Consequences of a global enzyme shortage of agalsidase beta in adult Dutch Fabry patients

Abstract

Background: Enzyme replacement therapy is currently the only approved therapy for Fabry disease. From June 2009 on, viral contamination of Genzyme's production facility resulted in a worldwide shortage of agalsidase beta leading to involuntary dose reductions (approved dose 1 mg/kg/eow, reduced dose 0.5 mg/kg/m), or switch to agalsidase alpha (administered dose 0.2 mg/kg/eow). An assessment report from the European Medicines Agency (EMA) raised serious concerns about an increase in adverse events at lower dosages of agalsidase beta. We determined the influence of the shortage on clinical event incidence and the most sensitive biochemical marker (lysoGb3) in Dutch Fabry patients.

Methods: The incidence of clinical events per person per year was calculated from start of agalsidase beta treatment until the shortage, and was compared to the incidence of clinical events during the shortage period. In addition, plasma lysoGb3, eGFR, quality of life (SF-36) and brief pain inventory (BPI) questionnaires were analysed.

Results: All thirty-five Dutch Fabry patients using agalsidase beta (17 males) were included. Mean clinical event incidence was unchanged: 0.15 events per person per year before versus 0.15 during the shortage (p = 0.68). In total 28 clinical events occurred in 14 patients during 4.6 treatment years, compared to 7 events in 6 patients during the 1.3 year shortage period. eGFR and BPI scores were not significantly altered. Two SF-36 subscales were significantly but minimally reduced in females. In males, lysoGb3 increased with a median of 8.1 nM (range 2.5-29.2) after 1 year of shortage (p = 0.001). Increases in lysoGb3 were found in both patients switching to agalsidase alpha and on a reduced agalsidase beta dose. Antibody status, treatment duration or clinical event incidence showed no clear correlation to lysoGb3 increases.

Conclusions: No increase in clinical event incidence was found in the adult Dutch Fabry cohort during the agalsidase beta shortage. Increases in lysoGb3, however, suggest recurrence of disease activity.

Figure 1

Course of preparations and dosages during agalsidase beta shortage. The numbers in the bars represent the number of patients in different dosage and preparation groups being the continued agalsidase beta group, the direct and later switch to agalsidase alpha group. The occurrence of clinical events during agalsidase dose reduction or during switch to agalsidase alpha is outlined on a schematic timeline below the figure. Abbreviations: CE: clinical events.'

Figure 2

Mean difference SF-36-scores in females. Error bars represent 95% confidence intervals. An asterisk represents statistical significance of p < 0.05.

Figure 3

Individual plasma lysoGb3 levels before and after approximately 1 year of shortage for 3a. males and 3b. females. In males a significant increase of lysoGb3 is seen after 1 year of shortage. 3c. Males with (AB+, solid line) and without antibodies (AB-, dashed line) do not show a significant difference in lysoGb3 increase. 3d. Percentage increase of lysoGb3 after 1 year of shortage in the continued agalsidase group vs. later switch group (males only). The continued agalsidase group was dose reduced from 0.5 mg to 0.25 mg/kg/eow. The later switch group was first dose reduced to 0.5 mg/kg/eow agalsidase beta and subsequently switched tot agalsidase alpha 0.2 mg/kg/eow. In the continued agalsidase beta group median lysoGb3 value at start of shortage (= 100%) was 31.5 nM and 16.4 nM in the switch group. Abbreviations: Fz: continued agalsidase beta group (blue line), switch: later switch group (red line).