Molecular Genetics and Metabolism 95 (2008) 114–115

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Molecular Genetics and Metabolism

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Letter to the Editor

Enzyme replacement therapy in Fabry disease: Comparison ofagalsidase alfa and agalsidase beta

Sir,The study described by Vedder and colleagues in their paper:

‘Treatment of Fabry disease with different dosing regimens ofagalsidase: effects on antibody formation and GL-3’ [1], togetherwith a previous study from this group [2] are the only publishedtrials in which the two available enzyme replacement therapiesfor the treatment of Fabry disease—agalsidase alfa and agalsidasebeta—have been tested in the same patient population. The authorsconclude that infusion of 1.0 mg agalsidase beta/kg (licensed dose)results in a more robust decline in globotriaosylceramide (Gb3)than does infusion of agalsidase alfa or agalsidase beta at a doseof 0.2 mg/kg (the licensed dose for agalsidase alfa) and alsoproduces a greater reduction in left ventricular mass (LVM). Theyinfer that the higher dose of agalsidase beta overcomes thenegative effects of antibody formation. We believe that the studydesign does not support the authors’ assertions.

The small number of patients led the authors to pool the treat-ment results obtained in the two 0.2 mg/kg groups. This pooling islogical only if one assumes that these two enzymes are identical,which—as stated in the paper and elsewhere [3]—they are not.

IgG antibody-positive patients in the pooled 0.2 mg/kg groupdid not demonstrate a persistent decrease in urinary Gb3, suggest-ing that the antibodies impair substrate clearance. This is not anew observation [4] and, as repeatedly stated by the authors, isof unknown significance given that the level of plasma and urinaryGb3 does not correlate with the clinical manifestations of the dis-ease. Furthermore, in the present study, kidney function remainedstable in both the pooled 0.2 mg/kg group and the agalsidase beta(1.0 mg/kg) group and was not influenced by antibody status.

The authors claim superiority for the 1.0 mg/kg dose (i.e., agalsi-dase beta) in reducing LVM in patients with baseline left ventricu-lar hypertrophy (LVH). However, baseline LVM values are notreported for the patients with LVH, and the authors use an uncon-ventional definition of LVH (i.e., one that is not indexed to height orbody size). It is apparent that patients in the group given agalsidasebeta at 1.0 mg/kg had a greater LVM than those in the pooled0.2 mg/kg group, which might explain the different reportedresponses to therapy. Moreover, it is clear that follow-up and base-line examinations were inconsistently performed in the patientstreated with 0.2 mg/kg, especially in men treated with agalsidasealfa. Furthermore, the authors present this observation withoutdiscussion of relevant studies. For example, in a double-blind pla-cebo-controlled trial in 15 men with LVH, 6 months of treatmentwith agalsidase alfa (0.2 mg/kg every other week) significantlyreduced LVM compared with placebo as determined by magneticresonance imaging [5]. Similar results were reported in an open-label study of women treated with agalsidase alfa [6]. These resultshave been confirmed in a larger number of patients for up to 3years who have participated in the Fabry Outcome Survey [7,8].It is inappropriate to consider LVM alone when examining the im-

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pact of ERT on advanced Fabry cardiomyopathy; reduction in LVMcould even be due to the onset of undesirable complications, suchas cell death or fibrosis. Additional evidence of a beneficial effect ofagalsidase alfa on cardiac function is the improvement in heart ratevariability found in treated male children and adolescents [9].

Vedder and colleagues report differences in the incidence ofantibodies observed in patients treated with agalsidase alfa oragalsidase beta. IgG antibodies were detected significantly morefrequently in males treated with agalsidase beta (1 mg/kg; 80% ofpatients) than males treated with agalsidase alfa (0.2 mg/kg; 40%of patients). The incidence of antibodies was also high in patientstreated with the lower (0.2 mg/kg) dose of agalsidase beta (75%of patients). These observations confirm the findings from separatestudies of the two enzymes in adults [4,10,11] and children [9,12],in which antibodies were reported more frequently in patientstreated with agalsidase beta than with agalsidase alfa. Those thatoccur in response to agalsidase alfa frequently have no impact onrenal function and disappear due to tolerization [4]. IgE antibodiesagainst agalsidase alfa have never been reported but have beenreported in all four of the major clinical trials of agalsidase beta[10–13].

We conclude that the results of the paper by Vedder et al. [1]cannot be used in isolation to claim superiority of the approveddose of agalsidase beta (1.0 mg/kg) over that of agalsidase alfa(0.2 mg/kg), both infused every 2 weeks. The design of the studywas flawed, particularly in respect to pooling of the groups ofpatients treated with agalsidase alfa or agalsidase beta at 0.2 mg/kgevery other week. Furthermore, the authors have failed to discussimportant relevant published studies; for example, that of Clarkeet al. [14], who recently showed that the standard dose of agalsi-dase alfa is sufficient to maximally reduce levels of plasma Gb3.Only when viewed within the context of published experiencewith these two distinct enzymes can the results of this study beproperly interpreted.

References

[1] A.C. Vedder, F. Breunig, W.E. Donker-Koopman, K. Mills, E. Young, B.Winchester, I.J. Ten Berge, J.E. Groener, J.M. Aerts, C. Wanner, C.E. Hollak,Treatment of Fabry disease with different dosing regimens of agalsidase:effects on antibody formation and GL-3, Mol. Genet. Metab. 94 (2008) 319–325.

[2] A.C. Vedder, G.E. Linthorst, G. Houge, J.E. Groener, E.E. Ormel, B.J. Bouma, J.M.Aerts, A. Hirth, C.E. Hollak, Treatment of Fabry disease: outcome of acomparative trial with agalsidase alfa or beta at a dose of 0.2 mg/kg, PLoSONE 2 (2007) e598.

[3] K. Lee, X. Jin, K. Zhang, L. Copertino, L. Andrews, J. Baker-Malcolm, L. Geagan, H.Qiu, K. Seiger, D. Barngrover, J.M. McPherson, T. Edmunds, A biochemical andpharmacological comparison of enzyme replacement therapies for theglycolipid storage disorder Fabry disease, Glycobiology 13 (2003) 305–313.

[4] R. Schiffmann, M. Ries, M. Timmons, J.T. Flaherty, R.O. Brady, Long-termtherapy with agalsidase alfa for Fabry disease: safety and effects on renalfunction in a home infusion setting, Nephrol. Dial. Transplant. 21 (2006) 345–354.

[5] D.A. Hughes, P.M. Elliott, J. Shah, J. Zuckerman, G. Coghlan, J. Brookes, A.B.Mehta, Effects of enzyme replacement therapy on the cardiomyopathy ofAnderson–Fabry disease: a randomized double-blind placebo-controlledclinical trial of agalsidase-alfa, Heart 94 (2008) 153–158.

Letter to the Editor / Molecular Genetics and Metabolism 95 (2008) 114–115 115

[6] F. Baehner, C. Kampmann, C. Whybra, E. Miebach, C.M. Wiethoff, M.Beck, Enzyme replacement therapy in heterozygous females with Fabrydisease: results of a phase IIIB study, J. Inherit. Metab. Dis. 26 (2003)617–627.

[7] M. Beck, R. Ricci, U. Widmer, F. Dehout, A.G. de Lorenzo, C. Kampmann, A.Linhart, G. Sunder-Plassmann, G. Houge, U. Ramaswami, A. Gal, A. Mehta,Fabry disease: overall effects of agalsidase alfa treatment, Eur. J. Clin. Invest. 34(2004) 838–844.

[8] C. Kampmann, Enzyme replacement therapy and the heart, in: A. Mehta, M.Beck, G. Sunder-Plassmann (Eds.), Fabry Disease: Perspectives From Five Yearsof FOS, Oxford PharmaGenesis, Oxford, 2006.

[9] M. Ries, J.T.R. Clarke, C. Whybra, M. Timmons, C. Robinson, B.L. Schlaggar, G.Pastores, Y.H. Lien, C. Kampmann, R.O. Brady, M. Beck, R. Schiffmann, Enzymereplacement therapy with agalsidase alfa in children with Fabry disease,Pediatrics 118 (2006) 924–932.

[10] C.M. Eng, N. Guffon, W.R. Wilcox, D.P. Germain, P. Lee, S. Waldek, L.Caplan, G.E. Linthorst, R.J. Desnick, International Collaborative FabryDisease Study Group, Safety and efficacy of recombinant human alpha-galactosidase A–replacement therapy in Fabry’s disease, N. Engl. J. Med.345 (2001) 9–16.

[11] M. Banikazemi, J. Bultas, S. Waldek, W.R. Wilcox, C.B. Whitley, M. McDonald, R.Finkel, S. Packman, D.G. Bichet, D.G. Warnock, R.J. Desnick, Fabry DiseaseClinical Trial Study Group, Agalsidase-beta therapy for advanced Fabrydisease: a randomized trial, Ann. Intern. Med. 146 (2007) 77–86.

[12] J.E. Wraith, A. Tylki-Szymanska, N. Guffon, Y.H. Lien, M. Tsimaratos, A. Vellodi,D.P. Germain, Safety and efficacy of enzyme replacement therapy withagalsidase beta: an international, open-label study in pediatric patients withFabry disease, J. Pediatr. 152 (2008) 563–570, e561.

[13] D. Bodensteiner, C.R. Scott, K.B. Sims, G.M. Sheperd, R.D. Cintron, D.P. Germain,Successful reinstitution of agalsidase beta therapy in Fabry disease patientswith previous IgE-antibody or skin-test reactivity to the recombinant enzyme,Genet. Med. 10 (2008) 353–358.

[14] J.T. Clarke, M.L. West, J. Bultas, R. Schiffmann, The pharmacology of multipleregimens of agalsidase alfa enzyme replacement therapy for Fabry disease,Genet. Med. 9 (2007) 504–509.

Atul MehtaDepartment of Academic Haematology,

Royal Free and University College Medical School,Pond Street, Hampstead, London NW3 2QG, UK

E-mail address: atul.mehta@royalfree.nhs.uk

Michael BeckChristoph Kampmann

University Children’s Hospital,Mainz, Germany

Andrea FrustaciHeart and Great Vessels Attilio Reale Department,

La Sapienza University, Rome, Italy

Dominique P. GermainUniversity of Versailles St Quentin en Yvelines,

UF de Génétique Médicale,Hôpital Raymond Poincaré (AP-HP),

Garches, France

Gregory M. PastoresDepartment of Neurology and Pediatrics,New York University School of Medicine,

New York, NY, USA

Gere Sunder-PlassmannDivision of Nephrology and Dialysis,Department of Internal Medicine III,

Vienna, Austria