Mucopolysaccharidosis type IIIA (MPS IIIA), also known as Sanfilippo syndrome Type A, progressively destroys cognitive and motor function in early childhood through a single missing enzyme: sulfamidase (SGSH), whose absence allows heparan sulfate (HS) to accumulate throughout the central nervous system (CNS). Children typically develop near-normally in infancy before the disease takes hold, stripping language, mobility, and self-care over several years and leading to death in the mid-teens. Prior to this approval, no therapy existed to slow or stop that trajectory.
The US Food and Drug Administration (FDA) granted standard full approval to Ultragenyx Pharmaceutical for FAYUVI (rebisufligene etisparvovec-hopf), an adeno-associated virus serotype 9 (AAV9) gene therapy for neurologic manifestations of MPS IIIA in pediatric patients with preserved neurodevelopmental function. The approval rests on data from the pivotal Transpher A trial (NCT02716246) and a long-term follow-up study (NCT04360265), with clinical data extending to nearly eight years of observation. FAYUVI is administered as a single intravenous dose.
How FAYUVI delivers sulfamidase across the blood-brain barrier
FAYUVI uses a self-complementary AAV9 vector to carry a functional SGSH gene directly into cells, restoring sulfamidase production without intracranial surgery. AAV9's well-characterized tropism for neurons and glial cells, together with its capacity to cross the blood-brain barrier after intravenous administration, sets it apart from earlier-generation serotypes that required direct injection into the CNS. Once transduced cells produce sulfamidase, the enzyme is secreted into the cerebrospinal fluid (CSF) and taken up by neighboring neurons through the mannose-6-phosphate receptor pathway, extending correction beyond the cells the vector directly reached.
- Single dose: One intravenous infusion of self-complementary AAV9 vector at 3 × 10^13 vector genomes per kilogram (vg/kg)
- Gene delivery: Carries a functional SGSH gene copy to restore sulfamidase enzyme production
- Biomarker reduction: Reduces CSF heparan sulfate accumulation across all treated age groups
- Indicated population: Pediatric patients with MPS IIIA and preserved neurodevelopmental function
- Monitoring requirement: Corticosteroid prophylaxis required before and after infusion to manage hepatic immune responses
Transpher A showed a 23.5-point cognitive advantage over untreated children
FAYUVI-treated children in the modified intention-to-treat (mITT) population scored 23.5 points higher on the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) cognitive raw scale than an external natural history cohort of 27 untreated children with Sanfilippo syndrome Type A (mITT: n=17; p<0.0001), a result that formed the primary efficacy basis for approval. Transpher A enrolled patients across multiple international sites and used external natural history controls rather than a placebo arm, a design choice reflecting the ethical difficulty of withholding treatment in an ultra-rare fatal childhood disease. CSF heparan sulfate levels fell and stayed low across all age groups throughout follow-up extending to nearly eight years, and data presented at WORLDSymposium 2026 showed children in their early teens still communicating, walking, and eating independently.
| Endpoint | FAYUVI-treated (mITT, n=17) | Natural history cohort (n=27) | Statistical outcome |
|---|---|---|---|
| Bayley-III Cognitive raw score advantage (ages 24-60 months) | +23.5 points versus natural history | Plateau followed by decline | p<0.0001 |
| CSF heparan sulfate reduction | Sustained reduction across all age groups | Uncontrolled accumulation | Durable through ~8 years of follow-up |
| Duration of follow-up | Up to nearly 8 years | N/A | Extended follow-up underpinning standard full approval |
| Approved patient population | Pediatric patients with preserved neurodevelopmental function | N/A | Standard full approval (September 17, 2026) |
Safety profile and monitoring requirements
Liver enzyme elevations were the most common finding in Transpher A: ALT, AST, and GGT increases occurred in 85 percent of participants and were managed with corticosteroid prophylaxis. Other adverse reactions included vomiting (67 percent), abnormal behavior (56 percent), diarrhea (48 percent), pyrexia (41 percent), and thrombocytopenia (19 percent). No cases of thrombotic microangiopathy (TMA) occurred in clinical studies, though TMA monitoring is required post-infusion given its association with AAV gene therapies; a long-term malignancy risk from potential AAV vector integration also warrants ongoing surveillance.
Kevin M. Flanigan, Director of the Center for Gene Therapy at Nationwide Children's Hospital and principal investigator on the study, said the result validates years of effort: "This gene therapy addresses a pressing unmet clinical need and offers families a promising therapeutic option. It is additionally gratifying in that this vector was first developed at Nationwide Children's more than a decade ago, and its approval highlights our commitment to developing therapies that meaningfully impact children's health."
From Nationwide Children's Hospital to FDA approval: FAYUVI's development history
Haiyan Fu and Doug McCarty first developed the vector underlying FAYUVI during their tenure at Ohio State University and Nationwide Children's Hospital, later licensing it to Abeona Therapeutics, which ran early clinical work under the name ABO-102. Funding pressures led Abeona to transfer global rights to Ultragenyx in 2022; the company resubmitted its Biologics License Application (BLA) in January 2026 after incorporating additional long-term data and resolving chemistry, manufacturing, and controls observations from a complete response letter issued in July 2025. With Priority Review granted and a Prescription Drug User Fee Act (PDUFA) action date of September 19, 2026, the FDA issued standard full approval two days ahead of schedule, also awarding Ultragenyx a Priority Review Voucher and marking its second gene therapy clearance and sixth FDA approval overall.
Emil D. Kakkis, CEO and President of Ultragenyx, underscored the urgency behind the program's final push. "The approval of FAYUVI reflects years of research from scientists and developers, as well as unwavering support from so many families and patient organizations in the face of a devastating, universally fatal disease with no treatment options. … Our focus now is on supporting timely access in the U.S. as we work closely with treatment centers and payers to support families on the gene therapy treatment journey," Kakkis said.
FAYUVI is the first MPS IIIA therapy, but gaps remain for other Sanfilippo subtypes
For families living with MPS IIIA, FAYUVI marks a shift from purely symptomatic care to a therapy that addresses the genetic root cause. The FDA's decision to grant standard full approval, rather than accelerated approval, based on external natural history controls rather than a placebo-controlled trial also establishes a precedent for regulatory review of other ultra-rare pediatric neurologic diseases where randomized designs are not practicable. MPS IIIB, IIIC, and IIID, each driven by a deficiency in a different lysosomal enzyme, remain without approved disease-modifying therapy.
The broader Sanfilippo pipeline spans all four subtypes at varying stages of development. An enzyme replacement therapy for MPS IIIB holds Breakthrough Therapy Designation and is expected to reach BLA submission in the fourth quarter of 2026. A separate receptor-targeted enzyme replacement approach for MPS IIIA is in earlier-stage development, while MPS IIIC and MPS IIID currently have no approved or late-stage programs.
| Sanfilippo subtype | Deficient enzyme | Approved therapy | Programs in development |
|---|---|---|---|
| MPS IIIA | Sulfamidase (SGSH) | FAYUVI (AAV9 gene therapy) | Receptor-targeted ERT (early-stage) |
| MPS IIIB | Alpha-N-acetylglucosaminidase (NAGLU) | None | Enzyme replacement therapy (BLA anticipated Q4 2026; Breakthrough Therapy Designation) |
| MPS IIIC | Heparan acetyl-CoA transferase (HGSNAT) | None | No approved or late-stage program identified |
| MPS IIID | N-acetylglucosamine-6-sulfatase (GNS) | None | No approved or late-stage program identified |
When will FAYUVI be available, and who qualifies?
FAYUVI is indicated for pediatric patients with MPS IIIA and preserved neurodevelopmental function. Ultragenyx expects commercial product to reach a network of US-based Qualified Treatment Centers (QTCs) within 30 to 60 days of approval, with the therapy manufactured entirely at domestic sites: Ultragenyx's Gene Therapy Manufacturing Facility in Bedford, Massachusetts, and Andelyn Biosciences in Columbus, Ohio. Patient access support is available through the UltraCare program, which connects enrolled families with dedicated Gene Therapy Guides for insurance navigation and treatment coordination.
Looking ahead for Sanfilippo syndrome Type A
FAYUVI's approval represents the first time a therapy has addressed the root cause of MPS IIIA, shifting the disease from one managed symptom by symptom to one where early genetic intervention is now possible. Ultragenyx has signaled plans to pursue international regulatory submissions, though timelines have not been announced. The clinical framework built through Transpher A, including CSF heparan sulfate as a validated surrogate endpoint, may inform how future lysosomal storage disease gene therapies navigate the regulatory path to approval.
This article is based on a press release issued by Ultragenyx Pharmaceutical and was produced under Drug Discovery News' AI Editorial Guidelines.
