Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is a progressive, devastating lysosomal storage disorder. It causes multisystem and neurologic decline. Current enzyme replacement therapies do not cross the blood-brain barrier. Consequently, physicians have an urgent, unmet need for treatments that address the central nervous system (CNS) manifestations of MPS II. The new investigational therapy, tividenofusp alfa, has been developed precisely to address both peripheral and neurologic symptoms. This novel intravenous enzyme comprises iduronate-2-sulfatase fused to an engineered transferrin receptor-binding Fc domain, allowing it to penetrate the brain.
Safety Profile of Tividenofusp Alfa in Clinical Trials
The primary goal of the Phase 1/2, open-label study was to evaluate the safety of this new therapy. The trial enrolled 47 male participants up to 18 years old. All 47 participants reported at least one adverse event (AE) during the initial 24-week treatment period. Infusion-related reactions (IRRs) were the most commonly reported side effect. Furthermore, pyrexia, urticaria, and vomiting were the most frequent symptoms of IRRs, occurring in over 40% of participants. These reactions were common despite routine premedication. Three participants experienced serious treatment-related AEs, but they continued to receive the therapy. Importantly, the incidence of infusion-related reactions decreased with continued use over the study period. This suggests the treatment is generally manageable in a clinical setting.
Significant Reduction in MPS II Biomarkers
Secondary objectives focused on central nervous system and peripheral effects. This Phase 1/2 study yielded encouraging results regarding disease biomarkers. Heparan sulfate (HS) is the primary substrate that accumulates in MPS II patients. Consequently, measuring HS levels in the cerebrospinal fluid (CSF) and urine is a key efficacy metric. At the 24-week primary analysis, CSF HS levels decreased by 91% from baseline. Urinary HS levels also decreased by 88%. Moreover, most participants reached HS levels comparable to children unaffected by the disease. Significantly, researchers observed these reductions were maintained through Week 153 for participants who continued follow-up. Exploratory data also showed a substantial reduction in serum neurofilament light (NfL) chain levels, a biomarker of neuronal injury, by Week 153.
Clinical Impact of Tividenofusp Alfa
The therapy also demonstrated positive effects on clinical endpoints. Investigators noted that adaptive behavior either stabilized or improved. Furthermore, liver volumes normalized or remained within the normal range. Current enzyme replacement therapies for MPS II do not address the progressive neurocognitive decline of the disease, so these results are promising. Since this was an open-label Phase 1/2 study, the primary focus was on safety and biomarkers. Therefore, a larger, randomized, controlled trial, the Phase 2/3 COMPASS study, is currently underway. This ongoing study will further evaluate the clinical effects and confirm the overall efficacy of tividenofusp alfa. This novel, brain-penetrant approach could mark a critical turning point in the management of MPS II, offering hope for comprehensive disease modification.
Frequently Asked Questions
Q1: What is the main benefit of tividenofusp alfa compared to older MPS II therapies?
The main benefit is its ability to cross the blood-brain barrier. Older enzyme replacement therapies (ERTs) cannot penetrate the CNS, meaning they do not treat the progressive neurologic and cognitive decline associated with Hunter syndrome. Tividenofusp alfa is specifically engineered to address the disease in both the brain and the body.
Q2: Were the adverse events from tividenofusp alfa serious?
Adverse events were common, with all 47 participants reporting at least one AE during the 24-week primary period. Most were mild to moderate infusion-related reactions (IRRs), such as vomiting or pyrexia. While three participants had serious treatment-related AEs, the AEs were generally manageable, and IRRs tended to decrease with continued treatment over time.
References
- Muenzer J et al. An Intravenous Brain-Penetrant Enzyme Therapy for Mucopolysaccharidosis II. N Engl J Med. 2026 Jan 01. doi: 10.1056/NEJMoa2508681. PMID: 41467650.
- Denali Therapeutics. The New England Journal of Medicine Publishes Phase 1/2 Study of Denali Therapeutics’ Tividenofusp Alfa (DNL310) for Hunter Syndrome (MPS II). Dec 30, 2025.