Long-term safety and clinical outcomes of intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A

Frits A. Wijburg, Fiona Heap, Stewart Rust, Jessica de Ruijter, Evelien Tump, Jan Pieter Marchal, Igor Nestrasil, Elsa Shapiro, Simon A. Jones, David Alexanderian

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Introduction: Currently, there is no effective therapy for mucopolysaccharidosis IIIA (MPS IIIA). Intravenously-administered enzyme replacement therapies, while effective in other forms of MPS without neurological involvement, have not been successful in patients with MPS IIIA, as they are unable to cross the blood-brain barrier to improve neurological symptoms. We evaluated the long-term safety, tolerability, and clinical outcomes of recombinant human heparan-N-sulfatase (rhHNS) administered intrathecally (IT) in children with MPS IIIA in a phase 1/2 extension study. Methods: Patients aged ≥3 years with MPS IIIA who had previously completed a phase 1/2 study and received ≥5 of the 6 planned rhHNS infusions via IT administration, were eligible for inclusion. Patients who received 10 mg in the phase 1/2 study had their dose increased to 45 mg. Patients who were treated with 45 mg or 90 mg rhHNS IT in the phase 1/2 study remained on this monthly dose in the extension study. rhHNS was administered via an intrathecal drug delivery device (IDDD). Primary endpoints included the type and severity of adverse events, presence of anti-rhHNS antibodies in the CSF and serum, and changes in laboratory values. Secondary endpoints included standardized neurocognitive assessments and brain magnetic resonance imaging. Results: In the extension study, 12 patients with a mean (SD) age of 9.6 (7.3) years continued treatment with rhHNS IT for a median of 264.4 weeks. Ten of 12 patients completed the extension study. rhHNS IT was generally well-tolerated. All patients experienced at least one treatment-emergent adverse event (TEAE), most being mild or moderate in severity. No serious adverse events (SAEs) were considered related to the study drug, and no deaths occurred. Most SAEs were related to malfunctions of the IDDD. Declines from baseline in Bayley Scales of Infant Development, Third Edition or Kaufman Assessment Battery for Children, Second Edition, Nonverbal Index developmental quotient scores were evident at all rhHNS dosing groups: −17.97%, −18.99%, and −12.12% in the 10/45, 45, and 90 mg groups, respectively, at Month 54. Conclusions: Overall, rhHNS IT was well tolerated in the extension study. However, rhHNS IT was unable to slow the neurocognitive decline of patients with MPS IIIA. This study was subsequently terminated early because pre-specified efficacy criteria were not met, and the study did not yield clinical proof of concept. (Clinicaltrials.gov Identifier NCT01299727).

Original languageEnglish (US)
Pages (from-to)317-322
Number of pages6
JournalMolecular Genetics and Metabolism
Issue number4
Early online dateSep 14 2021
StatePublished - Dec 2021

Bibliographical note

Funding Information:
The authors thank the patients and their families, and the Manchester NIHR children's CRF for their participation in this study, and Luying Pan, Shulian Shang, and Yuemei Wang, of Takeda, for their contribution to data analysis. Research was funded by the sponsor, Shire Human Genetic Therapies, a member of the Takeda group of companies. Under the direction of the authors, Latoya M. Mitchell, PhD, CMPP, of Excel Medical Affairs, provided writing assistance for this manuscript. Editorial assistance in formatting, proofreading, copy editing, and fact checking also was provided by Excel Medical Affairs and funded by Takeda Development Center Americas, Inc. Although the sponsor was involved in the study design, data collection, and analysis, interpretation of the data was made by the authors independently.

Funding Information:
Dr. Heap has received travel grants from Takeda.

Publisher Copyright:
© 2021 Elsevier Inc.


  • Intrathecal drug delivery device
  • Mucopolysaccharidosis IIIA
  • Recombinant human heparan-N-sulfatase
  • Sanfilippo syndrome type A


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