Intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A: A phase IIb randomized trial

Frits A. Wijburg, Chester B. Whitley, Joseph Muenzer, Serena Gasperini, Mireia del Toro, Nicole Muschol, Maureen Cleary, Caroline Sevin, Elsa Shapiro, Parul Bhargava, Douglas Kerr, David Alexanderian

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Background: Sanfilippo syndrome type A (mucopolysaccharidosis type IIIA) is a lysosomal disorder wherein deficient heparan-N-sulfatase (HNS) activity results in the accumulation of heparan sulfate in the central nervous system and is associated with progressive neurodegeneration in early childhood. We report on the efficacy, pharmacokinetics, safety, and tolerability of intrathecal (IT) administration of recombinant human HNS (rhHNS) from a phase IIb randomized open-label trial. Methods: Twenty-one patients, randomized 1:1:1 to rhHNS IT 45 mg administered every 2 weeks (Q2W), every 4 weeks (Q4W), or no treatment, were assessed for amelioration in neurocognitive decline as determined by the Bayley Scales of Infant and Toddler Development®, Third Edition. The primary efficacy goal was defined as ≤10-point decline (responder) in at least three patients in a dosing cohort after 48 weeks. Other efficacy assessments included adaptive behavioral function, assessments of cortical gray matter volume, and glycosaminoglycan (GAG) levels in urine. Results: A clinical response to rhHNS IT was observed in three treated patients (two in the Q2W group, one in the Q4W group). Cerebrospinal fluid heparan sulfate and urine GAG levels were reduced in all treated patients. However, most secondary efficacy assessments were similar between treated patients (n = 14; age, 17.8–47.8 months) and untreated controls (n = 7; age, 12.6–45.0 months). Treatment-emergent adverse events that occurred with rhHNS IT were mostly mild, none led to study discontinuation, and there were no deaths. Conclusion: rhHNS IT treatment reduced heparan sulfate and GAG levels in treated patients. Though the primary neurocognitive endpoint was not met, important lessons in the design and endpoints for evaluation of cognitive and behavioral diseases resulted. Trial registration: ClinicalTrials.govNCT02060526; EudraCT 2013-003450-24.

Original languageEnglish (US)
Pages (from-to)121-130
Number of pages10
JournalMolecular Genetics and Metabolism
Issue number2
StatePublished - Feb 2019

Bibliographical note

Funding Information:
Research was funded by the sponsor, Shire Human Genetic Therapies. Under the direction of the authors, Shirley Louise-May, PhD, and Sally Hassan, PhD, CMPP, employees 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 Shire International GmbH. Although the sponsor was involved in the study design, data collection, and analysis, interpretation of the data was made by the authors independently.

Publisher Copyright:
© 2018 Shire Development LLC and the Authors

Copyright 2019 Elsevier B.V., All rights reserved.


  • Clinical trial
  • Heparan-N-sulfatase
  • Intrathecal
  • Sanfilippo syndrome type a

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