Neurogene halts high dose cohort of Rett syndrome trial following serious adverse event

In the wake of a serious adverse event, Neurogene has halted the high-dose cohort of its phase 1/2 open-label clinical trial evaluating its investigational AAV9 gene therapy as a one-time treatment for Rett syndrome.

Neurogene had disclosed the SAE last week as a footnote in a press release about interim efficacy data from the first four low-dose pediatric patients, noting that the company had just become aware of an emerging treatment-related SAE consistent with known risks of AAV gene therapy in the third high-dose participant.

The patient, who had received NGN-401 at a dose of 3E15 vg on November 5, subsequently experienced signs of a systemic hyperinflammatory syndrome, a rare and life-threatening immune response that has been reported with systemic exposure to high doses of AAV. The participant is now critical condition, and the case is continuing to evolve, according to Neurogene’s most recent update.

Neurogene says the U.S. FDA has completed a review of the safety data for NGN-401 and allowed the company to proceed with the phase 1/2 trial using the 1E15 vg dose (low-dose cohort). Neurogene paused further use of the 3E15 vg dose upon initial notification of the SAE and does not plan to enroll any further participants at the 3E15 vg dose level. To date, there have been no other treatment-related SAEs in the clinical trial, including in the five participants who received the 1E15 vg dose and in the first two participants who received the 3E15 vg dose of NGN-401.

Back in June, Neurogene revealed that its NGN-401 program had been chosen as one of only three CBER programs for FDA’s Support for Clinical Trials Advancing Rare Disease Therapeutics (START) Pilot Program. The START program, which quickly picked up the nickname ‘Operation Warp Speed for Rare Diseases,’ is a joint CBER-CDER program designed to accelerate the development of cell and gene therapies for rare disease.