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. /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.

Long-term outcomes with agalsidase alfa enzyme replacement therapy: Analysis using deconstructed composite events

“…For consistency with our previous analysis [6], which compared treated patients from FOS with untreated patients in the published literature [16], the definition of events was broader in our FOS analysis than in the analysis of Germain et al [8], and therefore some of these events were less severe (e.g., transient ischemic attack, prolonged reversible ischemic neurologic deficit). In contrast, Germain et al focused on severe clinical events, which were defined as "chronic dialysis, kidney transplant, myocardial infarction, congestive heart failure, major cardiac procedures (i.e., implantation of a balloon pump, cardioverter-defibrillator or first pacemaker; or bypass surgery), stroke and death" [8].…”

“…The current analysis is an extension of our retrospective analysis [6], which found that agalsidase alfa ERT appeared to slow the progression of renal impairment and LVH, and composite morbidity events (including death) occurred later, in FOS patients receiving agalsidase alfa ERT compared with published findings in untreated patients with Fabry disease. The current work represents a purely descriptive analysis of the status of treated patients; because of the lack of external comparator groups, no comparison of agalsidase alfa treated and untreated patients was possible.…”

“…In a recent analysis, we retrospectively compared long-term composite morbidity outcomes in patients from the Fabry Outcome Survey (FOS; sponsored by Shire) who were receiving agalsidase alfa enzyme replacement therapy (ERT) with published outcomes in untreated patients with Fabry disease [6]. Long-term ERT appeared to slow the progression of renal impairment and cardiomyopathy, and composite morbidity events occurred later in treated patients.…”

Fabry Nephropathy: An Evidence-Based Narrative Review

“…The first reports of ERT efficacy on renal outcomes were encouraging [11,90]; reversal of renal glycosphingolipid accumulation in the vasculature and in other renal cell types and decrease of Gb3 in podocytes and distal tubular epithelium were observed after 11 months of agalsidase alfa treatment [91]. From the large international database Fabry Outcome Survey (FOS), several studies have confirmed that treatment with agalsidase alfa stabilizes or minimizes eGFR decline in both male and female Fabry patients [92][93][94][95]. The study by Feriozzi et al [93], in 165 patients followed for 3 years on treatment, also showed how proteinuria influences the loss of eGFR, with an average of 1.68 mL/min/1.73 m 2 /year in patients with baseline proteinuria <0.50 g/day (n = 40) and an average of 3.98 mL/min/1.73 m 2 /year in patients with values >0.50 g/ day (n = 14).…”

“…Apart from the reported benefits of ERT on kidney function, several studies point to an action of this therapy against progression to cardiac and cerebrovascular complications [12,94,95,99,100]. In fact, risk of morbidity was reduced and survival was improved in treated patients from the FOS database compared to untreated groups from published literature [95]: median age at first composite event (renal, cardiac or stroke event, or death) was greater in agalsidase alfa-treated males and females, at 48 years and 56.9 years, respectively, compared with untreated patients, at 41 years and 53 years, respectively, whereas the estimated median survival time was 77.5 years for male patients from FOS compared with 60 years in patients without ERT.…”