PMID- 34247932 OWN - NLM STAT- MEDLINE DCOM- 20220224 LR - 20220224 IS - 1096-7206 (Electronic) IS - 1096-7192 (Linking) VI - 134 IP - 1-2 DP - 2021 Sep-Oct TI - A multicenter open-label extension study of intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A. PG - 175-181 LID - S1096-7192(21)00743-5 [pii] LID - 10.1016/j.ymgme.2021.07.001 [doi] AB - Sanfilippo syndrome type A (mucopolysaccharidosis type IIIA) is a rare autosomal recessive lysosomal disorder characterized by deficient heparan-N-sulfatase (HNS) activity, and subsequent accumulation of heparan sulfate, especially in the central nervous system. The disease is associated with progressive neurodegeneration in early childhood. For this open-label extension study of a phase 2b clinical trial, we report on safety and cognitive decline in patients receiving intrathecal (IT) administration of recombinant human HNS (rhHNS). Of 21 patients who completed the phase 2b study, 17 continued in the open-label extension. Patients receiving rhHNS IT 45 mg continued to receive the same treatment regimen (i.e., every 2 weeks or every 4 weeks) throughout the extension. Patients receiving no treatment in the phase 2b study were re-randomized to the treatment groups. Neurocognition was assessed using the Bayley Scales of Infant and Toddler Development(R), Third Edition (BSID-III). Adverse events were recorded over the duration of the treatment period. Cognitive decline was observed in most patients in both treatment groups; however, improvements in BSID-III development quotient score were observed for two patients, in receptive and expressive communication scores for three patients each, in fine motor skills for one patient, and in gross motor skills for six patients. Treatment-emergent adverse events that occurred with rhHNS IT were mostly mild, none led to study discontinuation, and there were no deaths. The extension study was terminated early as the primary endpoints of the phase 2b study were not met, and no statistical analyses were carried out. Although cognitive decline was apparent in most patients, improvements were observed in a small group of patients. Greater declines were observed in patients at the higher end of the age range, suggesting earlier intervention may increase the possibility of a response to treatment. rhHNS IT treatment remained generally well tolerated up to 96 weeks. CI - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Wijburg, Frits A AU - Wijburg FA AD - Academic Medical Center, Amsterdam, the Netherlands. Electronic address: f.a.wijburg@amc.uva.nl. FAU - Whitley, Chester B AU - Whitley CB AD - University of Minnesota, Minneapolis, MN, USA. Electronic address: whitley@umn.edu. FAU - Muenzer, Joseph AU - Muenzer J AD - University of North Carolina, Chapel Hill, NC, USA. Electronic address: muenzer@med.unc.edu. FAU - Gasperini, Serena AU - Gasperini S AD - Fondazione MBBM, San Gerardo Hospital, Monza, Italy. Electronic address: s.gasperini@hsgerardo.org. FAU - Del Toro, Mireia AU - Del Toro M AD - Hospital Vall D'Hebron, Barcelona, Spain. Electronic address: mdeltoro@vhebron.net. FAU - Muschol, Nicole AU - Muschol N AD - University Medical Center Hamburg-Eppendorf, Department of Pediatrics, Hamburg, Germany. Electronic address: muschol@uke.de. FAU - Cleary, Maureen AU - Cleary M AD - Great Ormond Street Hospital, London, UK. Electronic address: Maureen.Cleary@gosh.nhs.uk. FAU - Sevin, Caroline AU - Sevin C AD - Unit, GHU Paris-Sud - Hopital de Bicetre, Le Kremlin Bicetre, Paris, France. Electronic address: caroline.sevin@inserm.fr. FAU - Shapiro, Elsa AU - Shapiro E AD - University of Minnesota, Minneapolis, MN, USA. Electronic address: shapi004@umn.edu. FAU - Alexanderian, David AU - Alexanderian D AD - Takeda Pharmaceutical Company Limited, Lexington, MA, USA. Electronic address: david.alexanderian@takeda.com. LA - eng PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20210707 PL - United States TA - Mol Genet Metab JT - Molecular genetics and metabolism JID - 9805456 RN - EC 3.1.6.- (Sulfatases) RN - EC 3.1.6.- (heparan sulfate sulfatase) SB - IM MH - Central Nervous System/*drug effects MH - Child, Preschool MH - Cognitive Dysfunction/drug therapy MH - Female MH - Humans MH - Infant MH - Injections, Spinal MH - Male MH - Mucopolysaccharidosis III/*drug therapy MH - Research Design MH - Sulfatases/*therapeutic use MH - Treatment Outcome OTO - NOTNLM OT - Enzyme replacement therapy OT - Lysosomal storage disease OT - Mucopolysaccharidosis type IIIA OT - Recombinant human heparan-N-sulfatase OT - Sanfilippo syndrome type A COIS- Declaration of Competing Interest FAW reports speaker fees, travel support, and consultation honoraria from Actelion, BioMarin, Lysogene, Sanofi-Genzyme, and Shire, and research grants from Actelion, BioMarin, and Sanofi-Genzyme. CBW has no conflicts of interests related to this study outside of institutional support for the conduct of this clinical trial. JM reports consultancy fees and/or advisory board membership for BioMarin, Takeda (Shire), PTC Therapeutics, Green Cross, Sanofi Genzyme, Eloxx, Regenxbio, Denali Therapeutics, Sangamo, JCR Pharmaceuticals and Bluebird Bio. SG reports honoraria and travel grants from Biomarin, Takeda, Sanofi Genzyme, and Ultragenyx. MdT reports consultancy fees from BioMarin, Sanofi-Genzyme, Shire/Takeda, and Ultragenyx, and honoraria and travel grants from Actelion, BioMarin, Sanofi-Genzyme, Shire/Takeda, and Ultragenyx. NM reports consultancy fees from BioMarin, Sanofi-Genzyme, Lysogene, Shire/Takeda, and Sobi; grant/research support from BioMarin, Sanofi-Genzyme, and Shire/Takeda; and honoraria and travel grants from Actelion, Amicus, BioMarin, Sanofi-Genzyme, and Shire/Takeda. MC reports grants, fees for consultations and speaker fees from Shire, a Takeda company, during the conduct of the study; grants, fees for consultations and speaker fees from BioMarin outside the submitted work; fees for consultations and speaker fees from Sanofi-Genzyme outside the submitted work. CS reports speaker fees, travel support, and consultation honoraria from Shire/Takeda, Bluebird Bio and Orchard Therapeutics. ES reports grants, personal fees, and other from Shire, a Takeda company, during the conduct of this study, and other from Shapiro Neuropsychology Consulting, LLC, outside of this submitted work. DA is an employee of Takeda Pharmaceutical Company Limited. EDAT- 2021/07/13 06:00 MHDA- 2022/02/25 06:00 CRDT- 2021/07/12 05:34 PHST- 2021/04/09 00:00 [received] PHST- 2021/06/30 00:00 [revised] PHST- 2021/07/01 00:00 [accepted] PHST- 2021/07/13 06:00 [pubmed] PHST- 2022/02/25 06:00 [medline] PHST- 2021/07/12 05:34 [entrez] AID - S1096-7192(21)00743-5 [pii] AID - 10.1016/j.ymgme.2021.07.001 [doi] PST - ppublish SO - Mol Genet Metab. 2021 Sep-Oct;134(1-2):175-181. doi: 10.1016/j.ymgme.2021.07.001. Epub 2021 Jul 7.