The FDA has approved Fayuvi (rebisufligene etisparvovec-hopf), the first treatment authorized in the US for Sanfilippo syndrome type A.
The one-time AAV9 gene therapy is indicated for the neurological manifestations of mucopolysaccharidosis type IIIA (MPS IIIA) in pediatric patients with preserved neurodevelopmental function.
MPS IIIA is an ultrarare lysosomal storage disorder caused by mutations in the SGSH gene. The resulting deficiency of the sulfamidase enzyme causes heparan sulfate to accumulate within cells, leading to progressive neurological damage and the loss of cognitive, language, and motor function.
Fayuvi delivers a functional copy of SGSH through a single intravenous infusion. Expression of the gene is intended to restore sulfamidase production in target tissues, including the central nervous system, and support the breakdown of accumulated heparan sulfate.
The approval was based primarily on an open-label, single-arm study and long-term follow-up data. Seventeen children who received the recommended dose and met neurodevelopmental criteria were compared with 27 untreated patients from an external natural history cohort.
Between 24 and 60 months of age, treated patients recorded a mean 16-point increase in Bayley-III Cognitive Scale raw score, compared with a 7.6-point decline among the untreated patients. The adjusted between-group difference was 23.5 points.
Cerebrospinal fluid heparan sulfate concentrations also fell following treatment. At 24 months, 15 of 16 evaluated patients maintained a reduction in exposure of at least 50 percent, according to the FDA prescribing information. Median follow-up in the primary efficacy population was 4.2 years.
The comparison with an external natural history cohort, rather than a randomized control group, reflects the rarity and severity of the disease but introduces greater uncertainty than a controlled trial.
“The road to approval has been long, as we dosed the first study participant in 2016,” said Kevin Flanigan, director of the Jerry R. Mendell Center for Gene Therapy at Nationwide Children’s Hospital, in a hospital announcement.
The most common adverse reaction was elevated liver enzymes, reported in 85 percent of patients receiving the recommended dose. Other warnings include thrombocytopenia, infusion reactions, thrombotic microangiopathy, and a potential risk of malignancy from vector DNA integration. Patients require corticosteroid treatment beginning before the infusion and continued monitoring afterward.
Originally developed at Nationwide Children’s, the program was licensed to Abeona Therapeutics before being transferred to Ultragenyx in 2022. Commercial supply will be produced at Ultragenyx’s Massachusetts facility and by Andelyn Biosciences in Ohio. Fayuvi is Andelyn’s first approved commercial product.
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