Long-term safety and efficacy of enzyme replacement therapy for Fabry disease

Abstract

Elsewhere, we reported the safety and efficacy results of a multicenter phase 3 trial of recombinant human alpha -galactosidase A (rh-alpha GalA) replacement in patients with Fabry disease. All 58 patients who were enrolled in the 20-wk phase 3 double-blind, randomized, and placebo-controlled study received subsequently 1 mg/kg of rh-alpha GalA (agalsidase beta, Fabrazyme, Genzyme Corporation) biweekly in an ongoing open-label extension study. Evidence of long-term efficacy, even in patients who developed IgG antibodies against rh- alpha GalA, included the continuously normal mean plasma globotriaosylceramide (GL-3) levels during 30 mo of the extension study and the sustained capillary endothelial GL-3 clearance in 98% (39/40) of patients who had a skin biopsy taken after treatment for 30 mo (original placebo group) or 36 mo (original enzyme-treated group). The mean serum creatinine level and estimated glomerular filtration rate also remained stable after 30-36 mo of treatment. Infusion-associated reactions decreased over time, as did anti-rh- alpha GalA IgG antibody titers. Among seroconverted patients, after 30-36 mo of treatment, seven patients tolerized (no detectable IgG antibody), and 59% had > or =4-fold reductions in antibody titers. As of 30 mo into the extension trial, three patients were withdrawn from the study because of positive serum IgE or skin tests; however, all have been rechallenged successfully at the time of this report. Thus, enzyme replacement therapy for 30-36 mo with agalsidase beta resulted in continuously decreased plasma GL-3 levels, sustained endothelial GL-3 clearance, stable kidney function, and a favorable safety profile.

Figure 1

Mean (±SD) plasma GL-3 concentration (μg/ml), measured by mass spectrometry at baseline and at 18 mo, 24 mo, and 30 mo into the phase 3 extension study, showing normalization of mean plasma GL-3 levels after agalsidase beta therapy. At 30 mo into the extension study, 94% of patients had normal plasma GL-3 values. The mean (±SD) values of the control group were 3.5 (±1.3) μg/ml. The number of patients is indicated in parentheses below the graphed points.

Figure 2

GL-3 clearance in dermal superficial endothelial cells in phase 3 double-blind trial and extension study (% zero scores). Clearance of GL-3 from the dermal capillaries was sustained after prolonged agalsidase beta therapy. PL = placebo; AB = agalsidase beta.

Figure 3

Mean (±SD) serum creatinine concentrations (mg/dl) at baseline during the phase 3 extension. A, Mean serum creatinine concentration, normal at baseline and during the phase 3 double-blind trial and phase 3 extension study. The increase in SD over time reflects the three patients who had >50% increase in serum creatinine from the start of treatment with agalsidase beta. B, Mean (±SD) serum creatinine concentration after the three patients with advance disease were removed from the analysis. The number of patients is indicated in parentheses below the graphed points.

Figure 4

Urinary protein excretion. Urine protein:urine creatinine, the ratio representing the approximate urine protein excretion ing/d, remained stable from the baseline of the double-blind study to 30 mo into the extension study. Change in urine protein excretion is associated with baseline proteinuria. This figure presents data on all 27 patients for whom data were available at both times.

Figure 5

Percentage of patients experiencing IARs during the phase 3 double-blind and phase 3 extension studies, decreasing over time. The number of patients is indicated in parentheses below the graphed points.