A phase I/II study of intrathecal idursulfase-IT in children with severe mucopolysaccharidosis II

Abstract

Purpose: Approximately two-thirds of patients with the lysosomal storage disease mucopolysaccharidosis II have progressive cognitive impairment. Intravenous (i.v.) enzyme replacement therapy does not affect cognitive impairment because recombinant iduronate-2-sulfatase (idursulfase) does not penetrate the blood-brain barrier at therapeutic concentrations. We examined the safety of idursulfase formulated for intrathecal administration (idursulfase-IT) via intrathecal drug delivery device (IDDD). A secondary endpoint was change in concentration of glycosaminoglycans in cerebrospinal fluid. Methods:Sixteen cognitively impaired males with mucopolysaccharidosis II who were previously treated with weekly i.v. idursulfase 0.5 mg/ kg for ≥6 months were enrolled. Patients were randomized to no treatment or 10-mg, 30-mg, or 1-mg idursulfase-IT monthly for 6 months (four patients per group) while continuing i.v. idursulfase weekly. Results:No serious adverse events related to idursulfase-IT were observed. Surgical revision/removal of the IDDD was required in 6 of 12 patients. Twelve total doses were administrated by lumbar puncture. Mean cerebrospinal fluid glycosaminoglycan concentration was reduced by approximately 90% in the 10-mg and 30-mg groups and approximately 80% in the 1-mg group after 6 months. Conclusions:These preliminary data support further development of investigational idursulfase-IT in MPS II patients with the severe phenotype who have progressed only to a mild-to-moderate level of cognitive impairment.

Survival in idursulfase‐treated and untreated patients with mucopolysaccharidosis type II: data from the Hunter Outcome Survey (HOS)

“…The multisystemic and progressive nature of MPS II means that a single cause of death is unlikely to reflect the full clinical picture in each patient. Nonetheless, the contribution of somatic aspects of disease to mortality is consistent with the positive impact of intravenous idursulfase on survival; approaches that aim to deliver therapeutic enzyme to the central nervous system are in development (Noh and Lee 2014;Muenzer et al 2016).…”

Levels of glycosaminoglycans in the cerebrospinal fluid of healthy young adults, surrogate-normal children, and Hunter syndrome patients with and without cognitive impairment

“…Data from study HGT-HIT-072, which enrolled both cognitively intact and cognitively impaired children with MPS II, as well as cognitively intact adults with MPS II are not shown separately, but per cognitive category. For instance, the data from the 3 cognitively impaired children whose CSF was obtained in study HGT-HIT-072 (previously published [16]), were analyzed together with the data from the 16 cognitively impaired boys with MPS II from the phase I-II idursulfase-IT study (HGT-HIT-045)(previously published [15]), leading to a total number of 19 data points for the category of cognitively affected children with MPS II between the ages of 2-11 years.…”

“…Patients were aged b 18 years, with cognitive impairment due to MPS II (IQ b77, or IQ decline of 15-30 IQ points in past 3 years). CSF samples were obtained at screening (prior to exposure to investigational treatment) [15]. 2.…”

“…This assay was used to measure the CSF GAG levels for all studies reported in this paper. The quantification of urinary GAG for HIT-045, HIT-072 and HIT-073 was performed by Cambridge Biomedical Inc. (Boston, MA, USA) using a Blyscan™ Glycosaminoglycan Assay kit (Biocolor Life Science Assays, Carrickfergus, United Kingdom), and results were normalized to urine creatinine [15,16].…”

Use of Implantable Venous Port Systems in the Treatment of Children with Orphan Diseases (Mucopolysaccharidosis and Pompe Disease): Case Series

“…Так, в нескольких ста-тьях проанализирован опыт применения ИВПС у детей с орфанными заболеваниями [25][26][27]; в 2 -у детей с гемофилиями [28,29]; в 3 -с ВИЧ-инфекциями [30][31][32], однако работы последней группы описыва-ют опыт применения преимущественно у взрослых пациентов, и по этой причине в литературный обзор включены не были. Обращает на себя внимание тот факт, что частота инфекционных осложнений у боль-ных ВИЧ была выше по сравнению с пациентами, кото-рым ИВПС устанавливали для лечения онкологических заболеваний [27].…”