Neurogene Shares Details on Patient Death in Rett Syndrome AAV Gene Therapy Trial, Implements New Safety Measures

Following the death of a young patient in its Rett syndrome gene therapy trial, Neurogene has released details regarding the event and outlined new safety protocols being implemented. The patient experienced hemophagocytic lymphohistiocytosis (HLH), a severe hyperinflammatory condition, linked to a high dose of the adeno-associated virus (AAV) vector therapy, NGN-401.

The patient, part of the high-dose arm of the phase 1/2 pediatric study, received a 3E15 vector genome dose of the AAV gene therapy on November 5, 2024. After initial discharge, she was readmitted with symptoms including fever, lethargy, and respiratory issues. Despite intensive care, her condition rapidly declined, and she died from HLH approximately two weeks post-dosing.

NGN-401 utilizes an AAV vector to deliver functional MECP2 genes to patients with Rett syndrome, a rare genetic disorder. HLH is a known, though uncommon, potential complication of AAV-based gene therapies.

Following this fatal event, Neurogene discontinued the high-dose arm of the NGN-401 trial but is continuing with a lower 1E15-vg dose arm with FDA permission. The company stated that HLH has not been previously reported at this lower AAV dose level.

Neurogene’s presentation cited an FDA analysis suggesting that about 1.3% of serious adverse events in high-dose AAV gene therapy trials show signs of HLH. The company is now incorporating standard HLH monitoring and a treatment algorithm into its trial, recommending that AAV gene therapies use doses below 1E14 vg per kilogram and monitor for fever, falling red blood cell counts, and raised ferritin levels (the “three F’s”).