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Enzyme replacement therapy in Fabry disease: Comparison of agalsidase alfa and agalsidase beta
Molecular Genetics and Metabolism 95 (2008) 114–115
Contents lists available at ScienceDirect
Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme
Letter to the Editor Enzyme replacement therapy in Fabry disease: Comparison of agalsidase alfa and agalsidase beta Sir, The study described by Vedder and colleagues in their paper: ‘Treatment of Fabry disease with different dosing regimens of agalsidase: effects on antibody formation and GL-3’ [1], together with a previous study from this group [2] are the only published trials in which the two available enzyme replacement therapies for the treatment of Fabry disease—agalsidase alfa and agalsidase beta—have been tested in the same patient population. The authors conclude 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 dose of 0.2 mg/kg (the licensed dose for agalsidase alfa) and also produces a greater reduction in left ventricular mass (LVM). They infer that the higher dose of agalsidase beta overcomes the negative effects of antibody formation. We believe that the study design does not support the authors’ assertions. The small number of patients led the authors to pool the treatment results obtained in the two 0.2 mg/kg groups. This pooling is logical 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 group did not demonstrate a persistent decrease in urinary Gb3, suggesting that the antibodies impair substrate clearance. This is not a new observation [4] and, as repeatedly stated by the authors, is of unknown significance given that the level of plasma and urinary Gb3 does not correlate with the clinical manifestations of the disease. Furthermore, in the present study, kidney function remained stable 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., agalsidase beta) in reducing LVM in patients with baseline left ventricular hypertrophy (LVH). However, baseline LVM values are not reported for the patients with LVH, and the authors use an unconventional definition of LVH (i.e., one that is not indexed to height or body size). It is apparent that patients in the group given agalsidase beta at 1.0 mg/kg had a greater LVM than those in the pooled 0.2 mg/kg group, which might explain the different reported responses to therapy. Moreover, it is clear that follow-up and baseline examinations were inconsistently performed in the patients treated with 0.2 mg/kg, especially in men treated with agalsidase alfa. Furthermore, the authors present this observation without discussion of relevant studies. For example, in a double-blind placebo-controlled trial in 15 men with LVH, 6 months of treatment with agalsidase alfa (0.2 mg/kg every other week) significantly reduced LVM compared with placebo as determined by magnetic resonance imaging [5]. Similar results were reported in an openlabel study of women treated with agalsidase alfa [6]. These results have been confirmed in a larger number of patients for up to 3 years who have participated in the Fabry Outcome Survey [7,8]. It is inappropriate to consider LVM alone when examining the im1096-7192/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2008.07.002
pact of ERT on advanced Fabry cardiomyopathy; reduction in LVM could even be due to the onset of undesirable complications, such as cell death or fibrosis. Additional evidence of a beneficial effect of agalsidase alfa on cardiac function is the improvement in heart rate variability found in treated male children and adolescents [9]. Vedder and colleagues report differences in the incidence of antibodies observed in patients treated with agalsidase alfa or agalsidase beta. IgG antibodies were detected significantly more frequently in males treated with agalsidase beta (1 mg/kg; 80% of patients) than males treated with agalsidase alfa (0.2 mg/kg; 40% of patients). The incidence of antibodies was also high in patients treated with the lower (0.2 mg/kg) dose of agalsidase beta (75% of patients). These observations confirm the findings from separate studies of the two enzymes in adults [4,10,11] and children [9,12], in which antibodies were reported more frequently in patients treated with agalsidase beta than with agalsidase alfa. Those that occur in response to agalsidase alfa frequently have no impact on renal function and disappear due to tolerization [4]. IgE antibodies against agalsidase alfa have never been reported but have been reported 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 approved dose 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 study was flawed, particularly in respect to pooling of the groups of patients treated with agalsidase alfa or agalsidase beta at 0.2 mg/kg every other week. Furthermore, the authors have failed to discuss important relevant published studies; for example, that of Clarke et al. [14], who recently showed that the standard dose of agalsidase alfa is sufficient to maximally reduce levels of plasma Gb3. Only when viewed within the context of published experience with these two distinct enzymes can the results of this study be properly 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 a comparative trial with agalsidase alfa or beta at a dose of 0.2 mg/kg, PLoS ONE 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 and pharmacological comparison of enzyme replacement therapies for the glycolipid storage disorder Fabry disease, Glycobiology 13 (2003) 305–313. [4] R. Schiffmann, M. Ries, M. Timmons, J.T. Flaherty, R.O. Brady, Long-term therapy with agalsidase alfa for Fabry disease: safety and effects on renal function 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 of Anderson–Fabry disease: a randomized double-blind placebo-controlled clinical trial of agalsidase-alfa, Heart 94 (2008) 153–158.
Letter to the Editor / Molecular Genetics and Metabolism 95 (2008) 114–115 [6] F. Baehner, C. Kampmann, C. Whybra, E. Miebach, C.M. Wiethoff, M. Beck, Enzyme replacement therapy in heterozygous females with Fabry disease: 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 Years of 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, Enzyme replacement 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 Fabry Disease Study Group, Safety and efficacy of recombinant human alphagalactosidase 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 Disease Clinical Trial Study Group, Agalsidase-beta therapy for advanced Fabry disease: 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 with agalsidase beta: an international, open-label study in pediatric patients with Fabry 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 patients with 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 multiple regimens of agalsidase alfa enzyme replacement therapy for Fabry disease, Genet. Med. 9 (2007) 504–509.
115
Atul Mehta Department of Academic Haematology, Royal Free and University College Medical School, Pond Street, Hampstead, London NW3 2QG, UK E-mail address: [email protected] Michael Beck Christoph Kampmann University Children’s Hospital, Mainz, Germany Andrea Frustaci Heart and Great Vessels Attilio Reale Department, La Sapienza University, Rome, Italy Dominique P. Germain University of Versailles St Quentin en Yvelines, UF de Génétique Médicale, Hôpital Raymond Poincaré (AP-HP), Garches, France Gregory M. Pastores Department of Neurology and Pediatrics, New York University School of Medicine, New York, NY, USA Gere Sunder-Plassmann Division of Nephrology and Dialysis, Department of Internal Medicine III, Vienna, Austria
Contents lists available at ScienceDirect
Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme
Letter to the Editor Enzyme replacement therapy in Fabry disease: Comparison of agalsidase alfa and agalsidase beta Sir, The study described by Vedder and colleagues in their paper: ‘Treatment of Fabry disease with different dosing regimens of agalsidase: effects on antibody formation and GL-3’ [1], together with a previous study from this group [2] are the only published trials in which the two available enzyme replacement therapies for the treatment of Fabry disease—agalsidase alfa and agalsidase beta—have been tested in the same patient population. The authors conclude 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 dose of 0.2 mg/kg (the licensed dose for agalsidase alfa) and also produces a greater reduction in left ventricular mass (LVM). They infer that the higher dose of agalsidase beta overcomes the negative effects of antibody formation. We believe that the study design does not support the authors’ assertions. The small number of patients led the authors to pool the treatment results obtained in the two 0.2 mg/kg groups. This pooling is logical 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 group did not demonstrate a persistent decrease in urinary Gb3, suggesting that the antibodies impair substrate clearance. This is not a new observation [4] and, as repeatedly stated by the authors, is of unknown significance given that the level of plasma and urinary Gb3 does not correlate with the clinical manifestations of the disease. Furthermore, in the present study, kidney function remained stable 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., agalsidase beta) in reducing LVM in patients with baseline left ventricular hypertrophy (LVH). However, baseline LVM values are not reported for the patients with LVH, and the authors use an unconventional definition of LVH (i.e., one that is not indexed to height or body size). It is apparent that patients in the group given agalsidase beta at 1.0 mg/kg had a greater LVM than those in the pooled 0.2 mg/kg group, which might explain the different reported responses to therapy. Moreover, it is clear that follow-up and baseline examinations were inconsistently performed in the patients treated with 0.2 mg/kg, especially in men treated with agalsidase alfa. Furthermore, the authors present this observation without discussion of relevant studies. For example, in a double-blind placebo-controlled trial in 15 men with LVH, 6 months of treatment with agalsidase alfa (0.2 mg/kg every other week) significantly reduced LVM compared with placebo as determined by magnetic resonance imaging [5]. Similar results were reported in an openlabel study of women treated with agalsidase alfa [6]. These results have been confirmed in a larger number of patients for up to 3 years who have participated in the Fabry Outcome Survey [7,8]. It is inappropriate to consider LVM alone when examining the im1096-7192/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2008.07.002
pact of ERT on advanced Fabry cardiomyopathy; reduction in LVM could even be due to the onset of undesirable complications, such as cell death or fibrosis. Additional evidence of a beneficial effect of agalsidase alfa on cardiac function is the improvement in heart rate variability found in treated male children and adolescents [9]. Vedder and colleagues report differences in the incidence of antibodies observed in patients treated with agalsidase alfa or agalsidase beta. IgG antibodies were detected significantly more frequently in males treated with agalsidase beta (1 mg/kg; 80% of patients) than males treated with agalsidase alfa (0.2 mg/kg; 40% of patients). The incidence of antibodies was also high in patients treated with the lower (0.2 mg/kg) dose of agalsidase beta (75% of patients). These observations confirm the findings from separate studies of the two enzymes in adults [4,10,11] and children [9,12], in which antibodies were reported more frequently in patients treated with agalsidase beta than with agalsidase alfa. Those that occur in response to agalsidase alfa frequently have no impact on renal function and disappear due to tolerization [4]. IgE antibodies against agalsidase alfa have never been reported but have been reported 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 approved dose 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 study was flawed, particularly in respect to pooling of the groups of patients treated with agalsidase alfa or agalsidase beta at 0.2 mg/kg every other week. Furthermore, the authors have failed to discuss important relevant published studies; for example, that of Clarke et al. [14], who recently showed that the standard dose of agalsidase alfa is sufficient to maximally reduce levels of plasma Gb3. Only when viewed within the context of published experience with these two distinct enzymes can the results of this study be properly 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 a comparative trial with agalsidase alfa or beta at a dose of 0.2 mg/kg, PLoS ONE 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 and pharmacological comparison of enzyme replacement therapies for the glycolipid storage disorder Fabry disease, Glycobiology 13 (2003) 305–313. [4] R. Schiffmann, M. Ries, M. Timmons, J.T. Flaherty, R.O. Brady, Long-term therapy with agalsidase alfa for Fabry disease: safety and effects on renal function 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 of Anderson–Fabry disease: a randomized double-blind placebo-controlled clinical trial of agalsidase-alfa, Heart 94 (2008) 153–158.
Letter to the Editor / Molecular Genetics and Metabolism 95 (2008) 114–115 [6] F. Baehner, C. Kampmann, C. Whybra, E. Miebach, C.M. Wiethoff, M. Beck, Enzyme replacement therapy in heterozygous females with Fabry disease: 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 Years of 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, Enzyme replacement 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 Fabry Disease Study Group, Safety and efficacy of recombinant human alphagalactosidase 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 Disease Clinical Trial Study Group, Agalsidase-beta therapy for advanced Fabry disease: 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 with agalsidase beta: an international, open-label study in pediatric patients with Fabry 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 patients with 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 multiple regimens of agalsidase alfa enzyme replacement therapy for Fabry disease, Genet. Med. 9 (2007) 504–509.
115
Atul Mehta Department of Academic Haematology, Royal Free and University College Medical School, Pond Street, Hampstead, London NW3 2QG, UK E-mail address: [email protected] Michael Beck Christoph Kampmann University Children’s Hospital, Mainz, Germany Andrea Frustaci Heart and Great Vessels Attilio Reale Department, La Sapienza University, Rome, Italy Dominique P. Germain University of Versailles St Quentin en Yvelines, UF de Génétique Médicale, Hôpital Raymond Poincaré (AP-HP), Garches, France Gregory M. Pastores Department of Neurology and Pediatrics, New York University School of Medicine, New York, NY, USA Gere Sunder-Plassmann Division of Nephrology and Dialysis, Department of Internal Medicine III, Vienna, Austria