Marketed as Fayuvi, the 1-time AAV9 gene therapy showed sustained cerebrospinal fluid heparan sulfate drops and developmental gains among pediatric patients with mucopolysaccharidosis type IIIA in prior studies.
The FDA has approved UX111 (Fayuvi; Ultragenyx Pharmaceutical), an adeno-associated virus serotype 9 (AAV9) gene therapy, for the treatment of pediatric patients with Sanfilippo syndrome type A (mucopolysaccharidosis type IIIA, or MPS IIIA), making it the first approved disease-modifying therapy for the condition.1
The approval was granted under the accelerated approval pathway based data from the Transpher A clinical program (NCT02716246) and its long-term follow-up study (NCT04360265), including reductions in cerebrospinal fluid (CSF) heparan sulfate and neurodevelopmental outcomes compared with natural history data.2
“The approval of Fayuvi marks a historic moment for children and families living with MPS IIIA, which is a disease that has, until now, offered no approved treatment to alter its devastating course,” Kyle Diamantas, JD, acting FDA Commissioner, said in a statement.1 “Gene therapy holds tremendous promise for rare diseases like Sanfilippo syndrome type A, and this milestone reflects the FDA's commitment to action.”
UX111 is administered as a single intravenous infusion and uses a modified, noninfectious AAV9 vector to deliver a functional copy of the SGSH gene to cells. The therapy is designed to enable production of sulfamidase, allowing heparan sulfate to be broken down and reducing its accumulation in the lysosomes.1
UX111 is administered as a 1-time intravenous infusion in a health care setting equipped to manage infusion reactions. Patients receive corticosteroid treatment beginning 1 day before the infusion and continuing for a minimum of 8 weeks afterward.
Ultragenyx sought accelerated approval of UX111 for patients with Sanfilippo syndrome type A, a rare, rapidly progressive neurodegenerative disorder with no FDA-approved treatments prior to this decision. The application was supported by biomarker and neurodevelopmental data from the pivotal Transpher A study and its long-term follow-up, rather than a conventional randomized, placebo-controlled efficacy trial, a distinction worth stating explicitly given the ultra-rare, rapidly progressive nature of the disease population.2
Ultragenyx's
Ultragenyx resubmitted the BLA on January 30, 2026, incorporating an additional year of long-term follow-up data across multiple biomarker and clinical measures.3 The FDA accepted the resubmission on April 2, 2026, and assigned a new PDUFA action date of September 19, 2026.4
The efficacy program centers on Transpher A, a multicenter, open-label, dose-ranging study of intravenous UX111 in patients with MPS IIIA, and its long-term follow-up study (NCT04360265), which has tracked treated patients for up to 8.5 years.7,8 Efficacy analyses have focused on the highest evaluated dose, 3 x 1013 vector genomes/kg, compared against well-characterized natural history cohorts rather than a concurrent placebo arm.2
In the most recent long-term update, reported in February 2026, the overall efficacy population of 27 patients receiving the highest dose showed a median reduction in CSF heparan sulfate of 63.98% from baseline as of the September 2025 data cutoff (P <.001), with 81.5% of the overall efficacy population and 88.2% of younger patients achieving at least a 50% reduction. Investigators reported that this reduction occurred within the first month of treatment and remained sustained through long-term follow-up, which ranged up to 8.5 years (median, 4.8 years).6
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Among younger patients treated earlier in the disease course (n = 17), UX111 was associated with a 23.2-point treatment effect in mean Bayley-III cognitive raw score versus natural history controls among children assessed between 24 and 60 months of age (P <.0001), with significant treatment effects also reported in the receptive and expressive communication domains.5,6
A separate cohort of 10 older or more advanced patients, treated later in their disease course, showed retention of function beyond the ages at which progressive loss is typically observed in natural history cohorts: all 10 retained verbal or nonverbal communication at last assessment (median age, 9.7 years), 9 of 10 remained independently ambulatory (median age, 9.05 years), and 9 of 10 retained oral or self-feeding ability (median age, 9.05 years).6
Because these comparisons are not randomized, this is more accurately described as retention of clinically meaningful function relative to natural history expectations rather than as UX111 having been shown to prevent loss of these abilities. For context, natural history studies of MPS IIIA have described rapid cognitive decline beginning around age 3, with regression in speech, motor, and cognitive abilities beginning at a mean age of approximately 3.3 years in one cohort.1
UX111 is a single intravenous infusion of an AAV9 vector carrying a functional copy of the human SGSH gene, which encodes the lysosomal enzyme deficient in MPS IIIA. SGSH deficiency impairs degradation of heparan sulfate, leading to its accumulation in the central nervous system and progressive lysosomal dysfunction and neurodegeneration. The agent is designed to restore SGSH enzyme activity and thereby reduce CNS heparan sulfate accumulation, with the goal of altering the neurodegenerative course of the disease rather than only managing symptoms.2
CSF heparan sulfate reduction served as the primary biomarker supporting accelerated approval. This reflected of the several years of discussion between the FDA and the neuronopathic MPS community about the use of CSF heparan sulfate as an intermediate end point in diseases where conventional long-duration, randomized neurodevelopmental trials are extraordinarily difficult to conduct.2
Across the clinical program, the most commonly reported treatment-related adverse events have been elevations in liver enzymes, a known complication of systemic AAV gene therapy. In the February 2024 data analysis of the 17-patient efficacy cohort, most of these events were grade 1 or grade 2 in severity, and one treatment-related grade 3 alanine aminotransferase (ALT) elevation was reported and subsequently resolved.5
Patients receive prophylactic immunomodulatory treatment around the time of UX111 administration, consistent with standard practice for managing immune responses to systemic AAV gene therapy. In its February 2026 update, Ultragenyx characterized the long-term safety profile as remaining acceptable, with no new long-term safety signal identified and no infusion-related hypersensitivity, anaphylaxis, thrombotic microangiopathy, myocarditis, dorsal root ganglia toxicity, or malignancy observed to date; that characterization comes from the sponsor and should be attributed accordingly.6
“The FDA's acceptance of the BLA for UX111 brings us closer to the possibility of a first-ever therapy for Sanfilippo syndrome type A,” Emil D. Kakkis, MD, PhD, chief executive officer and president of Ultragenyx, said in a statement following the April 2026 resubmission acceptance.4 Of the February 2026 long-term data, Kakkis said the results "continue to demonstrate a remarkable and unprecedented separation from the natural history," with sustained benefit through more than 8 years of follow-up.6
