Meaningful gains in skills seen with Rett gene therapy in trial: Data
Treatment with NGN-401 leads to new milestones for first 4 girls
The first four girls with Rett syndrome treated with a low dose of Neurogene‘s gene therapy candidate NGN-401 in a clinical trial have experienced new developmental milestones and seen meaningful gains in skills, according to new interim data.
Clinicians and caregivers both have confirmed the improvements seen in these four patients, all of whom are participating in the ongoing Phase 1/2 trial (NCT05898620). Each of the girls experienced fewer problems related to sleep, constipation, and swallowing following gene therapy, the data show.
“The totality of the outcomes shared today with NGN-401 gene therapy have never been seen before in the treatment of Rett syndrome,” Aleksandra Jacobs, MD, PhD, professor of pediatric neurology at Albert Einstein College of Medicine, in New York, said in a company press release.
“Notably, these initial participants acquired developmental skills post-treatment during the period in which the natural history of Rett syndrome indicates girls would not,” Jacobs said. “I look forward to the continued progress in this program and additional data to come.”
Meanwhile, Neurogene announced that enrollment in the study will expand to include three additional patients, ages 16 and older, to be treated with a high dose of NGN-401.
No seizures reported for Rett patients given the gene therapy low-dose
Enrollment in the low-dose group is expected to be completed by the end of the year, with additional interim Phase 1/2 clinical data reported in the second half of 2025, the company said.
In the first half of 2025, Neurogene also plans to provide an update on a registrational trial, which is a type of study designed to obtain sufficient data to support an approval application for a treatment candidate.
In most cases, Rett is caused by mutations in the MECP2 gene that disrupt the function of the similarly named MeCP2 protein. That protein controls the activity of other genes. The loss of MeCP2 particularly affects the growth and connectivity of nerve cells, leading to cognitive, emotional, sensory, and motor symptoms, as well as problems with the heart, breathing, and digestion.
“Rett syndrome is a devastating neurodevelopmental disease that is incredibly challenging for patients and their caregivers given there are no treatment options available to address the underlying cause of the disease,” said Jacobs, who also serves as the director of the Center for Rett Syndrome in the Children’s Hospital at Montefiore Medical Center in New York.
Packaged in a harmless adeno-associated virus, or AAV, NGN-401 is designed to deliver a full-length version of the MECP2 gene to nerve cells in the brain. It’s administered via a one-time intracerebroventricular infusion, or directly into the brain’s fluid-filled cavities.
Neurogene’s EXACT gene regulation technology was used to develop this Rett gene therapy. It helps control MECP2 gene activity to avoid potentially harmful side effects associated with high levels of the MeCP2 protein.
Earlier this year, the U.S. Food and Drug Administration (FDA) selected NGN-401 for its START pilot program — fully known as Support for Clinical Trials Advancing Rare Disease Therapeutics. This initiative allows for frequent advice and ad hoc conversations with the agency to address development issues.
According to new data from the Phase 1/2 trial, five girls have received a low dose of NGN-401 (1x1E 15 vector genomes) and two a high dose (3x1E 15 vector genomes). Treatment among these patients has been well tolerated and has a favorable safety profile.
In particular, there were no treatment-related serious adverse events, symptoms associated with the overproduction of MeCP2, or events related to intracerebroventricular infusion. None of the girls had seizures. Most treatment-related side effects were consistent with those associated with AAVs and have responded to immunosuppressant steroid treatment, the data showed.
In its release, the company did report an AAV-related serious adverse event in the third high-dose participant who was recently dosed.
Gains contrast with loss of skills typically seen in disease course
As part of the data, efficacy was assessed in the first four patients — who range in age from 4 to 7 — for as long as 15 months after receiving the first low dose.
On the clinician-rated Clinical Global Impression Scale of Improvement (CGI-I) scale, all participants achieved a rating of “much improved” or a score of 2 compared with pre-treatment. A score of at least 3 is considered clinically meaningful. All participants also saw improvement using the caregiver-completed Rett Syndrome Behavior Questionnaire (RSBQ). On the RSBQ, scores improved from 28% to 52% compared with the study’s start.
All participants acquired skills and/or achieved developmental milestones in one or more core features of Rett. Among these features are hand function and fine motor control, language and communication, and walking and gross motor function. According to Neurogene, new skills and milestones have advanced over time.
The first four participants demonstrated meaningful gains of skills and developmental milestones in core clinical domains of Rett syndrome, which are not expected to occur when compared to and contextualized against the natural history of Rett syndrome.
“Today marks an important day for Neurogene and the Rett syndrome community as we share positive interim data for NGN-401 from our low-dose cohort,” said Rachel McMinn, PhD, Neurogene’s founder and CEO. “The first four participants demonstrated meaningful gains of skills and developmental milestones in core clinical domains of Rett syndrome, which are not expected to occur when compared to and contextualized against the natural history of Rett syndrome.”
“Data were also concordant across multiple scales and show consistency of effect across patients, despite their unique clinical presentations at baseline,” McMinn added.
Neurogene said it has reached an agreement with the FDA on its potency assessment for NGN-401, which is needed before launching a registrational trial. The company also reached an agreement with the agency on its manufacturing plans for the Rett gene therapy. Both of these are important for a future commercial launch, according to Neurogene.
“We are incredibly thankful to the participants, caregivers and Rett syndrome trial sites who are participating in our study,” McMinn said.
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