Trial protocol of Rett gene therapy now only using low dose: Developer
Change made after serious immune reaction in girl given NGN-401 high dose
The protocol of the Phase 1/2 trial (NCT05898620) that’s evaluating Neurogene’s NGN-401 in girls with Rett syndrome has been amended to use the low treatment dose of the gene therapy for all future participants, the company announced.
The protocol alteration was submitted to the U.S. Food and Drug Administration (FDA) after one trial participant who received the high dose experienced a serious treatment-related immune reaction.
With enrollment ongoing, the age range of eligible participants also was expanded to include a new group of patients, ages 11 and older. Additional interim results from the trial are expected before the end of the year, Neurogene said in a company press release.
“We believe 2024 was a year of significant progress for our NGN-401 Phase 1/2 trial in Rett syndrome,” said Rachel McMinn, PhD, founder and CEO of Neurogene. “As we look ahead to the second half of 2025, we plan to share additional interim clinical data from [this] trial.”
Trial testing Rett gene therapy now enrolling older girls
Rett is chiefly caused by mutations in the MECP2 gene, which disrupt the function of a protein of the same name that controls the activity of other genes. This impairs the growth of and connections between nerve cells, resulting in disease symptoms.
NGN-401 is a one-time treatment meant to provide a full-length form of the MECP2 gene to patients. The gene therapy is carried by an adeno-associated virus (AAV) infused directly into the brain’s fluid-filled cavities. It aims to restore the production of functional MeCP2 protein, and reduce Rett symptoms.
The ongoing trial was initially designed to enroll an estimate 16 girls with Rett, ages 4-10, at five sites in the U.S., two in the U.K., and one in Australia. As of November 2024, five girls had received the therapy at a low dose (1E15 vector genomes), while three girls were treated with a high dose (3E15 vector genomes).
“We reported encouraging interim efficacy data and NGN-401 was generally well-tolerated at the [higher] dose in a pediatric cohort,” McMinn said.
However, after one of the girls who received the high dose experienced a serious, treatment-related immune reaction, the company pivoted to just the low dose. The trial now will proceed with the low-dose regimen for all future participants.
At the time it reported the adverse event, Neurogene stated that no other participants experienced serious treatment-related adverse events. Further, according to the company, all treatment-related adverse events in the low-dose group were mild. Interim efficacy data indicated that the first four girls given the gene therapy at the low dose achieved new developmental milestones and meaningful gains in skills.
Per the company, the trial remains on track to provide updates in the coming months on the plans for a future registrational trial, meant to obtain sufficient data supporting an application seeking regulatory approval. Neurogene said it expects to evaluate the treatment dose in that future registrational trial of NGN-401.
The company has received PRIME, or priority medicines, designation for NGN-401 from the European Medicines Agency. That designation is meant to support the development of medications targeting an unmet medical need, by showing meaningful improvements in patients’ clinical outcomes.
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