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Reduction of Plasma Globotriaosylsphingosine Levels After Switching from Agalsidase Alfa to Agalsidase Beta as Enzyme Replacement Therapy for Fabry Disease

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JIMD Reports, Volume 25

Part of the book series: JIMD Reports ((JIMD,volume 25))

Abstract

Introduction: Agalsidase alfa and agalsidase beta, recombinant enzyme preparations for treatment of Fabry disease (FD), have different approved dosing schedules: 0.2 mg/kg and 1.0 mg/kg every other week (EOW), respectively.

Methods: This open-label, multicenter, exploratory phase 4 study evaluated plasma globotriaosylsphingosine (lyso-GL-3) and plasma and urine globotriaosylceramide (GL-3) levels at baseline and 2, 4, and 6 months after the switch from agalsidase alfa (0.2 mg/kg EOW for ≥12 months) to agalsidase beta (1.0 mg/kg EOW) in 15 male patients with FD. Immunoglobulin (Ig)G antidrug antibody titers were assessed, and safety was monitored throughout the study.

Results: Plasma lyso-GL-3 concentrations decreased significantly within 2 months after switch and reductions continued through month 6 (mean absolute changes, −12.8, −16.1, and −16.7 ng/mL at 2, 4, and 6 months, respectively; all P < 0.001). The mean percentage reduction from baseline was 39.5% (P < 0.001) at month 6. For plasma GL-3, the mean absolute change from baseline (−0.9 μg/mL) and percentage reduction (17.9%) at month 6 were both significant (P < 0.05). Urine GL-3 measurements showed intra-patient variability and changes from baseline were not significant. No clinical outcomes were assessed in this 6-month study, and, therefore, no conclusions can be drawn regarding the correlation of observed reductions in glycosphingolipid concentrations with clinically relevant outcomes. There were no differences in IgG antidrug antibody titers between the two enzymes. The switch from agalsidase alfa to agalsidase beta was well tolerated.

Conclusion: Plasma lyso-GL-3 and GL-3 levels reduced after switching from agalsidase alfa to agalsidase beta, indicating that agalsidase beta has a greater pharmacodynamic effect on these markers at the recommended dose. These data further support the use of agalsidase beta 1.0 mg/kg EOW as enzyme replacement therapy in FD.

Competing interests: None declared

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Acknowledgments

The authors received editorial/writing support in the preparation of this manuscript provided by Alessia Piazza, PhD, of Excerpta Medica, funded by Genzyme. The authors were responsible for all content and editorial decisions and have not received honoraria related to the development of this publication.

The authors would like to acknowledge the staff at the Genzyme Clinical Specialty Laboratory (Framingham, MA, USA) for performing all laboratory assays.

We dedicate this manuscript to the memory of John A. Barranger who acted as the principal study investigator but sadly passed away.

Author information

Authors and Affiliations

  1. Lysosomal Disorders Research and Treatment Unit, Center for Clinical Trials, 11212 Waples Mill Road, Fairfax, VA, 22030, USA

    Ozlem Goker-Alpan

  2. Emory University School of Medicine, Atlanta, GA, USA

    Michael J. Gambello

  3. The Johns Hopkins School of Medicine, Baltimore, MD, USA

    Gustavo H. B. Maegawa

  4. Infusion Associates, Grand Rapids, MI, USA

    Khan J. Nedd

  5. Genzyme, A Sanofi Company, Cambridge, MA, USA

    Daniel J. Gruskin & Larry Blankstein

  6. University Research Foundation for Lysosomal Storage Diseases, Coral Springs, FL, USA

    Neal J. Weinreb

Authors
  1. Ozlem Goker-Alpan
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  2. Michael J. Gambello
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  3. Gustavo H. B. Maegawa
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  4. Khan J. Nedd
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  5. Daniel J. Gruskin
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  7. Neal J. Weinreb
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Corresponding author

Correspondence to Ozlem Goker-Alpan .

Editor information

Editors and Affiliations

  1. Tulane University Medical School , New Orleans, Louisiana, USA

    Eva Morava

  2. Division of Metabolism and Children’s Re, University Children's Hospital Zurich, Zurich, Switzerland

    Matthias Baumgartner

  3. Division of Child and Adolescent Neurolo, Mayo Clinic, Rochester, Minnesota, USA

    Marc Patterson

  4. Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, UK

    Shamima Rahman

  5. Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

    Johannes Zschocke

  6. Center for Child and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Baden-Württemberg, Germany

    Verena Peters

Additional information

Communicated by: Markus Ries, MD, PhD, MHSc, FCP

Appendices

Synopsis

Agalsidase beta at a dose of 1.0 mg/kg administered EOW may further reduce plasma and urine glycosphingolipid concentrations beyond reductions previously achieved with agalsidase alfa in patients with Fabry disease.

Compliance with Ethics Guidelines

Conflict of Interest

Ozlem Goker-Alpan has received research support (Actelion, Shire HGT, Genzyme, Amicus, Pfizer-Protalix Biotherapeutics), payments for consultancy (Actelion, Shire HGT, Pfizer-Protalix Biotherapeutics), and speaker bureaus (Actelion, Shire HGT, Genzyme). Daniel J. Gruskin and Larry Blankstein are Genzyme employees. Neal J. Weinreb receives travel reimbursements and/or honoraria and/or research support from Shire HGT, Genzyme, Pfizer Corporation, and Actelion Corporation. Michael J. Gambello, Gustavo H.B. Maegawa, and Khan J. Nedd declare that they have no conflict of interest.

The study is registered at www.ClinicalTrials.gov under the identifier NCT01650779 and was sponsored by Genzyme, a Sanofi company.

Patient Consent Statement

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients, or their parents, or legal guardians, for being included in the study.

Details of the Contributions of Individual Authors

Daniel J. Gruskin and Larry Blankstein were involved in the study planning and coordination of statistical analyses. Ozlem Goker-Alpan, Michael J. Gambello, Gustavo H.B. Maegawa, Khan J. Nedd, and Neal J. Weinreb were involved in the study conduct. All authors contributed to the first draft of the manuscript, were involved in the critical review and revision of subsequent drafts, and approved the final draft for submission.

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Goker-Alpan, O. et al. (2015). Reduction of Plasma Globotriaosylsphingosine Levels After Switching from Agalsidase Alfa to Agalsidase Beta as Enzyme Replacement Therapy for Fabry Disease. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 25. JIMD Reports, vol 25. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_483

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