Long-term biomarker and cognitive follow-up of children with Hunter syndrome receiving intrathecal enzyme replacement therapy

A phase I–II trial (NCT00920647) evaluating the effects of investigational recombinant iduronate-2-sulfatase formulated for intrathecal administration (idursulfase-IT) in cognitively impaired children with Hunter syndrome (MPS II), and its extension (NCT01506141), has been ongoing since 2010. In addition to safety assessments, changes in glycosaminoglycan (GAG) concentrations in cerebrospinal fluid (CSF) and change from baseline in standardized neurocognitive assessments are being assessed. Sixteen cognitively impaired children with MPS II were originally enrolled. Four patients per dose group received either no treatment, 10 mg, 30 mg, or 1 mg idursulfase-IT monthly for 6 months while continuing intravenous idursulfase 0.5 mg/kg weekly. Patients (currently n = 14) continued into an ongoing extension study, receiving either 10 or 30 mg monthly idursulfase-IT doses. To date, the range of patient exposure time to idursulfase-IT is approximately 2 to 4.5 years. Mean CSF GAG concentration was reduced by about 90% in the 10and 30-mg groups and by about 80% in the 1-mg group at month 6. Long-term follow-up indicates that these low CSF GAG values are maintained, despite occasional skipped doses or, in 1 patient, the development of neutralizing CSF antibodies. Only 5/16 patients were originally cognitively testable over time using the Differential Abilities Scale (2nd edition). Currently, there are 4 patients with cognitive data obtained by this assessment. Although the cognitive data shows large variability, all 4 patients, including 1 patient who was switched from 1 to 10 mg, appear to have experienced stabilization or decreased rate of decline. These data support further development of idursulfase-IT for the stabilization or decreased decline of cognitive function in moderately affected MPS II patients with the severe phenotype. These studies are funded by Shire.