@article{SpadaBaronElliottetal.2019, author = {Spada, Marco and Baron, Ralf and Elliott, Perry M. and Falissard, Bruno and Hilz, Max J. and Monserrat, Lorenzo and T{\o}ndel, Camilla and Tylki-Szymańska, Anna and Wanner, Christoph and Germain, Dominique P.}, title = {The effect of enzyme replacement therapy on clinical outcomes in paediatric patients with Fabry disease - A systematic literature review by a European panel of experts}, series = {Molecular Genetics and Metabolism}, volume = {126}, journal = {Molecular Genetics and Metabolism}, doi = {10.1016/j.ymgme.2018.04.007}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239287}, pages = {212-223}, year = {2019}, abstract = {Background Fabry disease is caused by a deficiency of the lysosomal enzyme α-galactosidase, resulting in progressive accumulation of globotriaosylceramide (GL-3). The disease can manifest early during childhood and adolescence. Enzyme replacement therapy (ERT) with recombinant human α-galactosidase is the first specific treatment for Fabry disease and has been available in Europe since 2001. This paper presents the findings of a systematic literature review of clinical outcomes with ERT in paediatric patients with Fabry disease. Methods A comprehensive systematic review of published literature on ERT in Fabry disease was conducted in January 2017. The literature analysis included all original articles reporting outcomes of ERT in paediatric patients. Results Treatment-related outcomes in the paediatric population were reported in six publications derived from open-label clinical trials and in 10 publications derived from observational or registry-based studies. ERT was shown to significantly reduce plasma and urine GL-3 levels in paediatric patients with Fabry disease. The effect of ERT on GL-3 clearance from renal podocytes appeared to be agalsidase dose-dependent. ERT relieved pain and improved gastrointestinal symptoms and quality of life. Conclusions Based on the published literature, the use of ERT in paediatric patients can significantly clear GL-3 accumulation, ameliorate the early symptoms of Fabry disease, and improve quality of life. Treatment with ERT in paediatric patients with Fabry disease may be important to prevent further disease progression and overt organ damage.}, language = {en} } @article{MuentzeGenslerManiucetal.2019, author = {M{\"u}ntze, Jonas and Gensler, Daniel and Maniuc, Octavian and Liu, Dan and Cairns, Tereza and Oder, Daniel and Hu, Kai and Lorenz, Kristina and Frantz, Stefan and Wanner, Christoph and Nordbeck, Peter}, title = {Oral Chaperone Therapy Migalastat for Treating Fabry Disease: Enzymatic Response and Serum Biomarker Changes After 1 Year}, series = {Clinical Pharmacology \& Therapeutics}, volume = {105}, journal = {Clinical Pharmacology \& Therapeutics}, doi = {10.1002/cpt.1321}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231626}, pages = {1224-1233}, year = {2019}, abstract = {Long-term effects of migalastat therapy in clinical practice are currently unknown. We evaluated migalastat efficacy and biomarker changes in a prospective, single-center study on 14 patients with Fabry disease (55 ± 14 years; 11 men). After 1 year of open-label migalastat therapy, patients showed significant changes in alpha-galactosidase-A activity (0.06-0.2 nmol/minute/mg protein; P = 0.001), left ventricular myocardial mass index (137-130 g/m2; P = 0.037), and serum creatinine (0.94-1.0 mg/dL; P = 0.021), accounting for deterioration in estimated glomerular filtration rate (87-78 mL/minute/1.73 m2; P = 0.012). The enzymatic increase correlated with myocardial mass reduction (r = -0.546; P = 0.044) but not with renal function (r = -0.086; P = 0.770). Plasma globotriaosylsphingosine was reduced in therapy-naive patients (10.9-6.0 ng/mL; P = 0.021) and stable (9.6-12.1 ng/mL; P = 0.607) in patients switched from prior enzyme-replacement therapy. These first real-world data show that migalastat substantially increases alpha-galactosidase-A activity, stabilizes related serum biomarkers, and improves cardiac integrity in male and female patients with amenable Fabry disease mutations.}, language = {en} } @article{KrieterKerwagenRuethetal.2019, author = {Krieter, Detlef H. and Kerwagen, Simon and R{\"u}th, Marieke and Lemke, Horst-Dieter and Wanner, Christoph}, title = {Differences in dialysis efficacy have limited effects on protein-bound uremic toxins plasma levels over time}, series = {Toxins}, volume = {11}, journal = {Toxins}, number = {4}, doi = {10.3390/toxins11010047}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201770}, pages = {47}, year = {2019}, abstract = {The protein-bound uremic toxins para-cresyl sulfate (pCS) and indoxyl sulfate (IS) are associated with cardiovascular disease in chronic renal failure, but the effect of different dialysis procedures on their plasma levels over time is poorly studied. The present prospective, randomized, cross-over trial tested dialysis efficacy and monitored pre-treatment pCS and IS concentrations in 15 patients on low-flux and high-flux hemodialysis and high-convective volume postdilution hemodiafiltration over six weeks each. Although hemodiafiltration achieved by far the highest toxin removal, only the mean total IS level was decreased at week three (16.6 ± 12.1 mg/L) compared to baseline (18.9 ± 13.0 mg/L, p = 0.027) and to low-flux dialysis (20.0 ± 12.7 mg/L, p = 0.021). At week six, the total IS concentration in hemodiafiltration reached the initial values again. Concentrations of free IS and free and total pCS remained unaltered. Highest beta2-microglobulin elimination in hemodiafiltration (p < 0.001) led to a persistent decrease of the plasma levels at week three and six (each p < 0.001). In contrast, absent removal in low-flux dialysis resulted in rising beta2-microglobulin concentrations (p < 0.001). In conclusion, this trial demonstrated that even large differences in instantaneous protein-bound toxin removal by current extracorporeal dialysis techniques may have only limited impact on IS and pCS plasma levels in the longer term.}, language = {en} } @article{KadowakiNangakuHanteletal.2019, author = {Kadowaki, Takashi and Nangaku, Masaomi and Hantel, Stefan and Okamura, Tomoo and von Eynatten, Maximilian and Wanner, Christoph and Koitka-Weber, Audrey}, title = {Empagliflozin and kidney outcomes in Asian patients with type 2 diabetes and established cardiovascular disease: Results from the EMPA-REG OUTCOME® trial}, series = {Journal of Diabetes Investigation}, volume = {10}, journal = {Journal of Diabetes Investigation}, doi = {10.1111/jdi.12971}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325246}, pages = {760-770}, year = {2019}, abstract = {Aims/Introduction In the EMPA-REG OUTCOME® trial, empagliflozin added to standard of care improved clinically relevant kidney outcomes by 39\%, slowed progression of chronic kidney disease, and reduced albuminuria in patients with type 2 diabetes and established cardiovascular disease. This exploratory analysis investigated the effects of empagliflozin on the kidneys in Asian patients. Materials and Methods Participants in the EMPA-REG OUTCOME® trial were randomized (1:1:1) to empagliflozin 10 mg, 25 mg or a placebo. In patients of Asian race, we analyzed incident or worsening nephropathy (progression to macroalbuminuria, doubling of serum creatinine, initiation of renal-replacement therapy or renal death) and its components, estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio changes, and renal safety. Results Of 7,020 treated patients, 1,517 (26.1\%) were Asian. In this subgroup, consistent with the overall trial population, empagliflozin reduced the risk of incident or worsening nephropathy (hazard ratio 0.64, 95\% confidence interval 0.49-0.83), progression to macroalbuminuria (hazard ratio 0.64, 95\% confidence interval 0.49-0.85) and the composite of doubling of serum creatinine, initiation of renal-replacement therapy or renal death (hazard ratio 0.48, 95\% confidence interval 0.25-0.92). Furthermore, empagliflozin-treated participants showed slower eGFR decline versus placebo, and showed rapid urine albumin-to-creatinine ratio reduction at week 12, maintained through week 164, with effects most pronounced in those with baseline microalbuminuria or macroalbuminuria. The kidney safety profile of empagliflozin in the Asian subgroup was similar to the overall trial population. Conclusions In Asian patients from the EMPA-REG OUTCOME® trial, empagliflozin improved kidney outcomes, slowed eGFR decline and lowered albuminuria versus placebo, consistent with the overall trial population findings.}, language = {en} } @article{GermainElliottFalissardetal.2019, author = {Germain, Dominique P. and Elliott, Perry M. and Falissard, Bruno and Fomin, Victor V. and Hilz, Max J. and Jovanovic, Ana and Kantola, Ilkka and Linhart, Aleš and Renzo, Mignani and Namdar, Mehdi and Nowak, Albina and Oliveira, Jo{\~a}o-Paulo and Pieroni, Maurizio and Viana-Baptista, Miguel and Wanner, Christoph and Spada, Marco}, title = {The effect of enzyme replacement therapy on clinical outcomes in male patients with Fabry disease: A systematic literature review by a European panel of experts}, series = {Molecular Genetics and Metabolism Reports}, volume = {19}, journal = {Molecular Genetics and Metabolism Reports}, doi = {10.1016/j.ymgmr.2019.100454}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232987}, year = {2019}, abstract = {Background Enzyme replacement therapy (ERT) with recombinant human α-galactosidase has been available for the treatment of Fabry disease since 2001 in Europe and 2003 in the USA. Treatment outcomes with ERT are dependent on baseline patient characteristics, and published data are derived from heterogeneous study populations. Methods We conducted a comprehensive systematic literature review of all original articles on ERT in the treatment of Fabry disease published up until January 2017. This article presents the findings in adult male patients. Results Clinical evidence for the efficacy of ERT in adult male patients was available from 166 publications including 36 clinical trial publications. ERT significantly decreases globotriaosylceramide levels in plasma, urine, and in different kidney, heart, and skin cell types, slows the decline in estimated glomerular filtration rate, and reduces/stabilizes left ventricular mass and cardiac wall thickness. ERT also improves nervous system, gastrointestinal, pain, and quality of life outcomes. Conclusions ERT is a disease-specific treatment for patients with Fabry disease that may provide clinical benefits on several outcomes and organ systems. Better outcomes may be observed when treatment is started at an early age prior to the development of organ damage such as chronic kidney disease or cardiac fibrosis. Consolidated evidence suggests a dose effect. Data described in male patients, together with female and paediatric data, informs clinical practice and therapeutic goals for individualized treatment.}, language = {en} } @article{GermainAradBurlinaetal.2019, author = {Germain, Dominique P. and Arad, Michael and Burlina, Alessandro and Elliott, Perry M. and Falissard, Bruno and Feldt-Rasmussen, Ulla and Hilz, Max J. and Hughes, Derralynn A. and Ortiz, Alberto and Wanner, Christoph and Weidemann, Frank and Spada, Marco}, title = {The effect of enzyme replacement therapy on clinical outcomes in female patients with Fabry disease - A systematic literature review by a European panel of experts}, series = {Molecular Genetics and Metabolism}, volume = {126}, journal = {Molecular Genetics and Metabolism}, doi = {10.1016/j.ymgme.2018.09.007}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232963}, pages = {224-235}, year = {2019}, abstract = {Background Heterozygous females with Fabry disease have a wide range of clinical phenotypes depending on the nature of their mutation and their X-chromosome inactivation pattern; it is therefore important to examine outcomes of enzyme replacement therapy (ERT) in the female patient population specifically. This paper presents the findings of a systematic literature review of treatment outcomes with ERT in adult female patients. Methods A comprehensive systematic literature review was conducted through January 2017 to retrieve published papers with original data on ERT in the treatment of Fabry disease. The review included all original articles that presented ERT outcomes data on patients with Fabry disease, irrespective of the study type. Results Clinical evidence for the efficacy of ERT in female patients was available from 67 publications including six clinical trial publications, and indicates significant reductions in plasma and urine globotriaosylceramide (GL-3) accumulation (in female patients with elevated pre-treatment levels) and improvements in cardiac parameters and quality of life (QoL). To date, data are insufficient to conclude on the effects of ERT on the nervous system, gastrointestinal manifestations, and pain in female patients with Fabry disease. Conclusions This review of available literature data demonstrates that ERT in adult female patients with Fabry disease has a beneficial effect on GL-3 levels and cardiac outcomes. The current evidence also suggests that ERT may improve QoL in this patient population, though further studies are needed to examine these results.}, language = {en} } @article{ElliotGermainHilzetal.2019, author = {Elliot, Perry M. and Germain, Dominique P. and Hilz, Max J. and Spada, Marco and Wanner, Christoph and Falissard, Bruno}, title = {Why systematic literature reviews in Fabry disease should include all published evidence}, series = {European Journal of Medical Genetics}, volume = {62}, journal = {European Journal of Medical Genetics}, doi = {10.1016/j.ejmg.2019.103702}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226654}, year = {2019}, abstract = {Fabry disease is an X-linked inherited, progressive disorder of lipid metabolism resulting from the deficient activity of the enzyme α-galactosidase. Enzyme replacement therapy (ERT) with recombinant agalsidase, with intravenous infusions of either agalsidase beta or agalsidase alfa, is available and clinical experience now exceeds 15 years. There are very few randomised, placebo-controlled clinical trials evaluating the outcomes of ERT. Data are often derived from observational, registry-based studies and case reports. Pooled analysis of data from different sources may be limited by the heterogeneity of the patient populations, outcomes and treatment. Therefore, comprehensive systematic literature reviews of unpooled data are needed to determine the effects of ERT on disease outcomes. A systematic literature search was conducted in the Embase and PubMed (MEDLINE) databases to retrieve original articles that evaluated outcomes of ERT in patients with Fabry disease; the outcome data were analysed unpooled. The literature analysis included the full range of published literature including observational studies and case series/case reports. Considerable heterogeneity was found among the studies, with differences in sample size, statistical methods, ERT regimens and patient demographic and clinical characteristics. We have demonstrated the value of performing an unpooled systematic literature review of all published evidence of ERT outcomes in Fabry disease, highlighting that in a rare genetic disorder like Fabry disease, which is phenotypically diverse, different patient populations can require different disease management and therapeutic goals depending on age, genotype, and disease severity/level of organ involvement. In addition, these findings are valuable to guide the design and reporting of new clinical studies.}, language = {en} }