Enzyme Replacement Therapy in Fabry Disease

Schiffmann, Raphael; Kopp, Jeffrey B.; Austin, Howard A.; Sabnis, Sharda G.; Moore, David F.; Weibel, Thais; Balow, James E.; Brady, Roscoe O.

doi:10.1001/jama.285.21.2743

Cited by 1,197 publications

(969 citation statements)

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“…Recently, clinical trials have shown that enzyme replacement with recombinant human a-galactosidase A can increase a-galactosidase A levels, decrease endothelial inclusions, and improve pain symptoms. 16,17 However, enzyme replacement therapy costs approximately $160 000 annually. 4 Thus, with this now readily available but expensive therapy, it is imperative for clinicians to be aware of the rare patient whose Fabry-like syndrome is iatrogenically induced and who does not require a-galactosidase A replacement.…”

Section: Discussionmentioning

confidence: 99%

Chloroquine-induced lipidosis mimicking Fabry disease

et al. 2005

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Section: Discussionmentioning

confidence: 99%

Chloroquine-induced lipidosis mimicking Fabry disease

et al. 2005

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“…Two of these trials (TKT003 and extension 12 and TKT005 and extension) 13 were singlecenter phase II trials, and one was a multicenter phase III trial (TKT010 and extension).…”

Section: Clinical Trial Designs and Treatmentsmentioning

confidence: 99%

Changes in plasma and urine globotriaosylceramide levels do not predict Fabry disease progression over 1 year of agalsidase alfa

Schiffmann¹,

Ries

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et al. 2013

Genetics in Medicine

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Original research articleGlobotriaosylceramide (Gb 3 ) is often elevated in the urine of patients with Fabry disease, 1 and some studies support its use as a diagnostic biomarker. [2][3][4] Plasma Gb 3 concentration has been found to be consistently elevated in hemizygous males with classic Fabry disease but variably elevated in some variant hemizygous males with residual enzyme activity and in heterozygous females. 5,6 No evidence has been published supporting the use of plasma or urine Gb 3 concentrations as a biomarker for disease progression or response to treatment. For patients with elevated plasma or urine Gb 3 concentrations before treatment, enzyme replacement therapy (ERT) results in an initial drop in Gb 3 concentrations. 5,7 The lower Gb 3 concentrations do not remain low in all patients and do not always coincide with clinical improvement. 8 Biomarkers are generally defined as measurements that reflect the activity of a disease process 9 and can be (i) prognostic, (ii) predictive, or (iii) pharmacodynamic. 10 The goal of this study was to assess the relationship of plasma and urine Gb 3 concentrations with renal or cardiac outcome measures. A previous analysis of pooled data from three randomized, placebo-controlled clinical trials and their open-label extensions (sponsored by Shire Human Genetic Therapies) of male patients with Fabry disease suggested a stabilizing effect of agalsidase alfa (agalα) on renal function assessed by measured glomerular filtration rate (GFR). 11 In that analysis, baseline GFR or elevated proteinuria category (≥1 g/24 h) significantly predicted GFR decline during treatment. Using a suitable selection approach of pooled data Purpose: Globotriaosylceramide concentrations were assessed as potential predictors of change from baseline after 12 months by estimated glomerular filtration rate and left-ventricular mass index using pooled data from three randomized, placebo-controlled agalsidase alfa trials and open-label extensions of patients with Fabry disease.Methods: Males (aged 18 years or older) with Fabry disease received agalsidase alfa (0.2 mg/kg every other week for 12 months). A backward-elimination approach evaluated potential predictors (baseline estimated glomerular filtration rate and left-ventricular mass index; age at first dose; baseline and change from baseline at 12 months of globotriaosylceramide (urine, plasma); urine protein excretion; and systolic and diastolic blood pressure). Subgroups included patients randomized to placebo or agalsidase alfa (double-blind phase), then to agalsidase alfa (open-label extensions; placebo→agalsidase alfa or agalsidase alfa→agalsidase alfa, respectively) and stage 2/3 chronic kidney disease patients.Results: Baseline estimated glomerular filtration rate, age at first dose, baseline urine globotriaosylceramide excretion, and baseline and change from baseline urine protein excretion significantly predicted change from baseline estimated glomerular filtration rate in the analysis population (N = 73; all P<0.05), although not in...

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“…Numerous clinical trials, observational studies, and registry data have provided some evidence for the safety and efficacy of ERT in improving disease symptoms, cardiac mass, renal function, and quality of life Schiffmann et al 2001;Weidemann et al 2003;Wilcox et al 2004;Banikazemi et al 2007;Hughes et al 2008;Koskenvuo et al 2008;Imbriaco et al 2009;Mehta et al 2009;Feriozzi et al 2012). To date, there have been limited comparisons of the two agents, from which no firm conclusion can be drawn regarding their relative efficacy and safety (Lidove et al 2010).…”

Section: Introductionmentioning

confidence: 99%