Treatment with UX111 Reduced Cerebrospinal Fluid (CSF) Heparan Sulfate (HS) Exposure and Stabilized or Improved Functioning Across Dose, Age, and Stage of MPS IIIA
Heather Lau1, Kaushik Patra1, Melissa Wolf1, Nicholas Smith2, María Luz Couce3, Deepa Rajan4, Kristen Truxal5, María Jose Lopez3, Maria Fuller6, Eines Monteagudo7, Lucy Dougherty8, Mireia del Toro8, Kevin Flanigan5
1Ultragenyx Pharmaceutical Inc, 2Women's and Children's Hospital and the University of Adelaide, 3Hospital Clínico Universitario de Santiago de Compostela, 4Childrens Hospital of Pittsburgh, 5Nationwide Children's Hospital, 6Adelaide Medical School, 7The Health Research Institute of Santiago de Compostela, 8Hospital Universitari Vall d’Hebron
Objective:
Describe safety and efficacy of UX111 in children with MPS IIIA
Background:
MPS IIIA (Sanfilippo type A) is a progressive neurodegenerative disease characterized by developmental arrest, regression, and early death. UX111 (rebisufligene etisparvovec) is an AAV9 viral vector encoding human SGSH under investigation for MPS IIIA.
Design/Methods:
Data were analyzed across 2 open-label studies (NCT02716246, NCT0408873) and the ongoing long-term follow up (NCT04360265). Children received a single UX111 infusion IV at low (0.5x1013 vg/kg, n=3), mid (1x1013 vg/kg, n=3), or high dose (3x1013 vg/kg, n=27). The mITT set (n=17) included children treated with high dose and either ≤2 years old or >2 years old with a BSID-III cognitive developmental quotient ≥60. CSF HS exposure was defined as time-normalized area under the curve of percentage change from baseline. Data cutoff was 01Aug2024.
Results:
33 children received UX111. Median (min-max) follow up was 43.96 (7.00-77.14) months. Median (95% CI) CSF HS exposure decreased by 57.86% (33.15, 61.44) relative to baseline for low dose, 42.81% (39.74, 62.75) for mid dose, 64.51% (56.29, 71.25, p<0.0001) for high dose, and 65.96% (56.86, 74.16, p<0.0001) for the mITT set.
In the mITT set, mean change in model-estimated BSID-III raw scores from 24-60 months of age was significantly improved for treated children vs Natural History for cognitive (22.7 points, p<0.0001), receptive communication (7.4 points, p=0.0212), and expressive communication (15.9 points, p=0.0011). Fine and gross motor skills showed separation from Natural History (7.3 points, p=0.050 and 2.0 points, p=0.360, respectively). Older children and those with more advanced disease at treatment (n=10) retained key communication, ambulation, and/or eating/self-feeding skills.
Most UX111-related TEAEs were mild to moderate and resolved spontaneously.
Conclusions:
UX111 showed a positive treatment effect and manageable safety across UX111 doses, age, and stage of disease at the time of treatment. LTFU continues with additional data forthcoming.
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