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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.

SUBMITTER: Beck M

PROVIDER: S-EPMC4750577 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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

Beck Michael M Hughes Derralynn D Kampmann Christoph C Larroque Sylvain S Mehta Atul A Pintos-Morell Guillem G Ramaswami Uma U West Michael M Wijatyk Anna A Giugliani Roberto R

Molecular genetics and metabolism reports 20150305

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 ...[more]

PMID: 26937390

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Project description:PurposeTo determine the impact of initiating enzyme replacement therapy (ERT) with agalsidase alfa early in the course of Fabry disease, we evaluated renal and cardiac outcomes for ≤10 years after ERT initiation in males from the Fabry Outcome Survey (FOS).Patients and methodsMale patients from FOS were stratified into three cohorts by age at ERT initiation: ≤18 years (cohort 1), >18 and ≤30 years (cohort 2), and >30 years (cohort 3). Analysis included age at symptom onset, diagnosis, and ERT initiation; ERT duration; FOS-Mainz Severity Score Index (FOS-MSSI); estimated glomerular filtration rate (eGFR); proteinuria level; and left ventricular mass indexed to height (LVMI). Mixed-effect models estimated renal and cardiac outcomes during follow-up between and within cohorts.FindingsThe analysis included 560 male patients: 151 (27.0%) in cohort 1, 155 (27.7%) in cohort 2, and 254 (45.4%) in cohort 3. Mean±SD duration of ERT for cohorts 1, 2, and 3 was 6.3±4.3, 8.6±4.9, and 7.9±4.9 years, respectively. Mean±SD baseline FOS-MSSI scores increased with age from 9.8±7.2 in cohort 1 to 24.7±11.4 in cohort 3. Cohort 3 showed the lowest baseline mean±SD value for eGFR (87.1±29.0 mL/min/1.73m2) and highest baseline mean±SD values for proteinuria (801.9±952.6 mg/day) and LVMI (56.7±16.0 g/m2.7) among the three cohorts. Evaluation of mean annual rates of change in eGFR, proteinuria, and LVMI revealed no significant differences in any parameter for cohort 1. For cohort 2, proteinuria and LVMI remained stable, whereas eGFR significantly deteriorated annually (-1.12 mL/min/1.73m2; P<0.001). Cohort 3 demonstrated significant annual deteriorations in eGFR (-2.60 mL/min/1.73m2; P<0.001), proteinuria (+34.10 mg/day; P<0.001), and LVMI (+0.59 g/m2.7; P=0.001).ImplicationsRenal and/or cardiac disease progression appears attenuated in patients starting ERT in childhood or early adulthood versus patients starting ERT in later adulthood. These findings support early ERT initiation in Fabry disease. ClinicalTrials.gov identifier: NCT03289065.

Project description:BackgroundFollowing a drug manufacturing process change, safety/efficacy of agalsidase alfa were evaluated in enzyme replacement therapy (ERT)-naïve children with Fabry disease.MethodsIn an open-label, multicenter, Phase II study (HGT-REP-084; Shire), 14 children aged ≥7 years received 0.2 mg/kg agalsidase alfa every other week for 55 weeks. Primary endpoints: safety, changes in autonomic function (2-hour Holter monitoring). Secondary endpoints: estimated glomerular filtration rate, left ventricular mass index (LVMI), midwall fractional shortening, pharmacodynamic parameters, and patient-reported quality-of-life.ResultsAmong five boys (median 10.2 [range 6.7, 14.4] years) and nine girls (14.8 [10.1, 15.9] years), eight patients experienced infusion-related adverse events (vomiting, n=4; nausea, n=3; dyspnea, n=3; chest discomfort, n=2; chills, n=2; dizziness, n=2; headache, n=2). One of these had several hypersensitivity episodes. However, no patient discontinued for safety reasons and no serious adverse events occurred. One boy developed immunoglobulin G (IgG) and neutralizing antidrug antibodies. Overall, no deterioration in cardiac function was observed in seven patients with low/abnormal SDNN (standard deviation of all filtered RR intervals; <100 ms) and no left ventricular hypertrophy: mean (SD) baseline SDNN, 81.6 (20.9) ms; mean (95% confidence interval [CI]) change from baseline to week 55, 17.4 (2.9, 31.9) ms. Changes in SDNN correlated with changes in LVMI (r=-0.975). No change occurred in secondary efficacy endpoints: mean (95% CI) change from baseline at week 55 in LVMI, 0.16 (-3.3, 3.7) g/m(2.7); midwall fractional shortening, -0.62% (-2.7%, 1.5%); estimated glomerular filtration rate, 0.15 (-11.4, 11.7) mL/min/1.73 m(2); urine protein, -1.8 (-6.0, 2.4) mg/dL; urine microalbumin, 0.6 (-0.5, 1.7) mg/dL; plasma globotriaosylceramide (Gb3), -5.71 (-10.8, -0.6) nmol/mL; urinary Gb3, -1,403.3 (-3,714.0, 907.4) nmol/g creatinine, or clinical quality-of-life outcomes.ConclusionFifty-five weeks' agalsidase alfa ERT at 0.2 mg/kg every other week was well tolerated. Disease progression may be slowed when ERT is started prior to major organ dysfunction.Trial registrationhttps://ClinicalTrials.gov identifier NCT01363492.

Project description:Background and objectiveFabry disease, an X-linked lysosomal storage disorder characterized by absent or reduced alpha-galactosidase activity, is a lifelong disease that impairs patients' quality of life. Patients with Fabry disease have a considerably shortened lifespan, with mortality being mainly due to renal failure, cardiovascular disease, or cerebrovascular disease. Enzyme replacement therapy with agalsidase alfa has been shown to attenuate the renal, cardiovascular, and neuropathic disease progression associated with Fabry disease. The objective of this study was to investigate the safety of a new animal component-free version of agalsidase alfa.MethodsA phase III/IV, open-label, single-arm, multicenter safety study was conducted in Canadian patients with Fabry disease between August 2011 and September 2017 as a regulatory requirement to assess the safety of agalsidase alfa produced using an animal component-free bioreactor process. Eligible patients had a documented diagnosis of Fabry disease and satisfied current Canadian guidelines for receiving enzyme replacement therapy for Fabry disease. Following treatment with animal component-free bioreactor-processed agalsidase alfa, treatment-emergent adverse events were monitored, and post hoc analyses of infusion-related reactions by antidrug antibody and neutralizing antibody statuses were conducted. The data were analyzed using descriptive statistics.ResultsA total of 167 patients (mean [standard deviation] age, 48.9 [14.8] years), including six pediatric patients (< 18 years of age), received at least one full or partial infusion of agalsidase alfa animal component-free. Fewer than 5% of treatment-emergent adverse events (212/4446) observed in 40 patients were reported as infusion-related reactions. Antidrug antibody and neutralizing antibody status did not affect the proportion of patients with infusion-related reactions. No clinically significant changes in vital signs were observed in patients over the course of the study.ConclusionsLong-term treatment with bioreactor-produced agalsidase alfa animal component-free did not reveal new safety signals in this population of Canadian patients with Fabry disease. The treatment-emergent adverse event profile was consistent with the clinical manifestations of the disease and the known safety profile of roller bottle-produced agalsidase alfa.Clinical trial registrationClinicalTrials.gov identifier NCT01298141.

Dataset Information

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

Publications

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

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