Ultragenyx Intends to Seek Accelerated Approval for MPSIII Gene Therapy BLA


The company anticipates that it will be able to submit a BLA in late 2024 or early 2025.

Heather Lau, MD, MS

Heather Lau, MD, MS
Credit: Global Oncology Academy

Following a meeting with the FDA, Ultragenyx stated that it will seek an accelerated approval pathway for a future biologics license application (BLA) submission 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

In the meeting, the agency came into alignment with the company regarding the use of cerebral spinal fluid (CSF) heparan sulfate (HS) as a surrogate end point. As such, Ultragenyx anticipates that it will be able to submit the BLA in late 2024 or early 2025. The company stated that another preBLA meeting with the FDA will be needed to clarify the details of the potential BLA submission, however.

“Gaining alignment with the FDA that CSF HS is a relevant biomarker to enable accelerated approval in Sanfilippo syndrome is a pivotal moment for the community and paves the way for treatments for all fatal types of neuronopathic mucopolysaccharidoses,” Emil D. Kakkis, MD, PhD, the chief executive officer and president of Ultragenyx, said in a statement.1 “We commend the FDA for appreciating the critical urgency to deliver potentially life-saving therapies to children with neurologically devastating diseases and we extend our gratitude to the patient and caregiver advocates, scientists and industry leaders that shared and collaborated to provide the comprehensive evidence needed to support this important decision.”

The BLA submission will be supported by data from the phase 1/2/3 Transpher A clinical trial (NCT02716246), findings from which were most recently presented by Heather Lau, MD, MS, the executive director of global clinical development at Ultragenyx Pharmaceutical, at the 2024 WORLDSymposium, held February 4-9, in San Diego, California.2 The data presented were from 17 children in the modified intent-to-treat group with a median follow-up of 23.9 months. 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).

Shortly after the conference, CGTLive® interviewed Lau to learn more. Lau noted that statistical analysis performed on the data indicated a correlation between the initial reductions in HS seen after treatment with the gene therapy and later improvement or stability on cognitive assessments. In terms of safety, Lau stated that there were no significant safety concerns associated with the gene therapy and that the most frequent adverse events were 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 told CGTLive in the interview. “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.”

Ultragenyx is developing several other gene therapy products besides UX111. One of these, DTX401, an investigational AAV serotype 8 vector-based gene therapy expressing the human G6PC gene, significantly reduced daily cornstarch intake compared to placebo treatment in patients with glycogen storage disease type Ia (GSDIa) who were treated in the phase 3 GlucoGene clinical trial (NCT05139316), according to a recent announcement from the company.3

Notably, Ultragenyx is currently facing a lawsuit filed on behalf of the estate of Henrietta Lacks over the use of the HeLa cell line in the production of AAV vector-based gene therapies.4 In May 2024, United States District Judge Deborah Boardman rejected the company’s motion to dismiss the case.

1. 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 June 20, 2024. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-plans-file-accelerated-approval-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 positive top-line results from phase 3 study of DTX401 gene therapy for glycogen storage disease type Ia (GSDIa). News release. Ultragenyx Pharmaceutical Inc. May 30, 2024. Accessed May 31, 2024. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-positive-top-line-results-phase-3-study
4. Ultragenyx must face Henrietta Lacks family lawsuit over HeLa cell profits. News article. Reuters, Blake Brittain. May 20, 2024. Accessed May 31, 2024. https://www.reuters.com/legal/litigation/ultragenyx-must-face-henrietta-lacks-family-lawsuit-over-hela-cell-profits-2024-05-20/#:~:text=The%20Lacks%20estate%20sued%20Novato,produce%20materials%20for%20gene%20therapy.
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