Ultragenyx Puts BLA for MPSIII Gene Therapy UX111 in Front of FDA

Ultragenyx has submitted a biologics license application (BLA) to the FDA for UX111 (ABO-102), its adeno-associated virus (AAV) vector-based gene therapy intended to treat mucopolysaccharidosis type IIIA (MPS IIIA, also known as Sanfilippo syndrome).¹

Notably, Ultragenyx is seeking accelerated approval for the BLA based on the use of cerebral spinal fluid (CSF) heparan sulfate (HS) data from the phase 1/2/3 Transpher A clinical trial (NCT02716246), which will be used as a surrogate end point. Findings from Transpher A from 17 children in the modified intent-to-treat group with a median follow-up of 23.9 months were presented by Heather Lau, MD, MS, the executive director of global clinical development at Ultragenyx Pharmaceutical, at the 2024 WORLDSymposium, held February 4-9, 2024, in San Diego, California.² The investigators found that mean CSF HS decreased 58.5% (SD, 13.8%) from baseline at month 1 posttreatment and that at the last follow-up, with a data cutoff date of August 16, 2023, CSF HS exposure was reduced by a mean 63.3% (95% CI, 56.9-69.7).

In June 2024, Ultragenyx announced that it had participated in a meeting with the FDA in which the company and the agency came to an agreement that CSF HS may be used as a surrogate end point for the accelerated approval.³ Although, at the time Ultragenyx stated that an additional meeting would be necessary to clarify further details with regard to BLA submission.

“The path to get a treatment to the point of a BLA filing has been long and perilous for the Sanfilippo community,” Emil D. Kakkis, MD, PhD, chief executive officer and president of Ultragenyx, said in the press release announcing the BLA submission.¹ “They have had to watch their children, once thriving, lose their ability to speak and walk, and eventually die, while research programs were shelved due to regulatory and funding hurdles. We commend the FDA’s detailed evaluation and acceptance of CSF HS as a well-characterized biomarker to support an accelerated approval pathway for MPS disorders, including Sanfilippo syndrome. The FDA’s acceptance of CSF HS, which we define as a disease-cause biomarker since it measures the underlying disease, enabled us to file our BLA and may unlock the future accelerated approvals of a host of new therapies for these devastating MPS diseases that affect the brain.”

In Transpher A, it was also found that sustained decrease in CSF HS over time correlated with improved long-term cognitive development in comparison to natural history data, which shows cognitive decline for patients in the same timeframe.¹ With regard to safety, Ultragenyx notes that elevations in liver enzymes were the most common treatment-related adverse events (AEs) in Transpher A, that the majority of these cases were grade 1 or grade 2, and that all these AEs resolved.

Following her presentation at WORLDSymposium, CGTLive® interviewed Lau about the data. Lau discussed the key results and touched on some of the additional positive observations made in the study. She also touched on limitations of the trial, noting that demonstrating a therapy’s effect on brain function in just 2 years of follow-up is difficult, and that longer follow-up will be needed to get a better understanding of UX111’s impact.

“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 told CGTLive. “There's also additional data that we're looking at that's showing preliminarily an impact on language, both expressive and receptive. So overall, we are showing initially positive results on the neurodevelopment of children with MPSIIIA.”

REFERENCES
1. Ultragenyx submits biologics license application to the U.S. FDA for UX111 AAV gene therapy for the treatment of Sanfilippo syndrome type A (MPS IIIA). News release. Ultragenyx Pharmaceutical Inc. December 19, 2024. Accessed January 7, 2024. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-submits-biologics-license-application-us-fda-ux111
2. Lau H, Patra K, Wolf M, et al. Reduction of heparan sulfate (HS) exposure in cerebrospinal fluid (CSF) correlates with improved long-term cognitive function in patients with mucopolysaccharidosis type IIIA (MPS IIIA) following treatment with UX111 gene therapy. Presented at: WorldSymposium; February 4-9; San Diego, California. Abstract #LB-35
3. Ultragenyx announces plans to file for accelerated approval of UX111 for the treatment of Sanfilippo syndrome type A (MPS IIIA). News release. Ultragenyx Pharmaceutical Inc. June 12, 2024. Accessed January 7, 2024. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-plans-file-accelerated-approval-ux111