Neurogene has announced a pause in the high-dose arm of its Phase 1/2 clinical trial (NCT05898620) evaluating NGN-401, an investigational adeno-associated viral (AAV) gene therapy for Rett syndrome, after a participant experienced a serious adverse event (SAE). The participant, who received the high dose (3E15 vg), developed systemic hyperinflammatory syndrome and is currently in critical condition.
The company, in consultation with the FDA through the START program, has decided to discontinue further enrollment in the high-dose cohort. Rachel McMinn, PhD, founder and chief executive officer at Neurogene, expressed the company's concern, stating, "We are deeply saddened for the family... The safety of the participants in our clinical trial is and remains our foremost priority."
Continued Dosing in Low-Dose Cohort
Following a safety review, the FDA has permitted Neurogene to continue dosing in the low-dose cohort (1E15 vg). To date, treatment-related adverse events observed in the low-dose cohort have been mild, consistent with known potential risks of AAV treatments, and responsive to steroid treatment. Neurogene is updating the trial protocol to reflect the discontinuation of the 3E15 vg dose, which will impact the expected completion of enrollment in the low-dose cohort.
Promising Early Data Preceded Safety Concerns
The announcement follows recent positive interim efficacy data from the first four participants in the low-dose cohort. These patients achieved a rating of "much improved" on the Clinician Global Impression Scale of Improvement from baseline. Caregiver-completed Rett Syndrome Behavior Questionnaire scores also showed improvements ranging from 28% to 52% from baseline. The data indicated progress in core Rett syndrome areas, including hand function, language, and ambulation, with gains in complex skills rarely seen after developmental regression.
At the time of the initial data release, NGN-401 was considered well-tolerated, with no signs or symptoms indicative of MECP2 overexpression toxicity. The therapy did not result in any intracerebroventricular-related adverse events or seizures, and most treatment-related adverse events were consistent with the known risks of AAV. However, Neurogene subsequently became aware of the emerging serious adverse event in the third high-dose participant.
NGN-401: Gene Therapy for Rett Syndrome
NGN-401 is an investigational gene therapy designed to deliver a functional copy of the MECP2 gene to cells in individuals with Rett syndrome. Rett syndrome is a rare genetic neurological disorder that primarily affects females, leading to developmental regression and various physical and cognitive impairments. The ongoing Phase 1/2 trial aims to assess the safety and efficacy of NGN-401 in pediatric patients with Rett syndrome.
