Frits A Wijburg1, Chester B Whitley2, Joseph Muenzer3, Serena Gasperini4, Mireia Del Toro5, Nicole Muschol6, Maureen Cleary7, Caroline Sevin8, Elsa Shapiro9, Parul Bhargava10, Douglas Kerr10, David Alexanderian11. 1. Department of Pediatrics, Academic Medical Center, Meibergdreef 9, Amsterdam, the Netherlands. 2. Gene Therapy Center, University of Minnesota, 420 Delaware St SE, Minneapolis, MN 55455, USA. 3. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7487, USA. 4. Department of Pediatrics, Fondazione MBBM, University of Milano Bicocca, San Gerardo Hospital, Monza, Italy. 5. Pediatric Neurology Unit, Hospital Universitari Vall D'Hebron, Barcelona, Spain. 6. Department of Pediatrics, University Medical Center Hamburg Eppendorf, Hamburg, Germany. 7. Great Ormond Street Hospital, London WC1N 3JH, UK. 8. Neuropediatrics Unit, GHU Paris-Sud - Hôpital de Bicêtre, Le Kremlin Bicêtre, Paris 94275, France. 9. Gene Therapy Center, University of Minnesota, 420 Delaware St SE, Minneapolis, MN 55455, USA; Shapiro Neuropsychology Consulting LLC, Portland, OR, USA. 10. Shire, Lexington, MA, USA. 11. Shire, Lexington, MA, USA. Electronic address: dalexanderia@shire.com.
Abstract
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.
RCT Entities:
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.
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