First FDA-Approved Treatment for Sanfilippo Syndrome Type A Offers Families New Hope

Families of children with mucopolysaccharidosis type IIIA (MPS IIIA), also known as Sanfilippo syndrome type A, have never had a treatment that addresses the disease itself. That changed when the U.S. Food and Drug Administration (FDA) granted standard full approval to Fayuvi (rebisufligene etisparvovec-hopf), a gene therapy developed by Ultragenyx and also known as UX111.

Kevin M. Flanigan, M.D., director of the Center for Gene Therapy at Nationwide Children’s Hospital and principal investigator on the study that led to the approval, said the therapy “changes the game,” especially for families of newly diagnosed children.

A disease often called “dementia of childhood”

Flanigan said children with Sanfilippo syndrome type A usually seem completely typical for their first 18 months to 2 years. Parents then begin to notice differences between their child and peers or siblings. By about age 3, development generally plateaus, and children begin losing skills they already had.

Over time, the disease can lead to loss of speech, behavioral problems, seizures and sleep problems. Flanigan noted that the condition is sometimes referred to as “dementia of childhood.” It eventually affects movement as well, and death commonly occurs in the second decade of life, often from infections, declining lung function and malnutrition.

Replacing a missing enzyme to protect neurons

The disease is caused by the lack of a working SGSH enzyme. Without it, complex sugars called glycosaminoglycans (GAGs) build up in cells throughout the body, including the liver, spleen and skin. When enough GAGs accumulate in neurons, those brain cells deteriorate.

Fayuvi delivers the gene for the missing enzyme. Flanigan said that addressing the root cause is critical because “neurons in general just don’t grow back” once they are lost. In the trial, investigators tracked markers of this damage in blood and spinal fluid, which he said can help predict better outcomes.

Durable results, with long-term questions still open

The approval rests on the pivotal Transpher A trial and long-term follow-up studies, with data now extending to nearly eight years. The first patient was treated in 2016, so Flanigan said durability beyond about 10 years is not yet known.

Still, he said, “we do not see evidence of a lack of durability for this,” and markers of GAG buildup have stayed lower over the course of the trial. He said full rather than accelerated approval reflects that “the confidence in the data and the markers of improvement were such that the FDA felt that it wasn’t required to do additional studies to show its benefit.”

Earlier treatment, broader eligibility and realistic expectations

For newly diagnosed families, Flanigan said, “the earlier we can treat, the better we might expect the outcome to be.” The youngest trial participants showed the most dramatic gains in function, although nearly everyone in the trial showed some benefit.

He said, “It’s not trivial to give gene therapy like this.” Timing for many families will depend on gaining access to treatment sites and securing insurance coverage. The label itself is broad: The therapy is indicated for patients with mutations in the gene who show evidence of preserved neurodevelopmental function.

Flanigan was careful about expectations for children whose disease is advanced. “It may well interrupt the disease where it is,” he said, but a child who is “nonverbal, immobile, and sort of in the end stages of the illness” should not be expected to regain those abilities. “We don’t have evidence of that,” he said.

For families receiving a diagnosis today, he said the therapy offers “a high likelihood of having a completely different clinical course” than what was possible before the approval. Flanigan added that Fayuvi is the fourth approved gene therapy to come out of Nationwide Children’s faculty.