Neurogene Inc. (Nasdaq: NGNE) announced an oral presentation at the American Society of Gene and Cell Therapy (ASGCT) Annual Meeting detailing a novel monitoring and treatment algorithm designed to reverse hemophagocytic lymphohistiocytosis (HLH), a rare and severe hyperinflammatory syndrome associated with high-dose adeno-associated virus (AAV) gene therapy.
The company's protocol specifically targets HLH cases linked to systemic exposure to AAV gene therapy at doses exceeding 1E14 vg/kg. According to Neurogene, early detection and prompt intervention have demonstrated effectiveness in reversing the condition in patients receiving high-dose AAV therapy.
"We appreciate the opportunity that ASGCT is providing for us to share findings related to HLH and the evidence-based recommendations for how to monitor, detect and treat this rare, hyperinflammatory syndrome in the context of AAV gene therapy," said Rachel McMinn, Ph.D., Founder and Chief Executive Officer of Neurogene. "As we connect with the gene therapy community to provide this information, our hope is that it spurs adoption of the early monitoring and treatment algorithm and increases propensity for sharing trial findings from which others can learn."
The "Three Fs" Monitoring Approach
The monitoring protocol focuses on what the company refers to as the "three Fs":
- Elevated ferritin levels
- Fever
- Falling blood counts (cytopenia)
These three initial signs were present in over 90% of patients with HLH in the HLH-2004 study, which forms the basis for current HLH treatment guidelines. Neurogene recommends daily monitoring for these indicators during the first week following AAV gene therapy administration.
Two-Tiered Treatment Strategy
The treatment algorithm includes:
- High-dose corticosteroids as first-line treatment
- Anakinra, an IL-1 receptor antagonist, as second-line treatment
Previous studies have demonstrated that early monitoring and prompt treatment can effectively reverse HLH in patients receiving high-dose AAV gene therapy. Neurogene has cited supporting evidence from clinical research published in the Journal of Clinical Pharmacy and Therapeutics (2022) and Molecular Therapy (2022).
Application in Rett Syndrome Trial
Despite using a lower dose in its Phase 1/2 trial of NGN-401 gene therapy for Rett syndrome, Neurogene has incorporated this monitoring and treatment protocol as a precautionary measure. The company's NGN-401 dose of 1E15 vg translates to the E13 vg/kg range, significantly lower than the threshold associated with HLH risk.
"The Company is not aware of any case of HLH ever being reported at this dose level in AAV gene therapy," Neurogene stated in its announcement, highlighting that their implementation of the protocol represents a proactive safety approach rather than a response to observed complications at their current dosing level.
Advancing Gene Therapy Safety Standards
This development represents an important step in addressing safety concerns related to high-dose AAV gene therapy. By sharing these findings with the broader gene therapy community, Neurogene aims to establish standardized monitoring and treatment protocols that could benefit patients across multiple clinical programs.
The company's approach aligns with growing industry efforts to enhance the safety profile of gene therapies while maintaining their therapeutic potential. By identifying and managing potential complications early, researchers hope to expand the applicability of these transformative treatments to more patients with rare genetic disorders.
Neurogene continues to advance its broader mission of developing novel approaches to address limitations of conventional gene therapy for central nervous system disorders. The company utilizes its proprietary EXACT™ transgene regulation platform technology, designed to deliver therapeutic levels while limiting transgene toxicity associated with conventional gene therapy.
The company has established a state-of-the-art gene therapy manufacturing facility in Houston, Texas, where CGMP production of NGN-401 was conducted to support pivotal clinical development activities for its Rett syndrome program.
