Reduction in kidney function decline and risk of severe clinical events in agalsidase beta-treated Fabry disease patients: A matched analysis from the Fabry Registry

Abstract

Background Patients with Fabry disease (FD, α-galactosidase A deficiency or absence) accumulate glycosphingolipids, leading to progressive dysfunction of kidneys, heart and nervous system. Generalisable real-world outcomes following agalsidase beta treatment initiation outside trials are limited. We investigated the associations of long-term agalsidase beta treatment with estimated glomerular filtration rate (eGFR) changes over time and the risk of developing a composite clinical event in a matched analysis of treated and untreated patients with FD. Methods Agalsidase beta-treated adult patients (aged ≥16 years) from the Fabry Registry and adult untreated patients from a natural history cohort were matched 1:1 and X:X (with one occurrence and multiple occurrences of each untreated patient, respectively) by sex, phenotype, age and (for eGFR slope analysis) baseline eGFR. Outcomes included eGFR slope over 5 years and composite clinical event risk (cardiovascular, cerebrovascular or renal event, or death) over 10+ years. As a surrogate indicator of therapeutic response in paediatric patients, the percentage experiencing normalisation in plasma globotriaosylceramide (GL-3) from treatment initiation was assessed in patients aged 2 to <16 years. Results Overall, eGFR slopes for 1:1-matched untreated and treated adult patients (122 pairs [72.1% male]) were −3.19 and −1.47 mL/min/1.73 m2/y, respectively (reduction in rate of decline=53.9%, P=0.007); for X:X-matched (122 untreated/950 treated [59.4% male]) were −3.29 and −1.56 mL/min/1.73 m2/y, respectively (reduction in rate of decline=52.6%, P<0.001). Agalsidase beta treatment was associated with lower risk of clinical events, with hazard ratios of 0.41 (P=0.003) and 0.67 (P=0.008) for 1:1-matched and X:X-matched analyses, respectively. Plasma GL-3 declined markedly in paediatric patients and normalised in most within 6 months of treatment initiation. Conclusion Agalsidase beta treatment preserves kidney function and delays progression to severe clinical events among adult patients with FD. Plasma GL-3 levels analysed in paediatric patients showed normalisation of elevated pre-treatment levels in most patients.