RegenxBio Reports Additional Positive Interim Data from Experimental Hunter Syndrome Gene Therapy

Rare Daily Staff

RegenxBio reported additional positive interim data from the phase 1/2/3 CAMPS2TE trial of its experimental therapy RGX-121 for the treatment of patients up to 5 years old diagnosed with the lysosomal storage disorder mucopolysaccharidosis type 2, also known as Hunter Syndrome.

Mucopolysaccharidosis type 2 (MPS 2), or Hunter Syndrome, is a rare, X-linked recessive disease caused by a deficiency in the lysosomal enzyme iduronate-2-sulfatase (I2S) leading to an accumulation of glycosaminoglycans (GAGs), including heparan sulfate (HS) in tissues that ultimately results in cell, tissue, and organ dysfunction, including in the central nervous system. MPS 2 is estimated to occur in 1 in 100,000 to 170,000 births. In severe forms of the disease, early developmental milestones may be met, but developmental delay is readily apparent by 18 to 24 months. Specific treatment to address the neurological manifestations of MPS 2 remains a significant unmet medical need. Key biomarkers of I2S enzymatic activity in MPS 2 patients include its substrate heparan sulfate (HS) D2S6, which has been shown to correlate with neurocognitive manifestations of the disorder.

RGX-121 is designed to use the AAV9 vector to deliver the human iduronate-2-sulfatase gene (IDS), which encodes the iduronate-2-sulfatase (I2S) enzyme, to the central nervous system (CNS). Delivery of the IDS gene within cells in the CNS could provide a permanent source of secreted I2S beyond the blood-brain barrier, allowing for long-term cross correction of cells throughout the CNS. RGX-121 has received orphan drug product, rare pediatric disease and Fast Track designations from the U.S. Food and Drug Administration.

The company reported data from the phase 1/2 portion of the CAMPS2TE trial in which the primary endpoint is to evaluate the safety of RGX-121. Secondary and exploratory endpoints include cerebral spinal fluid (CSF) glycosaminoglycans (GAGs), neurodevelopmental assessments, caregiver reported outcomes and systemic biomarkers. RGX-121 is administered directly to the central nervous system. The study findings are being presented at the 2023 WORLDSymposium.

“These new results demonstrate sustained reductions in CSF GAGs and an encouraging, long-term clinical profile of RGX-121 up to three years,” said Steve Pakola, chief medical officer of RegenxBio. “GAGs measured in CSF, specifically heparan sulfate, reflect disease manifestations in the CNS and are a direct cause of disease pathophysiology. Our data provide additional evidence to support the finding that meaningful changes in CSF heparan sulfate is an appropriate and reliable surrogate endpoint reasonably likely to predict the clinical benefit of CNS-targeted therapies for MPS 2.”

As of January 3, 2023, 15 patients had been treated across three dose levels. RGX-121 was well tolerated across all cohorts with no drug-related serious adverse events in 15 patients dosed. Time of post-administration follow-up ranges from eight weeks to more than three years. Thirteen patients have completed the 48-week immunosuppression regimen per study protocol. Twelve patients were receiving weekly, intravenous enzyme replacement therapy (ERT) at the time of enrollment, per standard of care; five of these patients remain discontinued from ERT at last time point available, per investigator discretion, as allowed in the protocol.

Biomarker data from patients in all three cohorts indicate encouraging, dose-dependent reductions of CSF GAGs following one-time administration of RGX-121. Heparan sulfate (HS) and D2S6, a component of HS closely correlated with severe MPS 2, are GAGs that are key biomarkers of I2S enzyme activity and are being measured in the CSF at baseline and after administration of RGX-121. CSF GAGs have the potential to be considered a surrogate endpoint that is reasonably likely to predict clinical benefit in MPS 2 disease under the accelerated approval pathway, as buildup of GAGs in the CSF of MPS 2 patients correlates with clinical manifestations including neurodevelopmental deficits.

The majority of patients in all cohorts demonstrated reductions of CSF HS from baseline at the last time point available with dose-dependent reductions seen at Weeks 8, 24, and 48 post RGX-121 administration. At Week 48, median reduction of CSF HS from baseline was 33.5 percent in Cohort 1, 48.9 percent in Cohort 2 and 64.7 percent in Cohort 3.

Similarly, dose-dependent reductions of CSF HS D2S6 from baseline were observed at last time point available in the majority of patients, with Cohort 3 patients approaching normal levels at 48 weeks. All three cohorts demonstrated a reduction in HS D2S6 with dose-dependent reductions seen at Weeks 8, 24, and 48. Median reductions from baseline of 31.9 percent in Cohort 1, 71.9 percent in Cohort 2 and 83.3 percent in Cohort 3 were seen at Week 48.

In addition, I2S protein concentration in the CSF, which was undetectable in all patients prior to dosing, was measurable in 10 of 11 Cohort 2 and 3 patients after RGX-121 administration.

Improvements in neurodevelopmental function and caregiver reported outcomes demonstrated CNS activity on two developmental scales up to three years after RGX-121 administration.

The company expects to seek U.S. Food and Drug Administration approval for the therapy in 2023 under the accelerated approval pathway.

“Treatment options to address the neurological manifestations of MPS 2 remain a significant unmet medical need for patients,” said Can Ficicioglu, professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania. “The data presented today are encouraging and continue to show the potential of a one- time gene therapy to provide meaningful, durable clinical benefits to the MPS 2 community.”

Photo: Steve Pakola, chief medical officer of RegenxBio