Interim analysis of post-marketing surveillance study of intracerebroventricular idursulfase therapy for neuronopathic mucopolysaccharidosis type II: Safety and effectiveness in clinical practice in Japan.

Mucopolysaccharidosis type II (MPS II) results from iduronate-2-sulfatase (IDS) enzyme deficiency due to IDS gene mutations. Most patients with neuronopathic MPS II experience progressive neurological decline; however, effectiveness of standard treatment, intravenous idursulfase, is limited by blood-brain barrier transfer. Intracerebroventricular (ICV) idursulfase beta, approved in Japan in 2021, directly delivers idursulfase beta into cerebral ventricles. This post-marketing surveillance reports long-term effectiveness and safety of ICV idursulfase beta (30 mg every 4 weeks) in all treated patients from April 2021 through August 2024. Outcomes included cerebrospinal fluid (CSF) heparan sulfate (HS) levels (quarterly), developmental age (DA; Kyoto Scale of Psychological Development, annually), and safety. Thirty-seven Japanese male patients across 21 sites were enrolled (safety population n = 36; effectiveness population n = 35). Mean CSF HS concentrations decreased from 7.36 to 3.19 μg/mL from baseline to week 24, with reduction sustained through week 100. Patients who initiated treatment within 3 years of age had DA progression aligned with healthy cohorts, regardless of mutation type; however, those starting later had no comparable benefit. Adverse events (AEs) occurred in 20 patients (55.6%). Procedure-related serious AEs (SAEs) occurred in 2 patients (bacterial meningitis, device-related infection, pyrexia). Treatment-related AEs affected 14 patients (38.9%), mainly pyrexia (27.8%, including one SAE). One SAE (membranous glomerulonephritis) was not intervention related. No deaths, anaphylaxis, or anti-IDS antibodies in CSF were detected. ICV idursulfase beta demonstrated sustained CSF HS reduction with no new safety signals. Earlier treatment initiation (≤3 years) was associated with improved neurodevelopmental outcomes, regardless of mutation type.