Impact of intracerebroventricular enzyme replacement therapy in patients with neuronopathic mucopolysaccharidosis type II.

This open-label, phase 1/2 study (JMACCT CTR JMA-IIA00350) evaluated the efficacy and safety of intracerebroventricular idursulfase beta in patients with mucopolysaccharidosis II (MPS II). Herein, we report the 100-week results. Six patients with severe MPS II aged 23-65 months were enrolled. Idursulfase beta (increasing from 1 to 30 mg between weeks 0 and 24, followed by a 30-mg final dose) was administered intracerebroventricularly once every 4 weeks using an implanted cerebrospinal fluid (CSF) reservoir; intravenous administration of idursulfase was also continued throughout the study. Efficacy endpoints included developmental age by the Kyoto Scale of Psychological Development 2001 and heparan sulfate (HS) concentration in CSF (primary outcome). In all six patients, HS concentrations decreased (40%-80%) from baseline to week 100. For overall developmental age, the difference in change from baseline to week 100 in each patient compared with patients treated by intravenous idursulfase administration (n = 13) was +8.0, +14.5, +4.5, +3.7, +8.2, and -8.3 months (mean, +5.1 months). Idursulfase beta was well tolerated. The most common adverse events were pyrexia, upper respiratory tract infection, and vomiting. The results suggest that intracerebroventricular idursulfase beta is well tolerated and can be effective at preventing and stabilizing developmental decline in patients with neuronopathic MPS II.