Neurogene Steps Up the Pace in Trial for Rett Syndrome Gene Therapy NGN-401


Cohort 1, which originally was set to enroll only 5 patients, has been expanded to allow for the inclusion of 8 patients in total.

Rachel McMinn, PhD, the founder and chief executive officer of Neurogene

Rachel McMinn, PhD
Credit: Neurogene

Neurogene has amended the protocol for its phase 1/2 pediatric clinical trial (NCT05898620) evaluating NGN-401, an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat Rett syndrome, to include additional patients in its first cohort, to enable parallel dosing in this cohort, and to add a second cohort.1

The first cohort in the trial (Cohort 1), which originally was set to enroll only 5 patients for treatment at a dose of 1×1015 total vector genomes (vg) of NGN-401, has been expanded to allow for the inclusion of 8 patients in total. Furthermore, patients in this cohort will no longer be dosed in a staggered manner as in the original protocol, but may now instead be dosed in parallel. The newly added second cohort (Cohort 2) will also seek to include a total of 8 patients. Although, the first 3 patients in Cohort 2 will be dosed in a staggered manner. After the first 3 patients have been dosed their safety outcomes will be reviewed by the Data and Safety Monitoring Board; based on this review, Cohort 2 may then also allow for parallel dosing of patients. Cohort 2 will treat patients at a dose of 3x1015 vg. In contrast to Cohort 1, which is using an immunosuppression regimen consisting of corticosteroids only, Cohort 2 will use an immunosuppression regimen that includes rituximab and sirolimus in addition to a shortened corticosteroids course.

The aforementioned protocol amendments apply to clinical trial activities in the United States, though Neurogene stated it that it has submitted a similar protocol amendment to the regulatory authorities in the United Kingdom. Neurogene noted that thus far, 3 patients have been treated in Cohort 1 of the clinical trial, with the third having been dosed early this year. The company stated that the gene therapy has been generally well-tolerated in the patients treated so far without any treatment-emergent or procedure-related serious adverse events having occurred, including any indication of overexpression-related toxicity. Announcements of interim clinical data from Cohort 1 and data from Cohort 2 are anticipated in the final quarter of 2024 and the second half of 2025, respectively.

“We are excited to share that we have met our first 2024 program milestones, including dosing the third patient in the NGN-401 phase 1/2 trial for Rett syndrome and expansion of the trial to include more patients in the current dosing cohort and the addition of a high dose cohort,” Rachel McMinn, PhD, the founder and chief executive officer of Neurogene, said in a statment.1 “Our clinical development strategy has been to build flexibility and optionality early in the program with 2 concurrent dose cohorts designed to generate a more complete data package, which we expect will inform future registration discussions with global health authorities. We expect that expansion of the clinical trial and the removal of staggered dosing in Cohort 1 will enable us to treat more patients in a shorter period of time. Based on this update, we expect to complete enrollment of Cohort 1 in the second half of 2024.”

The investigational new drug application for the clinical trial was originally cleared by the FDA in January 2023.2 NGN-401, which is being administered in the trial via intracerebroventricular (ICV) injection, uses a proprietary gene regulation platform technology, Expression Attenuation via Construct Tuning (EXACT), that the company developed in collaboration with the University of Edinburgh. EXACT is meant to address toxicities and limitations with conventional gene therapy and is compatible with both viral and nonviral delivery methods. NGN-401 delivers the full-length human MECP2 gene, expression of which will be regulated by EXACT with the intention of avoiding overexpression-related toxicities.

NGN-401 is not the only gene therapy currently in clinical development for the treatment of Rett syndrome. Taysha Gene Therapies is evaluating TSHA-102, an AAV vector-based gene therapy, in trials for both adult and pediatric patients with Rett syndrome.3 Taysha also recently announced updates regarding expanded and accelerated plans for its clinical trials, including escalation to the higher dose cohort in its phase 1/2 REVEAL adolescent and adult clinical trial (NCT05606614) for TSHA-102.

1. Neurogene announces expansion and plans for more rapid patient enrollment of Rett syndrome gene therapy clinical trial. News release.Neurogene Inc. March 4, 2024. Accessed March 7, 2024.
2. Neurogene announces FDA clearance of IND for NGN-401 gene therapy for children with Rett syndrome. News release. Neurogene. January 23, 2023.
3. Taysha gene therapies announces updates to TSHA-102 clinical program in Rett syndrome. News release. Taysha Gene Therapies, Inc. February 29, 2024. Accessed March 7, 2024.
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