REGENXBIO’s MPSII Gene Therapy RGX-121 Continues to Show Efficacy in Long-Term Trial Data
Among patients who received the pivotal dose level, a median reduction of 85% in HS D2S6 levels was seen in the CSF.
Paul Harmatz, MD
REGENXBIO’s RGX-121, an investigational adeno-associated virus vector-based gene therapy intended to treat mucopolysaccharidosis type 2 (MPSII, also known as Hunter syndrome), has continued to show signs of efficacy in long-term data from the pivotal phase 1/2/3 CAMPSIITE clinical trial (NCT03566043) that the company presented at the Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium 2024, held September 3-6, in Porto, Portugal.1
REGENXBIO reported that among patients who received the pivotal dose level (dose level 3, DL3) in the study, a median reduction of 85% in heparan sulfate (HS) D2S6 levels was seen in the cerebrospinal fluid (CSF). The company noted that these levels of the biomarker approach normal levels and were sustained for up to 2 years.
It was also noted that 80% of patients treated at DL3 were not taking standard of care enzyme replacement therapy (ERT) as of the most recent time point, for up to 18 months after receiving the gene therapy. In addition, 71% of patients treated at DL2 were ERT-free at the most recent time point, for up to nearly 3 years after treatment with the gene therapy. Some participants in the trial had entered ERT-naive and others discontinued receiving ERT while on-study.
"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 ERT for multiple years represents a meaningful option for patients and their families," Roberto Giugliani, MD, PhD, a professor in the Department of Genetics, UFRGS, Medical Genetics Service, 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."
In terms of safety, REGENXBIO continues to characterize RGX-121 as “well-tolerated” across 25 patients who have been treated throughout the CAMPSIITE study, with a data cutoff of January 5, 2024. The company additionally stated that in the third quarter of this year it anticipates submission of a rolling biologics license application (BLA) for RGX-121 via the FDA’s accelerated approval pathway. For the BLA, REGENXBIO expects to use CSF D2S6 as a surrogate end point for predicting clinical efficacy.
"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, the chief medical officer of REGENXBIO, added to the 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."
REGENXBIO additionally pointed out that data presented earlier this year showed that the pivotal phase of CAMPSIITE had met its primary end point with statistically significant results (P = .00016).1,2 Furthermore, in the dose finding phase of CAMPSIITE, with which the company states results in the pivotal phase were consistent, the majority of patients were surpassing expectations based on natural history data for up to 4 years with regard to neurdevelopmental function.
The data showing that the pivotal phase met its primary end point were presented at the 2024 WORLDSymposium, held February 4-9, in San Diego, California by Paul Harmatz, MD, a pediatric gastroenterologist and professor in residence at University of California at San Francisco. Around the time of the conference, CGTLive® interviewed Harmatz to learn more about D2S6 as a biomarker for MPSII compared with the more commonly used HS biomarker. He noted that D2S6 seems to be more sensitive to neuronopathic changes in MPSII and is thus a bespoke biomarker for brain disease activity.
“[T]he drug appears to have a long lifespan of up to 4 years so far,” Harmatz said in the interview. “It does show a dose response to all doses and moves the patient into the attenuated range - the highest dose actually reaches almost just above normal range. We're able to withdraw 70 to 80% of the patients or keep them off ERT and neurocognition looks really good if you can start early. Now with newborn screening in place, our hope is that this will be the breakthrough, we need to start patients in the first year of life and see an optimal outcome. The pivotal study met its endpoint, and this was sort of the composite that we really needed to move forward, out of the early phase into a later development phase. We're excited.”
