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Carla E M Hollak - One of the best experts on this subject based on the ideXlab platform.

  • Antibodies against recombinant alpha-galactosidase A in Fabry disease: Subclass analysis and impact on response to treatment
    Molecular Genetics and Metabolism, 2018
    Co-Authors: S.j. Van Der Veen, Paul H. P. Kaijen, Carla E M Hollak, Andre B P Van Kuilenburg, Jan Voorberg
    Abstract:

    Abstract Background Treatment of Fabry disease (FD) with recombinant alpha-galactosidase A (r-αGAL A) is complicated by the formation of anti-drug antibodies in the majority of male patients with the classical disease phenotype. Detailed information regarding antibody subtypes, onset and persistence of antibody development and their effect on treatment efficacy is sparse. Methods A retrospective study was carried out in 39 male patients with classical FD, treated with either Agalsidase-Alfa or Agalsidase-beta (mean follow up of 10 years). With six to twelve months intervals plasma-induced in vitro inhibition of enzyme activity, lysoglobotriaosylsphingosine (lysoGb3) levels and renal function were assessed. In a subset of 12 patients, additionally anti- r-αGAL A IgM, IgA and IgG1, 2, 3 and 4 levels were analyzed. Results In 23 out of 39 patients, plasma-induced in vitro inhibition of r-αGAL A activity was observed (inhibition-positive). The inhibition titer was strongly negatively correlated to the decrease in lysoGb3: Agalsidase-Alfa (FElog10(inhibition) = −10.3, P ≤.001), Agalsidase-beta (FElog10(inhibition) = −4.7, P ≤.001). Inhibition-positive patients had an accelerated decline in renal function (FE = 1.21, p = .042). During treatment IgG1 anti-r-αGAL A levels increased only in inhibition-positive patients (p = .0045). IgG4 anti-r-αGAL A antibodies developed in 7 out of 9 inhibition-positive patients. Other antibody subclasses were either not present or too low to quantify. Conclusion Development of inhibiting antibodies against r-αGAL A negatively affects the biochemical response to ERT and resulted in an accelerated decline in renal function. The presence of IgG1 and IgG4 anti-r-αGAL A antibodies is associated with in vitro αGAL A activity inhibition.

  • Treatment of Fabry Disease: Outcome of a Comparative Trial with Agalsidase Alfa or Beta at a Dose of 0.2 mg/kg
    2016
    Co-Authors: Anouk C Vedder, Gunnar Houge, Els E Ormel, Asle Hirth, Berto J Bouma, Johannes M F G Aerts, Johannna E M Groener, Gabor E Linthorst, Carla E M Hollak
    Abstract:

    registered for treatment of Fabry disease. We compared the efficacy of and tolerability towards the two Agalsidase preparations administered at identical protein dose in a randomized controlled open label trial. Methodology/Principal Findings. Thirty-four Fabry disease patients were treated with either Agalsidase Alfa or Agalsidase beta at equal dose of 0.2 mg/kg biweekly. Primary endpoint was reduction in left ventricular mass after 12 and 24 months of treatment. Other endpoints included occurrence of treatment failure (defined as progression of cardiac, renal or cerebral disease), glomerular filtration rate, pain, anti-Agalsidase antibodies, and globotriaosylceramide levels in plasma and urine. After 12 and 24 months of treatment no reduction in left ventricular mass was seen, which was not different between the two treatment groups. Also, no differences in glomerular filtration rate, pain and decline in globotriaosylceramide levels were found. Antibodies developed only in males (4/8 in the Agalsidase Alfa group and 6/8 in the Agalsidase beta group). Treatment failure within 24 months of therapy was seen in 8/34 patients: 6 male patients (3 in each treatment group) and 2 female patients (both Agalsidase Alfa). The occurrence of treatment failures did not differ between the two treatment groups; x2 = 0.38 p = 0.54. Conclusion. Our study revealed no difference in reduction of left ventricular mass or other disease parameters after 12 and 24 months of treatmen

  • recommendations on reintroduction of Agalsidase beta for patients with fabry disease in europe following a period of shortage
    JIMD reports, 2012
    Co-Authors: Gabor E Linthorst, Janice M Fletcher, Gunnar Houge, Carla E M Hollak, Derralynn Hughes, Ulla Feldtrasmussen, Alberto Burlina, Franco Cecchi, Roberto Giugliani, Iikka Kantola
    Abstract:

    The interruption of the manufacturing process of Agalsidase beta has led to a worldwide shortage of this drug. In the EU, nearly all patients initially reduced their Agalsidase beta dose, and many of these switched to Agalsidase Alfa (Replagal Shire HGT). The clinical consequences of this period of drug shortage need to be further evaluated. A gradual increase of Agalsidase beta supply is now expected. This implies that patients could resume or even commence Agalsidase beta treatment. Guidance for prioritization of patients is needed to support equitable distribution of Agalsidase beta to EU member states. To achieve this, in absence of level I clinical evidence, a draft consensus proposal was initiated and distributed. No full consensus was achieved, as there is disagreement regarding the indications for switching patients from Agalsidase Alfa to Agalsidase beta. Some physicians support the concept that the 1.0 mg/kg EOW dose of Agalsidase beta is more effective than Agalsidase Alfa at 0.2 mg/kg EOW, while others believe that at recommended dose, the preparations are equivalent. In light of these difficulties and the uncertainties with respect to supply of Agalsidase beta, recommendations were agreed upon by a subgroup of physicians. These current recommendations focus on prioritization of criteria indicative of disease progression.

  • reduction of elevated plasma globotriaosylsphingosine in patients with classic fabry disease following enzyme replacement therapy
    Biochimica et Biophysica Acta, 2011
    Co-Authors: Marielle J Van Breemen, Nick Dekker, Frank Breunig, Christoph Wanner, Johannes M F G Aerts, Saskia M Rombach, Ben J H M Poorthuis, Gabor E Linthorst, Aeilko H. Zwinderman, Carla E M Hollak
    Abstract:

    Fabry disease is treated by two-weekly infusions with a-galactosidase A. which is deficient in this X-linked globotriaosylceramide (Gb3) storage disorder. Elevated plasma globotriaosylsphingosine (lysoGb3) is a hallmark of classical Fabry disease. We investigated effects of enzyme replacement therapy (ERT) on plasma levels of lysoGb3 and Gb3 in patients with classical Fabry disease treated with Agalsidase Alfa at 02 mg/kg, Agalsidase beta at 02 mg/kg or at 1.0 mg/kg bodyweight. Each treatment regimen led to prominent reductions of plasma lysoGb3 in Fabry males within 3 months (P=0.0313), followed by relative stability later on. Many males developed antibodies against a-galactosidase A, particularly those treated with Agalsidase beta. Patients with antibodies tended towards smaller correction in plasma lysoGb3 concentration, whereas treatment with high dose Agalsidase beta allowed a reduction comparable to patients without antibodies. Pre-treatment plasma lysoGb3 concentrations of Fabry females were relatively low. In all females and with each treatment regimen, ERT gave reduction or stabilisation of plasma lysoGb3. Our investigation revealed that ERT of Fabry patients reduces plasma lysoGb3, regardless of the recombinant enzyme used. This finding shows that ERT can correct a characteristic biochemical abnormality in Fabry patients. (c) 2010 Elsevier B.V. All rights reserved

  • reduction of elevated plasma globotriaosylsphingosine in patients with classic fabry disease following enzyme replacement therapy
    Biochimica et Biophysica Acta, 2011
    Co-Authors: Marielle J Van Breemen, Nick Dekker, Frank Breunig, Christoph Wanner, Johannes M F G Aerts, Saskia M Rombach, Ben J H M Poorthuis, Gabor E Linthorst, Aeilko H. Zwinderman, Carla E M Hollak
    Abstract:

    Abstract Fabry disease is treated by two-weekly infusions with α-galactosidase A, which is deficient in this X-linked globotriaosylceramide (Gb3) storage disorder. Elevated plasma globotriaosylsphingosine (lysoGb3) is a hallmark of classical Fabry disease. We investigated effects of enzyme replacement therapy (ERT) on plasma levels of lysoGb3 and Gb3 in patients with classical Fabry disease treated with Agalsidase Alfa at 0.2 mg/kg, Agalsidase beta at 0.2 mg/kg or at 1.0 mg/kg bodyweight. Each treatment regimen led to prominent reductions of plasma lysoGb3 in Fabry males within 3 months ( P  = 0.0313), followed by relative stability later on. Many males developed antibodies against α-galactosidase A, particularly those treated with Agalsidase beta. Patients with antibodies tended towards smaller correction in plasma lysoGb3 concentration, whereas treatment with high dose Agalsidase beta allowed a reduction comparable to patients without antibodies. Pre-treatment plasma lysoGb3 concentrations of Fabry females were relatively low. In all females and with each treatment regimen, ERT gave reduction or stabilisation of plasma lysoGb3. Our investigation revealed that ERT of Fabry patients reduces plasma lysoGb3, regardless of the recombinant enzyme used. This finding shows that ERT can correct a characteristic biochemical abnormality in Fabry patients.

Markus Ries - One of the best experts on this subject based on the ideXlab platform.

  • enzyme replacement therapy with Agalsidase Alfa in patients with fabry s disease an analysis of registry data
    The Lancet, 2009
    Co-Authors: Atul Mehta, Frédéric Barbey, Perry M Elliott, Roberto Giugliani, M Beck, Ales Linhart, Gere Sunderplassmann, Markus Ries, Raphael Schiffmann, Jtr Clarke
    Abstract:

    Summary Background We analysed 5-year treatment with Agalsidase Alfa enzyme replacement therapy in patients with Fabry's disease who were enrolled in the Fabry Outcome Survey observational database (FOS). Methods Baseline and 5-year data were available for up to 181 adults (126 men) in FOS. Serial data for cardiac mass and function, renal function, pain, and quality of life were assessed. Safety and sensitivity analyses were done in patients with baseline and at least one relevant follow-up measurement during the 5 years (n=555 and n=475, respectively). Findings In patients with baseline cardiac hypertrophy, treatment resulted in a sustained reduction in left ventricular mass (LVM) index after 5 years (from 71·4 [SD 22·5] g/m 2·7 to 64·1 [18·7] g/m 2·7 , p=0·0111) and a significant increase in midwall fractional shortening (MFS) from 14·3% (2·3) to 16·0% (3·8) after 3 years (p=0·02). In patients without baseline hypertrophy, LVM index and MFS remained stable. Mean yearly fall in estimated glomerular filtration rate versus baseline after 5 years of enzyme replacement therapy was −3·17 mL/min per 1·73 m 2 for men and −0·89 mL/min per 1·73 m 2 for women. Average pain, measured by Brief Pain Inventory score, improved significantly, from 3·7 (2·3) at baseline to 2·5 (2·4) after 5 years (p=0·0023). Quality of life, measured by deviation scores from normal EuroQol values, improved significantly, from −0·24 (0·3) at baseline to −0·17 (0·3) after 5 years (p=0·0483). Findings were confirmed by sensitivity analysis. No unexpected safety concerns were identified. Interpretation By comparison with historical natural history data for patients with Fabry's disease who were not treated with enzyme replacement therapy, long-term treatment with Agalsidase Alfa leads to substantial and sustained clinical benefits. Funding Shire Human Genetic Therapies AB.

  • Agalsidase Alfa and kidney dysfunction in fabry disease
    Journal of The American Society of Nephrology, 2009
    Co-Authors: Michael West, Atul Mehta, Kathy Nicholls, M Beck, Joe T R Clarke, Robert D Steiner, Bruce Barshop, William J Rhead, Robert Mensah, Markus Ries
    Abstract:

    In male patients with Fabry disease, an X-linked disorder of glycosphingolipid metabolism caused by deficient activity of the lysosomal enzyme α-galactosidase A, kidney dysfunction becomes apparent by the third decade of life and invariably progresses to ESRD without treatment. Here, we summarize the effects of Agalsidase Alfa on kidney function from three prospective, randomized, placebo-controlled trials and their open-label extension studies involving 108 adult male patients. The mean baseline GFR among 54 nonhyperfiltrating patients (measured GFR <135 ml/min per 1.73 m2) treated with placebo was 85.4 ± 29.6 ml/min per 1.73 m2; during 6 mo of placebo, the mean annualized rate of change in GFR was −7.0 ± 32.9 ml/min per 1.73 m2. Among 85 nonhyperfiltrating patients treated with Agalsidase Alfa, the annualized rate of change was −2.9 ± 8.7 ml/min per 1.73 m2. Treatment with Agalsidase Alfa did not affect proteinuria. Multivariate analysis revealed that GFR and proteinuria category (<1 or ≥1 g/d) at baseline significantly predicted the rate of decline of GFR during treatment. This summary represents the largest group of male patients who had Fabry disease and for whom the effects of enzyme replacement therapy on kidney function have been studied. These data suggest that Agalsidase Alfa may stabilize kidney function in these patients.

  • weekly enzyme replacement therapy may slow decline of renal function in patients with fabry disease who are on long term biweekly dosing
    Journal of The American Society of Nephrology, 2007
    Co-Authors: Raphael Schiffmann, Markus Ries, Margaret Timmons, Chevalia Robinson, Roscoe O Brady, Hasan Askari, William Benko
    Abstract:

    Fabry disease is an X-linked glycosphingolipid disorder that is caused by an insufficient activity of the lysosomal enzyme α-galactosidase A (GALA) (1). This deficiency results in a systemic accumulation of α-D-galactosyl conjugates, particularly globotriaosylceramide (Gb3), in vascular endothelial cells, pericytes, and smooth muscle cells of the vascular system; renal epithelial cells; myocardial cells; and dorsal root ganglion neuronal cells (2). The incidence of Fabry disease in male individuals has been estimated to be 1:117,000 births (3). Hemizygous male patients with Fabry disease have a subtle but characteristic facial appearance (4). Clinical onset of the disease in both male hemizygotes and female heterozygotes typically occurs during childhood or adolescence with recurrent episodes of severe, often debilitating neuropathic pain in the extremities (5). However, the age of symptom onset and the age of diagnosis tend to be approximately 10 yr later in female compared with male individuals (6). Hypohidrosis and neuropathic pain contribute to poor tolerance to exercise and to heat (7,8). Proteinuria and progressive renal deterioration develop in nearly all male patients with Fabry disease (9,10) and are the result of intraglomerular deposition of Gb3, which is associated with histopathologic findings of mesangial widening and ultimately segmental and global glomerulosclerosis (10–12). Hypertrophic cardiomyopathy and coronary and cerebrovascular disease also contribute to early death in men at a median age of death of 50 to 55 yr (9). In recent years, enzyme replacement therapy (ERT) has become part of the standard medical care for Fabry disease (13,14). Although ERT reduces neuropathic pain and improves thermal sensing threshold (15) and gastrointestinal symptoms (16), its long-term effects on the progressive kidney dysfunction, the incidence of stroke, and progressive cardiac disease have not been established (13,15,17,18). Patients in controlled clinical trials showed significant reductions in certain biomarkers: Approximately 50% lowering of Gb3 levels in plasma as well as of Gb3 in urinary sediment and in renal interstitial capillary endothelium (13,19). Reduction of Gb3 storage in renal vascular endothelial cells was associated with an overall improvement in glomerular morphology, as assessed by a significant decrease in the percentage of glomeruli with mesangial widening and a significant increase in the percentage of normal glomeruli (13). Despite this histologic evidence of a renal benefit during ERT, conclusive evidence that ERT slows the progressive decline in renal function in Fabry disease has not been reported. In the long-term, open-label extensions of pivotal clinical trials, renal function remained stable in the majority of patients with Fabry disease who were treated with Agalsidase Alfa or Agalsidase beta for up to 4 yr (20,21). Most of the patients in these studies had relatively normal kidney function at baseline and might not be expected to experience a decline in kidney function during the studies. However, there are patients who demonstrated a continued progressive decline in renal function despite administration of either form of ERT (Agalsidase Alfa or beta) administered every other week (EOW) (20,21). Nevertheless, the rate of decline in the subgroup of patients with more severe renal dysfunction at pretreatment baseline did seem to be slower with Agalsidase Alfa treatment compared with the rate of decline in a comparable cohort of patients with untreated Fabry disease (10,20). In this study, we report the results of a clinical trial that was designed to test the hypothesis that increasing the frequency of ERT with 0.2 mg/kg Agalsidase Alfa from EOW to weekly could improve the slope of decline of estimated GFR (eGFR) in patients who have Fabry disease and whose eGFR had continued to decline at a relatively high rate despite treatment with Agalsidase Alfa 0.2 mg/kg EOW for 2 to 4 yr.

  • enzyme replacement therapy with Agalsidase Alfa in children with fabry disease
    Pediatrics, 2006
    Co-Authors: Markus Ries, Christoph Kampmann, Gregory M. Pastores, Joe T R Clarke, Catharina Whybra, Margaret Timmons, Chevalia Robinson, Bradley L Schlaggar, Howard Y Lien, Roscoe O Brady
    Abstract:

    CONTEXT. Fabry disease is an X-linked multisystem disorder. Enzyme-replacement therapy in adults has limited efficacy in treating major sequelae of advanced Fabry disease, such as kidney failure or stroke. This prompted a study of the safety and efficacy of enzyme replacement at an earlier stage of Fabry disease. OBJECTIVES. Our purpose with this work was to evaluate safety and to explore efficacy of enzyme treatment with Agalsidase Alfa in pediatric patients with Fabry disease. METHODS. We conducted a 6-month open-label study at 3 tertiary care centers with 24 children (19 boys and 5 girls) with a mean age of 11.8 (range: 6.5–18) years, to examine safety parameters, including infusion reactions and antiAgalsidase Alfa antibodies. RESULTS. Agalsidase Alfa was well tolerated, and all of the patients completed the study. Six boys and 1 girl had mild-to-moderate infusion reactions. One boy developed transient immunoglobulin G antibodies against Agalsidase Alfa. The boys showed a significant reduction in plasma globotriaosylceramide on treatment. Mean estimated glomerular filtration rate, cardiac structure, and function were normal and did not change over 26 weeks. Heart rate variability, as determined by 2-hour ambulatory monitoring, was decreased in the boys compared with the girls at baseline. All indices of heart rate variability improved significantly in the boys. Three patients with anhidrosis, as determined by quantitative sudomotor axon reflex testing, developed sweating. Six of 11 patients could reduce or cease their use of antineuropathic analgesics. CONCLUSIONS. Enzyme replacement with Agalsidase Alfa was safe in this study. The exploratory efficacy analysis documented increased clearance of globotriaosylceramide and improvement of autonomic function. Prospective long-term studies are needed to assess whether enzyme replacement initiated early in patients with Fabry disease is able to prevent major organ failure in adulthood.

  • long term therapy with Agalsidase Alfa for fabry disease safety and effects on renal function in a home infusion setting
    Nephrology Dialysis Transplantation, 2006
    Co-Authors: Raphael Schiffmann, Markus Ries, Margaret Timmons, John T Flaherty, Roscoe O Brady
    Abstract:

    Background. Fabry disease is an X-linked disorder of glycosphingolipid catabolism that is the result of an intracellular deficiency in the lysosomal enzyme a-galactosidase A (a-Gal A). This enzymatic defect results in the accumulation of globotriaosylceramide (Gb3) within cells and causes progressive neurological, cardiovascular and renal dysfunction. Our objective is to describe the safety and renal effects of long-term enzyme replacement therapy. Methods. This was a single centre, prospective openlabel treatment trial in 25 adult male Fabry patients who had completed a 6-month randomized placebocontrolled study and subsequently enrolled in an openlabel extension study. Patients were treated every other week with Agalsidase Alfa (0.2 mg/kg) infused intravenously over 40 min. The main outcome measures were safety, antibody response and renal glomerular filtration rate (GFR). Results. During the 4–4.5 years of enzyme replacement therapy, all eligible subjects were able to transition to home therapy. Eight patients developed persistent IgG antibodies to Agalsidase Alfa, but IgE antibodies were not detected in any patient. The development of IgG antibodies appeared not to affect any clinical end points. Estimated GFR remained stable in subgroups of patients with Stage I (GFR >90 ml/min) or Stage II (GFR 60–89 ml/min) chronic kidney disease at baseline. In contrast, in the subgroup of patients with Stage III chronic kidney disease (GFR 30–59 ml/min), the slope of the decline in GFR was reduced compared with comparable historical controls, suggesting that enzyme replacement therapy was slowing the decline of renal function in this susceptible population. Conclusions. Long-term enzyme replacement therapy with Agalsidase Alfa is safe and may slow the progressive decline in renal function that was commonly observed in adult males with Fabry disease.

Fellype C Barreto - One of the best experts on this subject based on the ideXlab platform.

  • enzyme replacement therapy for anderson fabry disease a complementary overview of a cochrane publication through a linear regression and a pooled analysis of proportions from cohort studies
    PLOS ONE, 2017
    Co-Authors: Huda Gomaa, Anil Kapoor, Juan Politei, Fellype C Barreto
    Abstract:

    Background Anderson-Fabry disease (AFD) is an X-linked recessive inborn error of glycosphingolipid metabolism caused by a deficiency of alpha-galactosidase A. Renal failure, heart and cerebrovascular involvement reduce survival. A Cochrane review provided little evidence on the use of enzyme replacement therapy (ERT). We now complement this review through a linear regression and a pooled analysis of proportions from cohort studies. Objectives To evaluate the efficacy and safety of ERT for AFD. Materials and methods For the systematic review, a literature search was performed, from inception to March 2016, using Medline, EMBASE and LILACS. Inclusion criteria were cohort studies, patients with AFD on ERT or natural history, and at least one patient-important outcome (all-cause mortality, renal, cardiovascular or cerebrovascular events, and adverse events) reported. The pooled proportion and the confidence interval (CI) are shown for each outcome. Simple linear regressions for composite endpoints were performed. Results 77 cohort studies involving 15,305 participants proved eligible. The pooled proportions were as follows: a) for renal complications, Agalsidase Alfa 15.3% [95% CI 0.048, 0.303; I2 = 77.2%, p = 0.0005]; Agalsidase beta 6% [95% CI 0.04, 0.07; I2 = not applicable]; and untreated patients 21.4% [95% CI 0.1522, 0.2835; I2 = 89.6%, p<0.0001]. Effect differences favored Agalsidase beta compared to untreated patients; b) for cardiovascular complications, Agalsidase Alfa 28% [95% CI 0.07, 0.55; I2 = 96.7%, p<0.0001]; Agalsidase beta 7% [95% CI 0.05, 0.08; I2 = not applicable]; and untreated patients 26.2% [95% CI 0.149, 0.394; I2 = 98.8%, p<0.0001]. Effect differences favored Agalsidase beta compared to untreated patients; and c) for cerebrovascular complications, Agalsidase Alfa 11.1% [95% CI 0.058, 0.179; I2 = 70.5%, p = 0.0024]; Agalsidase beta 3.5% [95% CI 0.024, 0.046; I2 = 0%, p = 0.4209]; and untreated patients 18.3% [95% CI 0.129, 0.245; I2 = 95% p < 0.0001]. Effect differences favored Agalsidase beta over Agalsidase Alfa or untreated patients. A linear regression showed that Fabry patients receiving Agalsidase Alfa are more likely to have higher rates of composite endpoints compared to those receiving Agalsidase beta. Conclusions Agalsidase beta is associated to a significantly lower incidence of renal, cardiovascular and cerebrovascular events than no ERT, and to a significantly lower incidence of cerebrovascular events than Agalsidase Alfa. In view of these results, the use of Agalsidase beta for preventing major organ complications related to AFD can be recommended.

  • Enzyme replacement therapy for Anderson-Fabry disease: A complementary overview of a Cochrane publication through a linear regression and a pooled analysis of proportions from cohort studies.
    PLOS ONE, 2017
    Co-Authors: Huda Gomaa, Anil Kapoor, Juan Politei, Alberto Ortiz, Fellype C Barreto
    Abstract:

    Background Anderson-Fabry disease (AFD) is an X-linked recessive inborn error of glycosphingolipid metabolism caused by a deficiency of alpha-galactosidase A. Renal failure, heart and cerebrovascular involvement reduce survival. A Cochrane review provided little evidence on the use of enzyme replacement therapy (ERT). We now complement this review through a linear regression and a pooled analysis of proportions from cohort studies. Objectives To evaluate the efficacy and safety of ERT for AFD. Materials and methods For the systematic review, a literature search was performed, from inception to March 2016, using Medline, EMBASE and LILACS. Inclusion criteria were cohort studies, patients with AFD on ERT or natural history, and at least one patient-important outcome (all-cause mortality, renal, cardiovascular or cerebrovascular events, and adverse events) reported. The pooled proportion and the confidence interval (CI) are shown for each outcome. Simple linear regressions for composite endpoints were performed. Results 77 cohort studies involving 15,305 participants proved eligible. The pooled proportions were as follows: a) for renal complications, Agalsidase Alfa 15.3% [95% CI 0.048, 0.303; I2 = 77.2%, p = 0.0005]; Agalsidase beta 6% [95% CI 0.04, 0.07; I2 = not applicable]; and untreated patients 21.4% [95% CI 0.1522, 0.2835; I2 = 89.6%, p

  • enzyme replacement therapy for anderson fabry disease
    Cochrane Database of Systematic Reviews, 2016
    Co-Authors: Huda Gomaa, Raissa Pierri Carvalho, Samira Esteves Afonso Camargo, Rodrigo Bazan, Pasqual Barretti, Fellype C Barreto
    Abstract:

    Background Anderson-Fabry disease is an X-linked defect of glycosphingolipid metabolism. Progressive renal insufficiency is a major source of morbidity, additional complications result from cardio- and cerebro-vascular involvement. Survival is reduced among affected males and symptomatic female carriers. This is an update of a Cochrane review first published in 2010, and previously updated in 2013. Objectives To evaluate the effectiveness and safety of enzyme replacement therapy compared to other interventions, placebo or no interventions, for treating Anderson-Fabry disease. Search methods We searched the Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register (date of the most recent search: 08 July 2016). We also searched 'Clinical Trials' on The Cochrane Library, MEDLINE, Embase and LILACS (date of the most recent search: 24 September 2015). Selection criteria Randomized controlled trials of Agalsidase Alfa or beta in participants diagnosed with Anderson-Fabry disease. Data collection and analysis Two authors selected relevant trials, assessed methodological quality and extracted data. Main results Nine trials comparing either Agalsidase Alfa or beta in 351 participants fulfilled the selection criteria. Both trials comparing Agalsidase Alfa to placebo reported on globotriaosylceramide concentration in plasma and tissue; aggregate results were non-significant. One trial reported pain scores measured by the Brief Pain Inventory severity, there was a statistically significant improvement for participants receiving treatment at up to three months, mean difference -2.10 (95% confidence interval -3.79 to -0.41; at up to five months, mean difference -1.90 (95% confidence interval -3.65 to -0.15); and at up to six months, mean difference -2.00 (95% confidence interval -3.66 to -0.34). There was a significant difference in the Brief Pain Inventory pain-related quality of life at over five months and up to six months, mean difference -2.10 (95% confidence interval -3.92 to -0.28) but not at other time points. Death was not an outcome in either of the trials. One of the three trials comparing Agalsidase beta to placebo reported on globotriaosylceramide concentration in plasma and tissue and showed significant improvement: kidney, mean difference -1.70 (95% confidence interval -2.09 to -1.31); heart, mean difference -0.90 (95% confidence interval -1.18 to -0.62); and composite results (renal, cardiac, and cerebrovascular complications and death), mean difference -4.80 (95% confidence interval -5.45 to -4.15). There was no significant difference between groups for death; no trials reported on pain. Only two trials compared Agalsidase Alfa to Agalsidase beta. One of them showed no significant difference between the groups regarding adverse events, risk ratio 0.36 (95% confidence interval 0.08 to 1.59), or any serious adverse events; risk ratio 0.30; (95% confidence interval 0.03 to 2.57). Two trials compared different dosing schedules of Agalsidase Alfa. One of them involved three different doses (0.2 mg/kg every two weeks; 0.1 mg/kg weekly and; 0.2 mg/kg weekly), the other trial evaluated two further doses to the dosage schedules: 0.4 mg/kg every week and every other week. Both trials failed to show significant differences with various dosing schedules on globotriaosylceramide levels. No significant differences were found among the schedules for the primary efficacy outcome of self-assessed health state, or for pain scores. One trial comparing Agalsidase Alfa to Agalsidase beta showed no significant difference for any adverse events such as dyspnoea and hypertension. The methodological quality of the included trials was generally unclear for the random sequence generation and allocation concealment. Authors' conclusions Trials comparing enzyme replacement therapy to placebo show significant improvement with enzyme replacement therapy in regard to microvascular endothelial deposits of globotriaosylceramide and in pain-related quality of life. There is, however, no evidence identifying if the Alfa or beta form is superior or the optimal dose or frequency of enzyme replacement therapy. With regards to safety, adverse events (i.e., rigors, fever) were more significant in the Agalsidase beta as compared to placebo. The long-term influence of enzyme replacement therapy on risk of morbidity and mortality related to Anderson-Fabry disease remains to be established. This review highlights the need for continued research into the use of enzyme replacement therapy for Anderson-Fabry disease.

Oliver Watkinson - One of the best experts on this subject based on the ideXlab platform.

  • Agalsidase Alfa versus Agalsidase beta for the treatment of fabry disease an international cohort study
    Journal of Medical Genetics, 2018
    Co-Authors: Maarten Arends, Marieke Biegstraaten, Atul Mehta, Daniel Oder, Oliver Watkinson, Perry M Elliott, Sandra Sirrs, Christoph Wanner
    Abstract:

    BACKGROUND: Two recombinant enzymes (Agalsidase Alfa 0.2 mg/kg/every other week and Agalsidase beta 1.0 mg/kg/every other week) have been registered for the treatment of Fabry disease (FD), at equal high costs. An independent international initiative compared clinical and biochemical outcomes of the two enzymes. METHODS: In this multicentre retrospective cohort study, clinical event rate, left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), antibody formation and globotriaosylsphingosine (lysoGb3) levels were compared between patients with FD treated with Agalsidase Alfa and beta at their registered dose after correction for phenotype and sex. RESULTS: 387 patients (192 women) were included, 248 patients received Agalsidase Alfa. Mean age at start of enzyme replacement therapy was 46 (±15) years. Propensity score matched analysis revealed a similar event rate for both enzymes (HR 0.96, P=0.87). The decrease in plasma lysoGb3 was more robust following treatment with Agalsidase beta, specifically in men with classical FD (β: -18 nmol/L, P<0.001), persisting in the presence of antibodies. The risk to develop antibodies was higher for patients treated with Agalsidase beta (OR 2.8, P=0.04). LVMI decreased in a higher proportion following the first year of Agalsidase beta treatment (OR 2.27, P=0.03), while eGFR slopes were similar. CONCLUSIONS: Treatment with Agalsidase beta at higher dose compared with Agalsidase Alfa does not result in a difference in clinical events, which occurred especially in those with more advanced disease. A greater biochemical response, also in the presence of antibodies, and better reduction in left ventricular mass was observed with Agalsidase beta.

  • Agalsidase Alfa versus Agalsidase beta for the treatment of fabry disease an international cohort study
    Journal of Medical Genetics, 2018
    Co-Authors: Maarten Arends, Marieke Biegstraaten, Atul Mehta, Daniel Oder, Oliver Watkinson, Perry M Elliott, Sandra Sirrs, Christoph Wanner
    Abstract:

    Background Two recombinant enzymes (Agalsidase Alfa 0.2 mg/kg/every other week and Agalsidase beta 1.0 mg/kg/every other week) have been registered for the treatment of Fabry disease (FD), at equal high costs. An independent international initiative compared clinical and biochemical outcomes of the two enzymes. Methods In this multicentre retrospective cohort study, clinical event rate, left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), antibody formation and globotriaosylsphingosine (lysoGb3) levels were compared between patients with FD treated with Agalsidase Alfa and beta at their registered dose after correction for phenotype and sex. Results 387 patients (192 women) were included, 248 patients received Agalsidase Alfa. Mean age at start of enzyme replacement therapy was 46 (±15) years. Propensity score matched analysis revealed a similar event rate for both enzymes (HR 0.96, P=0.87). The decrease in plasma lysoGb3 was more robust following treatment with Agalsidase beta, specifically in men with classical FD (β: −18 nmol/L, P Conclusions Treatment with Agalsidase beta at higher dose compared with Agalsidase Alfa does not result in a difference in clinical events, which occurred especially in those with more advanced disease. A greater biochemical response, also in the presence of antibodies, and better reduction in left ventricular mass was observed with Agalsidase beta.

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  • Agalsidase Alfa versus Agalsidase beta for the treatment of fabry disease an international cohort study
    Journal of Medical Genetics, 2018
    Co-Authors: Maarten Arends, Marieke Biegstraaten, Atul Mehta, Daniel Oder, Oliver Watkinson, Perry M Elliott, Sandra Sirrs, Christoph Wanner
    Abstract:

    BACKGROUND: Two recombinant enzymes (Agalsidase Alfa 0.2 mg/kg/every other week and Agalsidase beta 1.0 mg/kg/every other week) have been registered for the treatment of Fabry disease (FD), at equal high costs. An independent international initiative compared clinical and biochemical outcomes of the two enzymes. METHODS: In this multicentre retrospective cohort study, clinical event rate, left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), antibody formation and globotriaosylsphingosine (lysoGb3) levels were compared between patients with FD treated with Agalsidase Alfa and beta at their registered dose after correction for phenotype and sex. RESULTS: 387 patients (192 women) were included, 248 patients received Agalsidase Alfa. Mean age at start of enzyme replacement therapy was 46 (±15) years. Propensity score matched analysis revealed a similar event rate for both enzymes (HR 0.96, P=0.87). The decrease in plasma lysoGb3 was more robust following treatment with Agalsidase beta, specifically in men with classical FD (β: -18 nmol/L, P<0.001), persisting in the presence of antibodies. The risk to develop antibodies was higher for patients treated with Agalsidase beta (OR 2.8, P=0.04). LVMI decreased in a higher proportion following the first year of Agalsidase beta treatment (OR 2.27, P=0.03), while eGFR slopes were similar. CONCLUSIONS: Treatment with Agalsidase beta at higher dose compared with Agalsidase Alfa does not result in a difference in clinical events, which occurred especially in those with more advanced disease. A greater biochemical response, also in the presence of antibodies, and better reduction in left ventricular mass was observed with Agalsidase beta.

  • Agalsidase Alfa versus Agalsidase beta for the treatment of fabry disease an international cohort study
    Journal of Medical Genetics, 2018
    Co-Authors: Maarten Arends, Marieke Biegstraaten, Atul Mehta, Daniel Oder, Oliver Watkinson, Perry M Elliott, Sandra Sirrs, Christoph Wanner
    Abstract:

    Background Two recombinant enzymes (Agalsidase Alfa 0.2 mg/kg/every other week and Agalsidase beta 1.0 mg/kg/every other week) have been registered for the treatment of Fabry disease (FD), at equal high costs. An independent international initiative compared clinical and biochemical outcomes of the two enzymes. Methods In this multicentre retrospective cohort study, clinical event rate, left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), antibody formation and globotriaosylsphingosine (lysoGb3) levels were compared between patients with FD treated with Agalsidase Alfa and beta at their registered dose after correction for phenotype and sex. Results 387 patients (192 women) were included, 248 patients received Agalsidase Alfa. Mean age at start of enzyme replacement therapy was 46 (±15) years. Propensity score matched analysis revealed a similar event rate for both enzymes (HR 0.96, P=0.87). The decrease in plasma lysoGb3 was more robust following treatment with Agalsidase beta, specifically in men with classical FD (β: −18 nmol/L, P Conclusions Treatment with Agalsidase beta at higher dose compared with Agalsidase Alfa does not result in a difference in clinical events, which occurred especially in those with more advanced disease. A greater biochemical response, also in the presence of antibodies, and better reduction in left ventricular mass was observed with Agalsidase beta.

  • long term effectiveness of Agalsidase Alfa enzyme replacement in fabry disease a fabry outcome survey analysis
    Molecular genetics and metabolism reports, 2015
    Co-Authors: M Beck, Atul Mehta, Anna Wijatyk, Christoph Kampmann, Derralynn Hughes, Michael West, Uma Ramaswami, Sylvain Larroque, Guillem Pintosmorell, Roberto Giugliani
    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 m2 had a mean (standard error of the mean [SEM]) annualized change in eGFR of − 2.86 (0.53) mL/min/1.73 m2/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/m2.7/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.

  • Long-term effectiveness of Agalsidase Alfa enzyme replacement in Fabry disease: A Fabry Outcome Survey analysis
    Elsevier, 2015
    Co-Authors: M Beck, Atul Mehta, Anna Wijatyk, Christoph Kampmann, Derralynn Hughes, Guillem Pintos-morell, Michael West, Uma Ramaswami, Sylvain Larroque, Roberto Giugliani
    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

  • Management of Fabry Disease with Agalsidase Treatment
    SAGE Publishing, 2010
    Co-Authors: Guillem Pintos-morell, Olivier Lidove, Atul Mehta
    Abstract:

    Fabry disease is an X-linked lysosomal storage disorder that is caused by a deficiency in the enzyme α-galactosidase A. It results in a progressive multi systemic disorder with major organ involvement (principally renal, cardiac and cerebrovascular) as well as peripheral and autonomic nervous system leading to a poor quality of life, and early death. Enzyme replacement therapy with α-galactosidase A has been used to treat Fabry disease since 2001. Two preparations of the enzyme are available: Agalsidase Alfa, produced in a human cell line, and Agalsidase beta, produced in Chinese hamster ovary cells. Both products have a similar composition, mechanism of action and pharmacokinetic profile however major differences exist in the recommended dose, immunogenicity and rate of adverse reactions. Several clinical trials with the two enzyme preparations have assessed clinical efficacy with respect to impact of treatment on kidney function, cardiomyopathy, pain control and quality of life. Both preparations appear to be broadly equivalent. It has not yet been established that early initiation of enzyme replacement therapy (ERT) can prevent the emergence of disease manifestations. This review will cover the main aspects of clinical safety and efficacy of ERT for Fabry disease