FDA Accepts BLA for Ultragenyx’s MPSIIIA Gene Therapy UX111 With Priority Review

The FDA has accepted the biologics license application (BLA) that Ultragenyx submitted for UX111 (ABO-102), an AAV vector-based gene therapy intended to treat mucopolysaccharidosis type IIIA (MPS IIIA, also known as Sanfilippo syndrome), with priority review.¹ The Prescription Drug User Fee Act (PDUFA) action date for the BLA has been set at August 18, 2025, and no advisory committee meeting is currently planned for the BLA.

The company submitted the BLA to the agency in December of last year.² 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. Ultragenyx previously announced earlier in 2024 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 this purpose.³ In addition to the Transpher A data, the BLA is also supported by long-term safety findings from a separate phase 1/2 clinical trial (NCT04088734).² This trial, which was originally launched on September 18, 2019, has been formally terminated, but is continuing to follow up with patients annually until 5 years posttreatment to collect additional safety data.

“Acceptance of the UX111 BLA brings us closer to being able to provide a first-ever treatment for Sanfilippo syndrome type A and, if our application is successful, we’re prepared to launch this therapy for patients and their families,” Emil D. Kakkis, MD, PhD, the chief executive officer and president of Ultragenyx, said in a statement.¹ “By reaching alignment with the agency on a path forward for accelerated approval in neuronopathic MPS diseases, our UX111 program could serve as a step towards advancing drug development across multiple metabolic diseases of the brain.”

Data from Transpher A were most recently presented at the 21st Annual WORLDSymposium, held February 3 to 7, 2025, in San Diego, California.⁴ Ultragenyx reported that as of the August 2024 data cut-off date, a 65% median decrease in CSF-HS exposure (P < .0001) was seen in the group of all patients who were treated at the study’s high dose (3x10¹³ vg/kg, n = 22), who had a mean posttreatment follow-up time of 34 months. For the 17 patients in the modified intention to treat (mITT) group, who had a mean posttreatment follow-up time of 36 months, a 66% median decrease in CSF-HS exposure (P < .0001) was recorded. The mITT group includes patients who received the high dose and at the time of enrollment were either no more than 2 years of age or older than 2 years with a cognitive developmental quotient of 60 or above.

Shortly after the conference, CGTLive® spoke with Heather Lau, MD, MS, the executive director of global clinical development at Ultragenyx Pharmaceutical, about the data. She emphasized the importance of using CSF-HS as an indicator of clinical efficacy.

"...[I]deally with a biomarker such as CSF-HS, which is really intimately related to the disease—it's a disease-causing biomarker—we hope that by showing that CSF-HS is relevant in this particular neuronopathic MPS, that it will help accelerate drug development for all in this field—that we really shouldn't have to wait several years to see clinical benefit," Lau told CGTLive. "We are supportive of this as a biomarker that is likely to predict clinical outcomes, which is the definition used in the accelerated approval pathway, at least in the United States. We really want to understand very quickly when a new drug comes on, does it work or not? So it's actually beneficial not only to show efficacy, but to fail fast, as well. I think the benefit here is we did show this clinical improvement, but we contend that this biomarker is useful in overall drug development for an ultrarare disease like this.”

REFERENCES
1. Ultragenyx announces FDA acceptance and priority review of the biologics license application (BLA) for UX111 AAV gene therapy to treat Sanfilippo syndrome type A (MPS IIIA). News release. Ultragenyx Pharmaceutical Inc. February 18, 2025. Accessed February 19, 2025. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-fda-acceptance-and-priority-review
2. 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 February 19, 2025. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-submits-biologics-license-application-us-fda-ux111
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 February 19, 2025. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-plans-file-accelerated-approval-ux111
4. Ultragenyx announces new data demonstrating that treatment with UX111 AAV gene therapy significantly improved clinical function across multiple developmental domains in children with Sanfilippo syndrome type A (MPS IIIA) correlated with sustained reductions in CSF-HS. News release. Ultragenyx Pharmaceutical Inc. February 5, 2025. Accessed February 19, 2025. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-new-data-demonstrating-treatment-ux111-aav