Avlayah (tividenofusp alfa-eknm): FDA approval, pivotal trial and safety
Approved
Type
Therapeutic biologic · Powder,for solution
FDA-approved use
To treat certain individuals with Hunter syndrome (Mucopolysaccharidosis type II or MPS II)Wording from FDA's list of novel approvals.
FDA review
Priority reviewOrphan drug
Company
Denali Therapeutics
Application
BLA 761485
Specialty
Genetics
Boxed warning: Hypersensitivity reactions including anaphylaxis
At a glance
Avlayah (tividenofusp alfa-eknm) is an enzyme replacement therapy approved under accelerated approval for the neurologic manifestations of Hunter syndrome (MPS II) in pediatric patients weighing at least 5 kg, started before advanced neurologic impairment. In a single-arm phase 1/2 trial, cerebrospinal fluid heparan sulfate fell by a mean of 91% at Week 24 (95% CI 89% to 92%). Its boxed warning is for hypersensitivity reactions, including anaphylaxis.
What it is and how it works
Hunter syndrome results from a lack of iduronate-2-sulfatase, so heparan sulfate and dermatan sulfate build up in tissues, including the brain. Avlayah supplies the enzyme fused to an Fc fragment that binds the transferrin receptor. This lets the enzyme cross the blood-brain barrier by receptor-mediated transcytosis and reach the central nervous system as well as peripheral tissues. Existing enzyme replacement therapies are not designed to reach the brain this way.
Multicenter, international, multi-cohort, single-arm, open-label phase 1/2 trial. Part 1 ran up to Week 24, followed by extension periods.
Patients
47 male pediatric patients with Hunter syndrome (44 neuronopathic, 3 non-neuronopathic). Median age 5 years (range 3 months to 13 years). 15 were ERT-naive and 32 were ERT-experienced.
Compared with
None (single-arm).
Primary endpoint
Per the publication, safety. The label's accelerated approval relies on the change in CSF heparan sulfate from baseline to Week 24.
Result
Among 44 patients measured at Week 24, mean CSF heparan sulfate fell 91% from baseline (95% CI 89% to 92%; range 72% to 98%). No patient had CSF heparan sulfate below the upper limit of normal at baseline; 93% (41 of 44) did at Week 24.
Other results
Urinary heparan sulfate fell by 88%. Reductions appeared maintained through week 153. Adaptive behavior (Vineland) stabilized or improved, and liver volumes normalized or remained normal. These were uncontrolled observations.
Safety in the trial
All 47 patients had at least one treatment-emergent adverse event, most often infusion-related reactions (fever, urticaria, vomiting in more than 40%) despite premedication. Three patients had serious treatment-related events and all continued treatment. One patient stopped before Week 24 because of an adverse reaction. Dose interruptions for adverse reactions occurred in 91%, most often for infusion-associated reactions (66%). Median exposure was 117 weeks.
Muenzer et al., phase 1-2 open-label study NCT04251026
Design
Phase 1-2 open-label study: 24 weeks of weekly intravenous treatment, an 80-week safety extension, and a 157-week open-label extension.
Patients
47 male participants up to 18 years of age with MPS II.
Compared with
None.
Primary endpoint
Safety of tividenofusp alfa.
Result
All 47 participants had at least one treatment-emergent adverse event at the 24-week analysis. CSF heparan sulfate appeared reduced by 91% and urinary heparan sulfate by 88% from baseline, to levels within the range of unaffected children.
Other results
Heparan sulfate reductions appeared maintained through week 153. Adaptive behavior stabilized or improved. Liver volumes normalized or remained normal. A randomized trial is ongoing.
Safety in the trial
Adverse events were common across all study periods, most often infusion-related reactions. Pyrexia, urticaria, and vomiting occurred in more than 40% despite routine premedication. Three participants had serious treatment-related events and all continued treatment.
How does Avlayah (tividenofusp alfa-eknm) compare with the alternatives (Idursulfase (intravenous enzyme replacement), Pabinafusp alfa, Hematopoietic stem cell transplantation) for certain individuals with Hunter syndrome (Mucopolysaccharidosis type II or MPS II)? Summarize head-to-head and indirect evidence, efficacy, safety and where each fits, with citations.
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Safety signals
The boxed warning covers life-threatening hypersensitivity reactions, including anaphylaxis, which can occur early in treatment or after prolonged therapy. Treatment should be started in a healthcare setting with monitoring and resuscitation equipment available. If a severe reaction occurs, stop the drug and give epinephrine. Other warnings are infusion-associated reactions, anemia (check hemoglobin at baseline and at 3 months) and membranous nephropathy (monitor serum creatinine and urine protein to creatinine ratio). The most common adverse reactions were infusion-associated reactions, upper respiratory infection, ear infection, fever, and anemia. Dose interruptions for adverse reactions occurred in 91% of patients. The label advises against combining it with other enzyme replacement therapies.
What it competes with
Hunter syndrome is treated mainly with intravenous enzyme replacement therapy to address peripheral disease, plus supportive care. Other approaches are used in selected patients.
Idursulfase (intravenous enzyme replacement)Long-standing standard therapy for peripheral manifestations. It does not effectively cross the blood-brain barrier.
Pabinafusp alfaAnother enzyme fused to a transferrin receptor-binding antibody, designed to reach the brain. Availability varies by region.
Hematopoietic stem cell transplantationUsed in selected patients as a way to provide enzyme to the brain. It carries procedural risks and has limited availability.
Supportive and symptomatic careMultidisciplinary management of airway, cardiac, orthopedic, and neurodevelopmental problems remains part of care.
Bottom line for clinicians
Avlayah is for young children with Hunter syndrome, including those with neurologic involvement, who have not yet reached advanced neurologic impairment. The approval rests on a biomarker (CSF heparan sulfate) from a single-arm trial, and clinical benefit still needs confirmation. Weigh the anaphylaxis risk, the frequent infusion reactions and interruptions, and the need for monitoring of hemoglobin and kidney function.
Dosing, contraindications and full warnings are in the prescribing information.
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Last updated October 28, 2026 by 2 Minute Medicine.
For healthcare professionals. A summary of public FDA documents and published trials, not medical advice. Check the full prescribing information before prescribing.
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