FDA Approves Fayuvi, the First Treatment for Sanfilippo Syndrome Type A

On Sept. 17, the FDA approved Ultragenyx's Fayuvi, a one-time intravenous gene therapy that delivers a working copy of the SGSH gene and is the first treatment for Sanfilippo syndrome type A (MPS IIIA). In a single-arm study of children ages 2 to 5, treated patients maintained or improved cognitive function compared with untreated historical controls, though the therapy carries serious safety warnings and requires at least eight weeks of steroids.

A Disease That Steals Childhood Development

Mucopolysaccharidosis type IIIA, or MPS IIIA, also known as Sanfilippo syndrome type A, is a rare inherited disease that progressively damages the brain and nervous system. Children lose cognitive, language, and other developmental abilities over time. Until this approval, treatment was limited to managing symptoms, and there was no FDA-approved therapy designed to change the course of the disease, the agency said.

"For families living with Sanfilippo syndrome type A, the trajectory of this disease is heartbreaking — children who develop normally in their earliest years facing a relentless regression with no approved treatment to slow it," said Karim Mikhail, director of the FDA's Center for Biologics Evaluation and Research.

The root cause is a missing or deficient enzyme called sulfamidase, which the SGSH gene normally instructs cells to make. An enzyme is a protein that speeds up a specific chemical reaction. Without sulfamidase, cells cannot properly break down heparan sulfate, a complex sugar molecule, inside lysosomes, the cell's recycling compartments. Heparan sulfate then builds up throughout the body and brain.

How Fayuvi Works

Fayuvi (rebisufligene etisparvovec-hopf) is a gene therapy, meaning it treats disease by delivering genetic instructions rather than a conventional drug. It is given once, as an intravenous infusion into a vein.

The therapy uses a modified, non-infectious virus called adeno-associated virus serotype 9, or AAV9, as a delivery vehicle. AAV9 carries a working copy of the SGSH gene into the patient's cells, which can then produce sulfamidase and break down heparan sulfate properly, reducing its harmful buildup.

The fact that a single IV dose can help the brain is itself notable. "Achieving meaningful neurodevelopmental benefit through a single intravenous administration represents a significant scientific milestone — demonstrating that systemic AAV9-mediated gene delivery can reach the central nervous system at therapeutically relevant levels in pediatric patients," said Megha Kaushal, acting deputy director of the FDA's Office of Therapeutic Products.

According to the prescribing information, Fayuvi is indicated for the neurologic manifestations of MPS IIIA in pediatric patients with preserved neurodevelopmental function. In other words, it is meant for children who have not yet lost significant developmental ground.

What the Evidence Shows

The FDA evaluated Fayuvi in an open-label, single-arm, multicenter study in children with MPS IIIA. Open-label means everyone knew who was getting the treatment; single-arm means there was no randomized comparison group in the trial itself. The study measured mean changes in cognitive scores in patients between ages 2 and 5.

Fayuvi-treated patients maintained or improved cognitive function compared with an untreated historical control cohort, a group of untreated patients whose disease course was documented separately. The FDA called this "a meaningful divergence from the expected natural disease course of plateau and decline during this critical developmental window."

Historical controls are common in ultra-rare diseases, where randomizing children to no treatment raises ethical and practical problems. They also make the comparison less direct than a randomized trial, which is worth keeping in mind as long-term data accumulate.

Safety Warnings and Treatment Burden

The approval comes with significant safety considerations. The most common adverse reactions, reported in more than 5% of patients, included increased liver enzymes, nausea and vomiting, fever, decreased appetite, decreased white blood cell and platelet counts, and increased amylase, the FDA said.

The FDA highlighted the risk of thrombotic microangiopathy, or TMA, a condition in which small blood clots damage tiny blood vessels and can harm organs such as the kidneys. The prescribing information also includes warnings for liver toxicity, low platelet counts, and infusion reactions. As with other AAV-based gene therapies, there is a potential long-term risk that the inserted genetic material could integrate into the genome and lead to tumor development.

Fayuvi must be given in a healthcare setting equipped to manage infusion reactions. All patients receive corticosteroids, anti-inflammatory steroid drugs used here to dampen the immune response, beginning one day before the infusion and continuing for at least eight weeks afterward.

The therapy received Orphan Drug, Fast Track, and Breakthrough Therapy designations, programs the FDA uses to encourage and speed development of drugs for rare and serious conditions.

Part of a Wave of First-Ever Rare Disease Approvals

Fayuvi follows another first-of-its-kind neurology approval earlier this month. On Sept. 3, the FDA approved Ionis Pharmaceuticals' Zanvastro (formerly zilganersen) as the first disease-modifying treatment for Alexander disease, an ultra-rare genetic leukodystrophy, a disorder that damages the brain's white matter, BioSpace reported.

Zanvastro takes a different approach. It is an antisense oligonucleotide, or ASO, a short synthetic strand of genetic material that binds to RNA and, in this case, reduces the body's production of the toxic GFAP protein. In Ionis' pivotal Phase 3 trial of 49 patients at least 5 years old, the 50 mg dose produced statistically significant stabilization of gait speed on a 10-meter walk test compared with untreated patients at week 61. The approval came more than two weeks before its Sept. 22 target date.

Side by side, the two approvals show two leading strategies for genetic brain diseases: adding back a missing gene, as Fayuvi does, or turning down a harmful one, as Zanvastro does.

The field is not without setbacks. BioSpace reported that Ultragenyx's shares fell after the company said its separate antisense drug for Angelman syndrome, apazunersen, failed to improve cognition in a Phase 3 trial.

"For families living with Sanfilippo syndrome type A, the trajectory of this disease is heartbreaking — children who develop normally in their earliest years facing a relentless regression with no approved treatment to slow it," said Karim Mikhail, director of the FDA's Center for Biologics Evaluation and Research.

Why It Matters

• A first for families. Children with Sanfilippo syndrome type A now have an FDA-approved option aimed at the underlying disease, not just symptoms.
• One IV dose reaching the brain. Regulators say Fayuvi shows systemic AAV9 delivery can reach the central nervous system at meaningful levels in children.
• Timing is everything. The label targets children with preserved development, which puts a premium on early diagnosis.
• Real risks remain. TMA, liver and platelet warnings, and at least eight weeks of steroids mean treatment requires specialized care and monitoring.