Long-term open-label phase I/II extension study of intrathecal idursulfase-IT in the treatment of neuronopathic mucopolysaccharidosis II

Abstract

Purpose: Intrathecal (IT) idursulfase-IT for the treatment of cognitive impairment is being investigated in pediatric patients with neuronopathic mucopolysaccharidosis II (MPS II) in addition to intravenous idursulfase. In this article, we report the findings for 54 months of idursulfase-IT treatment in an ongoing phase I/II extension trial (NCT01506141).

Methods: A total of 15 male participants with neuronopathic MPS II (aged 3-11 years at enrollment) who were previously treated with intravenous idursulfase entered the extension study. Idursulfase-IT 10 mg or 30 mg was administered monthly via an IT drug delivery device or lumbar puncture, if indicated. The primary endpoint was safety and tolerability; secondary endpoints included pharmacokinetics, cerebrospinal fluid glycosaminoglycan levels, and cognitive function.

Results: In total, 15 participants received a median (range) of 50 (18-55) idursulfase-IT doses. Idursulfase-IT was generally well tolerated; there were no life-threatening adverse events (AEs) or deaths. Most serious AEs were related to the IT drug delivery device; only 2 serious AEs were related solely to idursulfase-IT. After treatment with idursulfase-IT, cerebrospinal fluid glycosaminoglycans were decreased in all participants; these decreases were maintained. Cognitive function was stabilized in 3 of 4 testable participants at month 55.

Conclusion: These long-term results support the clinical development of idursulfase-IT for patients with MPS II with cognitive impairment.

Keywords: Enzyme replacement therapy; Hunter syndrome; Neurocognitive status; Pediatric; Safety.

Conflict of interest statement

Conflict of Interest Joseph Muenzer has received consulting fees from and/or participated in advisory boards for bluebird bio, Inc; Denali Therapeutics; Homology Medicine, Inc; JCR Pharmaceuticals Co, Ltd; REGENXBIO Inc; Sanofi Genzyme; and Takeda Pharmaceutical Company Limited. He is a Principal Investigator for phase I/II and phase II/III intrathecal enzyme replacement trials for the neuronopathic form of mucopolysaccharidosis (MPS) II (sponsored by Shire [a Takeda company]), a phase I/II gene editing trial for adults with MPS II (sponsored by Sangamo Therapeutics), a phase I/II intravenous enzyme replacement therapy trial for MPS IIIA (sponsored by SOBI [Swedish Orphan Biovitrum AB]), and a phase I/II intravenous enzyme replacement trial for MPS II (sponsored by Denali Therapeutics) Suresh Vijayaraghavan is Principal Investigator for phase I/II and phase II/III intrathecal enzyme replacement trials for the neuronopathic form of MPS II (sponsored by Shire [a Takeda company]). Margot Stein is an investigator for phase I/II and phase II/III intrathecal enzyme replacement trials for the neuronopathic form of MPS II (sponsored by Shire [a Takeda company]). Shauna Kearney is an investigator for phase I/II and phase II/III intrathecal enzyme replacement trials for the neuronopathic form of MPS II (sponsored by Shire [a Takeda company]). Yuna Wu is an employee of Takeda Development Center Americas, Inc and a stockholder of Takeda Pharmaceuticals Company Limited. David Alexanderian was an employee of Takeda Development Center Americas, Inc at the time of this study and the writing of the manuscript, and is a stockholder of Takeda Pharmaceuticals Company Limited.

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