FDA has granted accelerated approval to Avlayah, the first therapy engineered to cross the blood-brain barrier and treat the neurological manifestations of Hunter syndrome.
FDA granted accelerated approval for Avlayah (tividenofusp alfa-eknm), the first therapy designed to cross the blood-brain barrier and treat the neurological manifestations of Hunter syndrome.
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In connection with the approval, FDA granted Denali a Rare Pediatric Disease Priority Review Voucher, which may be used to accelerate review of a future application or transferred to another sponsor.2
“Today is a milestone day for children and their families battling Hunter syndrome,” said FDA commissioner Marty Makary, M.D., M.P.H. “The FDA is capable of doing two things: one, exercising regulatory flexibility; and two, complying with our obligation under the law to approve drugs based on ‘substantial evidence’ of effectiveness.”2
Hunter syndrome (MPS II) is a rare lysosomal storage disorder caused by mutations in the IDS gene that result in deficiency of the iduronate 2-sulfatase enzyme. Without this enzyme, complex sugars called glycosaminoglycans accumulate in cells throughout the body, including the brain, causing progressive damage to organs and tissues.1
Symptoms include cognitive and behavioral decline, hearing loss, joint stiffness, and organ dysfunction.1 The disease primarily affects boys and impacts approximately 500 individuals in the U.S. and 2,000 worldwide.
Existing enzyme replacement therapies cannot cross the blood-brain barrier, meaning the neurological manifestations of Hunter syndrome, which affect nearly all patients, have remained largely untreatable. Avlayah is the first FDA-approved therapy engineered to overcome this barrier.
Avlayah fuses the IDS enzyme to Denali's proprietary TransportVehicle platform, which binds to the transferrin receptor expressed on cells throughout the body including those lining the blood-brain barrier.1 This enables the drug to cross into the central nervous system through receptor-mediated transcytosis, delivering the enzyme to both peripheral tissues and the brain. Once inside cells, Avlayah is transported into lysosomes where it reduces accumulated glycosaminoglycans.
The accelerated approval is based on results from a Phase I/II international, open-label trial enrolling 47 pediatric patients aged 0.3 to 13 years, both treatment-naïve and previously treated.2 Avlayah produced a 91% reduction in cerebrospinal fluid heparan sulfate levels from baseline by week 24, a key disease biomarker used as a surrogate endpoint.2
At week 24, 93% of treated patients had CSF heparan sulfate levels within the range seen in individuals without Hunter syndrome. The most common adverse reaction was infusion-related reactions. Results were published in the New England Journal of Medicine in January 2026.
Continued approval is contingent on results from the ongoing Phase II/III Compass confirmatory trial, which is randomizing participants 2:1 to Avlayah or the existing standard of care across sites in North America, South America, and Europe.1
Joseph Muenzer, lead investigator of the Phase 1/2 trial and director of the Muenzer MPS Research and Treatment Center at the University of North Carolina, called the approval a breakthrough advance, and the first meaningful therapeutic innovation for the Hunter syndrome community in nearly 20 years.1
“The neurologic manifestations of Hunter syndrome, which affect nearly all patients, have been one of the most challenging and persistent medical needs for the community and a central focus of many years of scientific research. As the first FDA-approved, brain-penetrant medicine for Hunter syndrome, Avlayah will substantially change how we treat patients and has the potential to become a new standard of care,” said Muenzer.
Avlayah is set to be available in the U.S. shortly following approval with patient support services available through Denali's dedicated program.1
