Neurogene has announced positive interim data from its Phase 1/2 clinical trial of NGN-401, a gene therapy for Rett syndrome, showcasing meaningful improvements in treated patients. The data, presented on October 17, 2024, highlight gains in core clinical domains, offering hope for a condition with limited treatment options.
Efficacy and Clinical Improvements
The efficacy analysis included four patients on a low dose (1E15 vg) of NGN-401. All participants achieved a rating of "much improved" on the Clinician Global Impression Scale of Improvement (CGI-I) from baseline, indicated by scores of 2. Furthermore, this group demonstrated improvements in the caregiver-completed Rett Syndrome Behavior Questionnaire (RSBQ), ranging from 28% to 52% 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," said Rachel McMinn, PhD, founder and chief executive officer at Neurogene.
Additional efficacy data indicated that all participants gained skills or developmental milestones in core clinical areas of Rett syndrome, including hand function/fine motor skills, language/communication, and ambulation/gross motor skills. These gains included complex skills seldom acquired in this population and rarely relearned after developmental regression, based on the NIH-sponsored Rett syndrome natural history.
Safety and Tolerability
As of the data cut-off, safety data were available for five patients in the low-dose cohort and two in the high-dose (3E15 vg) cohort. NGN-401 was well-tolerated, with no signs or symptoms indicative of MECP2 overexpression toxicity. The therapy did not result in any intracerebroventricular-related adverse events (AEs) or seizures. Most treatment-related AEs were known potential risks of AAV gene therapy. However, Neurogene reported an emerging treatment-related serious AE consistent with the known risks of AAV gene therapy in the third high-dose participant, who was recently dosed.
NGN-401: Mechanism and Design
NGN-401 is an adeno-associated virus 9 (AAV9) gene therapy designed to deliver the full-length human MECP2 gene under the control of Neurogene’s EXACT technology. This technology enables targeted levels of MECP2 transgene expression, mitigating overexpression-related toxic effects associated with conventional gene therapy. The FDA has granted NGN-401 Regenerative Medicine Advanced Therapy designation, orphan drug designation, fast track designation, and rare pediatric designation.
Future Directions
Neurogene 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. The company has also initiated an adolescent/adult cohort, including three participants ages 16 and above, to further understand the therapeutic potential of high-dose NGN-401. Neurogene has 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.
"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 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. "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."
