Positive Results for UX-111

These clinical endpoints were correlated with substantial and sustained reduction in levels of heparan sulfate (HS) in cerebrospinal fluid (CSF). These data will be presented at the WORLDSymposium  2025 21st Annual Research Meeting, taking place February 3-7 in San Diego.

“These very promising results are particularly gratifying to me as an investigator because this program began at Nationwide Children’s Hospital in the lab of our former center faculty members, Doug McCarty and Haiyan Fu, more than a decade ago. This is a devastating disorder, and it is quite meaningful to see not only this vector’s impact on biologic markers of the disease but also to see its clinical impact on both younger and older treated patients,” said Kevin Flanigan, M.D., director of the Jerry R. Mendell, M.D. Center for Gene Therapy at Nationwide Children’s.

Following treatment with UX 111 (3x10 vg/kg), levels of CSF-HS decreased within the first month post-treatment in all patients (N=27) irrespective of age or stage of disease progression at the time of treatment. As of the August 2024 cutoff date, the median reduction in CSF-HS exposure was 65% (p<0.0001) in all patients treated with the 3x10 vg/kg dose and 66% (p<0.0001) in the modified intention to treat (mITT) group (N=17). The mean duration of follow-up post-treatment was 34 months for all patients and 36 months for the mITT group with the longest follow-up being 77 months.

Function improved in mITT group compared to natural history; Cognitive function, expressive and receptive communication and fine and gross motor skills were measured using Bayley-III and compared to natural history data from untreated patients with reported rapid progressor phenotypes.  Mean observed raw scores on the Bayley-III domains improved compared to natural history. The model-based mean Bayley-III cognitive raw score from ages 24 to 60 months in the mITT group improved by +16 points compared to natural history patients who declined by -6.8 points, demonstrating a +22.7 point (p<0.0001) treatment effect. The raw scores were also significantly improved for model-based mean receptive and expressive communication (p<0.05) and fine motor function (p=0.05), while gross motor scores achieved numerical improvements. Gross motor function is generally lost later in the disease progression, and longer-term follow-up is needed to establish significant separation from the natural history data in untreated patients. Furthermore, there was a statistically significant correlation between CSF-HS exposure and estimated yearly rate of change (EYC) for all five Bayley-III subdomains.

“When we compare the impact of UX 111 to natural history in children 2 to 5 years of age, we see that as you correct the underlying enzymatic deficiency at a molecular level, you provide the ability to preserve neurons and for these children to gain new developmental skills,” said Eric Crombez, M.D., chief medical officer at Ultragenyx. “For older patients with severe disease, we know from caregivers and clinicians that stabilizing the disease, so that a child can retain or even slow down the loss of key skills like walking independently, communicating and self-feeding, would have a profound impact on their quality of life.”

Children who are older or with more advanced disease at the time of treatment retained functional abilities; In a pre-specified analysis, all 10 patients that were outside of the mITT group due to older age or having more advanced disease at the time of treatment showed retention of meaningful functional abilities at the time of last assessment. All 10 children, who were between the ages of 5.6 and 14.8 years old at the time of last assessment, retained communication skills (3 verbal and 7 non-verbal), 9 retained ambulation (8 independent and 1 supported) and 9 retained the ability to eat and/or self-feed. These findings are clinically significant as these functions significantly worsen and are eventually lost in late childhood and early adolescence.

Safety profile remains favorable; UX 111 was generally well tolerated across all doses (N=33), including the highest dose of 3x10 vg/kg. The most frequently reported treatment-emergent adverse events (TEAEs) to date were elevations in liver enzymes and the majority of these events were mild (Grade 1) or moderate (Grade 2) in severity and all resolved.

These data were included in the Biologics License Application (BLA) submission to the FDA seeking accelerated approval for UX111 that was filed by the company in December 2024. A Prescription Drug User Fee Act (PDUFA) decision on the application and potential U.S. launch are expected in the second half of 2025.

About the UX 111 Clinical Program; The Transpher A study (NCT02716246) has enrolled and treated 28 patients across 3 dose Cohorts at 5 sites in 3 countries. The high dose Cohort 3 (3x10¹vg/kg) consists of 22 patients, and 17 are in the mITT group. The mITT group is defined as patients who were either up to age 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 UX 111.

A separate study (NCT04088734) enrolled five patients. All participants received the highest dose of 3x10 vg/kg.

Subjects who participated in either clinical study were invited to enroll into a long-term follow-up study (NCT04360265). The Transpher A and long-term follow-up studies are ongoing, and patients will continue to be followed for a minimum of 5 years following treatment with UX 111.