An Intravenous Brain-Penetrant Enzyme Therapy for Mucopolysaccharidosis II

BACKGROUND: Tividenofusp alfa, comprising iduronate-2-sulfatase fused to an engineered transferrin receptor-binding Fc domain, has been developed to treat neurologic and peripheral manifestations of mucopolysaccharidosis type II (MPS II), a rare lysosomal disorder causing progressive multisystem and neurologic decline. METHODS: We conducted a phase 1-2, open-label study in which male participants up to 18 years of age with MPS II received weekly intravenous tividenofusp alfa for 24 weeks, followed by an 80-week safety extension and a 157-week open-label extension. The primary objective was to evaluate the safety of tividenofusp alfa. Secondary objectives were to evaluate central nervous system and peripheral effects as assessed by cerebrospinal fluid (CSF) and urinary heparan sulfate levels, adaptive behavior (as assessed with the Vineland Adaptive Behavior Scales), and liver volume. RESULTS: A total of 47 male participants were enrolled. At the 24-week primary analysis, all 47 participants reported at least one adverse event that emerged during the treatment period, most commonly infusion-related reactions. Pyrexia, urticaria, and vomiting were the most frequently reported symptoms of infusion-related reactions, occurring in more than 40% of the participants, despite routine premedication. Three participants had serious treatment-related adverse events; all continued to receive treatment. CSF and urinary heparan sulfate levels appeared to be reduced from baseline by 91% and 88%, respectively. Across all study periods, adverse events remained common. Reductions in heparan sulfate levels appeared to be maintained through week 153, adaptive behavior stabilized or improved, and liver volumes normalized or remained normal. CONCLUSIONS: In participants with MPS II, tividenofusp alfa treatment was commonly associated with adverse events. Heparan sulfate, the primary substrate that accumulates in the CSF and urine in persons with MPS II, appeared to decrease to levels within the range of unaffected children. A randomized trial is ongoing to further evaluate these effects. (Funded by Denali Therapeutics; ClinicalTrials.gov number, NCT04251026; EudraCT number, 2019-004909-27.).