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

Joo-Hyun Seo; Motomichi Kosuga; Takashi Hamazaki; Haruo Shintaku; Torayuki Okuyama

doi:10.1016/j.omtm.2021.02.018

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

Mol Ther Methods Clin Dev. 2021 Feb 27:21:67-75. doi: 10.1016/j.omtm.2021.02.018. eCollection 2021 Jun 11.

Authors

Joo-Hyun Seo¹, Motomichi Kosuga¹, Takashi Hamazaki², Haruo Shintaku², Torayuki Okuyama¹

Affiliations

¹ Department of Clinical Laboratory Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan.
² Department of Pediatrics, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.

Abstract

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.

Keywords: Kyoto Scale of Psychological Development 2001 (KSPD); developmental age; enzyme replacement therapy; heparan sulfate; idursulfase beta; infusions; intracerebroventricular; mucopolysaccharidosis II; pediatrics; psychology.