Gene Therapy Yields Neurodevelopmental Improvements in Children With MPSI

Most treated participants were within 2 SDs of normative mean in acquiring cognition, expressive language and fine motor skills.

RGX-111, REGENXBIO’s investigational gene therapy for the treatment of mucopolysaccharidosis type 1 (MPSI), was well-tolerated and showed signs of efficacy in children enrolled in a phase 1/2 trial (NCT03580083) as well as 1 child treated under a single-patient Investigational New Drug (IND) application.1

These data were presented by Ray Wang, MD, Campbell Foundation Director, Multidisciplinary Lysosomal Program, Division of Metabolic Disorders, CHOC Children's Hospital, Department of Pediatrics, University of California, Irvine, at theWORLDSymposium 2023, held February 22-26, in Orlando, Florida.

"There is a great need for new treatment options that provide lasting expression of the α-l-iduronidase (IDUA) enzyme and the reduction of glycosaminoglycans in the central nervous system," Wang said in a statement.2 "I am encouraged by the emerging clinical profile of RGX-111 based on this data, including the important neurodevelopment gains in cognition, language, fine motor skills and personal and social skills for daily living."

RGX-111 is an adeno-associated virus vector (AAV9) gene therapy that delivers the gene for the IDUAenzyme to the central nervous system. The FDA has granted orphan drug, rare pediatric disease, and Fast Track designations to the therapy. The phase 1/2 study is primarily evaluating the safety of RGX-111, and secondary and exploratory endpoints include biomarkers of IDUA enzyme activity in the cerebrospinal fluid (CSF), serum and urine, neurodevelopmental assessments, and caregiver reported outcomes.

READ MORE: MPSII Gene Therapy Shows Some Signs of Durable Efficacy

The trial has dosed 8 participants as of January 17, 2023, in a low-dose cohort of 1.0x1010 genome copies per gram (GC/g) of brain mass (n = 2) and a high-dose cohort of 5.0 x 1010 GC/g of brain mass (n = 6). The single patient under the IND was dosed with 1.0x1010 GC/g of brain mass. Ages in the trial ranged from 4 months to 13 years and age was 20 months in the IND. The 48-week immunosuppression regimen was discontinued per protocol in 5 trial participants and the IND patient. Time of post-administration follow-up ranged from 7 to 103 weeks in the trial and was 87 weeks in the single-patient IND.

Investigators found that RGX-111 was well-tolerated, with no serious treatment-related adverse events (AEs). Nine serious AEs occurred in 4 participants; these included bronchitis, bronchopneumonia, sinusitis, 2 central line infections, COVID19, respiratory syncytial virus, sepsis, and otitis media, which all resolved. Treatment-emergent AEs were mostly mild, and all AEs of special interest were related to immunosuppression, the most common of which was neutropenia. 

Investigators observed decreased heparan sulfate in most participants through last follow-up, and 4 of 5 evaluable patients in the trial, as well as the single IND patient, had measurable CSF IDUA enzyme activity. Neurodevelopmental assessments, 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 6 years, and the Vineland Adaptive Behavior Scale (VABS-III; across all age groups) showed that all participants continued to acquire skills and most participants with over 6 months of follow-up (n = 5) have function within 2 standard deviations of normative mean on cognition, expressive language, and fine motor subtests. Two participants, 1 from the trial and the single IND patient, had higher than the age equivalent scores in the available natural history data on cognitive function. Wang and colleagues noted that the patient that entered the trial at 13 years of age demonstrated neurodevelopmental improvements as measured by the WASI-II and showed improvement in the majority of subdomains of the VABS-III after 18 months post-treatment.

Other notable findings included biomarker data that showed decreases in plasma I0S6 in those with elevated levels at baseline, and that the majority of patients maintained low levels of total urine glycosaminoglycans.

"RGX-111 is our second-most advanced clinical candidate in our neurodegenerative disease pipeline and is part of our '5x'25' strategy to have 5 gene therapies either on the market or in late-stage development by 2025. We are encouraged to see that this potential 1-time gene therapy using our NAV AAV9 vector continues to demonstrate compelling evidence of CNS biomarker activity," Kenneth T. Mills, president and chief executive officer, REGENXBIO, added to the statement.2 "In connecting with MPS I families, we understand the need for new treatment options that can impact daily living, and we're pleased to see that most patients in this trial demonstrated continued skill acquisition across multiple neurodevelopmental assessments."

1. Wang RY, Ficicioglu CH, Giugliani R, et al. RGX-111 gene therapy for the treatment of severe mucopolysaccharidosis type I (MPS I): Interim analysis of data from the first in human study. Presented at: WORLDSymposium, February 22-26, 2023; Orlando, Florida. Abstract #371.
2. Additional positive interim data from phase I/II trial of REGENXBIO'S RGX-111 for the treatment of severe MPS I presented at WORLDSymposium. News release. REGENXBIO.Febraury 24, 2023.
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