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

Abstract

Outcomes from 5 years of treatment with agalsidase alfa enzyme replacement therapy (ERT) for Fabry disease in patients enrolled in the Fabry Outcome Survey (FOS) were compared with published findings for untreated patients with Fabry disease. Data were extracted from FOS, a Shire-sponsored database, for comparison with data from three published studies. Outcomes evaluated were the annualized rate of change in estimated glomerular filtration rate (eGFR) and left ventricular mass indexed to height (LVMI) as well as time to and ages at a composite morbidity endpoint and at death. FOS data were extracted for 740 treated patients who were followed for a median of ~ 5 years. Compared with no treatment, patients treated with agalsidase alfa demonstrated slower decline in renal function and slower progression of left ventricular hypertrophy. Treated male patients with baseline eGFR < 60 mL/min/1.73 m(2) had a mean (standard error of the mean [SEM]) annualized change in eGFR of - 2.86 (0.53) mL/min/1.73 m(2)/y compared with - 6.8 (1.5) in the published untreated cohort. The mean (SEM) rate of LVMI increase with treatment was 0.33 (0.10) g/m(2.7)/y in males and 0.48 (0.09) in females, compared with 4.07 (1.03) in untreated males and 2.31 (0.81) in untreated females. Morbidity occurred later in treated patients, with ~ 16% risk of a composite morbidity event (26% in males) after 24 months with ERT versus ~ 45% without treatment, with first events and deaths also occurring at older ages in patients administered ERT (e.g., estimated median survival in treated males was 77.5 years versus 60 years in untreated males). Findings from these retrospective comparisons of observational data and published literature support the long-term benefits of ERT with agalsidase alfa for Fabry disease in slowing the progression of renal impairment and cardiomyopathy. Treatment also appeared to delay the onset of morbidity and mortality. Interpretation of these findings should take into account that they are based on retrospective comparisons with previously published data.

Keywords: ACEI, Angiotensin-converting enzyme inhibitor; ARB, Angiotensin receptor blocker; Agalsidase alfa; CI, Confidence interval; ERT, Enzyme replacement therapy; Enzyme replacement therapy; FOS, Fabry Outcome Survey; Fabry disease; LVH, Left ventricular hypertrophy; LVMI, Left ventricular mass indexed to height; Long-term effectiveness; MDRD, Modification of Diet in Renal Disease; SE, Standard error; SEM, Standard error of the mean; eGFR, Estimated glomerular filtration rate.

Fig. 1

Disposition of agalsidase alfa–treated patients. The All Treated cohort of FOS was subdivided into an Evaluable Treated cohort and then further subdivided into Evaluable Treated Morbidity (and mortality), Renal, and Cardiac cohorts for comparison with untreated patients (shaded boxes) from studies by Banikazemi et al. , Kampmann et al. , and Schiffmann et al. . eGFR, estimated glomerular filtration rate; F, female; FOS, Fabry Outcome Survey; LVMI, left ventricular mass indexed to height; M, male.

Fig. 2

Kaplan–Meier survival analyses for morbidity. a. Time to first renal, cardiac or stroke event, or death for agalsidase alfa–treated patients from FOS and untreated (placebo arm) patients in a study by Banikazemi et al. . b. Age at first event for treated patients from FOS and untreated patients from a study by Schiffmann et al. . BL, baseline; CI, confidence interval; FOS, Fabry Outcome Survey. Right panel of Fig. 2a adapted with permission from Banikazemi et al. . Right panel of Fig. 2b was adapted from Schiffmann et al. with permission from Oxford University Press. *Cumulative probability function of these events. ^†Time to first composite event on or after start of agalsidase alfa. ^‡Time on study to first composite event. ^§Age at first composite event on or after start of agalsidase alfa. ^∥Age at first composite event.

Fig. 3

Kaplan–Meier survival analyses (mortality) in a. treated patients from FOS and b. untreated male patients from Schiffmann et al. . FOS, Fabry Outcome Survey.