Ultragenyx Pharmaceutical's investigational gene therapy, UX111, continues to show promising results in patients with mucopolysaccharidosis IIIA (MPS IIIA), also known as Sanfilippo syndrome type A. Data from the phase 1/2/3 Transpher A clinical trial (NCT02716246) indicate that UX111, an intravenously administered self-complementary AAV9-based gene therapy vector encoding hSGSH, is associated with rapid and sustained reductions in relevant cerebrospinal fluid (CSF) biomarker levels, particularly when administered prior to advanced neurodegeneration.
The findings, presented at the WORLDSymposium 2023, highlight the potential of UX111 to address the underlying enzyme deficiency in MPS IIIA, a rare and progressive genetic disorder. MPS IIIA is caused by a deficiency in the lysosomal enzyme N-sulfoglucosamine sulfohydrolase (SGSH), leading to the toxic accumulation of heparan sulfate (HS) in the brain and other tissues. This accumulation results in severe neurodegeneration in affected children.
Dose-Dependent Efficacy
The Transpher A trial evaluated various doses of UX111. In Cohort 3, 10 out of 22 patients received a dose of 3 x 10^13 vg/kg prior to advanced neurodegeneration. These patients, either younger than 2 years of age or with baseline Development Quotient (DQ) scores of 60 or higher, experienced a rapid reduction in CSF heparan sulfate (HS) levels. According to Kevin M. Flanagan, MD, from Nationwide Children’s Hospital, the reduction in HS levels was dose-dependent.
Cohort 1 received a dose of 5 × 10^12 vg/kg (n = 3), and Cohort 2 received a dose of 1 × 10^13 vg/kg (n = 3). The data indicated that higher doses correlated with greater reductions in CSF HS levels, suggesting a direct relationship between the administered dose and therapeutic effect.
Neurodevelopmental Gains and Safety Profile
In addition to biomarker reductions, the study reported neurodevelopmental gains in neurocognitive assessments and behavioral domains, which typically decline without treatment in MPS IIIA patients. Data were collected for up to 24 months post-treatment, after which patients were transitioned to a long-term follow-up study (NCT04360265) for up to 5 years post-treatment.
Importantly, the Transpher A trial reported no deaths, drug-related serious adverse events, or severe adverse events to date, underscoring the favorable safety profile of UX111. This is a critical consideration for gene therapies targeting pediatric populations with severe neurological conditions.
UX111's Development and Regulatory Status
Ultragenyx acquired UX111, previously known as ABO-102, from Abeona Therapeutics in May 2022. Emil D. Kakkis, MD, PhD, CEO and president of Ultragenyx, expressed the company's belief that UX111 could be a transformative therapy for MPS IIIA patients and potentially the company's first gene therapy to market.
The clinical development program for UX111 has received regenerative medicine advanced therapy, fast track, rare pediatric disease, and orphan drug designations in the United States, highlighting the urgent need for effective treatments for this devastating condition.
