The US Food and Drug Administration (FDA) has granted accelerated approval for AVLAYAH (tividenofusp alfa-eknm), the first FDA-approved biologic specifically designed to cross the blood-brain barrier and reach the whole body, including the brain. AVLAYAH is an enzyme replacement therapy indicated for the treatment of neurologic manifestations of Hunter syndrome (mucopolysaccharidosis type II, or MPS II) when initiated in pre-symptomatic or symptomatic paediatric patients weighing at least 5 kg prior to advanced neurologic impairment. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial.

“The approval of AVLAYAH is a new era for the Hunter syndrome community as we deliver the first FDA-approved therapy designed to cross the brain’s protective barrier for individuals and families living with this debilitating disease. This approval reflects the determination and partnership of the MPS community, as well as the FDA’s collaborative engagement to incorporate biomarker evidence to help accelerate the development of urgently needed treatments. This milestone validates our TransportVehicle platform and its potential to overcome the long-standing challenge of delivering biologic medicines across the blood-brain barrier, with the aim to transform the treatment of a wide range of neurodegenerative diseases, lysosomal storage disorders and other serious diseases that impact millions worldwide,” said Ryan Watts, PhD, Co-Founder and Chief Executive Officer (CEO), Denali Therapeutics.

Hunter syndrome is a rare genetic disease caused by a deficiency in the iduronate 2-sulfatase (IDS) enzyme, which is needed to break down complex sugars called glycosaminoglycans (GAGs). In individuals with Hunter syndrome, GAGs build up in cells throughout the body, including the brain, resulting in progressive damage to organs and tissues beginning at a young age. Individuals living with the disease can develop cognitive, behavioural, hearing and motor decline that may include losing the ability to speak and walk. 

“The FDA approval of AVLAYAH represents a breakthrough advance as the first therapeutic innovation for the Hunter syndrome community in nearly 20 years. The neurologic manifestations of Hunter syndrome, which affect nearly all patients, have been one of the most challenging and persistent medical needs for the community and a central focus of many years of scientific research. As the first FDA-approved, brain-penetrant medicine for Hunter syndrome, AVLAYAH will substantially change how we treat patients and has the potential to become a new standard of care,” said Joseph Muenzer, MD, PhD, lead investigator of the AVLAYAH phase-I / II clinical trial, Director, Muenzer MPS Research and Treatment Centre and the Bryson Distinguished Professor in Paediatric Genetics at the University of North Carolina at Chapel Hill.

The approval of AVLAYAH is based on the reduction of a key disease biomarker, cerebrospinal fluid heparan sulfate (CSF HS), as a surrogate endpoint reasonably likely to predict clinical benefit in the treatment of neurologic manifestations of Hunter syndrome. In a phase- I / II clinical trial, AVLAYAH demonstrated a 91 percent (95 percent CI: 89 percent, 92 percent) reduction in CSF HS levels from baseline by week 24 of treatment. At week 24, 93 percent (41 of 44) of AVLAYAH-treated patients had CSF HS levels within the range of individuals without Hunter syndrome. The most common adverse reaction in the study was infusion-related reactions. Results from the phase-I / II study were published in the 1st January, 2026, issue of The New England Journal of Medicine. The ongoing global phase-II / III COMPASS study is designed to generate confirmatory evidence and support global regulatory submissions for AVLAYAH. This study includes young adults living with Hunter syndrome.

“Today’s accelerated approval of AVLAYAH is an important advancement for the Hunter syndrome community as the first and only enzyme replacement therapy designed to reach the Central Nervous System (CNS) and periphery that is now FDA-approved to treat neurologic manifestations for individuals living with this disease. We extend our sincere gratitude to the study participants and families, investigators, clinicians and advocates whose courage and commitment made the approval of AVLAYAH possible. We continue to study AVLAYAH in our phase-II/III COMPASS study with the goal of confirming the clinical evidence across the MPS II patient spectrum,” said Peter Chin, MD, Chief Medical Officer (CMO) and Head of Development, Denali Therapeutics.

AVLAYAH is composed of the IDS enzyme fused to Denali’s proprietary TransportVehicle (TV) platform, which binds to the transferrin receptor (TfR) and delivers IDS to peripheral tissues and to CNS through receptor-mediated transcytosis across the blood-brain barrier. AVLAYAH is the first FDA-approved TfR-enabled medicine engineered to specifically cross the blood-brain barrier.