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Neurogene Reports Serious Adverse Event in Phase 1/2 Rett Study of Gene Therapy NGN-401
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Key Takeaways
- A serious adverse event in a high-dose participant led to a pause in high-dose enrollment of NGN-401 for Rett syndrome.
- The FDA approved continuation in the low-dose cohort, where adverse events were mild and manageable.
The company has decided to pause enrollment in the high-dose cohort of its phase 1 clinical trial for NGN-401 after a participant experienced a serious treatment-related adverse event.
Rachel McMinn, PhD
In a company update, Neurogene announced that a trial participant in its phase 1 study (NCT05898620) had experienced an emerging treatment-related serious adverse event (SAE) with high dose of NGN-401, an investigational adeno-associated viral (AAV) gene therapy for Rett syndrome. The participant developed systemic hyperinflammatory syndrome, is currently in critical condition, and the situation is ongoing, according to the company.1
Thus far, there have been no other treatment-related SAEs in the clinical trial, including the 5 patients who received the 1E15 vg dose (low-dose cohort) and the 2 patients in the 3E15 vg dose (high-dose cohort). Neurogene had conversations with the FDA about the SAE through the START program, and ultimately, the company decided to pause further use of the high-dose cohort upon initial notification of the SAE and does not intend to enroll any additional participants at that dose level going forward.
"We are deeply saddened for the family. 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," Rachel McMinn, PhD, founder and chief executive officer at Neurogene, said in a statement.1 "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."
After completing a safety review of the agent, the FDA decided to allow continued dosing in the low-dose cohort of the study. To date, the treatment-related AEs observed in that cohort have been mild in nature, with most known potential risks of AAV treatments, have been responsive to steroids, and have resolved or are resolving. Notably, Neurogene no longer expects to complete enrollment in the 1E15 vg (low-dose) cohort of NGN-401 by the fourth quarter of 2024, as the company is updating the protocol to reflect the discontinuation of the 3E15 vg dose.
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The news comes less than a week after the company announced positive data from 4 patients in the low-dose cohort of the study. All told, results showed that treatment with the gene therapy resulted in improvements in several scales as well as gains in skills and developmental milestones. In response to the data, the company stated its potential plans for a phase 3 registrational trial, with details to be released in the first half of next year.2
In the update, all 4 participants achieved a rating of “much improved” on Clinician Global Impression Scale of Improvement from baseline, as well as gained benefits in the caregiver-completed Rett Syndrome Behavior Questionnaire, ranging from 28% to 52% improvement from baseline. Additional efficacy data showed that all participants made progress in core Rett syndrome areas—hand function, language, and ambulation. These gains include complex skills rarely seen or relearned after developmental regression, as noted in the NIH-sponsored Rett syndrome natural history.
At the time of the update, 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 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.
REFERENCES
1. Neurogene Provides Update on NGN-401 Gene Therapy Clinical Trial for Rett Syndrome. News release. Neurogene. November 18, 2024. Accessed November 19, 2024. https://www.businesswire.com/news/home/20241118334218/en/Neurogene-Provides-Update-on-NGN-401-Gene-Therapy-Clinical-Trial-for-Rett-Syndrome
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. November 11, 2024. Accessed November 19, 2024. https://ir.neurogene.com/news-releases/news-release-details/neurogene-reports-positive-interim-efficacy-data-first-four-low
