Intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A: A phase IIb randomized trial
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Intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A: A phase IIb randomized trial. / Wijburg, Frits A; Whitley, Chester B; Muenzer, Joseph; Gasperini, Serena; Del Toro, Mireia; Muschol, Nicole; Cleary, Maureen; Sevin, Caroline; Shapiro, Elsa; Bhargava, Parul; Kerr, Douglas; Alexanderian, David.
in: MOL GENET METAB, Jahrgang 126, Nr. 2, 02.2019, S. 121-130.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A: A phase IIb randomized trial
AU - Wijburg, Frits A
AU - Whitley, Chester B
AU - Muenzer, Joseph
AU - Gasperini, Serena
AU - Del Toro, Mireia
AU - Muschol, Nicole
AU - Cleary, Maureen
AU - Sevin, Caroline
AU - Shapiro, Elsa
AU - Bhargava, Parul
AU - Kerr, Douglas
AU - Alexanderian, David
N1 - Copyright © 2018 Shire Development LLC and the Authors. Published by Elsevier Inc. All rights reserved.
PY - 2019/2
Y1 - 2019/2
N2 - 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.
AB - 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.
KW - Central Nervous System
KW - Child, Preschool
KW - Drug-Related Side Effects and Adverse Reactions
KW - Female
KW - Glycosaminoglycans/urine
KW - Humans
KW - Infant
KW - Injections, Spinal
KW - Male
KW - Mucopolysaccharidosis III/cerebrospinal fluid
KW - Recombinant Proteins/adverse effects
KW - Sulfatases/adverse effects
U2 - 10.1016/j.ymgme.2018.10.006
DO - 10.1016/j.ymgme.2018.10.006
M3 - SCORING: Journal article
C2 - 30528227
VL - 126
SP - 121
EP - 130
JO - MOL GENET METAB
JF - MOL GENET METAB
SN - 1096-7192
IS - 2
ER -
