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

“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.”

Ultragenyx Pharmaceutical's UX111 (also known as ABO-102), an investigational self-complementary adeno-associated virus (AAV) vector-based gene therapy, is currently being evaluated for the treatment of mucopolysaccharidosis type IIIA (MPS IIIA, also known as Sanfilippo syndrome) in the phase 1/2/3 Transpher A clinical trial (NCT02716246). UX111 is intended to deliver a functional copy of hSGSH, the gene for sulfamidase (SGSH), the enzyme responsible for breaking down the disease-associated substrate glycosaminoglycan heparan sulphate (HS). New data from Transpher A was presented at the 2024 WORLDSymposium, held February 4-9, in San Diego, California.

In an interview with CGTLive®, Heather Lau, MD, MS, the executive director of global clinical development at Ultragenyx Pharmaceutical, who presented the data at the conference, discussed the key results and their big-picture implications. Lau noted that statistical analysis performed on the data indicated a correlation between the initial reductions in HS seen after treatment with the gene therapy and later improvement or stability on cognitive assessments. She also pointed out that a similar correlation was seen with a reduction in gangliosides, a secondary storage marker. In terms of safety, Lau stated that there were no significant safety concerns associated with the gene therapy and that the most frequent adverse events were mild-to-moderate elevations in liver enzymes, a known class effect of gene therapy. She also touched on limitations of the trial, noting that demonstrating a therapy’s effect on brain function in just 2 years of follow-up is difficult, and that longer follow-up will be needed to get a better understanding of UX111’s impact. She concluded by emphasizing that establishing the correlation between biomarkers and cognitive outcomes will form the basis of an accelerated approval pathway that Ultragenyx is seeking for UX111.