Brain-penetrant enzyme replacement therapy improves biomarkers in mucopolysaccharidosis type II

1. In this open-label phase 1–2 study, pediatric patients with mucopolysaccharidosis type II treated with tividenofusp alfa showed substantial reductions in cerebrospinal fluid and urinary heparan sulfate levels.

2. Adverse events were extremely common, with infusion-related reactions occurring in more than three-quarters of the study population.

Evidence Rating Level: 2 (Good) 

Study Rundown: Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is a rare X-linked lysosomal storage disorder caused by a deficiency in iduronate-2-sulfatase. This results in the accumulation of glycosaminoglycans, particularly heparan sulfate, leading to multisystem disease and neurodegeneration in affected children. Current enzyme replacement therapies do not cross the blood-brain barrier, leaving neurologic decline largely unaddressed. This international, open-label, phase 1–2 trial evaluated tividenofusp alfa, an engineered fusion protein designed to penetrate the brain via transferrin receptor targeting, in male patients up to age 18 with MPS II. At 24 weeks, nearly all participants had reductions in cerebrospinal fluid (CSF) and urinary heparan sulfate to levels observed in unaffected children. In longer-term analysis, adaptive behavior remained stable or improved in about half the patients, and liver volumes also normalized. Notably, serum neurofilament light chain, a marker of neurodegeneration, was also noted to decline over time. Safety concerns centered on infusion-related reactions, anemia, and pyrexia, though these events were largely manageable with supportive care. Limitations of the study include a small sample size, an open-label design, and lack of a control group. Nonetheless, these results demonstrate a tolerable safety profile and biomarker evidence of sustained treatment response associated with a new therapy for MPS II, paving the way for larger studies focused on long-term safety and clinical endpoints.

Click to read the study in NEJM

Relevant Reading: Characterization of Fluid Biomarkers Reveals Lysosome Dysfunction and Neurodegeneration in Neuronopathic MPS II Patients

In-Depth [prospective cohort]: This international, open-label phase 1–2 clinical trial evaluated the safety and preliminary efficacy of tividenofusp alfa, a novel brain-penetrant enzyme replacement therapy, in pediatric patients with MPS II. Forty-seven male participants, most of whom had neuronopathic MPS II, received weekly intravenous infusions of tividenofusp alfa for 24 weeks, with follow-up to 157 weeks for safety and biomarker analysis. The treatment was associated with substantial biochemical improvements. At 24 weeks, cerebrospinal fluid (CSF) heparan sulfate levels had decreased by a mean of 91% from baseline (95% CI, 90 to 92), and urinary heparan sulfate dropped by 88% (95% CI, 85 to 90). Over 90% of patients achieved CSF heparan sulfate levels within the range of unaffected children. Reductions were durable through week 153. Additionally, serum neurofilament light chain, a marker of neuronal injury, decreased by 76% from baseline by week 153, with most patients reaching normal levels. Clinically, adaptive behavior was stabilized or improved in 49% of participants by week 49, as measured by the Vineland Adaptive Behavior Scales. Mean scores on the Bayley Scales of Infant Development (BSID-III) improved by 5.7 points (95% CI, 1.6 to 9.8), and auditory thresholds improved modestly. Liver volumes normalized in all participants with baseline hepatomegaly. Safety concerns were prevalent, with all participants experiencing at least one adverse event. Infusion-related reactions occurred in 87% of patients and were generally managed with premedication. Anemia was observed in 38%, though levels returned to baseline in most cases. No deaths occurred, and treatment adherence remained high throughout. These results support the potential of tividenofusp alfa to address both peripheral and central disease manifestations in MPS II. A randomized controlled phase 2–3 trial is ongoing to further evaluate its efficacy and long-term safety.

Image: PD

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