Ultragenyx Reports New Positive Data for MPS IIIA Gene Therapy

Rare Daily Staff

Ultragenyx Pharmaceutical said new data demonstrating treatment with its experimental gene therapy for the lysosomal storage disorder Sanfilippo syndrome (MPS IIIA) led to a statistically significant improvement in cognition, receptive communication and expressive communication compared to natural history data from untreated patients.

These clinical endpoints were correlated with substantial and sustained reduction in levels of heparan sulfate (HS) in cerebrospinal fluid. The data will be presented at the WORLDSymposium 2025 21st Annual Research Meeting in San Diego this week.

Sanfilippo syndrome type A (MPS IIIA) is a rare disease with no approved treatment. It primarily affects the brain and is characterized by rapid neurodegeneration, with onset in early childhood. Children with MPS IIIA present with global developmental delay which eventually leads to progressive cognitive, language and motor decline, behavioral abnormalities and early death. MPS IIIA is estimated to affect approximately 3,000 to 5,000 patients in commercially accessible geographies with a median life expectancy of 15 years.

MPS IIIA is caused by pathogenic variants in the SGSH gene that lead to a deficiency in the sulfamidase enzyme responsible for breaking down heparan sulfate, a glycosaminoglycans, which accumulate in cells throughout the body resulting in the observed rapid neurodegeneration that is associated with the disorder.

UX111 is an experimental in vivo gene therapy in phase 1/2/3 development for Sanfilippo syndrome type A. It is designed to be dosed in a one-time intravenous infusion using a self-complementary AAV9 vector to deliver a functional copy of the SGSH gene to cells. The therapy is designed to address the underlying SGSH enzyme deficiency responsible for abnormal accumulation of heparan sulfate in the brain that results in progressive cell damage and neurodegeneration. The UX111 program has received Regenerative Medicine Advanced Therapy, Fast Track, Rare Pediatric Disease, and Orphan Drug designations in the U.S., and PRIME and Orphan medicinal product designations in the European Union.

Following treatment with UX111, levels of CSF-HS decreased within the first month post-treatment in all patients 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 percent in all patients treated with the 3×10¹³ vg/kg dose and 66 percent in the modified intention to treat group (mITT). 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.

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 treatment effect.

The raw scores were also significantly improved for model-based mean receptive and expressive communication and fine motor function, 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 for all five Bayley-III subdomains.

“When we compare the impact of UX111 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, 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.”

Photo: Eric Crombez, chief medical officer at Ultragenyx