FDA approves Denali Therapeutics' Avlayah for neurologic symptoms of Hunter syndrome in pediatric patients

The US FDA has granted accelerated approval to AVLAYAH (tividenofusp alfa-eknm), an enzyme replacement therapy developed by Denali Therapeutics for the treatment of neurologic manifestations of Hunter syndrome (mucopolysaccharidosis type II, or MPS II). The decision, announced on March 25, 2026, marks the first FDA-approved biologic designed to cross the blood-brain barrier and the first new treatment option for MPS II in nearly 20 years. It is also Denali's first approved product, validating the company's proprietary TransportVehicle platform, which engineers therapeutic proteins to traverse the blood-brain barrier via transferrin receptor-mediated transcytosis. The FDA also awarded Denali a Rare Pediatric Disease Priority Review Voucher in connection with the approval.

AVLAYAH is indicated for the treatment of neurologic symptoms in pediatric patients weighing at least 5 kg with Hunter syndrome, provided treatment is initiated prior to advanced neurologic impairment. The drug carries Breakthrough Therapy, Fast Track, and Orphan Drug designations. Because the approval was granted under the accelerated pathway, it was based on a surrogate endpoint — reduction of cerebrospinal fluid heparan sulfate (CSF HS) — considered reasonably likely to predict clinical benefit. Continued approval may depend on verification of clinical benefit in a confirmatory trial. AVLAYAH is not recommended for use in combination with other enzyme replacement therapies. The label includes a boxed warning for hypersensitivity reactions, including anaphylaxis.

The approval rests on data from a Phase I/II international, multi-center, open-label trial enrolling 47 pediatric patients aged 0.3 to 13 years, including both enzyme replacement therapy-naïve and previously treated individuals. By week 24, AVLAYAH demonstrated a 91% reduction in CSF HS from baseline (95% CI: 89%, 92%), and 93% of treated patients (41 of 44) achieved CSF HS levels within the range observed 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. Denali is conducting the ongoing Phase II/III COMPASS study, a randomized trial comparing AVLAYAH to idursulfase, to generate confirmatory evidence and support global regulatory submissions. The European Medicines Agency has granted Priority Medicines designation to tividenofusp alfa, though the drug is not yet approved outside the United States.

Hunter syndrome affects approximately 500 individuals in the United States and 2,000 worldwide. It is caused by deficiency of the iduronate 2-sulfatase enzyme, leading to accumulation of glycosaminoglycans in tissues including the brain. The neurologic manifestations — cognitive decline, behavioral changes, loss of speech and mobility — affect nearly all patients and have represented the central unmet need in MPS II for decades. Since 2006, the only FDA-approved therapy has been idursulfase (Elaprase), marketed by Takeda, which addresses somatic symptoms but does not cross the blood-brain barrier. AVLAYAH, composed of the IDS enzyme fused to Denali's TransportVehicle platform, is engineered to bind the transferrin receptor on brain endothelial cells, enabling delivery to both peripheral tissues and the central nervous system. It joins a small but growing field of blood-brain barrier-crossing biologics; pabinafusp alfa (Izcargo), developed by JCR Pharmaceuticals using a different transferrin receptor-targeting approach, was approved in Japan in 2021 but has not received FDA or EMA approval. Gene therapy candidates, including RGX-121 from REGENXBIO, remain in clinical development. For Denali, the approval provides a commercial foundation and a proof of concept for the TransportVehicle platform, which the company said has five additional programs in clinical development across neurodegenerative diseases and lysosomal storage disorders.

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