Treatment of Fabry disease with different dosing regimens of agalsidase: Effects on antibody formation and GL-3

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Abstract

Two different enzyme preparations are used for the treatment of Fabry disease patients, agalsidase alfa (Replagal, Shire) and agalsidase beta (Fabrazyme, Genzyme). Therapeutic efficacy of both products has been variable probably due to differences in gender, severity, age and other patient characteristics. We studied the occurrence of α-Gal A antibodies and their effect on urinary and plasma globotriaosylceramide (GL-3), plasma chitotriosidase and clinical outcome in 52 patients after 12 months of treatment with either 0.2 mg/kg agalsidase alfa (10 males, 8 females) or beta (8 males, 5 females) or 1.0 mg/kg agalsidase beta (10 males, 11 females). Antibodies were detected in 18/28 male patients after 6 months. None of the females developed antibodies. Following 12 months of 0.2 mg/kg treatment, urinary GL-3 decreased in antibody negative (AB−) but increased in antibody positive (AB+) patients.

Treatment with 1.0 mg/kg gave a reduction in urinary GL-3 in both AB− and AB+ patients. Levels of plasma GL-3 and chitotriosidase decreased in all patient groups. Twelve months of 0.2 mg/kg treatment did not change renal function or left ventricular mass. Further, no change in renal function was seen following 1.0 mg/kg treatment and left ventricular mass decreased in both AB− and AB+ patients. In summary, α-Gal A antibodies frequently develop in male Fabry disease patients and interfere with urinary GL-3 excretion. Infusion of a dose of 1.0 mg/kg results in a more robust decline in GL-3, less impact, if any of antibodies, stable renal function and reduction of LVMass.

Section snippets

Comparative study

Thirty Fabry patients from the Academic Medical Center (AMC) and 1 patient from the Universitatsklinikum Wurzburg (UKW) who were treated with agalsidase alfa (n = 18) or beta (n = 13) at 0.2 mg/kg for a minimum of 12 months were included in the study. Twenty nine of the AMC patients had been part of the head-to-head study [11]. In addition 5 patients from the AMC and 16 patients from the UKW who had been receiving agalsidase beta at 1.0 mg/kg for at least 12 months were included.

Switch study

Biochemical

Baseline characteristics

The baseline characteristics of the 52 patients included in the study are shown in Table 1. There were no significant differences between the 3 treatment groups with respect to age, sex and levels of biochemical parameters at baseline. Patients in the switch study were 7 males (3, agalsidase alfa 0.2 mg/kg and 4, agalsidase beta 0.2 mg/kg) who switched to agalsidase beta 1.0 mg/kg because of progression of disease (i.e. treatment failure [11]). All patients had significant symptomatology before

Discussion

This study shows that neutralizing antibodies are produced in the majority of male Fabry disease patients undergoing ERT and that they interfere with the excretion of GL-3. Persistent high titers of antibodies occurred in males who had switched from 0.2 mg/kg to 1.0 mg/kg treatment In line with Linthorst et al [14] we found 64% (18/28) of male patients developing IgG antibodies with neutralizing capacities within the first 6 months of treatment. The occurrence of antibodies was not associated

Disclosure

Anouk C. Vedder, Johannes M.F.G. Aerts and Carla E.M. Hollak receive reimbursement of expenses and small honoraria for lectures on the management of lysosomal storage diseases, including Fabry disease, from Genzyme Corporation and Shire. All honoraria are donated to the Gaucher Stichting, a national foundation that supports research in the field of lysosomal storage disorders. Frank Breunig received lecture fees from Genzyme Corporation and Shire. Christoph Wanner received grant support for

Acknowledgments

The authors gratefully thank Sijmen Kuiper Aldi Poppema, Karen Ghauharali and Els Ormel for handling of blood and urine samples.

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