Neurogene Reaches Accord With FDA on Plan for Registrational Trial for Rett Syndrome Gene Therapy NGN-401

Neurogene has finished talks with the FDA regarding the protocol for the registrational Embolden clinical trial to evaluate NGN-401, an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat Rett syndrome.¹

As such, Neurogene expects to begin dosing patients in the trial before the end of this year. The company anticipates that the study will recruit patients at 13 different trial sites based on “strong interest from the Rett syndrome community.”¹ NGN-401 is currently being evaluated in a phase 1/2 clinical trial (NCT05898620). NGN-401 has previously received regenerative medicine advanced therapy (RMAT) designation from the FDA and was selected for the FDA’s Support for Clinical Trials Advancing Rare Disease Therapeutics (START) Pilot Program.^2,3

“In preparation for the Embolden registrational trial, we expanded our clinical trial footprint and have more than doubled our presence in the United States and plan to initiate dosing this quarter,” Rachel McMinn, PhD, the founder and chief executive officer of Neurogene, said in a statement.¹ “Being part of the FDA’s START pilot program and having RMAT designation, we are well-positioned to engage in early discussions with the FDA with the goal of an expedited biologics license application submission.”

Alongside the aforementioned update, Neurogene also relayed preclinical findings it is presenting at the European Society of Gene & Cell Therapy (ESGCT) Annual Congress, which is being held in Seville, Spain, from October 7 to 10, 2025. It pointed out that in nonhuman primates (NHPs) intracerebroventricular (ICV) delivery of NGN-401 enabled increased expression of NGN-401's transgene mRNA in regions of the brain considered key to Rett syndrome pathophysiology in comparison to intrathecal lumbar (IT-L) delivery of the product. Higher expression in key brain regions was seen with the ICV method both when ICV and IT-L used a dose that approximates the dose being used in human patients in the phase 1/2 trial (1x10¹⁵ vg) and when the IT-L method used a dose about 4 times higher than the clinically relevant dose being used with the ICV method. Neurogene also highlighted that in peripheral organs such as the liver peripheral exposure of vector genome biodistribution was comparable for equivalent ICV and IT-L doses.

“Feedback from the Rett syndrome community and key opinion leaders reinforce that the decision to undergo gene therapy treatment is driven by a single critical factor: the potential for meaningful improvement,” McMinn continued.¹ “The route of administration data presented at the ESGCT Congress this week provide a potential rationale for the global improvement and multidomain skill acquisition observed in our previously reported NGN-401 phase 1/2 efficacy data. Importantly, the comparable systemic exposure between ICV and IT-L confirms there is no liver-sparing benefit to IT-L administration, consistent with clinical data from intra-cerebrospinal fluid administered products.”

Notably, in November 2024, a patient treated with NGN-401 in the phase 1/2 study was reported to be in critical condition following a serious adverse event (SAE).^4,5 The SAE, which was previously reported by Neurogene as an emerging treatment-related SAE consistent with the known risks of AAV vector-based gene therapy, was then described as constituting signs of a rare and life-threatening immune response known as a systemic hyperinflammatory syndrome. According to Neurogene, systemic hyperinflammatory syndromes, which include hemophagocytic lymphohistiocytosis (HLH) and multisystem inflammatory syndrome, are associated with aberrant cytokine release and are known to have occurred in conjunction with systemic exposures to high doses of AAVs. The patient, who was the third to be treated in the study’s high dose cohort, had received a dose of 3x10¹⁵ vg of the gene therapy product.

REFERENCES
1. Neurogene Announces Positive Regulatory Update for NGN-401 Gene Therapy in Rett Syndrome with Plans to Initiate Dosing in Embolden™ Registrational Trial in Q4 2025. News release. Neurogene Inc. October 9, 2025. Accessed October 9, 2025. https://ir.neurogene.com/news-releases/news-release-details/neurogene-announces-positive-regulatory-update-ngn-401-gene
2. Neurogene Announces RMAT Designation for NGN-401 Investigational Gene Therapy for Rett Syndrome. News release. August 7, 2024. Accessed October 9, 2025. https://www.businesswire.com/news/home/20240807880017/en/Neurogene-Announces-RMAT-Designation-for-NGN-401-Investigational-Gene-Therapy-for-Rett-Syndrome
3. Neurogene Announces NGN-401 Gene Therapy for Rett Syndrome Selected by FDA for START Pilot Program. News release. Neurogene. June 3, 2024. Accessed October 9, 2025. https://ir.neurogene.com/news-releases/news-release-details/neurogene-announces-ngn-401-gene-therapy-rett-syndrome-selected
4. Neurogene provides update on NGN-401 gene therapy clinical trial for Rett syndrome. News release. Neurogene Inc. November 18, 2024. Accessed October 9, 2025. https://ir.neurogene.com/news-releases/news-release-details/neurogene-provides-update-ngn-401-gene-therapy-clinical-trial
5. Neurogene reports positive interim efficacy data from first four low-dose pediatric participants in NGN-401 gene therapy clinical trial for Rett syndrome. News release. Neurogene Inc. November 11, 2024. Accessed October 9, 2025. https://ir.neurogene.com/news-releases/news-release-details/neurogene-reports-positive-interim-efficacy-data-first-four-low