REGENXBIO's RGX-121, an investigational gene therapy, has shown promising long-term efficacy in the pivotal Phase 1/2/3 CAMPSIITE trial for patients with mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome. The data, presented at the Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium 2024, highlight significant reductions in cerebrospinal fluid (CSF) levels of heparan sulfate (HS) D2S6, a key biomarker of brain disease activity.
Sustained Reduction in Biomarkers
The multicenter, open-label study revealed an 85% median reduction in CSF levels of HS D2S6 in patients treated with RGX-121. These levels approached normal ranges and were sustained for up to two years, indicating a durable therapeutic effect. This reduction is clinically significant as elevated HS D2S6 levels correlate with neurodevelopmental deficits in MPS II patients.
Potential for Accelerated Approval
Based on these data, REGENXBIO is planning to initiate a rolling biologics license application (BLA) in the third quarter of 2024, seeking accelerated approval from the FDA. The BLA will utilize CSF D2S6 as a surrogate endpoint reasonably likely to predict clinical benefit. Approval could potentially lead to a priority review voucher in 2025.
Enzyme Replacement Therapy Independence
An important observation from the trial was the ability of patients to remain off standard intravenous enzyme replacement therapy (ERT) following RGX-121 treatment. At the pivotal dose level (level 3), 80% of patients remained ERT-free at the last follow-up, extending beyond 18 months post-dosing. At dose level 2, 71% of patients were ERT-free for nearly three years. This ERT-free status underscores the systemic activity of RGX-121.
Safety Profile
RGX-121 was generally well-tolerated in the 25 patients treated across all phases of the CAMPSIITE trial. The most common treatment-emergent adverse events (TEAEs) included vomiting (73.3%), pyrexia, cough, and gastroenteritis (60.0%). While 17 serious AEs were observed, none were considered related to RGX-121 or its administration procedure. No single AE was experienced by all participants, and no clear dose-response relationship was identified.
Expert Commentary
"As we quickly approach the BLA filing for RGX-121, we are very pleased with the data presented at SSIEM demonstrating encouraging evidence of systemic activity and long-term reductions of CSF D2S6," said Steve Pakola, MD, chief medical officer at REGENXBIO. "The data continue to support that by restoring the gene missing in boys with Hunter syndrome, RGX-121 changes the course of disease and has the potential to significantly improve both vital brain function and the systemic manifestations of this devastating disease."
Trial Design and MPS II Context
The CAMPSIITE trial is a two-part study, beginning with a Phase 1/2 dose-escalation phase followed by a pivotal expansion phase. The primary endpoint for accelerated approval is the change in CSF D2S6 levels over a 16-week period. MPS II, a rare X-linked recessive disease, results from a deficiency in the iduronate-2-sulfatase (IDS) enzyme. RGX-121 delivers the human IDS gene to the central nervous system (CNS) using the NAV AAV9 vector, aiming for long-term cross-correction of cells throughout the CNS and prevention of cognitive deficits.
