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An Intravenous Brain-Penetrant Enzyme Therapy for Mucopolysaccharidosis II
Joseph Muenzer1, Barbara K Burton2, Paul Harmatz3
1University of North Carolina School of Medicine, Chapel Hill.
The New England Journal of Medicine
|December 30, 2025
Summary
Tividenofusp alfa showed potential in treating mucopolysaccharidosis type II (MPS II) by reducing heparan sulfate levels. While adverse events were common, the treatment stabilized adaptive behavior and normalized liver volumes in participants.
Area of Science:
- Biochemistry
- Genetics
- Pharmacology
Background:
- Mucopolysaccharidosis type II (MPS II) is a rare lysosomal storage disorder.
- MPS II causes progressive multisystem and neurologic decline.
- Tividenofusp alfa is a novel fusion protein developed for MPS II treatment.
Purpose of the Study:
- To evaluate the safety and efficacy of tividenofusp alfa in MPS II patients.
- To assess the impact of tividenofusp alfa on neurologic and peripheral manifestations.
- To monitor cerebrospinal fluid (CSF) and urinary heparan sulfate levels, adaptive behavior, and liver volume.
Main Methods:
- Phase 1-2, open-label study of intravenous tividenofusp alfa in male participants up to 18 years old with MPS II.
- Treatment duration of 24 weeks, followed by safety and open-label extensions up to 157 weeks.
- Primary safety assessment, with secondary objectives including CSF/urinary heparan sulfate, adaptive behavior, and liver volume.
Main Results:
- 47 male participants enrolled; all experienced at least one adverse event, most commonly infusion reactions.
- Significant reductions in CSF (91%) and urinary (88%) heparan sulfate levels observed.
- Heparan sulfate reductions were maintained, adaptive behavior stabilized/improved, and liver volumes normalized.
Conclusions:
- Tividenofusp alfa treatment was associated with frequent adverse events in MPS II patients.
- Heparan sulfate levels decreased to the range of unaffected children.
- Further evaluation in an ongoing randomized trial is warranted.
