Ultragenyx Pharmaceutical intends to submit a biologics license application (BLA) seeking accelerated approval for UX111 (ABO-102), an adeno-associated virus (AAV) vector-based gene therapy designed to treat mucopolysaccharidosis type IIIA (MPS IIIA), also known as Sanfilippo syndrome. This decision follows a meeting with the FDA, where alignment was reached regarding the use of cerebral spinal fluid (CSF) heparan sulfate (HS) as a surrogate endpoint. The company anticipates submitting the BLA in late 2024 or early 2025.
Agreement on Surrogate Endpoint
The FDA's agreement on CSF HS as a relevant biomarker is a significant step forward. According to Ultragenyx, a pre-BLA meeting with the FDA will be scheduled to clarify the specifics of the potential BLA submission. Emil D. Kakkis, MD, PhD, CEO and president of Ultragenyx, emphasized the importance of this alignment, stating it "paves the way for treatments for all fatal types of neuronopathic mucopolysaccharidoses."
Clinical Trial Data
The BLA submission will be supported by data from the phase 1/2/3 Transpher A clinical trial (NCT02716246). Recent findings, presented at the 2024 WORLDSymposium, included data from 17 children in the modified intent-to-treat group with a median follow-up of 23.9 months. The results showed that mean CSF HS decreased 58.5% (SD, 13.8%) from baseline at month 1 post-treatment. At the last follow-up (data cutoff: August 16, 2023), CSF HS exposure was reduced by a mean 63.3% (95% CI, 56.9-69.7).
Heather Lau, MD, MS, executive director of global clinical development at Ultragenyx Pharmaceutical, noted a correlation between initial HS reductions and later improvement or stability in cognitive assessments. She added that there were no significant safety concerns, with the most frequent adverse events being mild-to-moderate elevations in liver enzymes, a known class effect of gene therapy. "By clearing out that toxic accumulation of heparin sulfate, over the long term, we're starting to see a benefit in the overall cognition of children," Lau stated.
Additional Ultragenyx Pipeline Developments
In addition to UX111, Ultragenyx is also developing DTX401, an investigational AAV serotype 8 vector-based gene therapy for glycogen storage disease type Ia (GSDIa). Phase 3 GlucoGene clinical trial (NCT05139316) data showed that DTX401 significantly reduced daily cornstarch intake compared to placebo in GSDIa patients.
Legal Challenges
Ultragenyx is currently involved in a lawsuit filed by the estate of Henrietta Lacks regarding the use of the HeLa cell line in AAV vector-based gene therapy production. The company's motion to dismiss the case was rejected in May 2024.
