UX111 Reduces Heparin Sulfate, Correlating With Benefit in Cognitive Function in Pediatric MPSIIIA


Investigators concluded that the data support the use of HS as a predictive biomarker in Sanfilippo syndrome.

Heather Lau, MD, MS

Heather Lau, MD, MS

Credit: Global Oncology Academy

UX111 gene therapy reduced heparin sulfate (HS) exposure in the cerebrospinal fluid (CSF), which correlated with stabilized or improved cognitive function in patients with mucopolysaccharidosis type IIIA (MPSIIIA), also known as Sanfilippo syndrome.1

These data, from the phase 1/2/3 UX111-CL301 clinical trial (NCT04088734) were presented by Heather Lau, MD, MS, executive director, global clinical development, Ultragenyx, at the 2024 WORLDSymposium, held February 4-9, in San Diego, California.

“By clearing out that toxic accumulation of heparin sulfate, over the long term, we're starting to see a benefit in the overall cognition of children. There's also additional data that we're looking at that's showing preliminarily an impact on language, both expressive and receptive. So overall, we are showing initially positive results on the neurodevelopment of children with MPSIIIA,” Lau told CGTLive.

UX111 is an AAV9 viral vector encoding human SGSH administrated in a single intravenous injection. Participants in the UX111-CL301 trial are followed for 24 months and then for at least 5 years in the long-term follow up study (NCT04360265).

WATCH NOW: Heather Lau, MD, MS, on Using Heparan Sulphate as a Biomarker in the Clinical Study of MPSIIIA Gene Therapy UX111

The data presented were from 17 children in the modified intent-to-treat group with a median follow-up of 23.9 months. The participants received 3.0 x 1013 vg/kg UX111 and were less than 24 months of age or at least 24 months with a baseline Bayley-III (BSITD-III) cognitive DQ >60). They had a median age of 21.8 months (standard deviation [SD], 9.9) at baseline.

The investigators found that mean CSF HS decreased 58.5% (SD, 13.8%) from baseline at month 1. At the last follow-up, with a data cutoff date of August 16, 2023, CSF HS exposure was reduced by a mean 63.3% (95% CI, 56.9-69.7). Treatment with UX111 also led to reductions in CSF gangliosides, including GM2 and GM3, and stabilized total cortical volume on brain MRI to within normal limits.

BSITD-III scores were stable or improved for most patients from a mean raw score of 47.6 (SD, 22.2). Estimated yearly rate of change in BSITD-III raw score was found to correlate to CSF HS exposure (Spearman’s correlation coefficient, −0.72; P = .0011).

UX-111 had a manageable safety profile, with 1 serious treatment-related adverse event (TEAE) of increased alanine aminotransferase that resolved. Common TEAEs included mild-to-moderate elevations in liver enzymes.

Overall, the investigators concluded that the data provided a basis for the use of HS as a predictive biomarker in pediatric patients with MPS IIIA.

“It's impressive to see how our study patients treated with UX111 have maintained their communication skills despite being the age in which regression begins to occur,” Mireia del Toro, MD, coordinator of the Metabolic Unit, Pediatric Neurology Department, Hospital Universitari Vall d´Hebron, Barcelona, said in a statement.2 “Sustaining the ability to communicate also has a very relevant impact on improving behavioral problems and thus family daily life.”2

View more coverage of WORLDSymposium here.

1. Lau H, Patra K, Wolf M, et al. Reduction of heparan sulfate (HS) exposure in cerebrospinal fluid (CSF) correlates with improved long-term cognitive function in patients with mucopolysaccharidosis type IIIA (MPS IIIA) following treatment with UX111 gene therapy. Presented at: WorldSymposium; February 4-9; San Diego, California. Abstract #LB-35
2. Ultragenyx Announces Data Demonstrating Treatment with UX111 Results in Significant Reduction in Heparan Sulfate Exposure in Cerebrospinal Fluid Correlated with Improved Long-term Cognitive Function in Patients with Sanfilippo Syndrome Type A (MPS IIIA). News release. Ultragenyx. February 6, 2024. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-data-demonstrating-treatment-ux111-results
Related Videos
Caspian Oliai, MD, MS, the medical director of the UCLA Bone Marrow Transplantation Stem Cell Processing Center
Frederick “Eric” Arnold, PhD
Genovefa (Zenia) Papanicolaou, MD, an infectious diseases specialist at Memorial Sloan Kettering Cancer Center
Jeffrey Chamberlain, PhD, on Exciting New Research at MDA 2024
Alan Beggs, PhD, on Challenges in Therapeutic Development for Rare Diseases
Akshay Sharma, MBBS, a bone marrow transplant physician at St. Jude Children’s Research Hospital
PJ Brooks, PhD
John DiPersio, MD, PhD, the director of the Center for Gene and Cellular Immunotherapy at Washington University School of Medicine
Carlos Moraes, PhD, on Understanding Mitochondrial Mutations for Neurodegenerative Diseases
Aude Chapuis, MD, an associate professor in the Translational Science and Therapeutics Division at Fred Hutch Cancer Center
© 2024 MJH Life Sciences

All rights reserved.