Rett gene therapy NGN-401 trial expanding, accelerating
Enrolling more girls, changing dosing to provide ‘more complete data’
Neurogene is expanding its ongoing Phase 1/2 clinical trial testing gene therapy candidate NGN-401 in girls with Rett syndrome and making some changes to the trial’s structure to accelerate enrollment and dosing.
Changes include adding more patients and removing dose staggering (one-at-a-time dosing) in the trial’s first low-dose group (cohort 1) and adding a second, high-dose group (cohort 2).
A third patient has been safely treated in cohort 1, Neurogene said. The entire group is expected to be dosed by the end of the year, when interim efficacy data are anticipated. Dosing in cohort 2 will begin in the coming months.
The Phase 1/2 trial (NCT05898620) is enrolling 4- to 10-year-old girls with Rett syndrome at sites in the U.S., with the amended protocol in place.
U.K. authorities have also cleared the trial, and Neurogene is working on establishing a first U.K. trial site while seeking similar protocol amendments there.
Rett gene therapy data ‘will inform future registration discussions’
“Our clinical development strategy has been to build flexibility and optionality early in the program … to generate a more complete data package, which we expect will inform future registration discussions with global health authorities,” Rachel McMinn, PhD, founder and CEO of Neurogene, said in a company press release.
In most cases of Rett syndrome, mutations in the MECP2 gene lead to widespread dysregulation of other genes important for brain development and function.
NGN-401 is designed to deliver a working version of MECP2 to Rett patients. It’s packaged in a harmless adeno-associated virus (AAV) and delivered directly into the fluid-filled cavities of the brain in a process known as intracerebroventricular infusion.
Neurogene developed NGN-401 using its Expression Attenuation via Construct Tuning (EXACT) gene regulation technology, designed to help fine-tune the amount of the lab-made MECP2 gene that’s used to make protein and avoid harmful effects from too much MECP2 gene activity, or overexpression toxicity.
It is well established that while Rett patients need an MECP2 boost, too much activity and the resulting overproduction of its protein product (MeCP2) can have negative consequences.
Safety data allow study participants to be treated in parallel
The goal of the Phase 1/2 trial, which was cleared by U.S. regulators last year, is to monitor the safety and tolerability of NGN-401 in girls with Rett syndrome for several years after they receive the one-time therapy.
Cohort 1, originally designed to include five patients who would receive a low dose of the gene therapy (1 x 10^15 vector genomes), has been expanded to eight patients.
The first two girls were dosed last year, and the third was treated recently. They were given the gene therapy one at a time to make sure no safety issues arose.
NGN-401 has been generally well tolerated in those patients, with no treatment-emergent or procedure-related serious adverse events and no signs of overexpression toxicity, Neurogene said.
Based on that safety data, staggered dosing has been removed, meaning all remaining patients can now be treated in parallel.
“We expect that expansion of the clinical trial and the removal of staggered dosing in Cohort 1 will enable us to treat more patients in a shorter period of time,” McMinn said.
In the newly added cohort 2, eight girls will receive a high dose of NGN-401 (3 x 10^15 vector genomes). The first three girls will be dosed in a staggered manner, and if the treatment is deemed safe, the rest will be dosed in parallel.
As in the original design, trial participants will begin a course of corticosteroids before the gene therapy to help prevent immune responses against the viral carrier. Patients in cohort 2 will receive a more intensive immunosuppression regimen that includes rituximab and sirolimus, because immune reactions have been seen with other AAV-based products at this dose range, Neurogene said.
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