Ultragenyx Pharmaceutical Inc. announced data demonstrating treatment with UX111 (ABO-102) AAV gene therapy resulted in rapid and sustained decreased levels of heparan sulfate (HS) in cerebrospinal fluid (CSF) in patients with Sanfilippo syndrome type A (MPS IIIA), and that sustained reduction in CSF HS exposure over time was correlated with improved long-term cognitive development. These data are from the modified intention to treat group (mITT) in the pivotal Transpher A study (N=17). The results of this study along with the additional data from the long-term follow-up study for these subjects will be presented at the WORLDSymposium?

2024 20th annual research meeting taking place February 4-9 in San Diego. Following treatment with UX111 (3x1013 vg/kg), levels of CSF-HS decreased within the first month post treatment in all patients. 8 of 17 patients in the mITT group who reached 24 months post-treatment achieved an overall mean percent reduction from baseline of 51% (p <0.0001).

An alternative way to assess CSF-HS is to look at the reduction in CSF HS exposure over time post-administration of UX111 using time-normalized area under curve (AUC). The 17 patients in the mITT group had a mean follow-up duration of 29 months (range = 11.3-60 months). There was a mean reduction in CSF HS exposure of 63% (p<0.0001) using time-normalized AUC.

This type of analysis incorporates all post-baseline reductions in CSF-HS available at the time of data cut-off (August 2023) and allows for a robust quantification of the treatment effect of UX111 on reduction of toxic CSF HS exposure over time. Cognitive function was measured using Bayley-III (BSITD-IIID) cognitive raw scores and an estimated yearly rate of change (EYC) was calculated to reflect a patient-specific rate of change in BSITD-III cognitive raw scores after UX111 treatment. At the time of the data cut-off, the individual EYC in cognitive raw scores showed a positive rate of change indicating either stability or gains from baseline in 16 of the 17 patients during the expected window of plateau into decline, defined as >30 months of age.

There was a statistically significant correlation between the CSF HS exposure and the EYC in cognitive raw score, which was maintained with and without adjustment for age, resulting in a Spearman?s Rank Order Correlation Coefficient of -0.64 (p=0.0076) and -0.72 (p=0.0011), respectively. Specifically, 15 of 17 patients had both a reduction in toxic CSF HS exposure and an improvement in cognitive function. The most frequently reported treatment-related adverse events to date were elevations in liver enzymes and the majority of these events were mild (Grade 1) or moderate (Grade 2) in severity.

The only treatment-related adverse event = Grade 3 reported to date was one event of increased alanine aminotransferase (ALT) that resolved, which is a known effect of AAV gene therapy. The Transpher A study has enrolled and treated 28 patients across 3 dose Cohorts at 5 sites in 3 countries. The high dose Cohort 3 (3x1013 vg/kg) consists of 22 patients, and 17 are in the mITT group. The mITT group is defined as patients who were either age 0-2 years old, or patients older than 2 years with a cognitive developmental quotient of 60 or above at time of enrollment.

These patients received the highest dose of UX111. Subjects who completed the Transpher A study were invited to enroll into a long term follow study. As of the data cut-off, 15 of the 17 patients were at least 2.5 years of age and 6 of 17 were over five years of age.

Mean duration of follow-up post-treatment was 29 months. Both trials are ongoing, and patients will continue to be followed for a minimum of 5 years following treatment with UX111.