Gene Therapy for Sanfilippo Syndrome Gets FDA Nod

The FDA on Thursday approved rebisufligene etisparvovec (Fayuvi) as the first treatment for pediatric patients with mucopolysaccharidosis type IIIA (MPS IIIA), also known as Sanfilippo syndrome type A, the agency announced Thursday. The therapy is approved to treat the neurologic manifestations of MPS IIIA in pediatric patients with preserved neurodevelopmental function, maker Ultragenyx Pharmaceutical said. MPS IIIA is an ultra-rare, fatal genetic disorder that triggers rapid neurodegeneration in early childhood. It's caused by a deficiency in the sulfamidase (SGSH) enzyme that leads to a buildup of heparan sulfate that progressively damages the central nervous system. Children with MPS IIIA experience global developmental delays followed by a steady loss of cognitive, language, and motor skills, and have a median life expectancy of 15 years. The condition is sometimes called a form of "childhood dementia." Rebisufligene etisparvovec is a one-time, intravenous gene therapy that uses adeno-associated virus serotype 9 (AAV9) to deliver a functional copy of the SGSH gene to produce sulfamidase, allowing heparan sulfate to be properly broken down and reducing its buildup in the body and brain. "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, MD, MSc, acting deputy director of the FDA's Office of Therapeutic Products. The safety and effectiveness of rebisufligene etisparvovec was evaluated in an open-label, single-arm, multicenter clinical trial of MPS IIIA patients. The study measured mean changes in cognitive scores in patients between ages 2 and 5 years. Those who received gene therapy maintained or improved cognitive function compared with an untreated historical control cohort, the FDA said. Across clinical studies, the most common adverse reactions were liver enzyme increases, nausea and vomiting, fever, decreased appetite, decreased white blood cell and platelet counts, and increased amylase. Safety warnings include the risk of thrombotic microangiopathy. "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 potentially lead to tumor development," the FDA warned. The rebisufligene etisparvovec approval comes a little more than a year after the FDA rejected the treatment due to related manufacturing concerns. Ultragenyx set a U.S. list price of $3.95 million for the one-time therapy.