**4. Efficacy of ERT**

In a 20-week multicenter, randomized, placebo-controlled, double-blind phase 3 clinical trial of 58 patients who were at least 16 years old and had enzymatically

#### *Enzyme-Replacement Therapy in Fabry Disease DOI: http://dx.doi.org/10.5772/intechopen.103799*

confirmed classic Fabry disease, agalsidase beta at 1 mg/kg/2 weeks cleared microvascular endothelial deposits of Gb3 from the kidneys, heart, and skin, reversing the chief clinical manifestation of this disease [39].

Further investigation was performed to analyze the pre- and post-treatment renal biopsies from these Fabry disease patients and the authors found that after 11 months of ERT, complete clearance of glycolipid storage was noted from the endothelium of all vasculature, the mesangial cells of the glomerulus, and interstitial cells of the cortex, while moderate clearance was noted from the smooth muscle cells of arterioles and small arteries [40]. Limited clearance of glycolipid storage was also observed from podocytes and distal tubular epithelium [40].

An open-label, phase 3 extension study was conducted involving these 58 patients who completed the 20-week study and were transitioned to an extension trial to receive agalsidase beta biweekly at 1 mg/kg for up to an additional 54 months [41]. Authors reported by month 54 all assessable patients maintained clearance of glycolipid storage clearance from multiple renal cell types, including renal capillary endothelial cells, mesangial cells, and noncapillary endothelial cells. Sustained clearance of skin and heart capillary endothelium was also demonstrated by month 54. Mean plasma Gb3 levels remained controlled in the normal range and kidney function remained stable in patients with data available. This study suggested baseline proteinuria (>1 g/24 h), >50% glomerulosclerosis, and age > 40 years at treatment baseline as important factors that limited renal response to therapy [41].

Furthermore, a study was conducted to investigate the long-term outcomes in 52 of these 58 patients including severe clinical events, renal function, and cardiac structure following treatment with agalsidase beta (1 mg/kg/2 weeks) over a 10-year median follow-up period. Authors reported that 81% of patients (42/52) did not experience any severe clinical event during the treatment interval and 94% (49/52) were alive at the end of the study period [17]. Mean slopes for eGFR for low renal involvement and high renal involvement were −1.89 mL/min/1.73 m2 / year and −6.82 mL/min/1.73 m<sup>2</sup> /year, respectively [17]. Patients with low renal involvement started therapy 13 years younger than those with high renal involvement. This 10-year study documented the effectiveness of agalsidase beta (1 mg/ kg/2 weeks) in patients with Fabry disease and suggested patients who initiated treatment at a younger age and with less kidney involvement benefited the most from therapy [17].

In addition, a recent meta-analysis with the evidence base including four Sanofi Genzyme studies and six studies from a systematic literature review suggested that treated (agalsidase beta) patients experienced a slower median eGFR decrease [2.46 mL/min/1.73 m<sup>2</sup> /year slower; 95% confidence interval (CI) 0.63–4.29; P ¼ 0.0087] than comparable untreated patients [22].
