UX111 gene therapy shows long-term benefit in Sanfilippo type A: Trial data
Single dose helped children maintain or improve developmental skills
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A single dose of UX111 (rebisufligene etisparvovec), an experimental gene therapy being developed by Ultragenyx Pharmaceutical, reduces the toxic buildup of heparan sulfate for more than eight years and helps children with Sanfilippo syndrome type A maintain or improve developmental skills, particularly when administered early.
These long-term results come from two open-label clinical studies — the ongoing TRANSPHER A (NCT02716246) and a smaller, terminated study (NCT04088734) — and their Phase 3 extension (NCT04360265), in which patients are being followed for at least five years. So far, UX111 has been well tolerated and remains safe.
“For the entire UX111 study program, we now have more than eight years of follow-up, and overall, these data continue to support a clinically meaningful and durable clinical effect of UX111, regardless of age or stage of disease,” Heather Lau, MD, Ultragenyx’s executive director of global clinical development, told Sanfilippo Syndrome News.
Based on these data, Ultragenyx has resubmitted its biologics license application to the U.S. Food and Drug Administration (FDA), seeking accelerated approval for UX111. A review is expected to take up to six months and a decision is likely in the third quarter of this year. The company had already submitted an application, but the FDA requested changes to the manufacturing process before UX111 could be considered for approval.
So far, clinical data have shown a “consistent improvement in the multiple relevant direct measures of disease activity… . For families, what matters most is time — preserving skills, slowing functional loss, and extending quality of life as long as possible. We remain committed to advancing with urgency to deliver this much-needed potential treatment option,” Lau said.
The data were presented orally at the WORLDSymposium 2026, held earlier this month.
“These data continue to demonstrate a remarkable and unprecedented separation from the natural history of Sanfilippo syndrome through more than eight years of follow-up, with children in their teens retaining skills at an age when many of their untreated peers have sadly lost their most basic abilities and succumbed to this disease,” Emil D. Kakkis, MD, PhD, Ultragenyx’s CEO and president, said in a company press release.
UX11 provides healthy copy of crucial gene
Sanfilippo syndrome, also known as mucopolysaccharidosis type III, is a rare inherited metabolic disorder in which genetic mutations prevent the body from producing enzymes that break down heparan sulfate, a complex sugar molecule.
Under normal conditions, heparan sulfate is continuously broken down and recycled within lysosomes, the cell’s waste-processing centers. In individuals with Sanfilippo syndrome, the missing or malfunctioning enzyme disrupts this process. As a result, heparan sulfate accumulates inside cells, particularly in the brain, leading to the disease’s symptoms.
In Sanfilippo syndrome type A, the mutated gene is SGSH, which leads to a deficiency in an enzyme of the same name.
Delivered by injection into the bloodstream, UX111 is a one-time gene therapy designed to provide the body with a healthy copy of the SGSH gene, enabling the production of the missing enzyme. This enzyme can be taken up by nerve and other cells, where it breaks down excess heparan sulfate. This is expected to slow or prevent neurodegeneration.
Levels of heparan sulfate decreased in children given highest dose
The TRANSPHER A study enrolled 28 children with Sanfilippo syndrome type A who received one of three dose levels of UX111. Seventeen were included in the high-dose modified intent-to-treat group, consisting of children younger than 2 or older than 2 with a developmental quotient of 60 or higher. The now-terminated open-label study treated five patients at the high dose. All patients who participated in these two studies were invited to join the ongoing extension study.
After treatment with the highest dose of UX111, levels of heparan sulfate in the cerebrospinal fluid (CSF) — the fluid surrounding the brain and spinal cord — dropped within the first month in a group of 27 patients studied. This decrease was seen in children of all ages and at all stages of the disease.
As of September 2025, the median reduction in CSF heparan sulfate levels was about 64%, which was statistically significant. Most children responded well to treatment: 88% of the younger patients and 81.5% of all treated patients had their CSF heparan sulfate levels reduced by at least half. The FDA has agreed that heparan sulfate levels in the CSF can be used when applying for UX111 approval.
Researchers measured cognitive ability, communication, and motor skills using the Bayley-III test, a standardized developmental assessment for young children. When compared with natural history data from untreated patients, who usually decline quickly, children treated early (before age 2 or at an earlier stage of the disease) showed a 23.2-point improvement in cognitive raw scores.
Our studies consistently show that reductions in heparan sulfate are associated with meaningful clinical benefits across multiple domains, underscoring the urgency to bring forward a treatment for families who currently have no options to stop or delay the heartbreaking and inevitable progression and loss of function associated with this disease.
Other developmental skills also improved. Receptive communication (understanding language) improved by 8.1 points, expressive communication (speaking or conveying messages) by 11.1 points, fine motor skills by 9 points, and gross motor skills by 3.9 points. Caregiver reports using the Vineland-2 adaptive behavior scale showed similar gains in communication, motor, and personal skills.
Eight children developed cognitive skills equivalent to those of a 3-year-old, enabling them to complete more advanced developmental tests. In comparison, none of the children in the natural history group reached this level.
All children who were older or had more advanced disease at treatment (10 patients) retained some form of communication at the last follow-up, at a median age of 9.7, compared with a typical loss at around 7.6 years in untreated patients. Nine of 10 children continued to walk independently, and nine could still eat by mouth or self-feed.
UX111 was generally well tolerated across all doses. During a median follow-up of 4.8 years, the most common treatment-emergent side effects were temporary increases in liver enzymes, which were mostly mild or moderate and resolved on their own.
“Our studies consistently show that reductions in heparan sulfate are associated with meaningful clinical benefits across multiple domains, underscoring the urgency to bring forward a treatment for families who currently have no options to stop or delay the heartbreaking and inevitable progression and loss of function associated with this disease,” Kakkis said.
