FDA Greenlights Avlayah (tividenofusp alfa-eknm) for Hunter Syndrome in Specific Patients on March 24
The U.S. Food and Drug Administration on March 24, 2026, granted accelerated approval to Avlayah (tividenofusp alfa-eknm) for treating neurologic manifestations of Hunter syndrome in pediatric patients weighing at least 5 kilograms. The approval, given to Denali Therapeutics, is based on clinical trial data showing significant reduction of cerebrospinal fluid heparan sulfate, a biomarker linked to the disease’s central nervous system involvement, officials said.
Avlayah is indicated for pediatric patients who are either presymptomatic or symptomatic and weigh at least 5 kilograms before the onset of advanced neurologic impairment, according to FDA documents. The therapy, developed by Denali Therapeutics of South San Francisco, marks the first approved treatment targeting central nervous system involvement in Hunter syndrome, also known as mucopolysaccharidosis type II (MPS II), officials said. The FDA granted Avlayah accelerated approval after reviewing data from a phase 1/2 clinical trial involving 47 pediatric patients aged between 3 months and 13 years.
At 24 weeks, the trial demonstrated a 91 to 93 percent reduction in cerebrospinal fluid heparan sulfate, a surrogate biomarker linked to the disease’s neurologic manifestations, according to published results in the New England Journal of Medicine in January 2026.
Ninety-three percent of patients achieved cerebrospinal fluid heparan sulfate levels within the range observed in individuals without Hunter syndrome, sources confirmed. The FDA determined that this surrogate endpoint is reasonably likely to predict clinical benefit, enabling the accelerated approval pathway.
Denali Therapeutics received multiple designations prior to approval, including breakthrough therapy, fast track, priority review, and orphan drug status, according to FDA announcements. Acting Director of the Center for Drug Evaluation and Research, Dr. Tracy Beth Hoeg, M.D., Ph.D., noted that Avlayah addresses neurologic complications affecting approximately 500 individuals in the United States, predominantly males. FDA Commissioner Marty Makary, M.D., M.P.H., described the approval as a milestone for children and families affected by the disease.
Avlayah is administered as an intravenous infusion once weekly, per FDA prescribing information. The therapy is engineered to cross the blood-brain barrier by utilizing a transferrin receptor-mediated transport mechanism, enabling central nervous system delivery that was previously unattainable with standard enzyme replacement therapies. It targets the underlying deficiency of iduronate 2-sulfatase (IDS) enzyme and the accumulation of glycosaminoglycans responsible for Hunter syndrome’s multisystemic effects, according to Denali’s press release.
Safety information includes a boxed warning for hypersensitivity reactions, including anaphylaxis, necessitating initiation under medical supervision. The most common adverse events reported were upper respiratory tract infections, fever, anemia, and gastrointestinal symptoms. Infusion-related reactions were the most frequent side effects but tended to decrease with continued treatment, sources said. Monitoring for anemia and renal complications is recommended during therapy.
Continued approval of Avlayah is contingent upon verification of clinical benefit in an ongoing phase 2/3 confirmatory trial named COMPASS. This randomized, controlled study enrolls children and young adults across North America, South America, and Europe, comparing Avlayah to standard care with idursulfase. The trial aims to confirm improvements in cognitive and functional outcomes beyond biomarker reductions, according to clinical trial registries and FDA communications.
Denali plans to make Avlayah available in the United States shortly after approval, supported by a patient assistance program, company representatives said. The FDA also awarded Denali a Rare Pediatric Disease Priority Review Voucher in conjunction with the approval.
Hunter syndrome is a rare X-linked lysosomal storage disorder caused by mutations in the IDS gene, leading to progressive accumulation of glycosaminoglycans in various tissues. The disease affects physical and mental development, the skeleton, heart, respiratory system, and brain, with neurologic decline nearly universal in affected boys, according to medical literature and FDA background documents. Approximately 500 patients in the U.S. live with the condition, predominantly males due to its X-linked inheritance pattern.
Avlayah represents the first Hunter syndrome therapy approved to address cognitive and neurologic manifestations in nearly two decades, analysts from William Blair noted in a recent report. They forecast peak U.S. sales exceeding $250 million by the late 2030s, with worldwide sales potentially reaching $1 billion. The approval underscores advances in central nervous system delivery technology, validating Denali’s Transport Vehicle chemistry platform for treating neurologic diseases.
