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. Generalizable 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 normalization 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/year, respectively (reduction in rate of decline = 53.9%, P = .007), and for X:X-matched [122 untreated/950 treated (59.4% male)] were -3.29 and -1.56 mL/min/1.73 m²/year, respectively (reduction in rate of decline = 52.6%, P < .001). Agalsidase beta treatment was associated with lower risk of clinical events, with hazard ratios of 0.41 (P = .003) and 0.67 (P = .008) for 1:1-matched and X:X-matched analyses, respectively. Plasma GL-3 declined markedly in paediatric patients and normalized 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 normalization of elevated pre-treatment levels in most patients.

Keywords: Fabry disease; agalsidase beta; composite clinical event; kidney function; matched analysis.

Graphical Abstract

Figure 1:

eGFR slopes in the overall populations of untreated and agalsidase beta–treated adult patients with FD. (A) Matching 1:1 based on age, sex, phenotype and baseline eGFR. Untreated: n = 122, eGFR slope −3.19 mL/min/1.73 m²/year; treated: n = 122, eGFR slope −1.47 mL/min/1.73 m²/year (both P_{from 0} < .001, P_difference = .007). (B) Matching X:X based on age, sex, phenotype and baseline eGFR. Untreated: n = 122, eGFR slope −3.29 mL/min/1.73 m²/year; treated: n = 950, eGFR slope −1.56 mL/min/1.73 m²/year (both P_{from 0} < .001, P_difference <.001). P_{from 0} is the P-value calculated to test whether the slope is different from 0. P_difference is the P-value comparing the slopes between groups.

Figure 2:

Time-to-composite clinical event in the overall populations of untreated and agalsidase beta–treated adult patients with FD. (A) Matching 1:1 by age, sex and phenotype. (B) Matching X:X by age, sex and phenotype. P_difference is the P-value from the Cox proportional hazards model comparing the risk between groups. Shading represents 95% Hall–Wellner bands.