8-K: Neurogene Pauses High-Dose Trial of Rett Syndrome Gene Therapy After Serious Adverse Event

Neurogene has paused the high-dose arm of its NGN-401 gene therapy trial for Rett syndrome following a serious adverse event in a participant, while continuing the low-dose arm after FDA review.

Summary

• Neurogene has provided an update on its Phase 1/2 clinical trial of NGN-401 gene therapy for Rett syndrome.
• A participant in the high-dose cohort (3E15 vg) experienced a serious adverse event (SAE), a systemic hyperinflammatory syndrome, which is a rare and life-threatening immune response.
• The participant is in critical condition, and the case is still evolving.
• Neurogene proactively engaged with the FDA under the START program following the notification of the SAE.
• The FDA completed a review of the safety data and allowed Neurogene to proceed with the Phase 1/2 trial using the low-dose (1E15 vg) cohort.
• Neurogene has paused further use of the 3E15 vg dose and does not plan to enroll any further participants at this dose level.
• To date, there have been no other treatment-related SAEs in the clinical trial, including in the five participants who received the 1E15 vg dose and the first two participants who received the 3E15 vg dose.
• All treatment-related adverse events in the 1E15 vg cohort have been Grade 1 (mild).
• Neurogene no longer anticipates completing enrollment in the 1E15 vg cohort in the fourth quarter of 2024 as the Company updates the protocol to reflect the discontinuation of the 3E15 vg dose.

Sentiment

Score: 3

Explanation: The document reports a serious adverse event and the pausing of a trial arm, which is a significant negative development. While the trial continues with the low dose, the overall tone is cautious and concerning.

Positives

• The FDA has allowed the trial to continue with the low-dose cohort after a safety review.
• No other treatment-related SAEs have been reported in the trial besides the one in the high-dose cohort.
• All treatment-related adverse events in the low-dose cohort have been mild (Grade 1).
• There have been no signs or symptoms indicative of MeCP2 overexpression toxicity.
• There have been no intracerebroventricular (ICV) procedure-related AEs.

Negatives

• A participant in the high-dose cohort experienced a serious adverse event (SAE), a systemic hyperinflammatory syndrome, which is a rare and life-threatening immune response.
• The participant who experienced the SAE is in critical condition.
• Enrollment completion for the low-dose cohort is delayed due to protocol updates.
• The high-dose arm of the trial has been paused and will not enroll further participants.

Risks

• The serious adverse event (SAE) highlights the risks associated with high-dose AAV gene therapy.
• There is a risk that other participants may experience similar adverse events.
• The delay in enrollment completion could impact the timeline for the trial.
• The company may face challenges in identifying potential indicators of predisposition to the serious adverse event (SAE).

Future Outlook

Neurogene will continue the Phase 1/2 trial with the low-dose cohort (1E15 vg) and is updating the protocol to reflect the discontinuation of the high-dose cohort (3E15 vg). The company will continue to work with the FDA and monitor the safety of participants.

Management Comments

• Rachel McMinn, Ph.D., Founder and Chief Executive Officer of Neurogene, stated that the safety of the participants in the clinical trial is the company's foremost priority.
• She also expressed sadness for the family of the participant who experienced the SAE and asked the Rett syndrome community to join in sending heartfelt thoughts to her family, friends and the dedicated clinicians who are caring for her.

Industry Context

This announcement highlights the challenges and risks associated with gene therapy, particularly with high doses of AAV vectors. The industry is closely watching the development of gene therapies for rare neurological diseases, and safety remains a critical concern. The pause of the high-dose arm of the trial may impact investor confidence in the short term.

Comparison to Industry Standards

• The use of AAV vectors for gene therapy is common, but the occurrence of a serious hyperinflammatory syndrome is a known risk, particularly at higher doses.
• Other companies developing gene therapies for neurological disorders, such as Sarepta Therapeutics and Biogen, have also faced challenges related to safety and efficacy.
• The proactive engagement with the FDA under the START program is consistent with industry best practices for managing safety concerns in clinical trials.
• The decision to pause the high-dose arm and continue with the low-dose arm is a common approach to mitigate risks in clinical trials.

Stakeholder Impact

• Shareholders may react negatively to the news of the serious adverse event and the pause of the high-dose arm of the trial.
• Patients and families affected by Rett syndrome may be concerned about the safety of the gene therapy.
• Employees of Neurogene may be affected by the uncertainty surrounding the trial.
• The FDA will continue to monitor the trial and may require further changes.

Next Steps

• Neurogene will continue the Phase 1/2 trial with the low-dose cohort (1E15 vg).
• The company will update the protocol to reflect the discontinuation of the high-dose cohort (3E15 vg).
• Neurogene will continue to work with the FDA and monitor the safety of participants.

Key Dates

Keywords

Rett syndrome, gene therapy, NGN-401, clinical trial, adverse event, hyperinflammatory syndrome, FDA, AAV, neurological diseases, rare diseases