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Prospective exploratory muscle biopsy, imaging, and functional assessment in patients with late-onset Pompe disease treated with alglucosidase alfa: The EMBASSY Study.
Mol Genet Metab 2016; 119(1-2):115-23MG

Abstract

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

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    • Authors+Show Affiliations

    van der Ploeg A
    Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands.
    Carlier PG
    Institut de Myologie, AIM and CEA NMR Laboratory - Spectroscopy Laboratory, Université Pierre et Marie Curie, Paris, France.
    Carlier RY
    Medical Imaging Department, Raymond Poincare University Hospital, Garches, France.
    Kissel JT
    Department of Neurology, Division of Neuromuscular Medicine, Ohio State University Wexner Medical Center, Columbus, OH, USA.
    Schoser B
    Friedrich-Baur-Institut, Neurologische Klinik, Klinikum der Universität München, München, Germany.
    Wenninger S
    Friedrich-Baur-Institut, Neurologische Klinik, Klinikum der Universität München, München, Germany.
    Pestronk A
    Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA.
    Barohn RJ
    Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA.
    Dimachkie MM
    Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA.
    Goker-Alpan O
    Lysosomal Disorders Unit and Center for Clinical Trials, O&O Alpan LLC, Fairfax, VA, USA.
    Mozaffar T
    Department of Neurology, University of California, Irvine, Irvine, CA, USA.
    Pena LD
    Division of Pediatric Medical Genetics, Duke University Medical Center, Durham, NC, USA.
    Simmons Z
    Penn State Hershey Neurology, Hershey, PA, USA.
    Straub V
    Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom.
    Guglieri M
    Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom.
    Young P
    Department of Sleep Medicine and Neuromuscular Disorders, University Hospital of Münster, Münster, Germany.
    Boentert M
    Department of Sleep Medicine and Neuromuscular Disorders, University Hospital of Münster, Münster, Germany.
    Baudin PY
    C.R.I.S., Tournai, France.
    Wens S
    Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands.
    Shafi R
    Sanofi Genzyme, Cambridge, MA, USA.
    Bjartmar C
    Sanofi Genzyme, Cambridge, MA, USA.
    Thurberg BL
    Sanofi Genzyme, Cambridge, MA, USA. Electronic address: Beth.Thurberg@genzyme.com.

    MeSH

    AdultAge of OnsetAgedBiopsyEnzyme Replacement TherapyFemaleGlycogenGlycogen Storage Disease Type IIHumansMagnetic Resonance ImagingMaleMiddle AgedMuscle, SkeletalPhysical Therapy ModalitiesTreatment Outcomealpha-Glucosidases

    Pub Type(s)

    Clinical Trial, Phase IV
    Journal Article
    Multicenter Study
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    27473031

    Citation

    van der Ploeg, Ans, et al. "Prospective Exploratory Muscle Biopsy, Imaging, and Functional Assessment in Patients With Late-onset Pompe Disease Treated With Alglucosidase Alfa: the EMBASSY Study." Molecular Genetics and Metabolism, vol. 119, no. 1-2, 2016, pp. 115-23.
    van der Ploeg A, Carlier PG, Carlier RY, et al. Prospective exploratory muscle biopsy, imaging, and functional assessment in patients with late-onset Pompe disease treated with alglucosidase alfa: The EMBASSY Study. Mol Genet Metab. 2016;119(1-2):115-23.
    van der Ploeg, A., Carlier, P. G., Carlier, R. Y., Kissel, J. T., Schoser, B., Wenninger, S., ... Thurberg, B. L. (2016). Prospective exploratory muscle biopsy, imaging, and functional assessment in patients with late-onset Pompe disease treated with alglucosidase alfa: The EMBASSY Study. Molecular Genetics and Metabolism, 119(1-2), pp. 115-23. doi:10.1016/j.ymgme.2016.05.013.
    van der Ploeg A, et al. Prospective Exploratory Muscle Biopsy, Imaging, and Functional Assessment in Patients With Late-onset Pompe Disease Treated With Alglucosidase Alfa: the EMBASSY Study. Mol Genet Metab. 2016;119(1-2):115-23. PubMed PMID: 27473031.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Prospective exploratory muscle biopsy, imaging, and functional assessment in patients with late-onset Pompe disease treated with alglucosidase alfa: The EMBASSY Study. AU - van der Ploeg,Ans, AU - Carlier,Pierre G, AU - Carlier,Robert-Yves, AU - Kissel,John T, AU - Schoser,Benedikt, AU - Wenninger,Stephan, AU - Pestronk,Alan, AU - Barohn,Richard J, AU - Dimachkie,Mazen M, AU - Goker-Alpan,Ozlem, AU - Mozaffar,Tahseen, AU - Pena,Loren D M, AU - Simmons,Zachary, AU - Straub,Volker, AU - Guglieri,Michela, AU - Young,Peter, AU - Boentert,Matthias, AU - Baudin,Pierre-Yves, AU - Wens,Stephan, AU - Shafi,Raheel, AU - Bjartmar,Carl, AU - Thurberg,Beth L, Y1 - 2016/05/19/ PY - 2016/03/01/received PY - 2016/05/16/revised PY - 2016/05/17/accepted PY - 2016/7/31/entrez PY - 2016/7/31/pubmed PY - 2017/12/8/medline KW - Alglucosidase alfa KW - Enzyme replacement therapy KW - Functional effects KW - Glycogen KW - Histopathology KW - Late-onset Pompe disease KW - Muscle pathology KW - Pompe disease SP - 115 EP - 23 JF - Molecular genetics and metabolism JO - Mol. Genet. Metab. VL - 119 IS - 1-2 N2 - BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. SN - 1096-7206 UR - https://www.unboundmedicine.com/medline/citation/27473031/Prospective_exploratory_muscle_biopsy_imaging_and_functional_assessment_in_patients_with_late_onset_Pompe_disease_treated_with_alglucosidase_alfa:_The_EMBASSY_Study_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1096-7192(16)30088-9 DB - PRIME DP - Unbound Medicine ER -