Neurogene’s Rett Syndrome Gene Therapy NGN-401 Demonstrates Efficacy in Low-Dose Cohort, But Serious Adverse Event in High-Dose Group Raises Concerns
Neurogene pointed out that the SAE is consistent with the known risks of AAV vector-based gene therapy.
Rachel McMinn, PhD
Credit: Neurogene
Neurogene’s NGN-401, an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat Rett syndrome, has generated positive efficacy results in the low-dose cohort of aphase 1/2 pediatric clinical trial (NCT05898620), but an emerging treatment-related serious adverse event (SAE) was reported in a patient treated in the study’s high-dose cohort.1
The low-dose cohort treated patients at a dose of 1×1015 total vector genomes (vg) of NGN-401 and the high-dose cohort treated patients at dose of 3x1015 vg. As of an October 17, 2024, data cut-off, 5 patients had received the low dose and 2 patients had received the high dose.
In the first 4 patients treated in the low-dose group, whose ages ranged from 4 to 7 years and who were assessed at 3, 9, 12, or 15 months posttreatment, all participants obtained a clinician-rated Clinical Global Impression Scale of Improvement score of 2 compared to baseline, constituting a rating of “much improved”. In addition, the patients improved from 28% to 52% from baseline on the caregiver-completed Rett Syndrome Behavior Questionnaire. Neurogene noted that the participants gained hand function/fine motor, language/communication, and/or ambulation/gross motor skills or developmental milestones, including complex skills rarely learned or relearned in the patient population represented.
“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, the founder and chief executive officer of 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. We are incredibly thankful to the participants, caregivers, and Rett syndrome trial sites who are participating in our study.”
With regard to safety, Neurogene stated that among the 7 aforementioned patients treated as of October 17, there were no treatment related SAEs, no signs of symptoms of toxicity from overexpression of the MeCP2 transgene provided by NGN-401, no intracerebroventricular-related AEs, and no seizures. The company noted that most treatment-related AEs that occurred in this group have been responsive to steroids and resolved or are resolving.
Notably, an SAE was reported in a third patient who was more recently treated in the high-dose cohort. Neurogene pointed out that the SAE is consistent with the known risks of AAV vector-based gene therapy.
Alongside the announcement of the interim data, Neurogene stated that a third cohort in the trial, which will treat up to 3 patients aged 16 years or older at the high dose, has been initiated. The company also reported that it has reached an accord with the FDA regarding plans for scaling up manufacturing and its potency assay strategy for the gene therapy product. Neurogene plans to have enrolled 8 patients in the low-dose cohort by the end of the year and expects to report updated data in the second half of next year. In the first half of 2025, the company also anticipates that it will release more information on its plan for a registrational clinical trial for NGN-401.
In June 2024, Neurogene announced that NGN-401 had been selected as part of the FDA’s Support for Clinical Trials Advancing Rare Disease Therapeutics (START) Pilot Program.2 The program will provide sponsors with the opportunity for frequent advice and regular communication as needed with regard to clinical trial design and other development issues particular to the investigational product being evaluated.
“We are honored that NGN-401 gene therapy for Rett syndrome has been chosen as one of only 3 Center for Biologics Evaluation and Research programs for FDA’s START Pilot Program and are grateful that the FDA has committed to investing significant Agency resources to accelerate development of NGN-401,” McMinn said at the time.2 “We are pleased our application demonstrated the potential clinical benefits of NGN-401, 1 of the factors evaluated by the FDA in making its selection. We look forward to participating in this landmark effort with the FDA as we seek to rapidly advance NGN-401 toward a potential registrational study for the patients and families who live with this devastating disease.”
Notably, Neurogene also stated that it has made the decision to discontinue the development of NGN-101, its investigational AAV vector-based gene therapy intended to treat neuronal ceroid lipofuscinosis (Batten) Subtype 5 (CLN5) disease, which is currently being assessed in a phase 1/2 clinical trial (NCT05228145).1 Neurogene cited the FDA’s denial of its application for regenerative medicine advance therapy designation for NGN-101 as the reason for the decision, as the company considered this designation necessary for continued investment in the product’s development. The company noted that options for what to do with the program are currently under evaluation.
NGN-101 is the latest in a line of gene therapy programs for Batten disease that have recently been discontinued. Earlier this year, CGTLive® spoke to Ineka Whiteman, PhD, head of research and medical affairs, BDSRA Australia, consultant to BDSRA Foundation (USA) and Beyond Batten Disease foundation, about the progress and setbacks that have been occurring in Batten disease research.
“Of course like so many in the rare disease world, our Batten disease community is unfortunately no stranger to disappointing news on the therapeutic development front,” Whiteman told CGTLive in June 2024. “Over the past 12 months, we saw discontinuation of multiple clinical gene therapy programs, including Lexeo Therapeutics' CLN2 disease program, and Amicus Therapeutics' clinical programs for both CLN3 disease and CLN6 disease. Along with its preclinical study for CLN8 disease, Amicus has now returned all rights and responsibilities for these programs to Nationwide Children's Hospital, Ohio, who are now evaluating next steps for each.”
