Sanfilippo type A children show gains with gene therapy UX111
Treatment is designed to provide brain cells with healthy copy of SGSH gene
Most children with Sanfilippo syndrome type A who received the one-time gene therapy UX111 early in life in a clinical trial continue to show cognitive development gains beyond the age where patients usually start regressing.
These improvements were associated with reductions in heparan sulfate (HS) in the children’s cerebrospinal fluid (CSF), which surrounds the brain and spinal cord. HS is the complex sugar molecule that builds up to toxic levels in Sanfilippo type A, causing damage to brain cells.
The findings come from data from a Phase 1/2 clinical trial, called Transpher A (NCT02716246), that were announced by Ultragenyx Pharmaceutical, which acquired the rights to UX111 (formerly ABO-102) in 2022.
“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,” said Mireia del Toro, MD, coordinator of the metabolic unit in the pediatric neurology department at Hospital Universitari Vall d´Hebron in Barcelona, Spain, in a press release from Ultragenyx. The hospital is one of the study’s sites.
Sanfilippo type A, the most common and usually most severe type of Sanfilippo syndrome, is caused by mutations in the SGSH gene that result in a nonworking version of the heparan N-sulfatase enzyme being produced. The enzyme is needed to break down HS, so mutations result in the complex sugar molecule accumulating to toxic levels, damaging brain cells and driving disease symptoms.
Testing UX111 in children with Sanfilippo type A
A one-time gene therapy, UX111 is designed to provide brain cells with a healthy copy of SGSH, allowing a working enzyme to be produced and the HS buildup to be cleared. This should help prevent, delay, or slow neurodegeneration in Sanfilippo type A patients.
UX111 is being tested in the Phase 1/2 Transpher A trial, whose data could support applications for its approval in the U.S. and elsewhere.
The international study enrolled 28 children with Sanfilippo type A, with all receiving a single UX111 dose at one of three doses. Participants are being followed for up to two years after a single infusion.
Those completing the Transpher A trial can enter a Phase 3 extension study (NCT04360265), where they and other Sanfilippo type A patients who received UX111 in trials will be followed for at least five years post-treatment.
The data concern 17 Transpher A participants who were part of the modified intent-to-treat (mITT) group. This group included children younger than 2 at their enrollment or older children with a developmental quotient (DQ) of 60 or higher. DQ is a measure of development compared with normative values for the population, akin to intelligence quotient, or IQ.
All the patients in the mITT group received the highest tested dose of UX111, 30 billion vector genomes per kg of body weight. As of the data cutoff date, the patients had been followed for more than two years on average.
HS levels in the CSF began to decrease within a month after treatment, results showed. In the eight children who’ve been followed for at least two years, average CSF HS levels decreased by 51%. Total exposure to HS, a measure calculated based on HS levels over time, decreased by an average of 63% in the mITT population.
“It’s important to look at the impact of CSF-HS as the brain’s length of exposure to a toxic substrate rather than just one moment in time and if you correct the underlying biochemical disease at a molecular level, you provide the ability for neurons to survive and the brain to maintain and gain function over time,” said Emil D. Kakkis, MD, PhD, CEO and president of Ultragenyx. “This recovery from exposure takes time, and while we’ll see rapid reduction in exposure, we then need to follow up over the course of several years to see the developmental gains in these children.”
At the analysis, 15 of the 17 patients in the mITT population were at least the age of 2.5, which is around when cognition typically starts worsening in Sanfilippo A patients. Six children were older than 5.
In 16 of the 17 children, scores of the Bayley Scales of Infant Development-III, a standard measure of cognitive function, showed a positive yearly rate of change, suggesting either stability or gains in cognitive function.
Statistical analyses showed a close association between cognitive improvements and reduction in CSF HS levels. All but two children showed a reduction in HS exposure and cognitive improvements.
UX111 has been generally well tolerated, with most treatment-related side effects being mild to moderate. The most common side effect was an increase in liver enzymes, a sign of liver damage that’s usually seen with viral gene therapies.
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