NGN-401

The clinical trial participant who was hospitalized for severe complications after receiving the high dose of Neurogene’s experimental Rett syndrome gene therapy has died. Neurogene disclosed the death in a regulatory filing after the market close Thursday. The company said the FDA is permitting the Phase 1/2 study to continue with the low dose of the therapy, code-named NGN-401. Neurogene added that it will incorporate this dose in planning the design of the clinical trial expected to support a regulatory submission seeking FDA approval of the gene therapy. Rett syndrome is a neurodevelopmental disorder stemming from a mutation in one copy of the MECP2 gene. Neurogene’s NGN-401 delivers to cells a functioning version of that gene with the goal of restoring expression of the key protein that’s important for brain function. The therapy reaches brain cells aboard an adeno-associated virus (AAV), a widely used delivery vehicle for genetic medicines. But these engineered viruses can trigger dangerous immune responses. presented by Market Trends to Watch for Health Systems and Their Specialty Pharmacies The future looks bright for the integrated specialty pharmacy model – for health systems, providers, and most importantly, for patients. By Jake Gaffey, MBA, Chief Strategy Officer at Shields Health Solutions Neurogene disclosed the patient complication last week, a late addition to an interim clinical trial update that showed the gene therapy was safe and well tolerated so far for five patients who received the low dose and two who received the high dose. The complication developed in a third patient in the high dose group who received that dose after the cutoff date for the interim update. Neurogene said the adverse effect was consistent with the known immune response risk associated with high doses of AAV. In a Monday update, Neurogene said the patient was in critical condition. Neurogene is conducting the NGN-401 clinical trial under Support for clinical Trials Advancing Rare disease Therapeutics (START), an FDA pilot program designed to accelerate the development of new therapies for rare diseases. Companies whose experimental treatments are selected for this program benefit from more frequent advice and communication with the agency. Neurogene is one of seven companies participating in START. Neurogene said after it learned of the serious adverse event, it “proactively engaged with the FDA under the START program.” The company said the regulator completed a review of the safety data and then allowed the study to proceed in the low-dose group. Use of the high dose was paused, and Neurogene said it does not plan to enroll more patients at that dose level. In a Tuesday research note sent to investors regarding Neurogene’s third quarter 2024 financial results, William Blair analyst Sami Corwin wrote that that she does not see the adverse event affecting Neurogene’s ability to develop the low dose of NGN-401, which showed an “impressive efficacy and tolerable safety profile.” She added that the adverse event and the subsequent FDA interactions underscore the advantages of the START program. Corwin said the agency was able to swiftly review the safety data, which likely prevented imposition of a clinical hold — traditionally the FDA’s only recourse while it investigated severe safety events in gene therapy studies. Exclusive Heard at HLTH 2024: Insights from Innovative Healthcare Executives Executives from Imagine360, Verily, BrightInsight, Lantern, and Rhapsody shared their approaches to reducing healthcare costs and facilitating digital transformation. By MedCity News “We continue to see NGN-401’s selection for the highly competitive and innovative START program as potentially accelerating the clinical development of NGN-401 and the decision to discontinue the development of the high-dose could speed up discussions regarding NGN-401’s regulatory pathway, as the company no longer has to wait to collect efficacy data from the high-dose cohort,” Corwin said. Neurogene previously said it expected to complete enrollment of the low-dose group by the end of this year. In its quarterly report, the company said the timeline has changed because of the need to update the clinical trial protocol to remove the high dose. Neurogene said it expects to resume dosing in the low-dose cohort once those revisions are complete. The company reiterated that it plans to provide an update on the design of NGN-401’s registrational study in the first half of next year; additional interim Phase 1/2 data are expected in the second half of 2025.

Neurogene has reported the death of a participant in its phase 1/2 clinical trial for Rett syndrome due to complications from a rare hyperinflammatory syndrome. The patient, who received a 3E15 vg dose of NGN-401 on November 5, experienced severe systemic exposure to high doses of adeno-associated virus (AAV), resulting in a fatal outcome. NGN-401 is a gene therapy candidate designed to address the genetic basis of Rett syndrome, a rare neurological condition. Following the incident, the FDA has permitted the trial to continue using a lower 1E15 vg dose for both pediatric and adolescent/adult cohorts. Neurogene has confirmed that this reduced dose will also be incorporated into the design of its future registrational trials. The decision reflects a cautious approach to patient safety while advancing therapy development. This development raises broader questions about the safety and regulation of experimental treatments for rare diseases. Neurogene has not disclosed further details about the impact on its timeline or any additional changes to its clinical program.