Ultragenyx Puts BLA for MPS IIIA Gene Therapy UX111 in Front of FDA Again

Ultragenyx has resubmitted a biologics license application (BLA) for UX111 (rebisufligene etisparvovec), an AAV9 vector-based gene therapy intended to treat mucopolysaccharidosis type IIIA (MPS IIIA, also known as Sanfilippo syndrome), to the FDA.¹

The new BLA includes “substantial longer-term data on multiple measures of neurologic benefit”, and is aimed at obtaining an accelerated approval for the gene therapy product.¹ Notably, a previous BLA submission for UX111 was met with a complete response letter from the FDA in July 2025. According to Ultragenyx, the CRL related to a need for additional chemistry, manufacturing and controls (CMC) information and improvements and observations from inspections of manufacturing facilities that had recently been conducted.² At the time, the company noted its perception that the FDA’s concerns were related to facilities and processes rather than to the quality of the gene therapy product itself, and that the observations were “readily addressable”. The new BLA submission contains “comprehensive responses” to the CMC concerns from the CRL, according to Ultragenyx.¹

“Today, with no approved treatment options to address the relentless progression of Sanfilippo syndrome type A, families must watch helplessly as their children lose the ability to communicate, play, move, and even eat before ultimately succumbing to this devastating and fatal disease,” Emil D. Kakkis, MD, PhD, the chief executive officer and president of Ultragenyx, said in a statement.¹ “We recognize the extraordinary stakes facing the Sanfilippo community as they await a first-ever treatment option and look forward to working with the Agency as it completes its review of this urgently needed therapy. There is no time to waste, and we believe we have addressed all of the Agency’s concerns to avoid further delays. Patients, and their families, need access now.”

UX111 was previously granted priority review by the FDA in February 2025, and Ultragenyx anticipates that a Prescription Drug User Fee Act action date will be given to the new BLA in less than a month. The company is seeking accelerated approval for the BLA based on measures of neurologic benefit and the use of cerebral spinal fluid (CSF) heparan sulfate (HS) data from the phase 1/2/3 Transpher A clinical trial (NCT02716246).

Updated clinical data from the UX111 program were recently announced at the 22nd Annual WORLDSymposium, held February 2 to 6, 2026, in San Diego, CA.³ It was reported that a group of 17 treated children who were aged under 2 years or had earlier stage disease at the time of treatment showed, in comparison to natural history data from untreated patients with reported rapid progressor phenotypes during 24 to 60 months of age, a 23.2 point (P < .0001) treatment effect in the mean Bayley-III cognitive raw score. Additional improvements were also seen for the treated patients in comparison to natural history data for several other Bayley-III subtests. These included an 8.1 point improvement in receptive communication (P = .0076), an 11.1 point improvement in expressive communication (P = .0008), a 9 point improvement in fine motor (P = .0026), and a 3.9 point improvement in gross motor (P = .070).

Ultragenyx also reported that in the overall efficacy set, which included 27 patients treated with UX111 at a dose of 3x10¹³ vg/kg, CSF-HS levels decreased within the first month posttreatment. Furthermore, a median decrease in CSF-HS exposure of 63.98% (P < .001) was seen as of the September 2025 cutoff. It was additionally noted that a 50% or greater decrease was seen in 81.5% of the overall efficacy set and in 88.2% of younger patients.

With regard to safety, UX111 was characterized as “well-tolerated” at all doses. The safety set includes 33 patients whose follow-up ranges from 0.6 to 8.5 years (median, 4.5). Elevations in liver enzymes constituted the most commonly observed treatment-emergent adverse events (AEs). AEs related to the treatment were mostly deemed mild or moderate in severity and spontaneously resolved.

“These data continue to demonstrate a remarkable and unprecedented separation from the natural history of Sanfilippo syndrome through more than 8 years of follow-up, with children in their teens retaining skills at an age when many of their untreated peers have sadly lost their most basic abilities and succumbed to this disease,” Kakkis said in a statement.³ “Our studies consistently show that reductions in heparan sulfate are associated with meaningful clinical benefits across multiple domains, underscoring the urgency to bring forward a treatment for families who currently have no options to stop or delay the heartbreaking and inevitable progression and loss of function associated with this disease.”

REFERENCES
1. Ultragenyx resubmits biologics license application for UX111 AAV gene therapy to treat Sanfilippo syndrome type A (MPS IIIA) to U.S. FDA. News release. Ultragenyx Pharmaceutical Inc. January 30, 2026. Accessed February 6, 2026. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-resubmits-biologics-license-application-ux111-aav
2. Ultragenyx receives complete response letter from FDA for UX111 AAV gene therapy to treat sanfilippo syndrome type A (MPS IIIA). News release. Ultragenyx Pharmaceutical Inc. July 11, 2025. Accessed July 14, 2025. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-receives-complete-response-letter-fda-ux111-aav-gene
3. Ultragenyx announces positive longer-term data demonstrating treatment with UX111 gene therapy results in sustained, significant reductions in CSF-HS and continued meaningful improvements in clinical function across multiple developmental domains in children with Sanfilippo syndrome (MPS IIIA). News release. Ultragenyx Pharmaceutical Inc. February 3, 2026. Accessed February 6, 2026. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-positive-longer-term-data-demonstrating