Denali's Blood-Brain Barrier Breakthrough: Hunter Syndrome Therapy Achieves NEJM Publication and Awaits Historic FDA Decision

Denali Therapeutics has achieved a significant milestone in rare disease treatment with the publication of its Phase 1/2 clinical trial results for tividenofusp alfa in the January 1, 2026 issue of The New England Journal of Medicine. The investigational therapy for Hunter syndrome represents a potential paradigm shift in treating lysosomal storage diseases, as it becomes the first enzyme replacement therapy specifically engineered to cross the blood-brain barrier and address both neurological and physical manifestations of this devastating condition.

The publication comes at a critical juncture, with the FDA conducting a Priority Review of Denali's Biologics License Application under the accelerated approval pathway. A decision is expected by April 5, 2026, which could mark the approval of the first brain-penetrant enzyme replacement therapy for Hunter syndrome, also known as mucopolysaccharidosis type II (MPS II).

Addressing an Urgent Unmet Medical Need

Hunter syndrome affects approximately 1 in 100,000 to 170,000 male births worldwide, caused by mutations in the iduronate-2-sulfatase (IDS) gene. This deficiency leads to the accumulation of complex sugars called glycosaminoglycans throughout the body, including the brain. The neurological impact is particularly devastating, with approximately two-thirds of patients developing progressive cognitive decline, behavioral abnormalities, and loss of developmental milestones.

Current standard-of-care enzyme replacement therapies, while beneficial for physical symptoms, cannot cross the blood-brain barrier and therefore fail to address the neurological deterioration that defines the most severe forms of the disease. Children with neuronopathic MPS II typically lose the ability to hear, speak, and walk as the disease progresses, creating an urgent need for treatments that can reach the brain.

Revolutionary Clinical Results

The Phase 1/2 study enrolled 47 participants ranging from 0.3 to 13 years of age, including both treatment-naïve and previously treated patients across the disease severity spectrum. The results demonstrate tividenofusp alfa's ability to achieve what no previous Hunter syndrome therapy has accomplished: meaningful reduction of disease substrates in the brain.

The most striking finding was the 91% reduction in cerebrospinal fluid levels of heparan sulfate, the primary substrate that accumulates in the brains of Hunter syndrome patients. Remarkably, 93% of participants achieved levels within the normal range observed in unaffected children by week 24, with these improvements maintained through 153 weeks of treatment.

Equally impressive were the reductions in serum neurofilament light chain, a well-established biomarker of neuronal injury. Levels decreased by 76% at week 153, with 85% of participants reaching normal ranges. This suggests that tividenofusp alfa may not only clear accumulated substrates but also halt or reverse ongoing neuronal damage.

Clinical improvements included normalization of liver volume, hearing threshold improvements, and skill gains in adaptive behavior and cognition measures. The safety profile was consistent with other enzyme replacement therapies, with infusion-related reactions being the most common treatment-related adverse events, decreasing with continued use.

Platform Technology with Broader Implications

Tividenofusp alfa's success validates Denali's TransportVehicle platform, which engineers therapeutic proteins to hijack natural transport mechanisms like the transferrin receptor to cross the blood-brain barrier. In animal studies, this technology has demonstrated 10- to 30-fold greater brain exposure for antibodies and enzymes, and over 1,000-fold improvement for oligonucleotides compared to conventional approaches.

The platform's potential extends far beyond Hunter syndrome. Denali is pursuing applications across lysosomal storage disorders and neurodegenerative diseases, with three TransportVehicle-enabled programs currently in clinical development. Success with tividenofusp alfa could establish a new therapeutic class and validate the approach for treating other brain-involved genetic diseases.

Regulatory and Commercial Outlook

The FDA has granted tividenofusp alfa multiple regulatory designations, including Breakthrough Therapy, Fast Track, Orphan Drug, and Rare Pediatric Disease designations. The European Medicines Agency has awarded Priority Medicines status, indicating global regulatory recognition of the therapy's potential.

Denali is simultaneously conducting the Phase 2/3 COMPASS study, a randomized controlled trial comparing tividenofusp alfa to standard-of-care idursulfase across North America, South America, and Europe. This study will provide additional evidence to support global regulatory submissions and commercial launch preparations.

Transforming Lives and Setting Precedents

For families affected by Hunter syndrome, tividenofusp alfa represents hope for preserving cognitive function and developmental progress in their children. The therapy's potential to address both brain and body manifestations could fundamentally alter the disease trajectory and quality of life for patients.

More broadly, the development demonstrates how innovative platform technologies can overcome seemingly insurmountable biological barriers. As the pharmaceutical industry increasingly focuses on precision medicine and targeted therapies, Denali's approach provides a roadmap for addressing other brain-involved genetic diseases that have historically been considered untreatable.

With the April 5 FDA decision approaching, the rare disease community watches with anticipation. Approval would not only provide a transformative treatment option for Hunter syndrome patients but also validate a new therapeutic paradigm that could benefit countless individuals suffering from other neurological genetic disorders.