Gene therapy NGN-401 leads to functional gains in Rett syndrome
CEO of developer Neurogene says results offer 'hope for brighter future'
NGN-401, an experimental gene therapy for Rett syndrome, led to functional improvements in all the girls who received the treatment in an early clinical trial, according to new data announced by its developer, Neurogene.
Caregivers of the eight girls “have shared feedback on how the outcomes their daughters are experiencing matter to them – including the ability of their daughters to participate in activities of daily living and improvements in health-related quality of life,” Rachel McMinn, PhD, founder and CEO of Neurogene, told Rett Syndrome News in a written Q&A.
“The girls in the trial are now able to do things they could not before, such as being able to hold a basket while shopping with mom, getting into a car independently, eating with a utensil, using their hands to communicate needs and wants, giving mom a kiss for the first time ever, and speaking to their parents,” McMinn said, adding that the interim result “continues to give us hope for a brighter future for people affected by Rett syndrome.”
Dosing recently began in crucial Phase 3 trial
These new interim findings come shortly after Neurogene began dosing participants in the Phase 3 Embolden clinical trial (NCT05898620), which aims to test NGN-401 in 20 female Rett patients ages 3 and older. The study is actively enrolling participants at sites across the U.S.
McMinn noted that the trial is designed to serve as a basis for applications seeking approval from agencies such as the U.S. Food and Drug Administration, which signed off on the trial’s design a few months ago.
The Phase 3 study’s main goal is to evaluate how many patients experience meaningful clinician-rated improvement and/or gains in a list of 28 prespecified developmental milestones and skills. Natural history data have indicated that Rett patients older than 3 typically do not acquire these particular skills.
“A significant heartbreak for families who have children with Rett syndrome is that their children start off on a developmentally delayed trajectory, where children gain milestones but then regress and lose many of the milestones gained, and in many cases never gain other important milestones,” McMinn said. “We are thankful to the families who have contributed to the Rett syndrome natural history study — because of them, we know a lot about the natural history of Rett syndrome.”
Safety data from Phase 1/2 trial generally favorable
The new interim data come from a Phase 1/2 clinical trial. Safety data, covering 10 patients across a range of ages who were given a dose of 1E15 (one quadrillion) vector genomes (vg), showed a generally favorable profile, with no serious side effects reported.
“From a safety perspective, NGN-401 remains generally well tolerated at the 1E15 vg dose in the pediatric and older cohorts. All NGN-401-related adverse events have been mild or moderate, and the majority have resolved or are resolving as of the data cutoff date of our November data release,” McMinn said.
Late last year, Neurogene reported that a trial participant given a higher dose of NGN-401 (3E15 vg) had developed an inflammatory reaction called hemophagocytic lymphohistiocytosis (HLH), which led to the patient’s death. McMinn noted that HLH is a known yet rare risk of gene therapies such as NGN-401 that use an adeno-associated virus (AAV) vector, which is basically a modified virus engineered to deliver the therapeutic gene instead of causing infection. Following this death, Neurogene immediately stopped testing the higher dose of NGN-401.
“HLH is extremely rare and linked only to much higher doses of AAV gene therapy. The dose we are continuing to use is far below that range, and no HLH cases have ever been reported at this level,” she said, noting that the ongoing Phase 3 trial has additional precautions in place to guard against any potential risk of HLH.
All girls showed ‘showed functional gains across spectrum of disease severity’
Efficacy data were reported for eight girls who received treatment with NGN-401 between the ages of 4 and 10. In a company press release, Neurogene reported that all of these girls “showed functional gains across spectrum of disease severity,” with a total of 35 developmental milestones or new skills acquired across the eight girls.
“The sheer number of skills across multiple facets of disease — and the durability of these gains over time — give us confidence that NGN-401 has the potential to meaningfully alter the natural history of this disease,” McMinn said. “We observed developmental milestone/skill gains in hand function, communication, and gross motor function, which are the key functional deficits observed in Rett syndrome. Importantly, these gains have been durable, meaning once gained, the participants have maintained these skills. Additionally, participants have continued to develop skills well after dosing, up to 24 months, as seen in the longest follow-up data available.”
Rett syndrome is primarily caused by mutations in the MECP2 gene, resulting in low levels of the MeCP2 protein, which is crucial for brain development and nerve cell communication. Gene therapy for Rett syndrome essentially aims to deliver a healthy version of the gene to brain cells to restore MeCP2 protein production. Safeguards are in place to prevent abnormally high MeCP2 levels, as this can also cause problems.
The sheer number of skills across multiple facets of disease — and the durability of these gains over time — give us confidence that NGN-401 has the potential to meaningfully alter the natural history of this disease.
For that reason, NGN-401 is delivered directly into fluid-filled cavities of the brain through a process called an intracerebroventricular (ICV) infusion.
McMinn said that experiments done by Neurogene show that the ICV route “results in 10 [to] 100 times higher MeCP2 levels in the brain when compared to other routes of administration that do not deliver [the gene therapy] directly into the brain.” She also noted that Neurogene’s EXACT technology, which regulates gene activity, “allows for the delivery of consistent, tightly controlled therapeutic levels of MeCP2 protein on a cell-by-cell basis, and avoids overexpression toxicity.”
“We believe these unique features of NGN-401 have led to promising efficacy results observed in our Phase 1/2 data, including the data we recently reported from the pediatric cohort of female participants,” she said.
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