Neurogene Abandons High-Dose Arm Following Patient Fatality in Rett Syndrome Clinical Trial

Neurogene Abandons High-Dose Arm Following Patient Fatality in Rett Syndrome Clinical Trial

Neurogene Abandons High-Dose Arm Following Patient Fatality in Rett Syndrome Clinical Trial

Neurogene reported in an SEC filing on Thursday that a patient has passed away during its Phase I/II clinical trial for Rett syndrome after receiving its experimental gene therapy.

The patient was administered the higher dosage of 3E15-vg of NGN-401 when they faced what was initially labeled as a serious treatment-related adverse event (SAE). Following a subsequent announcement on Monday, Neurogene informed that the patient had developed systemic hyperinflammatory syndrome, a known, albeit severe, side effect associated with adeno-associated virus (AAV) gene therapies, and was in critical condition.

In a note for investors, BMO Capital Markets analysts Keith Tapper and Evan Seigerman labeled the incident as “tragic.” They noted that while hyperinflammatory syndrome is “rare,” it has been previously recorded in other AAV gene therapies, particularly at dosages above the 1E14vg/kg threshold, which appears to be a toxicity cutoff.

“The entire Neurogene team extends our heartfelt condolences to her family and friends,” stated a company representative in comments to BioSpace. “Neurogene remains motivated by the improvements seen in various aspects of Rett syndrome in those treated with the 1E15 vg dose, and we are eager to continue our work with NGN-401.”

Neurogene’s SEC filing on Thursday also stated that the FDA has approved the continuation of the Phase I/II trial, but only utilizing the lower 1E15 vg dosage, which has been authorized for use in pediatric, adolescent, and adult patients. Depending on trial outcomes, the biotech aims to progress the gene therapy into registrational studies with the 1E15 vg dosage.

“Crucially, this outcome was documented by the FDA when considering that the low-dose group could carry on,” the BMO analysts noted concerning the patient’s death. “This indicates that the FDA understands the nature of the SAE and likely concurs that it is associated with AAV overexposure.”

Rett syndrome is a rare genetic condition impacting one in every 10,000 female births globally, with even fewer cases in males. Children with the disorder experience a gradual decline in motor function, alongside impaired language and development. The condition may also present with breathing issues, scoliosis, and seizures.

In a recent data release, Neurogene indicated that even with the lower 1E15 vg dosage, NGN-401 could provide clinically significant advantages, as the first four treated patients received a “much improved” assessment on the clinician-rated Clinical Global Impression Scale of Improvement.

Additionally, patients reached essential developmental milestones or acquired skills in at least one primary domain of Rett syndrome, like language, communication, hand function, ambulation, and both gross and fine motor abilities. According to Tapper and Seigerman, more updates about the registrational trial strategy for NGN-401 are expected in the first half of 2025, with additional data from the Phase I/II study anticipated later in the upcoming year.

Aside from the setbacks in Rett syndrome, Neurogene also revealed on Tuesday that it has halted its Batten disease program after not obtaining the FDA’s Regenerative Medicine Advanced Therapy designation.