Hunter Syndrome Treatment: FDA Approves Avlayah as First Brain-Penetrant Therapy

On March 25, 2026, the FDA granted accelerated approval to Avlayah (tividenofusp alfa-eknm), the first Hunter syndrome treatment designed to cross the blood-brain barrier. Pediatricians now have a once-weekly intravenous option that targets the neurologic decline existing enzyme replacement therapies cannot reach.

March 26, 2026 · 4 min read

The Story at a Glance:

Avlayah (tividenofusp alfa-eknm) becomes the first FDA-approved Hunter syndrome treatment engineered to penetrate the blood-brain barrier.
Accelerated approval was granted March 25, 2026 to Denali Therapeutics on a CSF biomarker surrogate endpoint.
In phase 1/2, CSF heparan sulfate dropped an average 91% by Week 24, with 93% of patients reaching normal levels.
Indication is restricted to pediatric patients ≥5 kg, started before advanced neurologic impairment.

What Happened

The first Hunter syndrome treatment engineered to cross the blood-brain barrier received FDA accelerated approval on March 25, 2026. Avlayah (tividenofusp alfa-eknm), developed by Denali Therapeutics, is indicated for the neurologic manifestations of Hunter syndrome — also known as mucopolysaccharidosis type II (MPS II) — in pediatric patients weighing at least 5 kg.

The label restricts initiation to presymptomatic or symptomatic children before advanced neurologic decline. Avlayah is a fusion of the iduronate-2-sulfatase (IDS) enzyme with Denali’s TransportVehicle platform, which binds the transferrin receptor and ferries the enzyme across the blood-brain barrier through receptor-mediated transcytosis. It is administered as a once-weekly intravenous infusion.

The drug holds Breakthrough Therapy, Fast Track, Priority Review, and Orphan Drug designations, and Denali also received a Rare Pediatric Disease Priority Review Voucher at approval. Continued marketing authorization depends on the confirmatory phase 2/3 COMPASS trial (NCT05371613), which is more than 95% enrolled.

Why This Hunter Syndrome Treatment Matters

This is the first new Hunter syndrome treatment in nearly two decades and the first to address the central nervous system. Conventional enzyme replacement with idursulfase, approved in 2006, does not cross the blood-brain barrier and so leaves the cognitive, behavioral, and motor decline that affects nearly all severely affected patients largely untouched.

Hunter syndrome is an X-linked recessive lysosomal storage disorder caused by IDS enzyme deficiency. Glycosaminoglycans (GAGs) — including heparan sulfate and dermatan sulfate — accumulate across tissues, including the brain. Roughly 500 individuals in the United States and 2,000 worldwide are affected, almost exclusively boys. Because neurologic damage is progressive and partially irreversible, treatment timing is the central clinical issue.

Key Numbers from the Hunter Syndrome Treatment Trial

Approval rests on a phase 1/2 multi-cohort, single-arm, open-label study of 47 pediatric patients aged 3 months to 13 years. The primary surrogate endpoint was reduction in cerebrospinal fluid (CSF) heparan sulfate (HS), a glycosaminoglycan biomarker the FDA review team judged reasonably likely to predict clinical benefit.

CSF heparan sulfate at Week 24: 91% average decrease from baseline (95% CI, 89%–92%), in 44 evaluable patients.
Range of response: minimum 72%, maximum 98% reduction.
Normalization: 93% of treated patients reached CSF HS within the normal range by Week 24, after starting above the upper limit of normal.
Confirmatory data: COMPASS, a phase 2/3 randomized 2:1 trial against idursulfase over 96 weeks, is >95% enrolled.

Boxed warnings include hypersensitivity reactions and anaphylaxis, which occurred both early and after many doses. Renal monitoring and hemoglobin monitoring are recommended, and the label specifies that Avlayah should not be used together with other enzyme replacement therapies.

What Experts Are Saying

Tracy Beth Hoeg, MD, PhD, acting director of the FDA’s Center for Drug Evaluation and Research, emphasized the regulatory rationale for accepting a CSF biomarker as the basis for accelerated approval.

“Avlayah is the first product approved to address neurologic complications of Hunter syndrome.” — Tracy Beth Hoeg, MD, PhD, Acting Director, FDA Center for Drug Evaluation and Research

Joseph Muenzer, MD, PhD, the phase 1/2 lead investigator and director of the Muenzer MPS Research and Treatment Center at the University of North Carolina at Chapel Hill, has framed the approval as the first therapeutic advance for the Hunter community in nearly twenty years and a likely shift in standard of care. Note that Dr. Muenzer led the pivotal trial and so is not an independent commentator.

What’s Next for Hunter Syndrome Treatment

Denali expects U.S. commercial supply to begin shortly after approval through a dedicated patient support program. Continued FDA approval depends on the COMPASS confirmatory readout, which will compare cognitive, adaptive, and motor outcomes against idursulfase rather than against placebo.

The European Medicines Agency has granted Priority Medicines designation, but Avlayah is not yet authorized outside the United States. Pediatric clinicians can also expect renewed advocacy for adding MPS II to state newborn screening panels, since the label’s “before advanced neurologic impairment” wording makes early identification a prerequisite to benefit. The FDA’s acceptance of CSF heparan sulfate as a surrogate may also influence development pathways for related lysosomal storage and neurodegenerative programs.

Bottom Line

Identify candidates for this Hunter syndrome treatment early: any boy with developmental regression, coarsening features, hepatosplenomegaly, or recurrent ENT and airway issues warrants urinary GAG screening and IDS enzyme assay.
Confirm the diagnosis with IDS gene sequencing and refer promptly to a metabolic or genetics center, since Avlayah is restricted to patients before advanced neurologic decline.
Counsel families that Avlayah requires weekly intravenous infusions, carries a risk of anaphylaxis even after many doses, and is not used alongside idursulfase or other enzyme replacement therapies.
Build a monitoring plan that includes infusion-reaction preparedness, periodic renal function and hemoglobin checks, and tracking of cognitive, adaptive, and motor milestones.
Watch for the COMPASS confirmatory trial readout — continued FDA approval and broader access decisions will depend on it.

Sources

U.S. Food and Drug Administration. FDA Approves Drug to Treat Neurologic Manifestations of Hunter Syndrome. March 25, 2026. FDA Press Announcement — Avlayah Approval
Denali Therapeutics, Inc. Denali Therapeutics Announces U.S. FDA Approval of AVLAYAH (tividenofusp alfa-eknm) for Treatment of Hunter Syndrome (MPS II). March 25, 2026. Denali Therapeutics Press Release
U.S. Department of Health and Human Services. WTAS: FDA Approves Drug to Treat Neurologic Manifestations of Hunter Syndrome. March 25, 2026. HHS Press Room — Avlayah Approval Statements
Ciccone I. FDA Grants Accelerated Approval to Tividenofusp Alfa for Neurologic Hunter Syndrome. NeurologyLive, March 25, 2026. NeurologyLive — Tividenofusp Alfa Coverage
Contemporary Pediatrics editors. FDA approves Avlayah for Hunter syndrome. Contemporary Pediatrics, March 25, 2026. Contemporary Pediatrics — Avlayah Approval
Halpern L. FDA Approves Tividenofusp alfa-eknm, Targeting Neurologic Manifestations of Hunter Syndrome. Pharmacy Times, March 25, 2026. Pharmacy Times — Tividenofusp Alfa Approval
National Library of Medicine. COMPASS Trial: A Study of DNL310 in Children With Hunter Syndrome (NCT05371613). ClinicalTrials.gov. ClinicalTrials.gov — COMPASS Confirmatory Trial