FDA Grants Priority Review, Sets PDUFA Date for Hunter Syndrome Treatment Tividenofusp Alfa

Carole Ho, MD

The FDA has accepted Denali Therapeutics’ biologics license application (BLA) for tividenofusp alfa, an investigational agent, as a potential treatment for Hunter syndrome, a rare genetic lysosomal disease. Along with granting priority acceptance review, the agency assigned a PDUFA date of January 5, 2026, for the iduronate-2-sulfatase (IDS)-targeting therapy.¹

Hunter syndrome results from a lack of the IDS enzyme, causing harmful sugar buildup throughout the body and brain in early childhood. Existing treatments can't reach the brain, leaving cognitive and behavioral symptoms unaddressed. Tividenofusp alfa, a next-gen therapy, aims to overcome this by delivering IDS across the blood-brain barrier using Denali’s TransportVehicle™ platform.

The therapy’s submission, coming through the accelerated approval pathway, was based on data from a phase 1/2, open-label, single-arm study of 47 patients with the disease that lasted 24 weeks. In the study, treatment with the investigational agent led to reductions to normal and near-normal levels in central nervous system (CNS) and peripheral biomarkers of the disease after 24 weeks, as well as noted changes in cerebrospinal fluid heparan sulfate (CSF HS) and neurofilament light, biomarkers of neuroaxonal damage.²

"We are grateful to the FDA for their recognition of the urgent need for new therapies that could offer a significant improvement in the treatment of Hunter syndrome, as reflected by their priority review designation for our Biologics License Application for tividenofusp alfa,” Carole Ho, MD, chief medical officer and head of development at Denali, said in a statement.¹ "If FDA-approved, tividenofusp alfa would mark the first significant advancement in nearly two decades for enzyme replacement therapy for individuals living with Hunter syndrome because of its potential for delivery to tissues throughout the brain and the body. This is also a pivotal milestone for our TransportVehicle platform, which continues to progress with the aim of treating a wide range of lysosomal storage diseases and neurodegenerative disorders."

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In the phase 1/2 study, tividenofusp alfa was considered safe and well tolerated, with most treatment-related adverse events (TEAEs) mild or moderate in nature. Over the 24-week treatment period, the most common TEAEs were infusion-related reactions, anemia, vomiting, pyrexia, respiratory infections, and rash. Serious TEAEs occurred in only 3 participants (6.4%), were manageable with continued treatment, and led to discontinuation in just 1 patient due to a moderate IRR and unrelated adverse events.

Tividenofusp alfa remains in trial settings through the phase 2/3 COMPASS study (NCT05371613), a large-scale study of 54 patients with Hunter syndrome across 2 cohorts (ages ≥2 to <6; ≥6 to 26 years). The study, which lasts 96 weeks total, uses change in CSF HS over the initial 24 weeks as the primary outcome, with additional changes in the Vineland Adaptive Behavior Scale, Third Edition over 96 weeks as an additional key outcome.

CSF HS has been considered a valuable biomarker for monitoring Hunter syndrome because its accumulation reflects the extent of glycosaminoglycan buildup in the central nervous system–a key driver of the disease’s neurological symptoms. Denali and the FDA have had previous conversations which have led to an agreement that CSF HS may be used as a surrogate end point for accelerated approval based on its ability to predict clinical benefit. If approved under this pathway, the company will still look for a traditional, full approval as well.³

In addition to using CSF HS as the primary end point, COMPASS will include several other secondary outcome measures including change in neurofilament light, 6-Minute Walk Test, and change in sum of urine and dermatan sulfate concentrations. Investigators will also assess liver volume through MRI, spleen volume, and improvement in Parent/Caregiver Global Impression of Change Overall MPS II.

REFERENCES
1. Denali Therapeutics Announces FDA Acceptance and Priority Review of Biologics License Application (BLA) for Tividenofusp Alfa for Hunter Syndrome (MPS II). News release. July 7, 2025. Accessed July 7, 2025. https://www.globenewswire.com/news-release/2025/07/07/3110980/0/en/Denali-Therapeutics-Announces-FDA-Acceptance-and-Priority-Review-of-Biologics-License-Application-BLA-for-Tividenofusp-Alfa-for-Hunter-Syndrome-MPS-II.html
2. Denali Therapeutics Announces Primary Analysis and Long-Term Follow-Up of Phase 1/2 Study in Hunter Syndrome (MPS II) with Tividenofusp Alfa. News release. Denali Therapeutics. February 6, 2025. Accessed July 7, 2025. https://www.globenewswire.com/news-release/2025/02/06/3022238/0/en/Denali-Therapeutics-Announces-Primary-Analysis-and-Long-Term-Follow-Up-of-Phase-1-2-Study-in-Hunter-Syndrome-MPS-II-with-Tividenofusp-Alfa.html
3. Denali Therapeutics Announces Successful Meeting with the FDA and Plans to File for Accelerated Approval of Tividenofusp Alfa (DNL310) for the Treatment of MPS II (Hunter Syndrome). News release. Denali Therapeutics. September 3, 2024. Accessed July 7, 2025. https://finance.yahoo.com/news/denali-therapeutics-announces-successful-meeting-120000316.html