title: Prospective exploratory muscle biopsy, imaging, and functional assessment in patients with late-onset Pompe disease treated with alglucosidase alfa: The EMBASSY Study.
abstract: Late-onset Pompe disease is characterized by progressive skeletal myopathy followed by respiratory muscle weakness, typically leading to loss of ambulation and respiratory failure. In this population, enzyme replacement therapy (ERT) with alglucosidase alfa has been shown to stabilize respiratory function and improve mobility and muscle strength. Muscle pathology and glycogen clearance from skeletal muscle in treatment-naïve adults after ERT have not been extensively examined.
  
  
  
  This exploratory, open-label, multicenter study evaluated glycogen clearance in muscle tissue samples collected pre- and post- alglucosidase alfa treatment in treatment-naïve adults with late-onset Pompe disease. The primary endpoint was the quantitative reduction in percent tissue area occupied by glycogen in muscle biopsies from baseline to 6months. Secondary endpoints included qualitative histologic assessment of tissue glycogen distribution, secondary pathology changes, assessment of magnetic resonance images (MRIs) for intact muscle and fatty replacement, and functional assessments.
  
  
  
  Sixteen patients completed the study. After 6months of ERT, the percent tissue area occupied by glycogen in quadriceps and deltoid muscles decreased in 10 and 8 patients, respectively. No changes were detected on MRI from baseline to 6months. A majority of patients showed improvements on functional assessments after 6months of treatment. All treatment-related adverse events were mild or moderate.
  
  
  
  This exploratory study provides novel insights into the histopathologic effects of ERT in late-onset Pompe disease patients. Ultrastructural examination of muscle biopsies demonstrated reduced lysosomal glycogen after ERT. Findings are consistent with stabilization of disease by ERT in treatment-naïve patients with late-onset Pompe disease.
authors.affiliation: Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands.
authors.forename: Ans
authors.initials: A
authors.lastname: van der Ploeg
authors.affiliation: Institut de Myologie, AIM and CEA NMR Laboratory - Spectroscopy Laboratory, Université Pierre et Marie Curie, Paris, France.
authors.forename: Pierre G
authors.initials: PG
authors.lastname: Carlier
authors.affiliation: Medical Imaging Department, Raymond Poincare University Hospital, Garches, France.
authors.forename: Robert-Yves
authors.initials: RY
authors.lastname: Carlier
authors.affiliation: Department of Neurology, Division of Neuromuscular Medicine, Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Kissel
authors.affiliation: Friedrich-Baur-Institut, Neurologische Klinik, Klinikum der Universität München, München, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Schoser
authors.affiliation: Friedrich-Baur-Institut, Neurologische Klinik, Klinikum der Universität München, München, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Wenninger
authors.affiliation: Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Pestronk
authors.affiliation: Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Barohn
authors.affiliation: Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Mazen M
authors.initials: MM
authors.lastname: Dimachkie
authors.affiliation: Lysosomal Disorders Unit and Center for Clinical Trials, O&O Alpan LLC, Fairfax, VA, USA.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Goker-Alpan
authors.affiliation: Department of Neurology, University of California, Irvine, Irvine, CA, USA.
authors.forename: Tahseen
authors.initials: T
authors.lastname: Mozaffar
authors.affiliation: Division of Pediatric Medical Genetics, Duke University Medical Center, Durham, NC, USA.
authors.forename: Loren D M
authors.initials: LD
authors.lastname: Pena
authors.affiliation: Penn State Hershey Neurology, Hershey, PA, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Simmons
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom.
authors.forename: Volker
authors.initials: V
authors.lastname: Straub
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom.
authors.forename: Michela
authors.initials: M
authors.lastname: Guglieri
authors.affiliation: Department of Sleep Medicine and Neuromuscular Disorders, University Hospital of Münster, Münster, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Young
authors.affiliation: Department of Sleep Medicine and Neuromuscular Disorders, University Hospital of Münster, Münster, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Boentert
authors.affiliation: C.R.I.S., Tournai, France.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Baudin
authors.affiliation: Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands.
authors.forename: Stephan
authors.initials: S
authors.lastname: Wens
authors.affiliation: Sanofi Genzyme, Cambridge, MA, USA.
authors.forename: Raheel
authors.initials: R
authors.lastname: Shafi
authors.affiliation: Sanofi Genzyme, Cambridge, MA, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Bjartmar
authors.affiliation: Sanofi Genzyme, Cambridge, MA, USA. Electronic address: Beth.Thurberg@genzyme.com.
authors.forename: Beth L
authors.initials: BL
authors.lastname: Thurberg
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D001706:Biopsy; D056947:Enzyme Replacement Therapy; D005260:Female; D006003:Glycogen / Q000302:isolation & purification / Q000378:metabolism; D006009:Glycogen Storage Disease Type II / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D026741:Physical Therapy Modalities; D016896:Treatment Outcome; D000520:alpha-Glucosidases / Q000008:administration & dosage* / Q000235:genetics
chemical_list: D006003:Glycogen; C509951:GAA protein, human; D000520:alpha-Glucosidases
keywords: Alglucosidase alfa; Enzyme replacement therapy; Functional effects; Glycogen; Histopathology; Late-onset Pompe disease; Muscle pathology; Pompe disease