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Time to treatment benefit for adult patients with Fabry disease receiving agalsidase ?: data from the Fabry Registry.

ABSTRACT: BACKGROUND:Agalsidase ? is a form of enzyme replacement therapy for Fabry disease, a genetic disorder characterised by low ?-galactosidase A activity, accumulation of glycosphingolipids and life-threatening cardiovascular, renal and cerebrovascular events. In clinical trials, agalsidase ? cleared glycolipid deposits from endothelial cells within 6?months; clearance from other cell types required sustained treatment. We hypothesised that there might be a 'lag time' to clinical benefit after initiating agalsidase ? treatment, and analysed the incidence of severe clinical events over time in patients receiving agalsidase ?. METHODS:The incidence of severe clinical events (renal failure, cardiac events, stroke, death) was studied in 1044 adult patients (641 men, 403 women) enrolled in the Fabry Registry who received agalsidase ? (average dose 1?mg/kg every 2?weeks) for up to 5?years. RESULTS:The incidence of all severe clinical events was 111 per 1000 person-years (95% CI 84 to 145) during the first 6?months. After 6?months, the incidence decreased and remained stable within the range of 40-58 events per 1000 patient-years. The largest decrease in incidence rates was among male patients and those aged ?40?years when agalsidase ? was initiated. CONCLUSIONS:Contrary to the expected increased incidence of severe clinical events with time, adult patients with Fabry disease had decreased incidence of severe clinical events after 6?months treatment with agalsidase ? 1 mg/kg every 2?weeks. TRIAL REGISTRATION NUMBER:NCT00196742.

SUBMITTER: Ortiz A

PROVIDER: S-EPMC4941144 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Time to treatment benefit for adult patients with Fabry disease receiving agalsidase β: data from the Fabry Registry.

Ortiz Alberto A Abiose Ademola A Bichet Daniel G DG Cabrera Gustavo G Charrow Joel J Germain Dominique P DP Hopkin Robert J RJ Jovanovic Ana A Linhart Aleš A Maruti Sonia S SS Mauer Michael M Oliveira João P JP Patel Manesh R MR Politei Juan J Waldek Stephen S Wanner Christoph C Yoo Han-Wook HW Warnock David G DG

Journal of medical genetics 20160318 7

<h4>Background</h4>Agalsidase β is a form of enzyme replacement therapy for Fabry disease, a genetic disorder characterised by low α-galactosidase A activity, accumulation of glycosphingolipids and life-threatening cardiovascular, renal and cerebrovascular events. In clinical trials, agalsidase β cleared glycolipid deposits from endothelial cells within 6 months; clearance from other cell types required sustained treatment. We hypothesised that there might be a 'lag time' to clinical benefit aft ...[more]

PMID: 26993266

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Project description:Enzyme replacement therapy is currently the only approved therapy for Fabry disease. From June 2009 on, viral contamination of Genzyme's production facility resulted in a worldwide shortage of agalsidase beta leading to involuntary dose reductions (approved dose 1 mg/kg/eow, reduced dose 0.5 mg/kg/m), or switch to agalsidase alpha (administered dose 0.2 mg/kg/eow). An assessment report from the European Medicines Agency (EMA) raised serious concerns about an increase in adverse events at lower dosages of agalsidase beta. We determined the influence of the shortage on clinical event incidence and the most sensitive biochemical marker (lysoGb3) in Dutch Fabry patients.The incidence of clinical events per person per year was calculated from start of agalsidase beta treatment until the shortage, and was compared to the incidence of clinical events during the shortage period. In addition, plasma lysoGb3, eGFR, quality of life (SF-36) and brief pain inventory (BPI) questionnaires were analysed.All thirty-five Dutch Fabry patients using agalsidase beta (17 males) were included. Mean clinical event incidence was unchanged: 0.15 events per person per year before versus 0.15 during the shortage (p = 0.68). In total 28 clinical events occurred in 14 patients during 4.6 treatment years, compared to 7 events in 6 patients during the 1.3 year shortage period. eGFR and BPI scores were not significantly altered. Two SF-36 subscales were significantly but minimally reduced in females. In males, lysoGb3 increased with a median of 8.1 nM (range 2.5-29.2) after 1 year of shortage (p = 0.001). Increases in lysoGb3 were found in both patients switching to agalsidase alpha and on a reduced agalsidase beta dose. Antibody status, treatment duration or clinical event incidence showed no clear correlation to lysoGb3 increases.No increase in clinical event incidence was found in the adult Dutch Fabry cohort during the agalsidase beta shortage. Increases in lysoGb3, however, suggest recurrence of disease activity.

Project description:BackgroundPatients 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.MethodsAgalsidase 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.ResultsOverall, 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.ConclusionAgalsidase 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.

Project description:AimsLong-term treatment effect studies in large female Fabry patient groups are challenging to design because of phenotype heterogeneity and lack of appropriate comparison groups, and have not been reported. We compared long-term cardiomyopathy and kidney function outcomes after agalsidase beta treatment with preceding treatment-naive outcomes.Methods and resultsSelf-controlled pretreatment and post-treatment comparison (piecewise mixed linear modelling) included Fabry female patients ≥18 years at treatment initiation who received agalsidase beta (0.9-1.1 mg/kg every other week) for ≥2 years, with ≥2 pretreatment and ≥2 post-treatment outcome measurements during 10-year follow-up. Left ventricular posterior wall thickness (LVPWT)/interventricular septal thickness (IVST) and estimated glomerular filtration rate (eGFR, Chronic Kidney Disease Epidemiology Collaboration creatinine equation) analyses included 42 and 86 patients, respectively, aged 50.0 and 46.3 years at treatment initiation, respectively. LVPWT and IVST increased pretreatment (follow-up 3.5 years) but stabilized during 3.6 years of treatment (LVPWT: n = 38, slope difference [95% confidence interval (CI)] = -0.41 [-0.68, -0.15] mm/year, Ppre-post difference <0.01; IVST: n = 38, slope difference = -0.32 [-0.67, 0.02] mm/year, Ppre-post difference = 0.07). These findings were not modified by renal involvement or antiproteinuric agent use. Compared with the treatment-naive period (follow-up 3.6 years), eGFR decline remained modest and stabilized within normal ranges during 4.1 years of treatment (slope difference, 95% CI: -0.13 [-1.15, 0.89] mL/min/1.73m2 /year, Ppre-post difference = 0.80).ConclusionsCardiac hypertrophy, progressing during pretreatment follow-up, appeared to stabilize during sustained agalsidase beta treatment. eGFR decline remained within normal ranges. This suggests that treatment may prevent further Fabry-related progression of cardiomyopathy in female patients and maintain normal kidney function.

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Time to treatment benefit for adult patients with Fabry disease receiving agalsidase ?: data from the Fabry Registry.

Publications

Time to treatment benefit for adult patients with Fabry disease receiving agalsidase β: data from the Fabry Registry.

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