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Changes in Plasma and Urine Globotriaosylceramide Levels Do Not Predict Fabry Disease Progression Over 1 Year of Agalsidase Alfa

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Changes in Plasma and Urine Globotriaosylceramide Levels Do Not Predict Fabry Disease Progression Over 1 Year of Agalsidase Alfa © American College of Medical Genetics and Genomics ORIGINAL RESEARCH ARTICLE Open Changes in plasma and urine globotriaosylceramide levels do not predict Fabry disease progression over 1 year of agalsidase alfa Raphael Schiffmann, MD1, Markus Ries, MD, PhD2, Derek Blankenship, PhD3, Kathy Nicholls, MD4, Atul Mehta, MD5, Joe T.R. Clarke, MD, PhD6, Robert D. Steiner, MD7, Michael Beck, MD8, Bruce A. Barshop, MD, PhD9, William Rhead, MD10, Michael West, MD, FRCPC11, Rick Martin, MD12, David Amato, PhD13, Nitin Nair, PhD12 and Pedro Huertas, MD, PhD14,15 Purpose: Globotriaosylceramide concentrations were assessed as Results: Baseline estimated glomerular filtration rate, age at first potential predictors of change from baseline after 12 months by dose, baseline urine globotriaosylceramide excretion, and base- estimated glomerular filtration rate and left-ventricular mass index line and change from baseline urine protein excretion significantly using pooled data from three randomized, placebo-controlled predicted change from baseline estimated glomerular filtration rate agalsidase alfa trials and open-label extensions of patients with in the analysis population (N = 73; all P<0.05), although not in all Fabry disease. subgroups. Change from baseline urine and plasma globotriaosylce- ramide (baseline and change from baseline) concentrations did not Methods: Males (aged 18 years or older) with Fabry disease received predict change from baseline estimated glomerular filtration rate. No agalsidase alfa (0.2 mg/kg every other week for 12 months). A back- predictors of left-ventricular mass index were significant. ward-elimination approach evaluated potential predictors (baseline estimated glomerular filtration rate and left-ventricular mass index; Conclusion: Changes in globotriaosylceramide concentrations age at first dose; baseline and change from baseline at 12 months of do not appear to be useful biomarkers for prediction of Fabry dis- globotriaosylceramide (urine, plasma); urine protein excretion; and ease–related changes in estimated glomerular filtration rate or left-­ systolic and diastolic blood pressure). Subgroups included patients ventricular mass index. randomized to placebo or agalsidase alfa (double-blind phase), then Genet Med advance online publication 16 May 2013 to agalsidase alfa (open-label extensions; placebo→agalsidase alfa or agalsidase alfa→agalsidase alfa, respectively) and stage 2/3 chronic Key Words: agalsidase alfa; biomarkers; enzyme replacement kidney disease patients. ­therapy; Fabry disease; globotriaosylceramide Globotriaosylceramide (Gb3) is often elevated in the urine of Biomarkers are generally defined as measurements that patients with Fabry disease,1 and some studies support its use reflect the activity of a disease process9 and can be (i) prognos- 2–4 10 as a diagnostic biomarker. Plasma Gb3 concentration has tic, (ii) predictive, or (iii) pharmacodynamic. been found to be consistently elevated in hemizygous males The goal of this study was to assess the relationship of with classic Fabry disease but variably elevated in some vari- plasma and urine Gb3 concentrations with renal or cardiac ant hemizygous males with residual enzyme activity and in outcome measures. A previous analysis of pooled data from heterozygous females.5,6 No evidence has been published sup- three randomized, placebo-controlled clinical trials and their porting the use of plasma or urine Gb3 concentrations as a open-label extensions (sponsored by Shire Human Genetic biomarker for disease progression or response to treatment. Therapies) of male patients with Fabry disease suggested a For patients with elevated plasma or urine Gb3 concentra- stabilizing effect of agalsidase alfa (agalα) on renal function tions before treatment, enzyme replacement therapy (ERT) assessed by measured glomerular filtration rate (GFR).11 In 5,7 results in an initial drop in Gb3 concentrations. The lower that analysis, baseline GFR or elevated proteinuria category Gb3 concentrations do not remain low in all patients and do (≥1 g/24 h) significantly predicted GFR decline during treat- not always coincide with clinical improvement.8 ment. Using a suitable selection approach of pooled data The first two authors contributed equally to this work. 1Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas, USA; 2Pediatric Neurology, Center for Pediatric and Youth Medicine, University Clinic Heidelberg, Heidelberg, Germany; 3Department of Quantitative Sciences, Baylor Institute for Health Care Research and Improvement, Dallas, Texas, USA; 4Department of Nephrology, Royal Melbourne Hospital and University of Melbourne, Parkville, Australia; 5Lysosomal Storage Disorders Unit, Department of Haematology, Royal Free Hospital, London, UK; 6Division of Clinical and Metabolic Genetics, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada; 7Department of Pediatrics and Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon, USA; 8Centre for Lysosomal Storage Disorders, University of Mainz, Mainz, Germany; 9Metabolic Genetics, Rady Children’s Hospital-San Diego, University of California, San Diego, San Diego, California, USA; 10Department of Pediatrics and Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; 11Division of Nephrology, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; 12Shire Human Genetic Therapies, Lexington, Massachusetts, USA; 13Vertex Pharmaceuticals, Cambridge, Massachusetts, USA; 14Medicines Development Group, Neurosciences, Pfizer Inc, Cambridge, Massachusetts, USA; 15Massachusetts General Hospital and Division of Health Sciences and Technology, Harvard Medical School–Massachusetts Institute of Technology, Boston, Massachusetts, USA. Correspondence: Raphael Schiffmann ([email protected]) Submitted 12 February 2013; accepted 26 March 2013; advance online publication 16 May 2013. doi:10.1038/gim.2013.56 GENETIcS in mEDIcINE | Volume 15 | Number 12 | December 2013 983 SCHIFFMANN et al | Gb levels in plasma and urine do not predict Fabry disease progression ORIGINAL RESEARCH ARTICLE 3 from the same three clinical trials, we asked whether Gb3 (TKT005). None of these trials had specific renal inclusion concentrations could also be a predictor of changes in kid- criteria. ney function and/or left-ventricular mass index (LVMI) in a For inclusion in these post hoc analyses, patients in the renal large study population of patients with Fabry disease receiv- analysis population were required to have available data on 14 ing agalα ERT. estimated GFR (eGFR), plasma Gb3 concentration, urine Gb3 excretion, urine protein excretion, systolic and diastolic blood MATERIALS AND METHODS pressure, and age at baseline and 12 months of agalα treatment. Clinical trial designs and treatments The cardiac analysis population must have had cardiac mag- Data were pooled from three 24-week, randomized, double- netic resonance imaging measurements for LVMI. All patients blind, placebo-controlled trials (RCTs) and their open-label should have received at least one dose of agalα during the treat- extension studies (EXTs; TKT003/TKT006; TKT005/TKT007; ment period assessed. In addition, subpopulations were evalu- TKT010/TKT013; and TKT015). Two of these trials (TKT003 ated comprising patients who were initially randomized to the and extension12 and TKT005 and extension)13 were single- placebo group in the 6-month RCTs and transitioned to 12 center phase II trials, and one was a multicenter phase III trial months of agalα in the EXTs (placebo→agalα; Figure 1), who (TKT010 and extension). were initially randomized to agalα (6-month RCTs) and con- Treatments in these trials included agalα (0.2 mg/kg body tinued on to 6 months of agalα during the EXTs (agalα→agalα; weight) infused intravenously over a 40-min period every other Figure 1), or who had stage 2/3 chronic kidney disease (CKD week or placebo (infused on the same schedule). For these anal- 2/3) at baseline (defined as patients with baseline eGFR of yses, patient data were analyzed for 12 months of total agalα 30−90 ml/min/1.73 m2). treatment (Figure 1). Patients were either treated with agalα for All studies included in these analyses were approved by the 6 months (RCTs), followed by an additional 6 months of agalα appropriate institutional review boards of the investigators’ (EXTs), or they received placebo for 6 months (RCTs) and then institutions, and all patients provided written informed consent. transitioned to 12 months of agalα (EXTs). Measurement of eGFR and LVMI Patient selection These analyses use eGFR instead of measured GFR because Patients were adult males (aged 18 years or older) with Fabry eGFR allows for the inclusion of more patients in the analysis disease (OMIM 301500) confirmed by clinical characteristics population. eGFR (ml/min/1.73 m2) was calculated using the and alpha-galactosidase A deficiency, who were otherwise con- Chronic Kidney Disease Epidemiology Collaboration equa- sidered to have adequate general health. Each individual RCT tion,14 which incorporates serum creatinine (SCr [mg/dl]), also had specific inclusion criteria, including symptoms of neu- the patient’s age, sex, and race. κ Corresponds to a value of 0.7 ropathic pain (TKT003, TKT010), medication for neuropathic (females) or 0.9 (males), and α is –0.329 (females) or –0.411 pain at screening (TKT010), and left-ventricular hypertrophy (males). The “min” value indicates the minimum of SCr/κ or 1, Placebo-controlled
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