The U.S. FDA has granted accelerated approval to Denali Therapeutics’ AVLAYAH (tividenofusp alfa-eknm), the first brain-penetrant enzyme replacement therapy for neurologic manifestations of Hunter syndrome (MPS II), supported by Phase 1/2 trial data.
Written By: Chikkula Pavan Kumar, PharmD
Reviewed By: Pharmacally Editorial Team
The U.S. Food and Drug Administration 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, MPS II) in pediatric patients weighing at least 5 kg when initiated before advanced neurologic impairment. The therapy is the first FDA-approved biologic engineered to cross the blood–brain barrier, enabling treatment of disease pathology in both the central nervous system and peripheral tissues.
AVLAYAH addresses a key limitation of conventional enzyme replacement therapies, which have been unable to adequately reach the brain. The therapy combines the iduronate-2-sulfatase (IDS) enzyme with Denali’s proprietary TransportVehicle™ platform, which binds to the transferrin receptor and enables receptor-mediated transport across the blood–brain barrier. This allows delivery of the enzyme to the central nervous system to reduce accumulated glycosaminoglycans (GAGs), a key driver of disease progression in Hunter syndrome.
Ryan Watts, Ph.D., co-founder and CEO of Denali Therapeutics, said the FDA approval of AVLAYAH marks a major milestone for the Hunter syndrome community and validates the company’s TransportVehicle platform designed to deliver biologic therapies across the blood–brain barrier.
Dr. Tracy Beth Hoeg, M.D., Ph.D., Acting Director of the Center for Drug Evaluation and Research (CDER) at the U.S. FDA, noted that the accelerated approval was based on a surrogate biomarker endpoint, with reductions in cerebrospinal fluid heparan sulfate (CSF HS) considered reasonably likely to predict clinical benefit.
The approval was supported by data from a Phase 1/2 international, multicenter, open-label trial (NCT04251026) involving 47 pediatric patients with Hunter syndrome, including enzyme replacement therapy-naïve and previously treated participants. AVLAYAH reduced cerebrospinal fluid heparan sulfate levels by 91% at week 24, and 93% of treated patients achieved biomarker levels comparable to individuals without Hunter syndrome. The most common adverse events were infusion-related reactions.
Commenting on the approval, Joseph Muenzer, M.D., Ph.D., lead investigator of the AVLAYAH Phase 1/2 trial at the University of North Carolina, said neurologic complications of Hunter syndrome have long represented a major unmet medical need. He noted that AVLAYAH, the first brain-penetrant therapy for the disease in nearly two decades, could significantly change treatment approaches and may become a new standard of care.
Hunter syndrome is a rare X-linked lysosomal storage disorder caused by deficiency of the IDS enzyme, leading to accumulation of GAGs throughout the body, including the brain. The disease results in progressive organ damage and neurological decline beginning in early childhood, with symptoms including developmental delay, behavioral changes, hearing loss, and loss of motor or cognitive function.
Clinical benefit will be further evaluated in the ongoing Phase 2/3 COMPASS study (NCT05371613), designed to confirm AVLAYAH’s efficacy across the broader MPS II patient population and support global regulatory submissions. The trial randomizes participants to receive either AVLAYAH or idursulfase and is enrolling patients across North America, South America, and Europe.
Kristin McKay, President and Executive Director of Project Alive, whose child lives with Hunter syndrome, said families have long awaited therapies capable of reaching the brain, adding that the availability of AVLAYAH brings renewed optimism for addressing the disease’s cognitive and neurological progression.
In connection with the approval, the FDA granted Denali a Rare Pediatric Disease Priority Review Voucher, which may be used for priority review of another marketing application or transferred to another sponsor. AVLAYAH will be administered as a once-weekly intravenous infusion and is expected to become available in the United States shortly.
The approval represents the first therapeutic innovation for the Hunter syndrome community in nearly two decades and a significant step toward addressing the neurological burden of the disease. AVLAYAH previously received Breakthrough Therapy, Fast Track, Priority Review, and Orphan Drug designations from the U.S. FDA, supporting its accelerated regulatory pathway.
Reference
Denali Therapeutics Announces U.S. FDA Approval of AVLAYAH™ (tividenofusp alfa-eknm) for Treatment of Hunter Syndrome (MPS II), 25 March 2026, Denali Therapeutics Announces U.S. FDA Approval of AVLAYAH™ (tividenofusp alfa-eknm) for Treatment of Hunter Syndrome (MPS II) | Denali Therapeutics
FDA Approves Drug to Treat Neurologic Manifestations of Hunter Syndrome, 25 March 2026, https://www.fda.gov/news-events/press-announcements/fda-approves-drug-treat-neurologic-manifestations-hunter-syndrome
A Study of Tividenofusp Alfa (DNL310) in Pediatric Participants with Hunter Syndrome, ClinicalTrials.gov ID NCT04251026, https://clinicaltrials.gov/study/NCT04251026
A Study to Determine the Efficacy and Safety of Tividenofusp Alfa (DNL310) vs Idursulfase in Pediatric and Young Adult Participants with Neuronopathic (nMPS II) or Non-Neuronopathic Mucopolysaccharidosis Type II (nnMPS II) (COMPASS), ClinicalTrials.gov ID NCT05371613, https://clinicaltrials.gov/study/NCT05371613
About the Writer
Chikkula Pavan Kumar, PharmD is a Doctor of Pharmacy with a keen interest in clinical pharmacy, pharmacovigilance, and evidence-based practice. In his words, he is passionate about patient safety and translating complex medical information into clear, research-driven communication.