RegenxBio Reports Positive Interim Results for MPS I Gene Therapy, Expanding Study

RegenxBio reported positive interim data at the 18th Annual WORLDSymposium from five patients in the ongoing phase 1/2 trial and one patient from a single-patient Investigational New Drug application of RGX-111 for the treatment of severe Mucopolysaccharidosis type I.

Photo: Steve Pakola, chief medical officer of RegenxBio

MPS I is a rare autosomal recessive genetic disease caused by a deficiency in the lysosomal enzyme alpha-L-iduronidase (IDUA), leading to an accumulation of glycosaminoglycans (GAGs) including heparan sulfate (HS) in tissues which ultimately results in cell, tissue, and organ dysfunction, including in the central nervous system (CNS). This can include excessive accumulation of fluid in the brain, spinal cord compression, and cognitive impairment. MPS I is estimated to occur in 1 in 100,000 births.

Current disease modifying therapies for MPS I include hematopoietic stem cell transplant (HSCT) and enzyme replacement therapy with a recombinant form of human IDUA administered intravenously. However, intravenous enzyme therapy does not treat the CNS manifestations of MPS I, and HSCT can be associated with clinically significant morbidity and mortality. Key biomarkers of IDUA enzymatic activity in MPS I patients include its substrate heparan sulfate, which has been shown to correlate with neurocognitive manifestations of the disorder.

RGX-111 is designed to use the AAV9 vector to deliver the α-l-iduronidase (IDUA) gene to the central nervous system. Delivery of the IDUA gene within the cells in the central nervous system could provide a permanent source of secreted IDUA beyond the blood-brain barrier, allowing for long-term cross-correction of cells throughout the CNS. By providing rapid IDUA delivery to the brain, RGX-111 could potentially help prevent the progression of cognitive deficits that otherwise occurs in MPS I patients. RGX-111 has received orphan drug product, rare pediatric disease and Fast Track designations from the U.S. Food and Drug Administration.

The primary endpoint of the trial is to evaluate the safety of RGX-111. Secondary and exploratory endpoints include biomarkers of α-l-iduronidase (IDUA) enzyme activity in the cerebrospinal fluid (CSF), serum and urine, neurodevelopmental assessments, and caregiver reported outcomes.

Patients were treated across two dose cohorts: 1.0×1010 genome copies per gram (GC/g) of brain mass and 5.0×1010 GC/g of brain mass. In the single-patient IND for RGX-111, a severe MPS I patient was dosed with 1×1010 GC/g of brain mass.

RegenxBio plans to immediately expand enrollment of patients in Cohort 2 of the phase 1/2 trial based on support from MPS I treating-physicians and the Independent Data Monitoring Committee, to enroll up to six additional patients.

As of December 20, 2021, RGX-111 is reported to be well-tolerated in the five patients enrolled in the phase 1/2 clinical trial with no drug-related serious adverse events (SAEs). Time of post-administration follow-up ranges from three weeks to 56 weeks. One patient in Cohort 1 has completed the 48-week immunosuppression regimen per the study protocol. Two patients were not receiving enzyme replacement therapy (ERT) at the time of enrollment, and they continue to not receive ERT.

RGX-111 continues to be well-tolerated in the single-patient IND with no drug-related SAEs as of December 20, 2021. Time of post-administration follow-up is 87 weeks. This patient has completed the 48-week immunosuppression regimen, per the study protocol, and continues to receive weekly ERT.

Data from patients in the phase 1/2 trial and the single-patient IND indicate positive IDUA biomarker activity in the CNS following one-time administration of RGX-111. Heparan sulfate (HS) is a glycosaminoglycan (GAG) that is a key biomarker of IDUA enzyme activity. In the phase 1/2 trial, a decrease in HS in the CSF from baseline was observed through the last timepoint available in all four patients following administration of RGX-111. Measurable IDUA enzyme activity in the CSF was detected after RGX-111 administration in three of the four patients, all of whom had undetectable levels of IDUA activity at baseline.

The patient dosed with RGX-111 under the single-patient IND demonstrated a decrease from baseline in HS in the CSF at 59 weeks after dosing, the last timepoint available. IDUA enzyme activity in the CSF, which was at undetectable at baseline, was detected following RGX-111 administration.

Patients in the phase 1/2 trial and the single-patient IND demonstrated encouraging continued neurodevelopment, as measured by age and using developmentally appropriate validated instruments for neurodevelopmental testing, including the Bayley Scales of Infant Development (BSID-III) for chronological or developmental ages 0-42 months,  Wechsler Abbreviated Scale of Intelligence (WASI-II) for chronological and developmental age greater than six years, and the Vineland Adaptive Behavior Scale (VABS-III).

Three patients in the phase 1/2 trial had neurodevelopmental assessments with at least one post-baseline assessment after administration of RGX-111. Early assessments from the two patients under the age of six years old demonstrated continued skill acquisition within two standard deviations of the normative mean at last assessment on the BSID-III cognition, expressive language and fine motor subtests. One patient in Cohort 1 who entered the trial at the age of 13 years old demonstrated neurodevelopmental improvements as measured by the WASI-II and six of the nine scales of the VABS-III at one year after RGX-111 administration.

The single-patient IND patient demonstrated continued skill acquisition within two standard deviations of the normative mean on the BSID-III cognition, expressive language and fine motor subtests, as well as higher age equivalent scores than available natural history data at last assessment, 20 months after administration of RGX-111.

Evidence of systemic biomarker activity was observed in patients in both cohorts of the phase 1/2 trial and the single-patient IND. Patients who had elevated baseline levels of I0S6 in plasma, a key biomarker of IDUA enzyme activity in MPS I patients, demonstrated decreases in I0S6 levels following administration of RGX-111. In addition, patients dosed with RGX-111 maintained low levels of total urine GAGs at the last timepoint available, regardless of ERT treatment.

“This marks our first data presentation from the phase 1/2 trial evaluating RGX-111 as a potential one-time gene therapy delivered directly to the central nervous system for the treatment of severe MPS I,” said Steve Pakola, chief medical officer of RegenxBio. “We are encouraged to see that RGX-111 has been well-tolerated with emerging evidence of CNS biomarker activity and improvements in neurodevelopmental function, which suggest biological activity in the CNS following one-time administration of RGX-111. We also saw emerging evidence of biomarker activity outside of the CNS.”

Author: Rare Daily Staff