A newly published Phase 1/2 study in The New England Journal of Medicine, and reported on by the Manila Times, highlights promising early results for tividenofusp alfa (DNL310), Denali Therapeutics’ investigational enzyme replacement therapy designed to treat both the cognitive and physical manifestations of Hunter syndrome (MPS II). The data support the therapy’s ongoing FDA Priority Review, with a regulatory decision anticipated by April 5, 2026.
A Next‑Generation Therapy Aiming to Reach the Brain
Hunter syndrome is caused by deficiency of the iduronate 2‑sulfatase (IDS) enzyme, leading to buildup of glycosaminoglycans that damage multiple organs, including the brain. Roughly two‑thirds of affected individuals experience progressive neurocognitive decline—a feature existing enzyme replacement therapies cannot address, as they cannot cross the blood‑brain barrier.
Tividenofusp alfa is engineered using Denali’s TransportVehicle™ platform, which uses receptor‑mediated transport to deliver therapeutic enzymes directly into the central nervous system. The investigational therapy has received multiple FDA designations, including Breakthrough Therapy and Rare Pediatric Disease status.
Phase 1/2 Trial Demonstrates Broad Biomarker and Clinical Improvements
The open‑label study enrolled 47 children ranging from infancy to age 13, including both treatment‑naïve patients and those who had previously received standard ERT. Safety remained consistent with earlier reports, with infusion‑related reactions being the most common treatment‑related event and showing decreased frequency over time.
Key findings included:
- Substantial reduction of heparan sulfate (HS) in cerebrospinal fluid, with average levels dropping more than 90% by Week 24 and remaining stable beyond two years. Most children reached ranges typical of unaffected peers.
- Urine HS reductions approaching 90%, sustained through long‑term follow‑up.
- Marked declines in serum neurofilament light chain, a marker of neuronal injury, with reductions deepening over extended treatment.
- Clinical improvements, including normalization of liver volume within 24 weeks, better hearing thresholds, and developmental gains across adaptive behavior and cognitive assessments.
Investigators characterized these combined biomarker and clinical trends as highly encouraging for a disease known for rapid multisystem deterioration.
Implications for the Hunter Syndrome Community
Because neurologic decline is a major driver of disability in MPS II, the ability of tividenofusp alfa to reach the brain represents a potential breakthrough. Denali leaders emphasized that the treatment may become the first approved brain‑penetrant ERT for Hunter syndrome if cleared by the FDA.
The therapy is also being evaluated in the global Phase 2/3 COMPASS trial, which compares tividenofusp alfa with idursulfase, the current standard of care.
Expanding the TransportVehicle™ Platform
Denali’s TransportVehicle technology aims to overcome the long‑standing challenge of delivering large therapeutics across the blood‑brain barrier. Early programs suggest substantially increased CNS exposure in animal and human studies. Beyond lysosomal storage disorders, the company is exploring applications for antibodies and oligonucleotides targeting a range of neurological conditions.
