Avlayah (tividenofusp alfa)

The first treatment for the neurologic manifestations of Hunter syndrome. Elaprase remains the treatment for the body's symptoms in patients whose brain is not affected or who fall outside Avlayah's label; for children with neuronopathic disease caught early enough, Avlayah is designed to do both jobs in one infusion.

Hunter syndrome is caused by a shortage of iduronate-2-sulfatase, the enzyme that breaks down 2 sugar chains called heparan sulfate and dermatan sulfate. Without it, those chains build up in cells throughout the body, including the brain. The existing enzyme replacement, Elaprase, supplies the enzyme by infusion but cannot cross the blood-brain barrier, which is why it helps the body and not the mind. Avlayah solves that with a piece of engineering: the enzyme is fused to an antibody fragment that binds the transferrin receptor, a doorway that cells lining the brain's blood vessels use to import iron. The receptor ferries the whole molecule across into the brain, where cells take it up and use it to clear the stored sugar chains. It is the same enzyme with a delivery system attached.

Avlayah carries a boxed warning for life-threatening hypersensitivity reactions including anaphylaxis, which the label notes have occurred both early in treatment and after years of it, so every infusion is given under supervision with resuscitation equipment on hand. Beyond that, the label warns of infusion-associated reactions, anemia, which is checked at baseline and again at 3 months, and membranous nephropathy, a kidney condition monitored through creatinine and urine protein. The most common reactions, in at least 20% of patients, were infusion-associated reactions, upper respiratory infections, ear infections, fever, anemia, cough, vomiting, diarrhea, rash, COVID-19, runny nose, nasal congestion, falls, headache, skin abrasions and hives. Suspected reactions can be reported to Denali at 1-833-663-3654.

A weekly, lifelong, brain-penetrant biologic for an ultra-rare disease, replacing rather than adding to an existing enzyme replacement that already costs several hundred thousand dollars a year. Expect the prior authorization to turn on the label's wording about neurologic involvement and disease stage.

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The label covers pediatric patients weighing at least 5 kg who are presymptomatic or symptomatic and have not yet reached advanced neurologic impairment. That last clause is the one to read twice: like most therapies aimed at a degenerative brain disease, Avlayah is meant to preserve what is there rather than restore what is gone, and the label reflects that. Children already on Elaprase are inside the studied population, since 32 of the 47 trial participants switched from it, but the label advises against using the two together. There is no adult indication.

Source: FDA Drugs@FDA (BLA 761485)

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Approval rested on Trial 1 (NCT04251026), a Phase 1/2 open-label, single-arm study of 47 boys with Hunter syndrome, 44 with the neuronopathic form, with a median age of 5 and a range of 3 months to 13 years. Fifteen had never received enzyme replacement and 32 were switching from it after a median of 26 months. The measure that supported approval was heparan sulfate in cerebrospinal fluid, the biomarker of disease in the brain. At 24 weeks it had fallen by a mean of 91% (95% CI 89% to 92%), with every child falling at least 72%, and 41 of 44 children, 93%, had levels within the normal range where none had at baseline. Doubling the dose to 30 mg/kg produced no further reduction. This is an accelerated approval, which means the FDA accepted the biomarker as reasonably likely to predict benefit and requires a confirmatory trial demonstrating clinical benefit for the approval to continue.

Denali built Avlayah on its transport vehicle platform, designed to move large molecules across the blood-brain barrier by hijacking the transferrin receptor. The program entered the clinic as DNL310 in 2020. The FDA granted accelerated approval on March 24, 2026, making it the first therapy for the neurologic disease in Hunter syndrome, 20 years after Elaprase became the first treatment for the rest of it. The approval is conditional on a confirmatory trial verifying that lowering the biomarker translates into preserved cognition and function.