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

  • Ozlem Goker-AlpanEmail author
  • Michael J. Gambello
  • Gustavo H. B. Maegawa
  • Khan J. Nedd
  • Daniel J. Gruskin
  • Larry Blankstein
  • Neal J. Weinreb
Research Report
Part of the JIMD Reports book series (JIMD, volume 25)


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.


Enzyme Replacement Therapy Fabry Disease Agalsidase Beta Fabry Disease Patient Agalsidase Alfa 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



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.


  1. Aerts JM, Groener JE, Kuiper S et al (2008) Elevated globotriaosylsphingosine is a hallmark of Fabry disease. Proc Natl Acad Sci U S A 105:2812–2817CrossRefPubMedPubMedCentralGoogle Scholar
  2. Barbey F, Brakch N, Linhart A et al (2006) Cardiac and vascular hypertrophy in Fabry disease: evidence for a new mechanism independent of blood pressure and glycosphingolipid deposition. Arterioscler Thromb Vasc Biol 26:839–844CrossRefPubMedGoogle Scholar
  3. Barbey F, Lidove O, Schwarting A (2008) Fabry nephropathy: 5 years of enzyme replacement therapy – a short review. NDT Plus 1:11–19Google Scholar
  4. Biegstraaten M, Hollak CE, Bakkers M, Faber CG, Aerts JM, van Schaik IN (2012) Small fiber neuropathy in Fabry disease. Mol Genet Metab 106:135–141CrossRefPubMedGoogle Scholar
  5. Blanch LC, Meaney C, Morris CP (1996) A sensitive mutation screening strategy for Fabry disease: detection of nine mutations in the alpha-galactosidase A gene. Hum Mutat 8:38–43CrossRefPubMedGoogle Scholar
  6. Blom D, Speijer D, Linthorst GE, Donker-Koopman WG, Strijland A, Aerts JM (2003) Recombinant enzyme therapy for Fabry disease: absence of editing of human alpha-galactosidase A mRNA. Am J Hum Genet 72:23–31CrossRefPubMedGoogle Scholar
  7. Chambless LE, Folsom AR, Clegg LX et al (2000) Carotid wall thickness is predictive of incident clinical stroke: the Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol 151:478–487CrossRefPubMedGoogle Scholar
  8. Chien YH, Bodamer OA, Chiang SC, Mascher H, Hung C, Hwu WL (2013) Lyso-globotriaosylsphingosine (lyso-Gb3) levels in neonates and adults with the Fabry disease later-onset GLA IVS4+919G>A mutation. J Inherit Metab Dis 36:881–885CrossRefPubMedGoogle Scholar
  9. Clarke JT, West ML, Bultas J, Schiffmann R (2007) The pharmacology of multiple regimens of agalsidase alfa enzyme replacement therapy for Fabry disease. Genet Med 9:504–509CrossRefPubMedGoogle Scholar
  10. DeGraba T, Azhar S, Dignat-George F et al (2000) Profile of endothelial and leukocyte activation in Fabry patients. Ann Neurol 47:229–233CrossRefPubMedGoogle Scholar
  11. Desnick RJ (2004) Enzyme replacement therapy for Fabry disease: lessons from two alpha-galactosidase A orphan products and one FDA approval. Expert Opin Biol Ther 4:1167–1176CrossRefPubMedGoogle Scholar
  12. Desnick RJ, Schuchman EH (2012) Enzyme replacement therapy for lysosomal diseases: lessons from 20 years of experience and remaining challenges. Annu Rev Genomics Hum Genet 13:307–335CrossRefPubMedGoogle Scholar
  13. Eng CM, Resnick-Silverman LA, Niehaus DJ, Astrin KH, Desnick RJ (1993) Nature and frequency of mutations in the alpha-galactosidase A gene that cause Fabry disease. Am J Hum Genet 53:1186–1197PubMedPubMedCentralGoogle Scholar
  14. Eng CM, Niehaus DJ, Enriquez AL, Burgert TS, Ludman MD, Desnick RJ (1994) Fabry disease: twenty-three mutations including sense and antisense CpG alterations and identification of a deletional hot-spot in the alpha-galactosidase A gene. Hum Mol Genet 3:1795–1799CrossRefPubMedGoogle Scholar
  15. Eng CM, Ashley GA, Burgert TS, Enriquez AL, D’Souza M, Desnick RJ (1997) Fabry disease: thirty-five mutations in the alpha-galactosidase A gene in patients with classic and variant phenotypes. Mol Med 3:174–182PubMedPubMedCentralGoogle Scholar
  16. Eng CM, Guffon N, Wilcox WR et al (2001) Safety and efficacy of recombinant human alpha-galactosidase A – replacement therapy in Fabry’s disease. N Engl J Med 345:9–16CrossRefPubMedGoogle Scholar
  17. Eng CM, Fletcher J, Wilcox WR et al (2007) Fabry disease: baseline characteristics of a cohort of 1765 males and females in the Fabry Registry. J Inherit Metab Dis 30:184–192CrossRefPubMedGoogle Scholar
  18. Fabrazyme® Summary of product characteristics, last updated October 2014. Accessed 23 Jul 2015
  19. Fabrazyme® Prescribing information, last updated May 2010. Accessed 23 Jul 2015
  20. Ferraz MJ, Kallemeijn WW, Mirzaian M et al (2014) Gaucher disease and Fabry disease: new markers and insights in pathophysiology for two distinct glycosphingolipidoses. Biochim Biophys Acta 1841:811–825CrossRefPubMedGoogle Scholar
  21. Germain DP (2010) Fabry disease. Orphanet J Rare Dis 5:30CrossRefPubMedPubMedCentralGoogle Scholar
  22. Hopkin RJ, Bissler J, Banikazemi M et al (2008) Characterization of Fabry disease in 352 pediatric patients in the Fabry Registry. Pediatr Res 64:550–555CrossRefPubMedGoogle Scholar
  23. Keslová-Veselíková J, Hůlková H, Dobrovolný R et al (2008) Replacement of alpha-galactosidase A in Fabry disease: effect on fibroblast cultures compared with biopsied tissues of treated patients. Virchows Arch 452:651–665CrossRefPubMedPubMedCentralGoogle Scholar
  24. Lee K, Jin X, Zhang K et al (2003) A biochemical and pharmacological comparison of enzyme replacement therapies for the glycolipid storage disorder Fabry disease. Glycobiology 13:305–313CrossRefPubMedGoogle Scholar
  25. Lee BH, Heo SH, Kim GH et al (2010) Mutations of the GLA gene in Korean patients with Fabry disease and frequency of the E66Q allele as a functional variant in Korean newborns. J Hum Genet 55:512–517CrossRefPubMedGoogle Scholar
  26. Lenders M, Stypmann J, Duning T, Schmitz B, Brand SM, Brand E (2015) Serum-mediated inhibition of enzyme replacement therapy in Fabry disease. J Am Soc Nephrol. pii: ASN.2014121226 (Epub ahead of print)Google Scholar
  27. Lin HY, Huang YH, Liao HC et al (2014) Clinical observations on enzyme replacement therapy in patients with Fabry disease and the switch from agalsidase beta to agalsidase alfa. J Chin Med Assoc 77:190–197CrossRefPubMedGoogle Scholar
  28. Linthorst GE, Hollak CE, Donker-Koopman WE, Strijland A, Aerts JM (2004) Enzyme therapy for Fabry disease: neutralizing antibodies toward agalsidase alpha and beta. Kidney Int 66:1589–1595CrossRefPubMedGoogle Scholar
  29. Meaney C, Blanch LC, Morris CP (1994) A nonsense mutation (R220X) in the alpha-galactosidase A gene detected in a female carrier of Fabry disease. Hum Mol Genet 3:1019–1020CrossRefPubMedGoogle Scholar
  30. Nelson BC, Roddy T, Araghi S et al (2004) Globotriaosylceramide isoform profiles in human plasma by liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 805:127–134CrossRefPubMedGoogle Scholar
  31. Niemann M, Rolfs A, Störk S et al (2014) Gene mutations versus clinically relevant phenotypes: lyso-Gb3 defines Fabry disease. Circ Cardiovasc Genet 7:8–16CrossRefPubMedGoogle Scholar
  32. Park S, Kim JA, Joo KY et al (2011) Globotriaosylceramide leads to K(Ca)3.1 channel dysfunction: a new insight into endothelial dysfunction in Fabry disease. Cardiovasc Res 89:290–299CrossRefPubMedGoogle Scholar
  33. Pisani A, Spinelli L, Visciano B et al (2013) Effects of switching from agalsidase beta to agalsidase alfa in 10 patients with Anderson-Fabry disease. JIMD Rep 9:41–48CrossRefPubMedGoogle Scholar
  34. Replagal® Summary of product characteristics, last updated September 2014. Accessed 23 Jul 2015
  35. Roddy TP, Nelson BC, Sung CC et al (2005) Liquid chromatography-tandem mass spectrometry quantification of globotriaosylceramide in plasma for long-term monitoring of Fabry patients treated with enzyme replacement therapy. Clin Chem 51:237–240CrossRefPubMedGoogle Scholar
  36. Rombach SM, Dekker N, Bouwman MG et al (2010) Plasma globotriaosylsphingosine: diagnostic value and relation to clinical manifestations of Fabry disease. Biochim Biophys Acta 1802:741–748CrossRefPubMedGoogle Scholar
  37. Rombach SM, van den Bogaard B, de Groot E et al (2012) Vascular aspects of Fabry disease in relation to clinical manifestations and elevations in plasma globotriaosylsphingosine. Hypertension 60:998–1005CrossRefPubMedGoogle Scholar
  38. Sakuraba H, Murata-Ohsawa M, Kawashima I et al (2006) Comparison of the effects of agalsidase alfa and agalsidase beta on cultured human Fabry fibroblasts and Fabry mice. J Hum Genet 51:180–188CrossRefPubMedGoogle Scholar
  39. Sanchez-Niño MD, Sanz AB, Carrasco S et al (2011) Globotriaosylsphingosine actions on human glomerular podocytes: implications for Fabry nephropathy. Nephrol Dial Transplant 26:1797–1802CrossRefPubMedGoogle Scholar
  40. Schaefer RM, Tylki-Szymańska A, Hilz MJ (2009) Enzyme replacement therapy for Fabry disease: a systematic review of available evidence. Drugs 69:2179–2205CrossRefPubMedGoogle Scholar
  41. Schellekens H (2008) The immunogenicity of therapeutic proteins and the Fabry antibody standardization initiative. Clin Ther 30(Suppl B):S50–S51CrossRefPubMedGoogle Scholar
  42. Schiffmann R, Murray GJ, Treco D et al (2000) Infusion of alpha-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease. Proc Natl Acad Sci U S A 97:365–370CrossRefPubMedPubMedCentralGoogle Scholar
  43. Schiffmann R, Martin RA, Reimschisel T et al (2010) Four-year prospective clinical trial of agalsidase alfa in children with Fabry disease. J Pediatr 156:832–837CrossRefPubMedGoogle Scholar
  44. Shabbeer J, Yasuda M, Benson SD, Desnick RJ (2006) Fabry disease: identification of 50 novel alpha-galactosidase A mutations causing the classic phenotype and three-dimensional structural analysis of 29 missense mutations. Hum Genomics 2:297–309CrossRefPubMedPubMedCentralGoogle Scholar
  45. Shen JS, Meng XL, Moore DF et al (2008) Globotriaosylceramide induces oxidative stress and up-regulates cell adhesion molecule expression in Fabry disease endothelial cells. Mol Genet Metab 95:163–168CrossRefPubMedPubMedCentralGoogle Scholar
  46. Sirrs SM, Bichet DG, Casey R et al (2014) Outcomes of patients treated through the Canadian Fabry disease initiative. Mol Genet Metab 111:499–506CrossRefPubMedGoogle Scholar
  47. Smid BE, Rombach SM, Aerts JM et al (2011) Consequences of a global enzyme shortage of agalsidase beta in adult Dutch Fabry patients. Orphanet J Rare Dis 6:69CrossRefPubMedPubMedCentralGoogle Scholar
  48. Togawa T, Kodama T, Suzuki T et al (2010) Plasma globotriaosylsphingosine as a biomarker of Fabry disease. Mol Genet Metab 100:257–261CrossRefPubMedGoogle Scholar
  49. Togawa T, Takada M, Aizawa Y, Tsukimura T, Chiba Y, Sakuraba H (2014) Comparative study on mannose 6-phosphate residue contents of recombinant lysosomal enzymes. Mol Genet Metab 111:369–373CrossRefPubMedGoogle Scholar
  50. Tøndel C, Bostad L, Larsen KK et al (2013) Agalsidase benefits renal histology in young patients with Fabry disease. J Am Soc Nephrol 24:137–148CrossRefPubMedGoogle Scholar
  51. Topaloglu AK, Ashley GA, Tong B et al (1999) Twenty novel mutations in the alpha-galactosidase A gene causing Fabry disease. Mol Med 5:806–811PubMedPubMedCentralGoogle Scholar
  52. Tsuboi K, Yamamoto H (2014) Clinical course of patients with Fabry disease who were switched from agalsidase-β to agalsidase-α. Genet Med 16:766–772CrossRefPubMedPubMedCentralGoogle Scholar
  53. van Breemen MJ, Rombach SM, Dekker N et al (2011) Reduction of elevated plasma globotriaosylsphingosine in patients with classic Fabry disease following enzyme replacement therapy. Biochim Biophys Acta 1812:70–76CrossRefPubMedGoogle Scholar
  54. Vedder AC, Linthorst GE, Houge G et al (2007) Treatment of Fabry disease: outcome of a comparative trial with agalsidase alfa or beta at a dose of 0.2 mg/kg. PLoS One 2: e598CrossRefPubMedPubMedCentralGoogle Scholar
  55. Warnock DG, Mauer M (2014) Fabry disease: dose matters. J Am Soc Nephrol 25:653–655CrossRefPubMedPubMedCentralGoogle Scholar
  56. Weidemann F, Krämer J, Duning T et al (2014) Patients with Fabry disease after enzyme replacement therapy dose reduction versus treatment switch. J Am Soc Nephrol 25:837–849CrossRefPubMedPubMedCentralGoogle Scholar
  57. Wilcox WR, Banikazemi M, Guffon N et al (2004) Long-term safety and efficacy of enzyme replacement therapy for Fabry disease. Am J Hum Genet 75:65–74CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Ozlem Goker-Alpan
    • 1
    Email author
  • Michael J. Gambello
    • 2
  • Gustavo H. B. Maegawa
    • 3
  • Khan J. Nedd
    • 4
  • Daniel J. Gruskin
    • 5
  • Larry Blankstein
    • 5
  • Neal J. Weinreb
    • 6
  1. 1.Lysosomal Disorders Research and Treatment Unit, Center for Clinical TrialsFairfaxUSA
  2. 2.Emory University School of MedicineAtlantaUSA
  3. 3.The Johns Hopkins School of MedicineBaltimoreUSA
  4. 4.Infusion AssociatesGrand RapidsUSA
  5. 5.Genzyme, A Sanofi CompanyCambridgeUSA
  6. 6.University Research Foundation for Lysosomal Storage DiseasesCoral SpringsUSA

Personalised recommendations