose level. Neurogene remains on track to share updated clinical efficacy and safety data in the second half of 2025.

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Source – businesswire