After a patient died following a high dose of Neurogene’s Rett syndrome gene therapy candidate, the biotech is sharing details about the event and the new safety protocols being incorporated into the ongoing trial.
The young girl had experienced a severe hyperinflammatory condition called hemophagocytic lymphohistiocytosis (HLH) associated with high doses of the adeno-associated virus (AAV) vector therapy, Neurogene said in a presentation set to be shared at 3 p.m. ET on May 16 at the American Society of Gene & Cell Therapy annual meeting in New Orleans.
Neurogene first disclosed the adverse event on Nov. 11, 2024. The patient's condition had turned critical by Nov. 18. The patient then passed away on Nov. 20. Neurogene detailed the timeline of events for the first time in the May 16 presentation.
The patient received 3E15 vector genomes of gene therapy NGN-401 on Nov. 5 as part of the high-dose arm of Neurogene’s ongoing phase 1/2 open-label, pediatric study. She developed a fever before being discharged from the hospital after treatment and was readmitted the next day with a fever, lethargy, vomiting, sleepiness, cough and poor appetite, according to the presentation.
Once back in the hospital, doctors treated her with antibiotics, supplemental oxygen, IV fluids and a high dose of steroids. However, her condition declined rapidly and she was admitted to the ICU with respiratory failure, acute kidney injury and extremely low blood pressure.
“Despite maximal supportive care,” Neurogene said in the presentation, “multi-system failure was too far advanced.”
The patient died from HLH about two weeks after dosing.
NGN-401 is designed to use an AAV vector to deliver functional copies of the MECP2 gene to patients with Rett syndrome, a rare genetic disease that emerges within a few years of birth. Most Rett syndrome cases involve mutations in MECP2, with symptoms including slowed growth, trouble with movement, coordination and communication, and intellectual disabilities.
HLH is an uncommon but known potential side effect of AAV-based gene therapies and is otherwise a rare inherited condition that typically affects children and young adults. The disease causes a variety of symptoms, including vomiting, breathing difficulties and liver enlargement, and is characterized by “immune dysregulation, cytokine storm and multi-organ damage,” Neurogene said in the presentation.
Following the girl’s death, Neurogene dropped the high-dose arm of the NGN-401 trial, continuing with a lower dose 1E15-vg arm with the permission of the FDA.
“The company is not aware of any case of HLH ever being reported at this dose level in AAV gene therapy,” Neurogene said in a May 16 release.
About 1.3% of serious adverse events in patients receiving high AAV doses show signs of HLH, according to the Neurogene presentation, which cites an FDA analysis of 4,500 Zolgensma treatment cases.
The biotech is now incorporating standard HLH monitoring and an HLH treatment algorithm into the trial. The biotech recommends that all AAV gene therapies use doses below 1E14 vg per kilogram and monitor patients for signs of HLH using the three F’s: fever, falling red blood cell counts and raised ferritin levels.
Numerous gene therapy outfits have moved away from AAV recently. Earlier this month, Vertex Pharmaceuticals announced it would no longer pursue the viral vectors as a gene therapy delivery tool. Likewise, Takeda announced it was ending early-stage AAV work in 2023.
On the approved drug side, Pfizer pulled the AAV-using hemophilia B gene therapy Beqvez from shelves earlier this year, citing limited interest from patients and doctors. No patients seem to have received commercial Beqvez since it was approved by the FDA in April 2024.