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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.

Authors+Show Affiliations

Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands.Institut de Myologie, AIM and CEA NMR Laboratory - Spectroscopy Laboratory, Université Pierre et Marie Curie, Paris, France.Medical Imaging Department, Raymond Poincare University Hospital, Garches, France.Department of Neurology, Division of Neuromuscular Medicine, Ohio State University Wexner Medical Center, Columbus, OH, USA.Friedrich-Baur-Institut, Neurologische Klinik, Klinikum der Universität München, München, Germany.Friedrich-Baur-Institut, Neurologische Klinik, Klinikum der Universität München, München, Germany.Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA.Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA.Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA.Lysosomal Disorders Unit and Center for Clinical Trials, O&O Alpan LLC, Fairfax, VA, USA.Department of Neurology, University of California, Irvine, Irvine, CA, USA.Division of Pediatric Medical Genetics, Duke University Medical Center, Durham, NC, USA.Penn State Hershey Neurology, Hershey, PA, USA.Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom.Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom.Department of Sleep Medicine and Neuromuscular Disorders, University Hospital of Münster, Münster, Germany.Department of Sleep Medicine and Neuromuscular Disorders, University Hospital of Münster, Münster, Germany.C.R.I.S., Tournai, France.Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands.Sanofi Genzyme, Cambridge, MA, USA.Sanofi Genzyme, Cambridge, MA, USA.Sanofi Genzyme, Cambridge, MA, USA. Electronic address: Beth.Thurberg@genzyme.com.

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 -