Agalsidase Alfa and Kidney Dysfunction in Fabry Disease

Abstract

In male patients with Fabry disease, an X-linked disorder of glycosphingolipid metabolism caused by deficient activity of the lysosomal enzyme ␣-galactosidase A, kidney dysfunction becomes apparent by the third decade of life and invariably progresses to ESRD without treatment. Here, we summarize the effects of agalsidase alfa on kidney function from three prospective, randomized, placebo-controlled trials and their open-label extension studies involving 108 adult male patients. The mean baseline GFR among 54 nonhyperfiltrating patients (measured GFR Ͻ135 ml/min per 1.73 m 2 ) treated with placebo was 85.4 Ϯ 29.6 ml/min per 1.73 m 2 ; during 6 mo of placebo, the mean annualized rate of change in GFR was Ϫ7.0 Ϯ 32.9 ml/min per 1.73 m 2 . Among 85 nonhyperfiltrating patients treated with agalsidase alfa, the annualized rate of change was Ϫ2.9 Ϯ 8.7 ml/min per 1.73 m 2 . Treatment with agalsidase alfa did not affect proteinuria. Multivariate analysis revealed that GFR and proteinuria category (Ͻ1 or Ն1 g/d) at baseline significantly predicted the rate of decline of GFR during treatment. This summary represents the largest group of male patients who had Fabry disease and for whom the effects of enzyme replacement therapy on kidney function have been studied. These data suggest that agalsidase alfa may stabilize kidney function in these patients.

Effect and Tolerability of Agalsidase Alfa in Patients with Fabry Disease Who Were Treatment Naïve or Formerly Treated with Agalsidase Beta or Agalsidase Alfa

“…Given the substantial heterogeneity in our patient population and lack of pre-enrollment renal history, it is difficult to compare these outcomes with those reported in previous clinical trials and observational studies of either agala or agalb. However, our results are generally similar to those from previous studies with agala or agalb, which have shown positive effects of ERT to slow down the decline of eGFR Germain et al 2007;Mehta et al 2009;West et al 2009;Rombach et al 2013;Weidemann et al 2013;Anderson et al 2014).…”

Changes in plasma and urine globotriaosylceramide levels do not predict Fabry disease progression over 1 year of agalsidase alfa

“…A previous analysis of pooled data from three randomized, placebo-controlled clinical trials and their open-label extensions (sponsored by Shire Human Genetic Therapies) of male patients with Fabry disease suggested a stabilizing effect of agalsidase alfa (agalα) on renal function assessed by measured glomerular filtration rate (GFR). 11 In that analysis, baseline GFR or elevated proteinuria category (≥1 g/24 h) significantly predicted GFR decline during treatment. Using a suitable selection approach of pooled data Purpose: Globotriaosylceramide concentrations were assessed as potential predictors of change from baseline after 12 months by estimated glomerular filtration rate and left-ventricular mass index using pooled data from three randomized, placebo-controlled agalsidase alfa trials and open-label extensions of patients with Fabry disease.…”

Long-term effectiveness of agalsidase alfa enzyme replacement in Fabry disease: A Fabry Outcome Survey analysis

“…This leads to progressive accumulation of glycosphingolipids, particularly globotriaosylceramide, in almost all tissues and organs. The most serious complications in adult patients are progressive renal impairment, cardiomyopathy, and cerebrovascular events, all of which lead to significant morbidity and mortality and reduced life expectancy [2][3][4][5][6][7][8].…”