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Neurogene Eyes Phase 3 Registrational Study for Gene Therapy NGN-401 Following Positive Phase 1/2 Data
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Key Takeaways
- NGN-401 gene therapy showed significant improvements in Rett syndrome clinical domains and developmental milestones in low-dose participants.
- The therapy uses AAV9 to deliver the MECP2 gene, avoiding overexpression toxicity and demonstrating consistent efficacy across scales.
NGN-401, an AAV9 gene therapy in development for Rett syndrome, was considered well-tolerated, with treated patients showing consistent gains in skill and developmental milestones.
Rachel McMinn, PhD
In newly announced interim data from a phase 1/2 open-label trial (NCT05898620), treatment with low doses of Neurogene’s NGN-401, an investigational gene therapy, resulted in improvements in several scales as well as gains in skills and developmental milestones for patients with Rett syndrome. Based on the totality of the data, the company plans to initiate a registrational trial, with details expected to be released in the first half of 2025.
In the efficacy analysis, which included 4 patients on low dose (1E15 vg) NGN-401, all participants achieved a rating of “much improved,” on Clinician Global Impression Scale of Improvement (CGI-I) from baseline, indicated by scores of 2. In addition, this group also showed enhancements in the caregiver-completed Rett Syndrome Behavior Questionnaire (RSBQ), ranging from 28% to 52% improvement from baseline.
"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 that shows 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," Rachel McMinn, PhD, founder and chief executive officer at Neurogene, said in a statement.1 "Data were also concordant across multiple scales and show consistency of effect across patients, despite their unique clinical presentations at baseline."
NGN-401, an adeno-associated virus 9 (AAV9) gene therapy, is the first clinical candidate to deliver the full-length human MECP2 gene under the control of Neurogene’s EXACT technology. According to the company, through this technology, the treatment enables targeted levels of MECP2 transgene expression without causing overexpression-related toxic effects associated with conventional gene therapy. To date, the agent has received Regenerative Medicine Advance Therapy designation, orphan drug designation, fast track designation, and rare pediatric designation from the FDA.
Additional efficacy data showed that all participants gained skills or developmental milestones in core clinical areas of Rett syndrome—hand function/fine motor, language/communication, and ambulation/gross motor. These gains include complex skills that are seldom acquired in this population and are rarely relearned after developmental regression, based on the NIH-sponsored Rett syndrome natural history. New skills and milestones have not only increased but have also strengthened over time.
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As of the data cut-off of October 17, 2024, 5 patients in the low-dose cohort and 2 in the high-dose (3E15 vg) cohort had safety data available on the agent. NGN-401 was considered well-tolerated, with no signs or symptoms indicative of MECP2 overexpression toxicity. The therapy did not result in any intracerebroventricular-related adverse events (AEs), no seizures, and most treatment-related AEs were known potential risks of AAV. Notably, the company did mention that it become aware of an emerging treatment-related serious AE consistent with the known risks of AAV gene therapy in the third high-dose participants who was recently dosed after originally noting no treatment-related serious AEs.
"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,” Aleksandra Jacobs, MD, PhD, a professor of neurology at Albert Einstein College of Medicine and director of the Center for Rett Syndrome in the Children’s Hospital at Montefiore Medical Center, said in a statement.1 "The totality of the outcomes shared today with NGN-401 gene therapy have never been seen before in the treatment of Rett syndrome. Notably, these initial participants acquired developmental skills post-treatment during the period in which the natural history of Rett syndrome indicates girls would not. I look forward to the continued progress in this program and additional data to come."
Neurogene also provided several updates to the trial, including that it expects to complete enrollment in the low-dose pediatric cohort (n = 8) in the fourth quarter of 2024, with additional interim phase 1/2 data anticipated in the second half of 2025. In addition, the company also initiated an adolescent/adult cohort, which will include 3 participants ages 16 and above, to further understand the therapeutic potential of high-dose NGN-401. Neurogene announced FDA alignment on its potency assay strategy and manufacturing scale-up plans for NGN-401, supporting its path to a future trial and potential product launch.
