Gene Therapy RGX-121 Demonstrates Promising Results in Pivotal CAMPSIITE Trial of Hunter Syndrome

Steve Pakola, MD

New data from the phase 1/2/3 CAMPSIITE trial (NCT03566043) showed that treatment with RGX-121 (REGENXBIO), an investigational gene therapy, resulted in critical reductions in cerebrospinal fluid (CSF) levels of heparan sulfate (HS) D2S6, a key biomarker of brain disease activity, in patients with mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome. Overall, the totality of the evidence from the study supports RGX-121 as the potential first gene therapy for this patient population.^1,2

In the multicenter, open-label study, patients on the investigational adeno-associated vector (AAV) therapeutic demonstrated an 85% median reduction of CSF levels of HS D2S6, with levels approaching normal and sustained for up to 2 years. Based on these data, as well as previously reported topline results earlier this year, REGENXBIO is planning to initiate a rolling biologics license application (BLA) using the accelerated approval pathway in the third quarter of 2024. Approval of the planned BLA could result in a receipt of a priority review voucher in 2025.

RGX-121, a one-time therapy, was considered well tolerated in 25 treated patients across all phases of CAMPSIITE as of January 5, 2024. The most common treatment-emergent adverse events (TEAEs) were vomiting in 11 (73.3%) participants, followed by pyrexia, cough, and gastroenteritis in 9 (60.0%) participants. During the study, 17 serious AEs were observed; however, none were considered related to RGX-121 or its administration procedure. Furthermore, no single AE was experienced by all participants, and no clear dose-response relationship could be discerned.

In the dose-finding phase of the trial, most patients either discontinued standard intravenous enzyme replacement therapy (ERT) or remained ERT-naïve. 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 at the last follow-up, for nearly three years. Overall, ERT free status supported the systemic activity of RGX-121.

"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,” Steve Pakola, MD, chief medical officer at REGENXBIO, said in a statement.¹ "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."

READ MORE: Denali’s DNL310 Eyes Accelerated FDA Approval With Encouraging Phase 1/2 Data in Hunter Syndrome

The planned BLA will use CSF D2S6 as a surrogate end point reasonably likely to predict clinical benefit. Previous research has shown that a buildup of GAGs in the CSF of patients with MPS II correlates with clinical manifestations, including neurodevelopmental deficits. HS D2S6 levels in CSF have been also used to distinguish between patients with neuronopathic MPS II and those with attenuated disease.

CAMPSIITE is a unique trial that includes 2 sequential parts. Part 1 is a phase 1/2, first-in-human, multicenter, open-label, single arm dose escalation study of RGX-121 where 3 doses are tested. This part of the trial primarily assesses safety of the gene therapy over a 24-week period, with patients on treatment for a total of 104 weeks. Part 2 is a pivotal expansion, multicenter, open-label, single arm portion in which 10 patients with neuronopathic MPS II are dosed for a 24-month period. Investigators are expected to use data from the primary end point, change in CSF D2S6 levels over a 16-week period, as part of the accelerated approval BLA.

Earlier this year, in February, the company announced topline results from CAMPSIITE, revealing that the study met its primary end point of change in CSF levels of D2S6 with statistical significance. In the dose-finding phase, the majority of patients were reportedly exceeding expectations in neurodevelopmental function compared with natural history data up to 4 years.^3,4

MPS II, a rare, X-linked recessive disease, is caused by a deficiency in the lysosomal enzyme human iduronate-2-sulfatase (IDS). RGX-121 is designed to use the NAV AAV9 vector to deliver the human IDS gene to the central nervous system (CNS), allowing for long-term cross correction of cells throughout the CNS. REGENXBIO believes that this strategy could also provide rapid IDS delivery to the brain, potentially preventing the progression of cognitive deficits that otherwise occur in MPS II.

"A potential one-time treatment that can allow these boys to exceed the natural history of this disease in their neurocognitive development, as well as the ability to remain off enzyme replacement therapy for multiple years represents a meaningful option for patients and their families," Roberto Giugliani, MD, PhD, a professor in the department of genetics at HCPA, Porto Alegre, Brazil, said in a statement.¹ "I continue to be very encouraged by the data supporting RGX-121 and look forward to the seeing this program advance towards potential approval for this community."

REFERENCES
1. REGENXBIO Announces Positive Data from Pivotal Dose Level of RGX-121 Demonstrating Long-Term Systemic Effect. News release. REGENXBIO. September 3, 2024. Accessed September 12, 2024. https://regenxbio.gcs-web.com/news-releases/news-release-details/regenxbio-announces-positive-data-pivotal-dose-level-rgx-121
2. Giugliani R, Ficicioglu C, Harmatz P, et al. CAMPSIITE Phase 1/2/3: interim clinical update of RGX-121, an investigational gene therapy for treatment of neuronopathic mucopolysaccharidosis type II (MPS II). Presented at: Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium 2024.
3. REGENXBIO Announces Pivotal Trial of RGX-121 for the Treatment of MPS II Achieves Primary Endpoint. News release. REGENXBIO. February 7, 2024. Accessed September 12, 2024. https://www.prnewswire.com/news-releases/regenxbio-announces-pivotal-trial-of-rgx-121-for-the-treatment-of-mps-ii-achieves-primary-endpoint-302056283.html
4. Harmatz P. RGX-121 Gene therapy for the treatment of severe mucopolysaccharidosis type II (MPS II): CAMPSIITE phase 1/2/3: a clinical trial study update. https://www.regenxbio.com/getattachment/353ec3e0-e8ab-4545-bc5f-2b54e4b23c17/HARMATZ-RGX-121-WORLD-web-FINAL.pdf?lang=en-US&ext=.pdf