Treatment with UX111 Gene Therapy Rapidly Reduced Heparan Sulfate (HS) Exposure in Cerebrospinal Fluid (CSF) and Improved Long-term Cognitive Function in Children with Mucopolysaccharidosis IIIA (MPS IIIA)
Heather Lau1, Kaushik Patra1, Melissa Wolf1, Nichola J. C. Smith2, Maria Luz Couce3, Deepa S. Rajan4, Kristen V. Truxal5, Maria J. de Castro3, Maria Fuller6, Eines Monteagudo7, Lucy Dougherty8, Mireia del Toro8, Kevin M. Flanigan5
1Ultragenyx Pharmaceutical Inc, 2Paediatric Neurodegenerative Diseases Research Group, Women's and Children's Hospital and the University of Adelaide, 3Metabolic Unit, Department of Paediatrics, Hospital Clínico Universitario de Santiago de Compostela, 4University of Pittsburgh UPMC Children’s Hospital of Pittsburgh, 5Center for Gene Therapy, Nationwide Children's Hospital, 6Genetics and Molecular Pathology, SA Pathology, and School of Biological Sciences and Adelaide Medical School, University of Adelaide, 7The Health Research Institute of Santiago de Compostela, 8Hospital Universitari Vall d’Hebron
Objective:
Describe safety and efficacy of a single administration of UX111 in children with MPS IIIA
Background:
MPS IIIA is a rare, progressive, childhood-onset neurodegenerative lysosomal storage disease resulting in toxic accumulation of HS in the brain leading to irreversible neurocognitive decline and early death. UX111 is an AAV9 viral vector encoding human SGSH being investigated for efficacy and safety in children with MPS IIIA.
Design/Methods:
UX111-CL301 (NCT04088734) is an ongoing, open-label phase 1/2/3 trial. Children received a single IV injection of UX111 and were followed for 24 months (parent study) then for at least 5 years after UX111 administration in the long-term follow up study (NCT04360265). The primary efficacy endpoint was CSF HS exposure, measured by time-normalized area under the curve (AUC). A key secondary endpoint was BSITD-III cognitive raw score. Data cutoff was 01Aug2024.
Results:
Seventeen children were in the mITT group (3.0 x 1013 vg/kg UX111 and ≤24 months of age or >24 month with a baseline Bayley cognitive DQ ≥60). Baseline mean (SD) age was 21.8 (9.9) months. Median CSF HS exposure was significantly reduced by >50% relative to baseline, and these reductions were rapid and sustained, with a median follow up of 31 months. Gangliosides GM2 and GM3 also showed rapid and sustained decreases relative to baseline. BSITD-III cognitive raw scores were significantly improved relative to untreated children with MPS IIIA during the ages when untreated children tend to plateau or lose skills. Similar improvements were seen across BSITD-III domains, including receptive and expressive communication and gross and fine motor. The only treatment-related adverse event ≥grade 3 was one event of increased alanine aminotransferase that resolved.
Conclusions:
UX111 appears safe and effective in children with MPS IIIA leading to reduced CSF HS exposure and improved cognitive function.
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