Weekly enzyme replacement therapy may slow decline of renal function in patients with Fabry disease who are on long-term biweekly dosing.

Fabry disease is an X-linked glycosphingolipid disorder that is caused by an insufficient activity of the lysosomal enzyme α-galactosidase A (GALA) (1). This deficiency results in a systemic accumulation of α-D-galactosyl conjugates, particularly globotriaosylceramide (Gb3), in vascular endothelial cells, pericytes, and smooth muscle cells of the vascular system; renal epithelial cells; myocardial cells; and dorsal root ganglion neuronal cells (2). The incidence of Fabry disease in male individuals has been estimated to be 1:117,000 births (3). Hemizygous male patients with Fabry disease have a subtle but characteristic facial appearance (4). Clinical onset of the disease in both male hemizygotes and female heterozygotes typically occurs during childhood or adolescence with recurrent episodes of severe, often debilitating neuropathic pain in the extremities (5). However, the age of symptom onset and the age of diagnosis tend to be approximately 10 yr later in female compared with male individuals (6). Hypohidrosis and neuropathic pain contribute to poor tolerance to exercise and to heat (7,8). Proteinuria and progressive renal deterioration develop in nearly all male patients with Fabry disease (9,10) and are the result of intraglomerular deposition of Gb3, which is associated with histopathologic findings of mesangial widening and ultimately segmental and global glomerulosclerosis (10–12). Hypertrophic cardiomyopathy and coronary and cerebrovascular disease also contribute to early death in men at a median age of death of 50 to 55 yr (9). In recent years, enzyme replacement therapy (ERT) has become part of the standard medical care for Fabry disease (13,14). Although ERT reduces neuropathic pain and improves thermal sensing threshold (15) and gastrointestinal symptoms (16), its long-term effects on the progressive kidney dysfunction, the incidence of stroke, and progressive cardiac disease have not been established (13,15,17,18). Patients in controlled clinical trials showed significant reductions in certain biomarkers: Approximately 50% lowering of Gb3 levels in plasma as well as of Gb3 in urinary sediment and in renal interstitial capillary endothelium (13,19). Reduction of Gb3 storage in renal vascular endothelial cells was associated with an overall improvement in glomerular morphology, as assessed by a significant decrease in the percentage of glomeruli with mesangial widening and a significant increase in the percentage of normal glomeruli (13). Despite this histologic evidence of a renal benefit during ERT, conclusive evidence that ERT slows the progressive decline in renal function in Fabry disease has not been reported. In the long-term, open-label extensions of pivotal clinical trials, renal function remained stable in the majority of patients with Fabry disease who were treated with agalsidase alfa or agalsidase beta for up to 4 yr (20,21). Most of the patients in these studies had relatively normal kidney function at baseline and might not be expected to experience a decline in kidney function during the studies. However, there are patients who demonstrated a continued progressive decline in renal function despite administration of either form of ERT (agalsidase alfa or beta) administered every other week (EOW) (20,21). Nevertheless, the rate of decline in the subgroup of patients with more severe renal dysfunction at pretreatment baseline did seem to be slower with agalsidase alfa treatment compared with the rate of decline in a comparable cohort of patients with untreated Fabry disease (10,20). In this study, we report the results of a clinical trial that was designed to test the hypothesis that increasing the frequency of ERT with 0.2 mg/kg agalsidase alfa from EOW to weekly could improve the slope of decline of estimated GFR (eGFR) in patients who have Fabry disease and whose eGFR had continued to decline at a relatively high rate despite treatment with agalsidase alfa 0.2 mg/kg EOW for 2 to 4 yr.