Patient Treated With Neurogene’s Investigational Rett Syndrome Gene Therapy NGN-401 in Critical Condition After Developing Life-Threatening Immune Response

A patient treated with Neurogene’s NGN-401, an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat Rett syndrome, in the context of a phase 1/2 pediatric clinical trial (NCT05898620) has developed a life-threatening immune response to the treatment and is now in critical condition.¹

The serious adverse event (SAE), which was previously reported by Neurogene as an emerging treatment-related SAE consistent with the known risks of AAV vector-based gene therapy, has now been described as constituting signs of a rare and life-threatening immune response known as a systemic hyperinflammatory syndrome.^1,2 According to Neurogene, systemic hyperinflammatory syndromes, which include hemophagocytic lymphohistiocytosis (HLH) and multisystem inflammatory syndrome, are associated with aberrant cytokine release and are known to have occurred in conjunction with systemic exposures to high doses of AAVs.

The patient was the third participant to be treated in the study’s high-dose cohort, which had beenutilizing a dose of 3x10¹⁵ vg of NGN-401. The patient received the gene therapy on November 5, 2024. Following the occurrence of the SAE, Neurogene engaged with the FDA via the agency’s Support for Clinical Trials Advancing Rare Disease Therapeutics (START) Pilot Program, for which NGN-401 had been previously selected in June 2024.^1,3 Neurogene has made the decision to cease dosing patients at the high-dose going forward, but it noted that upon a review of the safety data the FDA has given the company the green light to continue dosing patients at the trial’s low dose, which is 1x10¹⁵ vg.

“We are deeply saddened for the family,” Rachel McMinn, PhD, the founder and chief executive officer of Neurogene, said in a statement.¹ “While no words could possibly provide comfort to her family, we ask the Rett syndrome community to join us in sending heartfelt thoughts to her family, friends and the dedicated clinicians who are caring for her. The safety of the participants in our clinical trial is and remains our foremost priority as we work to find solutions for this devastating disease.”

Notably, not other SAEs have been reported in the patients treated in the study, which include 2 other patients treated at the high dose and 5 patients treated at the low dose. Notably, all treatment-related AEs reported in the low-dose cohort were deemed grade 1 in severity. Furthermore, Neurogone pointed out that most of the AEs that have occurred in the trial have constituted known risks of AAV vector-based therapies, responded to treatment with steroids, and resolved or are resolving. In addition, it was noted that there were no AEs related to the intracerebroventricular administration procedure and no signs or symptoms of toxicity related to overexpression of MECP2, the disease-targeted gene that NGN-401 provides a functional full-length copy of, and which NGN-401 regulates expression of via Neurogene’s EXACT technology.^1,4

Neurogene stated that it is working on updating the trial’s protocol with regard to the discontinuation of the high-dose cohort. Its expectations for completion of enrollment in the low-dose cohort have been adjusted, with this goal no longer expected to be reached before the end of the year.

Earlier in November, Neurogene reported positive interim efficacy results from the first 4 patients to have been treated in the trial’s low-dose cohort, whose ages ranged from 4 to 7 years and who were assessed at 3, 9, 12, or 15 months posttreatment.² Notably, 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.

“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 4 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,” McMinn said in a statement at the time.² “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.”

REFERENCES
1. Neurogene provides update on NGN-401 gene therapy clinical trial for Rett syndrome. News release. Neurogene Inc. November 18, 2024. Accessed November 18, 2024. https://ir.neurogene.com/news-releases/news-release-details/neurogene-provides-update-ngn-401-gene-therapy-clinical-trial
2. Neurogene reports positive interim efficacy data from first four low-dose pediatric participants in NGN-401 gene therapy clinical trial for Rett syndrome. News release. Neurogene Inc. November 11, 2024. Accessed November 18, 2024. https://ir.neurogene.com/news-releases/news-release-details/neurogene-reports-positive-interim-efficacy-data-first-four-low
3. Neurogene Announces NGN-401 Gene Therapy for Rett Syndrome Selected by FDA for START Pilot Program. News release. Neurogene. June 3, 2024. Accessed November 18, 2024. https://ir.neurogene.com/news-releases/news-release-details/neurogene-announces-ngn-401-gene-therapy-rett-syndrome-selected
4. Neurogene Announces RMAT Designation for NGN-401 Investigational Gene Therapy for Rett Syndrome. News release. August 7, 2024. Accessed November 18, 2024. https://www.businesswire.com/news/home/20240807880017/en/Neurogene-Announces-RMAT-Designation-for-NGN-401-Investigational-Gene-Therapy-for-Rett-Syndrome