Ultragenyx’s self-complementary AAV9-based gene therapy reduced levels of relevant CSF biomarkers, as well as improvements in neurocognitive assessments and behavioral domains, among patients without neurodegeneration.
The administration of the investigational treatment UX111, an intravenously administered self-complementary AAV9-based gene therapy vector encoding hSGSH in development by Ultragenyx to treat patients with mucopolysaccharidosis IIIA (MPS IIIA)—also known as Sanfilippo syndrome type A—is associated with rapid and sustained reductions of relevant cerebrospinal fluid (CSF) biomarker levels in those treated prior to advanced neurodegeneration.1
All told, in Cohort 3 of the phase 1/2/3 Transpher A clinical trial (NCT02716246), 10 of 22 patients were treated with a dose of 3 x 1013 vg/kg in the period prior to advanced neurodegeneration occurring.These 10 individuals were either younger than 2 years of age, or had baseline Development Quotient (DQ) scores of 60 or higher calculated by the Bayley Scales of Infant and Toddler Development–Third Edition (BSDIII), and ultimately, they reported a rapid reduction of CSF heparan sulfate (HS) levels.
Importantly, regarding safety, there were no deaths, drug-related serious adverse events, or severe adverse events reported to date in the Transpher A trial.
The data were compiled by Kevin M. Flanagan, MD, the Robert F. and Edgar T. Wolfe Foundation Endowed Chair in Neuromuscular Research and the director of the Center for Gene Therapy in The Research Institute at Nationwide Children’s Hospital, and a professor of pediatrics and neurology at The Ohio State University College of Medicine, and colleagues. They were presented at the annual WORLDSymposium 2023, held February 22-26, in Orlando, Florida.
“[MPS IIIA] is caused by a deficiency in the lysosomal enzyme N-sulfoglucosamine sulfohydrolase, resulting in toxic accumulation of lysosomal HS in the brain and other tissues,” Flanagan and colleagues wrote, adding that “neurodegeneration occurs in children with MPS IIIA, and that preclinical data have thus suggested that administration of UX111 “results in expression of SGSH in the brain in MPS IIIA animal models.”
Notably, this reduction was dose dependent, according to Flanagan et al. Those Cohort 1 were treated with a dose of 5 × 1012 vg/kg (n = 3), and those in Cohort 2 were treated with a dose of 1 × 1013 vg/kg (n = 3). Additionally, there were “neurodevelopmental gains in neurocognitive assessments and behavioral domains that typically progressively decline without treatment in patients with MPS IIIA,” they wrote.
Data were collected up to 24 months posttreatment, at which time the treated patients were transferred to a long-term follow-up study (NCT04360265). That study is expected to take place for 3 years, for a total of up to 5 years post treatment for those who rollover. Participants in the follow-up study will have up to 5 scheduled visits with assessments. The clinical development program for UX111 has received previously received regenerative medicine advanced therapy, fast track, rare pediatric disease, and orphan drug designations in the United States.2
UX111 was previously known as ABO-102, until the product and its development were acquired from Abeona Therapeutics by Ultragenyx in May 2202 via an exclusive license agreement.3 At the time, Emil D. Kakkis, MD, PhD, CEO and president of Ultragenyx, noted the company’s belief that UX111 could be a “transformative therapy for patients with MPS IIIA,” and that Ultragenyx’s team was poised to integrate the product and capture its “potential to be [Ultragenyx’s] first gene therapy to market.”3
This is not the first dataset on UX111 that was presented at WORLDSymposium. In 2021, Flanagan presented a similar interim update from Transpher A, which had shown early signs fo the trend displayed in the 2023 update, as well as statistically significant reductions of plasma and urine HS, total urine glycosaminoglycans, and liver volumes among those in Cohort 3. Later in 2021 at the 16th International Symposium on MPS and Related Diseases, MRI data from Transpher A showed that the gene therapy increased grey matter, corpus callosum, and amygdala volumes in the brain in 3 patients at 24 months compared with placebo.4