Neurogene has paused dosing in the high-dose arm of its Phase 1/2 clinical trial (NCT05898620) evaluating NGN-401, an investigational adeno-associated virus (AAV) vector-based gene therapy for Rett syndrome, after a patient developed a life-threatening immune response. The patient, the third in the high-dose cohort (3x10^15 vg), experienced a systemic hyperinflammatory syndrome following treatment on November 5, 2024.
The serious adverse event (SAE) was previously reported by Neurogene as treatment-related and consistent with known risks associated with AAV vector-based gene therapies. Systemic hyperinflammatory syndromes, including hemophagocytic lymphohistiocytosis (HLH) and multisystem inflammatory syndrome, are characterized by aberrant cytokine release and have been observed with high doses of AAVs.
Following the SAE, Neurogene consulted with the FDA through the Support for Clinical Trials Advancing Rare Disease Therapeutics (START) Pilot Program, for which NGN-401 had been selected. The company has decided to discontinue dosing at the high dose. However, after reviewing safety data, the FDA has allowed Neurogene to continue dosing patients at the low dose (1x10^15 vg).
"We are deeply saddened for the family," said Rachel McMinn, PhD, founder and chief executive officer of Neurogene. "The safety of the participants in our clinical trial is and remains our foremost priority as we work to find solutions for this devastating disease."
No other SAEs have been reported among the other patients treated in the study, which includes two other patients in the high-dose cohort and five in the low-dose cohort. All treatment-related adverse events in the low-dose cohort were grade 1 in severity. Most adverse events in the trial were known risks of AAV vector-based therapies, responded to steroid treatment, and resolved or are resolving. There were no adverse events related to the intracerebroventricular administration procedure or signs of toxicity related to overexpression of MECP2, the gene targeted by NGN-401, which is regulated by Neurogene’s EXACT technology.
Neurogene is updating the trial protocol to reflect the discontinuation of the high-dose cohort. Completion of enrollment in the low-dose cohort is not expected before the end of the year.
Positive Interim Data from Low-Dose Cohort
Earlier in November, Neurogene reported positive interim efficacy results from the first four patients in the low-dose cohort, aged 4 to 7 years, assessed at 3, 9, 12, or 15 months post-treatment. All participants achieved a Clinical Global Impression Scale of Improvement score of 2, indicating "much improved" compared to baseline. Patients also improved by 28% to 52% from baseline on the Rett Syndrome Behavior Questionnaire.
"Today marks an important day for Neurogene and the Rett syndrome community as we share positive interim data for NGN-401 from our low-dose cohort that shows the first 4 participants demonstrated meaningful gains of skills and developmental milestones in core clinical domains of Rett syndrome, which are not expected to occur when compared to and contextualized against the natural history of Rett syndrome," McMinn stated previously. "Data were also concordant across multiple scales and show consistency of effect across patients, despite their unique clinical presentations at baseline."
