FDA approves rebisufligene etisparvovec, first gene therapy for Sanfilippo syndrome type A

The FDA has approved rebisufligene etisparvovec-hopf (Fayuvi), a one-time intravenous gene therapy, as the first treatment for pediatric patients with mucopolysaccharidosis type IIIA (MPS IIIA), also known as Sanfilippo syndrome type A.¹ Until now, management of this rare, fatal neurodegenerative disease has been limited to supportive care, with no therapy available to alter its underlying course.¹

"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," said Kyle Diamantas, JD, acting commissioner of the FDA. "Gene therapy holds tremendous promise for rare diseases like Sanfilippo syndrome type A."¹

Trial design and efficacy data supporting Fayuvi approval in MPS IIIA

The approval was supported by an open-label, single-arm, multicenter study (NCT02716246) that evaluated pediatric patients with MPS IIIA, most between ages 2 and 5 years, after a single intravenous infusion.¹ Investigators tracked mean changes in cognitive scores against an untreated historical control cohort.² Treated patients maintained or improved cognitive function relative to the expected natural history of plateau and decline during this developmental window, a divergence the agency called clinically meaningful.¹ Longer-term data reported separately by the manufacturer showed sustained reductions in cerebrospinal fluid heparan sulfate and continued functional gains across developmental domains, with follow-up extending to 8.5 years and a median of 4.8 years.²

Pooled safety data identified adverse reactions in more than 5% of patients, including elevated liver transaminases, nausea, vomiting, fever, decreased appetite, cytopenias, and elevated amylase.¹ Labeling carries a warning for thrombotic microangiopathy and, as with other AAV-based gene therapies, a theoretical long-term risk that the inserted genetic material could integrate into the genome and contribute to tumor development.¹ Fayuvi must be given in a setting equipped for infusion reactions, and patients require corticosteroid prophylaxis starting one day before infusion and continuing at least eight weeks afterward.¹

Disease burden and unmet need in Sanfilippo syndrome type A

MPS IIIA results from biallelic loss-of-function variants in SGSH, the gene encoding sulfamidase, and is the most common and severe Sanfilippo subtype.³ Birth prevalence estimates run up to roughly 1.6 per 100,000 live births, with wide geographic variation and likely underascertainment.³ Affected children typically develop normally in infancy before losing language, cognition, and motor skills in early childhood; mean age at death has been reported at approximately 15 years.⁴ Before this approval, care was limited to symptom management.

Mechanism of action and regulatory pathway for the AAV9 gene therapy

Fayuvi uses a modified, non-infectious adeno-associated virus serotype 9 (AAV9) vector to deliver a functional SGSH copy, enabling cells to produce sulfamidase so heparan sulfate can be properly broken down in lysosomes.¹ Karim Mikhail, BPharm, MS, director of the FDA's Center for Biologics Evaluation and Research, called the approval "a meaningful step forward … for the promise of gene therapy to address rare and devastating diseases."¹ The program held orphan drug, fast track, and breakthrough therapy designations; the FDA had previously issued a complete response citing manufacturing issues before accepting the resubmission that led to approval.¹

Expert interpretation and limitations of the neurodevelopmental findings

Megha Kaushal, MD, MSc, acting deputy director of the FDA's Office of Therapeutic Products, framed the result as evidence "that systemic AAV9-mediated gene delivery can reach the central nervous system at therapeutically relevant levels in pediatric patients."¹ That framing is notable because pivotal efficacy rests on comparison with a historical, rather than concurrent, control group — a design more vulnerable to confounding, drawn from a small cohort typical of ultra-rare disease programs. Long-term oncogenic risk from genomic integration remains theoretical and will require extended pharmacovigilance, and clinicians must weigh the one-time, irreversible nature of gene transfer against a safety profile that includes thrombotic microangiopathy. Durability of benefit beyond the reported follow-up, and applicability outside the studied age range, remain open questions as postmarketing data accumulate.

References

1. US Food and Drug Administration. FDA approves first gene therapy for pediatric patients with Sanfilippo syndrome type A. Published September 17, 2026. Accessed September 17, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-pediatric-patients-sanfilippo-syndrome-type

2. Ultragenyx Pharmaceutical Inc. 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). Published February 3, 2026. Accessed September 17, 2026. https://ir.ultragenyx.com/node/18341

3. Zelei T, Csetneki K, Vokó Z, Siffel C. Epidemiology of Sanfilippo syndrome: results of a systematic literature review. Orphanet J Rare Dis. 2018;13:53. doi:10.1186/s13023-018-0796-4

4. Lavery C, Hendriksz CJ, Jones SA. Mortality in patients with Sanfilippo syndrome. Orphanet J Rare Dis. 2017;12:168. doi:10.1186/s13023-017-0717-y