Sustained, Long-Term Renal Stabilization After 54 Months of Agalsidase β Therapy in Patients with Fabry Disease

Abstract

Fabry disease, an inherited deficiency of the lysosomal enzyme ␣-galactosidase A, causes progressive intralysosomal accumulation of globotriaosylceramide (GL-3) and premature death from renal, cardiac, and cerebrovascular manifestations. To determine the long-term safety and efficacy of recombinant human ␣-galactosidase A, an open-label, phase III extension study was conducted, involving 58 patients who had classic Fabry disease and completed a 20-wk, double-blind, randomized, placebo-controlled, phase III study of agalsidase ␤ and were transitioned to an extension trial to receive biweekly 1 mg/kg agalsidase ␤ for up to an additional 54 mo. GL-3 accumulation was evaluated in the capillary endothelia of the skin, kidney, and heart. Renal function was assessed. By month 54, all patients with optional kidney biopsies (n ‫؍‬ 8) maintained complete GL-3 clearance in renal capillary endothelial cells and multiple cell types. Continued, complete clearance of skin (31 of 36) and heart (six of eight) capillary endothelium was demonstrated. Mean plasma GL-3 levels remained decreased in the normal range. Median serum creatinine and estimated GFR remained stable (normal) in patients with renal data at month 54 (n ‫؍‬ 41). Six patients had renal disease progression; most (four of six) were older than 40 yr and had significant proteinuria at baseline and evidence of sclerotic glomeruli pretreatment. Adverse events were generally mild and unrelated to treatment. The most common treatment-related adverse events were infusion-associated reactions, which decreased over time. Long-term agalsidase ␤ therapy stabilizes renal function in patients without renal involvement at baseline, maintains reduction of plasma GL-3, and sustains GL-3 clearance in capillary endothelial cells and multiple renal cell types.

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).…”

Analysis of left ventricular mass in untreated men and in men treated with agalsidase-β: data from the Fabry Registry

“…Of note, agalsidase-β has been similarly shown to be most beneficial, in terms of renal function, when initiated before the onset of advanced renal disease. 15,16,30 It is important to note that agalsidase-β was not an approved therapy at the time that most of these patients began experiencing disease symptoms. Therefore, most men in this cohort did not begin receiving agalsidase-β until many years after the onset of their Fabry symptoms (median: 19 years in Q1 and 31 years in Q4).…”

Effects of Switching from Agalsidase Beta to Agalsidase Alfa in 10 Patients with Anderson-Fabry Disease

“…Results of the current study were in agreement with the majority of these studies, i.e., LV mass and wall thickness decreased significantly from pre-ERT values after initiation of ERT, which in this case was with agalsidase beta (retrospective data; see Table 1). In particular, Eng et al (2001) demonstrated in a placebo-controlled, double-blind study that agalsidase beta (1 mg/kg) resulted in a histological clearance of Gb3 deposits in myocardial endothelial cells; this effect was sustained over 54 months of therapy (Germain et al 2007). Furthermore, Weidemann et al suggested that clearance of Gb3 by agalsidase beta leads to a regression of LV hypertrophy, which was documented by echocardiography and confirmed by MRI (Weidemann et al 2003).…”