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Dominique P Germain - One of the best experts on this subject based on the ideXlab platform.
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MO035HISTORICAL CONTROL ANALYSIS DEMONSTRATES SUPERIOR REDUCTION OF PLASMA GLOBOTRIAOSYLCERAMIDE BY VENGLUSTAT COMPARED WITH PLACEBO OR Agalsidase Beta IN CLASSIC FABRY DISEASE PATIENTS
Nephrology Dialysis Transplantation, 2020Co-Authors: Dominique P Germain, William Wilcox, Patrick Deegan, Eric Hailman, Alberto Ortiz, Vijay ModurAbstract:Abstract Background and Aims Fabry disease (FD) is a rare, X-linked, genetic disorder caused by pathogenic variants in the gene for the lysosomal enzyme alpha-galactosidase A (αGal-A). The progressive accumulation of glycosphingolipids, most notably globotriaosylceramide (GL-3), leads to renal, cardiovascular, and other clinical manifestations over decades. In a single-arm phase 2 study, glucosylceramide synthase inhibition with venglustat led to a reduction in lysosomal GL-3 inclusions in skin capillary endothelial cells, as well as a progressive reduction in plasma GL-3 to normal levels by 26 weeks, with a continued decrease to low-normal levels after 3 years of therapy. We used patient data from a previously completed placebo-controlled phase 3 study of Agalsidase Beta (Fabrazyme) as historical control to compare the effect of venglustat treatment with placebo over 6 months and with Agalsidase Beta over 3 years. Methods In the venglustat phase 2 study, previously untreated classic FD patients were treated with daily venglustat for up to 3 years (NCT02228460, NCT02489344). For comparison to placebo, change in plasma GL-3 levels after 26 weeks of venglustat treatment was compared with matched historical control data from previously untreated classic FD patients who were treated for 20 weeks with placebo in the phase 3 Agalsidase Beta study (Eng et al, N Engl J Med 345:9, 2001). For comparison to Agalsidase Beta, the historical control arm was matched patients treated with Agalsidase Beta in the phase 3 study; change in plasma GL-3 was compared at multiple time points up to 3 years. Entry criteria and baseline characteristics were similar between the two studies. Due to the much larger numbers of patients in the phase 3 Agalsidase Beta study, venglustat patients were matched 1:X (variable match) with control (placebo or Agalsidase Beta) patients based on propensity scores using baseline variables of age, plasma GL-3, gender, UPCR (< 500 vs 500-1000 vs >1000 mg/g), and eGFR (<80 vs >= 80 mL/min/1.73m2) as matching variables. Plasma GL-3 was measured at Sanofi Genzyme by LC/MS/MS, using the same method for the two studies, with controls in place to assure assay consistency. Results Venglustat patients (N=11) were matched to 19 patients for the placebo comparison and to 28 patients for comparison to Fabrazyme. All patients in all 3 groups were male and had elevated plasma GL-3, UPCR <500 mg/g, and eGFR ≥80 mL/min/1.73m2 at baseline. Mean ages in the 3 groups were 26.6, 25.7, and 26.5 years after matching, respectively. Venglustat treatment for ∼6 months led to a highly significant reduction in plasma GL-3 compared to placebo of 3.62 vs 1.06 µg/mL (p <0.0001). Long-term treatment with venglustat yielded similar reductions in plasma GL-3 compared to Agalsidase Beta for the first year of treatment, but while GL-3 levels reached a plateau with Agalsidase Beta, the reduction with venglustat continued with longer treatment and was significantly greater than that of Agalsidase Beta after 2 years (p=0.0351) or 3 years (p=0.0081) (Figure). Plasma GL-3 levels after 3 years of treatment were 1.90 and 4.44 µg/mL for venglustat and Agalsidase Beta, respectively (normal range ≤7.02 µg/mL). Conclusions Glucosylceramide synthase inhibition with venglustat led to a significantly greater reduction in plasma GL-3 compared to placebo after 6 months, and treatment for 2-3 years led to a significantly greater reduction in plasma GL-3 compared with Agalsidase Beta. These results highlight the potential of long-term treatment venglustat to reverse the accumulation of GL-3 in classic FD.
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cardiomyopathy and kidney function in Agalsidase Beta treated female fabry patients a pre treatment vs post treatment analysis
Esc Heart Failure, 2020Co-Authors: Christoph Wanner, Dominique P Germain, Ulla Feldtrasmussen, Derralynn Hughes, Elvira Ponce, Ana Jovanovic, Ales Linhart, Meng Yang, Eva Brand, John L JefferiesAbstract:AIMS: Long-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 RESULTS: Self-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). CONCLUSIONS: Cardiac 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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Cardiomyopathy and kidney function in Agalsidase Beta‐treated female Fabry patients: a pre‐treatment vs. post‐treatment analysis
Esc Heart Failure, 2020Co-Authors: Christoph Wanner, Dominique P Germain, Derralynn Hughes, Elvira Ponce, Ana Jovanovic, Ales Linhart, Meng Yang, Eva Brand, Ulla Feldt-rasmussen, John L JefferiesAbstract:AIMS: Long-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 RESULTS: Self-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
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significant abdominal and acute pain improvements in young patients with fabry disease initiated on Agalsidase Beta treatment before age 30 a fabry registry analysis
Molecular Genetics and Metabolism, 2019Co-Authors: Robert J Hopkin, Nathalie Guffon, Dominique P Germain, Ulla Feldtrasmussen, Ana Jovanovic, Eva Brand, John L Jefferies, Gustavo Cabrera, Ilkka Kantola, Amel KaraaAbstract:Fabry disease (FD) is a progressive X-linked disorder from deficiency of α-galactosidase. Gastrointestinal symptoms, neuropathic pain, and attacks of excruciating pain are among the earliest symptoms. This Fabry Registry (NCT00196742) analysis assessed changes in symptom reports from male and female patients on Agalsidase Beta with age at first treatment of 5-30 years. GLA variants were classic or unclassified (fabry-database.org), which shared similar clinical features. We compared patient-reported binary responses (yes [present]/no [not present]) for abdominal pain, diarrhea, and peripheral and acute pain between baseline and last follow-up ≥0.5 or ≥2.5 years on treatment separately. Ages at first treatment and follow-up durations were expressed as group medians. Of the early symptoms, peripheral pain was most frequently reported at baseline by the vast majority of the patients. Acute pain was least frequently reported. Compared to baseline, significantly fewer males with ≥0.5 years follow-up reported acute pain after 2.1-year follow-up (17/78 [21.8%] vs. 7/78 [9%], P=0.012, age at first treatment 17.3 years). Data was more limited for patients with ≥2.5 year responses. Among males, the significant decrease in acute pain reports remained after median 4.2-year follow-up (baseline 11/31 [35.3%], follow-up 1/31 [3.2%], P=0.002). Additionally, much fewer males and females reported abdominal pain after median 4.2- and 3.6-year follow-ups, respectively, compared to baseline (males: 21/29 [72.4%] vs. 10/29 [34.5%], P=0.002 females: 12/18 [66.7%] vs. 6/18 [33.3%], P=0.034, ages at first treatment were 21.3 and 22.4 years, respectively). There were no significant changes in yes/no responses for diarrhea or peripheral pain. In conclusion, in young FD patients a reduction in reported acute pain in treated males was sustained over the duration of follow-up. Furthermore, there were fewer reports of abdominal pain in both males and females after sustained Agalsidase Beta treatment. Funding (Fabry Registry, abstract): Sanofi Genzyme.
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renal and cardiac outcomes of young male patients with fabry disease initiated on Agalsidase Beta treatment before age 30 a fabry registry analysis
Molecular Genetics and Metabolism, 2019Co-Authors: Robert J Hopkin, Nathalie Guffon, Dominique P Germain, Ulla Feldtrasmussen, Ana Jovanovic, Eva Brand, John L Jefferies, Gustavo Cabrera, Ilkka Kantola, Amel KaraaAbstract:Fabry disease (FD) is a progressive X-linked disorder from deficiency of α-galactosidase and lysosomal accumulation of glycolipids. This Fabry Registry (NCT00196742) analysis assessed renal and cardiac outcomes of Agalsidase Beta treatment (1 mg/kg 2-weekly) for ≥2 years in male patients with age at first treatment (AFT) of 5-30 years. GLA variants were classic or unclassified (fabry-database.org), which shared similar clinical features. Longitudinal post-treatment analyses included estimated glomerular filtration rate (eGFR, bedside Schwartz equation) stratified by low (LRI, urine protein-to-creatinine ratio [UPCR] ≤0.5 or albumin-to-creatinine ratio [UACR] ≤0.3), or high renal involvement (HRI, UPCR >0.5 or UACR >0.3), and Z-scores of cardiac interventricular septum thickness (IVST) and left ventricular posterior wall thickness (LVPWT), stratified by median AFT. The 31 HRI patients had higher AFT and lower baseline eGFR compared to 189 LRI patients (median AFT: 26.1 vs. 17.1 years eGFR: 81 vs. 92.6 ml/min/1.73m2 P
Robert J Hopkin - One of the best experts on this subject based on the ideXlab platform.
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Low-dose Agalsidase Beta treatment in male pediatric patients with Fabry disease: A 5-year randomized controlled trial.
Molecular Genetics and Metabolism, 2019Co-Authors: Uma Ramaswami, Robert J Hopkin, Daniel G Bichet, Lorne A. Clarke, Gabriela Dostálová, Alejandro Fainboim, Andreas Fellgiebel, Cassiano Mateus Forcelini, Kristina An Haack, Michael MauerAbstract:Abstract Background Fabry disease is a rare, X-linked, lifelong progressive lysosomal storage disorder. Severely deficient α-galactosidase A activity in males is associated with the classic phenotype with early-onset, multisystem manifestations evolving to vital organ complications during adulthood. We assessed the ability of 2 low-dose Agalsidase Beta regimens to lower skin, plasma, and urine globotriaosylceramide (GL-3) levels, and influence clinical manifestations in male pediatric Fabry patients. Methods In this multicenter, open-label, parallel-group, phase 3b study, male patients aged 5–18 years were randomized to receive Agalsidase Beta at 0.5 mg/kg 2-weekly (n = 16) or 1.0 mg/kg 4-weekly (n = 15) for 5 years. All had plasma/urine GL-3 accumulation but no clinically evident organ involvement. The primary outcome was GL-3 accumulation in superficial skin capillary endothelium (SSCE). Results The mean age was 11.6 (range: 5–18) years and all but one of the 31 patients had classic GLA mutations. In the overall cohort, shifts from non-0 to 0-scores for SSCE GL-3 were significant at years 1, 3, and 5, but results were variable. Plasma GL-3 normalized and urine GL-3 reduced substantially. Higher anti-Agalsidase Beta antibody titers were associated with less robust SSCE GL-3 clearance and higher urine GL-3 levels. Renal function remained stable and normal. Most Fabry signs and symptoms tended to stabilize; abdominal pain was significantly reduced (−26.3%; P = .0215). No new clinical major organ complications were observed. GL-3 accumulation and cellular and vascular injury were present in baseline kidney biopsies (n = 7). Treatment effects on podocyte GL-3 content and foot process width were highly variable. Fabry arteriopathy overall increased in severity. Two patients withdrew and 2 had their Agalsidase Beta dose increased. Conclusions Our findings increase the limited amount of available data on long-term effects of enzyme replacement therapy in pediatric, classic Fabry patients. The low-dose regimens studied here over a period of 5 years did not demonstrate a consistent benefit among the patients in terms of controlling symptomatology, urine GL-3 levels, and pathological histology. The current available evidence supports treatment of pediatric, classic male Fabry patients at the approved Agalsidase Beta dose of 1.0 mg/kg 2-weekly if these patients are considered for enzyme replacement therapy with Agalsidase Beta.
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significant abdominal and acute pain improvements in young patients with fabry disease initiated on Agalsidase Beta treatment before age 30 a fabry registry analysis
Molecular Genetics and Metabolism, 2019Co-Authors: Robert J Hopkin, Nathalie Guffon, Dominique P Germain, Ulla Feldtrasmussen, Ana Jovanovic, Eva Brand, John L Jefferies, Gustavo Cabrera, Ilkka Kantola, Amel KaraaAbstract:Fabry disease (FD) is a progressive X-linked disorder from deficiency of α-galactosidase. Gastrointestinal symptoms, neuropathic pain, and attacks of excruciating pain are among the earliest symptoms. This Fabry Registry (NCT00196742) analysis assessed changes in symptom reports from male and female patients on Agalsidase Beta with age at first treatment of 5-30 years. GLA variants were classic or unclassified (fabry-database.org), which shared similar clinical features. We compared patient-reported binary responses (yes [present]/no [not present]) for abdominal pain, diarrhea, and peripheral and acute pain between baseline and last follow-up ≥0.5 or ≥2.5 years on treatment separately. Ages at first treatment and follow-up durations were expressed as group medians. Of the early symptoms, peripheral pain was most frequently reported at baseline by the vast majority of the patients. Acute pain was least frequently reported. Compared to baseline, significantly fewer males with ≥0.5 years follow-up reported acute pain after 2.1-year follow-up (17/78 [21.8%] vs. 7/78 [9%], P=0.012, age at first treatment 17.3 years). Data was more limited for patients with ≥2.5 year responses. Among males, the significant decrease in acute pain reports remained after median 4.2-year follow-up (baseline 11/31 [35.3%], follow-up 1/31 [3.2%], P=0.002). Additionally, much fewer males and females reported abdominal pain after median 4.2- and 3.6-year follow-ups, respectively, compared to baseline (males: 21/29 [72.4%] vs. 10/29 [34.5%], P=0.002 females: 12/18 [66.7%] vs. 6/18 [33.3%], P=0.034, ages at first treatment were 21.3 and 22.4 years, respectively). There were no significant changes in yes/no responses for diarrhea or peripheral pain. In conclusion, in young FD patients a reduction in reported acute pain in treated males was sustained over the duration of follow-up. Furthermore, there were fewer reports of abdominal pain in both males and females after sustained Agalsidase Beta treatment. Funding (Fabry Registry, abstract): Sanofi Genzyme.
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renal and cardiac outcomes of young male patients with fabry disease initiated on Agalsidase Beta treatment before age 30 a fabry registry analysis
Molecular Genetics and Metabolism, 2019Co-Authors: Robert J Hopkin, Nathalie Guffon, Dominique P Germain, Ulla Feldtrasmussen, Ana Jovanovic, Eva Brand, John L Jefferies, Gustavo Cabrera, Ilkka Kantola, Amel KaraaAbstract:Fabry disease (FD) is a progressive X-linked disorder from deficiency of α-galactosidase and lysosomal accumulation of glycolipids. This Fabry Registry (NCT00196742) analysis assessed renal and cardiac outcomes of Agalsidase Beta treatment (1 mg/kg 2-weekly) for ≥2 years in male patients with age at first treatment (AFT) of 5-30 years. GLA variants were classic or unclassified (fabry-database.org), which shared similar clinical features. Longitudinal post-treatment analyses included estimated glomerular filtration rate (eGFR, bedside Schwartz equation) stratified by low (LRI, urine protein-to-creatinine ratio [UPCR] ≤0.5 or albumin-to-creatinine ratio [UACR] ≤0.3), or high renal involvement (HRI, UPCR >0.5 or UACR >0.3), and Z-scores of cardiac interventricular septum thickness (IVST) and left ventricular posterior wall thickness (LVPWT), stratified by median AFT. The 31 HRI patients had higher AFT and lower baseline eGFR compared to 189 LRI patients (median AFT: 26.1 vs. 17.1 years eGFR: 81 vs. 92.6 ml/min/1.73m2 P
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risk factors for severe clinical events in male and female patients with fabry disease treated with Agalsidase Beta enzyme replacement therapy data from the fabry registry
Molecular Genetics and Metabolism, 2016Co-Authors: Robert J Hopkin, Joel Charrow, Alberto Ortiz, Michael Mauer, Ana Maria Martins, Roberta Lemay, Gustavo Cabrera, Manesh R Patel, Katherine B SimsAbstract:Abstract Background Fabry disease, an X-linked lysosomal storage disorder, causes intracellular accumulation of glycosphingolipids leading to progressive renal, cardiovascular, and cerebrovascular disease, and premature death. Methods This longitudinal Fabry Registry study analyzed data from patients with Fabry disease to determine the incidence and type of severe clinical events following initiation of enzyme replacement therapy (ERT) with Agalsidase Beta, as well as risk factors associated with occurrence of these events. Severe events assessed included chronic dialysis, renal transplantation, cardiac events, stroke, and death. Results The analyses included 969 male and 442 female Fabry patients. The mean age at first Agalsidase Beta infusion was 35 and 44, and median treatment follow-up 4.3 years and 3.2 years, respectively. Among males, cardiac events were the most common on-ERT events, followed by renal, stroke, and non-cardiac death. Among females, cardiac events were also most common followed by stroke and renal events. Patients with on-ERT events had significantly more advanced cardiac and renal disease at baseline as compared with patients without on-ERT events. Severe events were also associated with older age at ERT initiation (males and females), a history of pre-ERT events (females; approaching statistical significance in males), and a higher urinary protein/creatinine ratio (females). Approximately 65% of patients with pre-ERT events did not experience subsequent on-ERT events. Of patients without pre-ERT events, most (84% of males, 92% of females) remained event-free. Conclusions Patients with on-ERT severe events had more advanced Fabry organ involvement at baseline than those without such events and patients who initiated ERT at a younger age had less residual risk of on-ERT events. The observed patterns of residual risk may aid clinicians in multidisciplinary monitoring of male and female patients with Fabry disease receiving ERT, and in determining the need for administration of adjunctive therapies.
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Risk factors for severe clinical events in male and female patients with Fabry disease treated with Agalsidase Beta enzyme replacement therapy: Data from the Fabry Registry.
Molecular genetics and metabolism, 2016Co-Authors: Robert J Hopkin, Joel Charrow, Alberto Ortiz, Michael Mauer, Ana Maria Martins, Roberta Lemay, Gustavo Cabrera, Manesh R Patel, Katherine Sims, Stephen WaldekAbstract:Fabry disease, an X-linked lysosomal storage disorder, causes intracellular accumulation of glycosphingolipids leading to progressive renal, cardiovascular, and cerebrovascular disease, and premature death. This longitudinal Fabry Registry study analyzed data from patients with Fabry disease to determine the incidence and type of severe clinical events following initiation of enzyme replacement therapy (ERT) with Agalsidase Beta, as well as risk factors associated with occurrence of these events. Severe events assessed included chronic dialysis, renal transplantation, cardiac events, stroke, and death. The analyses included 969 male and 442 female Fabry patients. The mean age at first Agalsidase Beta infusion was 35 and 44, and median treatment follow-up 4.3years and 3.2years, respectively. Among males, cardiac events were the most common on-ERT events, followed by renal, stroke, and non-cardiac death. Among females, cardiac events were also most common followed by stroke and renal events. Patients with on-ERT events had significantly more advanced cardiac and renal disease at baseline as compared with patients without on-ERT events. Severe events were also associated with older age at ERT initiation (males and females), a history of pre-ERT events (females; approaching statistical significance in males), and a higher urinary protein/creatinine ratio (females). Approximately 65% of patients with pre-ERT events did not experience subsequent on-ERT events. Of patients without pre-ERT events, most (84% of males, 92% of females) remained event-free. Patients with on-ERT severe events had more advanced Fabry organ involvement at baseline than those without such events and patients who initiated ERT at a younger age had less residual risk of on-ERT events. The observed patterns of residual risk may aid clinicians in multidisciplinary monitoring of male and female patients with Fabry disease receiving ERT, and in determining the need for administration of adjunctive therapies. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
William R Wilcox - One of the best experts on this subject based on the ideXlab platform.
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Agalsidase Beta therapy for advanced fabry disease
Annals of Internal Medicine, 2020Co-Authors: Maryam Banikazemi, William R Wilcox, Stephen Waldek, Jan Bultas, Chester B Whitley, Marie Mcdonald, Richard S Finkel, Seymour Packman, Daniel G Bichet, David G WarnockAbstract:Fabry disease is a rare, X-linked lysosomal storage disorder that can cause early death from renal, cardiac, and cerebrovascular involvement. In this double-blind multicenter trial, 82 adults with ...
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improvement of fabry disease related gastrointestinal symptoms in a significant proportion of female patients treated with Agalsidase Beta data from the fabry registry
JIMD reports, 2017Co-Authors: William R Wilcox, Dominique P Germain, Ulla Feldtrasmussen, Kathy Nicholls, Alberto Ortiz, Ana Maria Martins, Ana Jovanovic, Roberta Lemay, Carmen VarasAbstract:Fabry disease, an X-linked inherited lysosomal storage disorder, is caused by mutations in the gene encoding α-galactosidase, GLA. In patients with Fabry disease, glycosphingolipids accumulate in various cell types, triggering a range of cellular and tissue responses that result in a wide spectrum of organ involvement. Although variable, gastrointestinal symptoms are among the most common and significant early clinical manifestations; they tend to persist into adulthood if left untreated. To further understand the effects of sustained enzyme replacement therapy (ERT) with Agalsidase Beta on gastrointestinal symptoms in heterozygotes, a data analysis of female patients enrolled in the Fabry Registry was conducted. To be included, females of any age must have received Agalsidase Beta (average dose 1.0 mg/kg every 2 weeks) for at least 2.5 years. Measured outcomes were self-reported gastrointestinal symptoms (abdominal pain, diarrhea). Outcomes at baseline and last follow-up, and their change from baseline to last follow-up, were assessed. Relevant data were available for 168 female patients. Mean age at the start of ERT was 43 years and mean treatment duration 5.7 years. Baseline pre-treatment abdominal pain was reported by 45% of females and diarrhea by 39%. At last follow-up, 31% reported abdominal pain (p < 0.01) and 27% diarrhea (p < 0.01). The results of this Fabry Registry analysis suggest that while on sustained treatment with Agalsidase Beta (1.0 mg/kg every 2 weeks), both abdominal pain and diarrhea improved in many female patients with Fabry disease.
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antiproteinuric therapy and fabry nephropathy factors associated with preserved kidney function during Agalsidase Beta therapy
Journal of Medical Genetics, 2015Co-Authors: David G Warnock, William R Wilcox, Christie P Thomas, Bojan Vujkovac, Ruth C Campbell, Joel Charrow, Dawn Laney, Leslie L Jackson, Christoph WannerAbstract:Background Nephropathy is an important feature of classical Fabry disease, which results in alpha-galactosidase A deficiency and cellular globotriaosylceramide accumulation. We report the safety and efficacy of antiproteinuric therapy with ACE inhibitors or angiotensin II receptor blockers (ARBs) in a study of classical Fabry patients receiving recombinant Agalsidase-Beta therapy. Methods and design The goal was maintenance of urine protein to creatinine ratio (UPCR) <0.5 g/g or a 50% reduction in baseline UPCR for 24 patients at eight study sites. The change in estimated glomerular filtration rate (eGFR) was assessed over 21 months of treatment. Results 18 out of 24 patients achieved the UPCR goal with eGFR slopes that were significantly better than six patients who did not achieve the UPCR goal (−3.6 (−4.8 to −1.1) versus −7.0 (−9.0 to −5.6) mL/min/1.73 m2/year, respectively, p=0.018). Despite achieving the UPCR goal, 67% (12/18 patients) still progressed with an eGFR slope <−2 mL/min/1.73 m2/year. Regression analysis showed that increased age at initiation of Agalsidase-Beta therapy was significantly associated with worsened kidney outcome. Hypotension and hyperkalaemia occurred in seven and eight patients, respectively, which required modification of antiproteinuric therapy but was not associated with serious adverse events. Conclusions This study documents the effectiveness of Agalsidase-Beta (1 mg/kg/2 weeks) and antiproteinuric therapy with ACE inhibitors and/or ARB in patients with severe Fabry nephropathy. Patients had preservation of kidney function if Agalsidase-Beta treatment was initiated at a younger age, and UPCR maintained at or below 0.5 g/g with antiproteinuric therapy. Trial registration number NCT00446862.
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Antiproteinuric therapy and Fabry nephropathy: factors associated with preserved kidney function during Agalsidase-Beta therapy.
Journal of Medical Genetics, 2015Co-Authors: David G Warnock, William R Wilcox, Christie P Thomas, Bojan Vujkovac, Ruth C Campbell, Joel Charrow, Dawn Laney, Leslie L Jackson, Christoph WannerAbstract:Background Nephropathy is an important feature of classical Fabry disease, which results in alpha-galactosidase A deficiency and cellular globotriaosylceramide accumulation. We report the safety and efficacy of antiproteinuric therapy with ACE inhibitors or angiotensin II receptor blockers (ARBs) in a study of classical Fabry patients receiving recombinant Agalsidase-Beta therapy. Methods and design The goal was maintenance of urine protein to creatinine ratio (UPCR)
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anti α galactosidase a antibody response to Agalsidase Beta treatment data from the fabry registry
Molecular Genetics and Metabolism, 2012Co-Authors: William R Wilcox, Stephen Waldek, Gabor E Linthorst, Dominique P Germain, Ulla Feldtrasmussen, Susan Richards, Dana Beitnerjohnson, Marta Cizmarik, Alexander J ColeAbstract:Abstract Agalsidase Beta, a form of recombinant human α-galactosidase A (αGAL), is approved for use as enzyme replacement therapy (ERT) for Fabry disease. An immunogenic response against a therapeutic protein could potentially impact its efficacy or safety. The development of anti-αGAL IgG antibodies was evaluated in 571 men and 251 women from the Fabry Registry who were treated with Agalsidase Beta. Most men developed antibodies (416 of 571, 73%), whereas most women did not (31 of 251, 12%). Women were also significantly more likely to tolerize than men; whereas 18 of 31 women tolerized (58%, 95%CI: 52%–64%), only 47 of 416 men tolerized during the observation period (11%, 95% CI: 8%–15%). Patients who eventually tolerized had lower median peak anti-αGAL IgG antibody titers than patients who remained seropositive at their most recent assessment (400 versus 3200 in men, 200 versus 400 in women, respectively). Patients with nonsense mutations in the GLA gene were more likely to develop anti-αGAL IgG antibodies than patients with missense mutations. Approximately 26% of men (151 of 571) reported infusion-associated reactions (IARs), compared to 11% of women (27 of 251). Men who developed anti-αGAL IgG antibodies were more likely to experience IARs compared to those who remained seronegative. Nine percent of seronegative men and women (34 of 375) reported IARs. The majority of IARs occurred during the first 6 to 12 months of Agalsidase Beta treatment and decreased over time, in both seroconverted and seronegative patients.
Gabor E Linthorst - One of the best experts on this subject based on the ideXlab platform.
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Current Treatment Trends in Fabry Disease
Clinical Therapeutics, 2020Co-Authors: Gabor E LinthorstAbstract:found that there was more robust clearance of GL-3 in plasma and urine in patients treated with the recom mended dose of Agalsidase Beta (1 mg/kg) compared with those treated with Agalsidase alfa or Agalsidase Beta 0.2 mg/kg. Treatment with a higher dose could overcome the negative influence of antiAgalsidase antibodies on plasma and urine GL-3 that is seen with the lower dose (0.2 mg/kg every other week). However, the clinical sig nificance of more robust urinary and plasma GL-3 clearance is unknown. Currently, various treatment strategies are being studied with Agalsidase alfa (0.2 mg/kg weekly and 0.4 mg/kg every other week) and with Agalsidase Beta (6 months of 1 mg/kg every other week followed by 0.3 mg/kg every other week). The outcome of 1 of these studies was recently published 9 ; results from the other study are eagerly awaited. In addition, in an ongoing Canadian study, patients were randomized to receive either 0.2-mg/kg Agalsidase alfa or I-mg/kg Agalsidase Beta every other week. lo Results from these patients will be analyzed and compared using several clinical and bio chemical end points. These research efforts should lead to more informed decisions regarding the timing of Fabry disease treatment as well as the choice of preparation or dose. Moreover, the goal of future studies will be to confirm whether anti body formation against the infused enzyme is dose related and whether the emergence of antibodies might result in reduced therapeutic efficacy. ACKNOWLEDG M ENTS
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ten year outcome of enzyme replacement therapy with Agalsidase Beta in patients with fabry disease
Journal of Medical Genetics, 2015Co-Authors: Dominique P Germain, Nathalie Guffon, Gabor E Linthorst, Robert J Desnick, Seymour Packman, Joel Charrow, Roberta Lemay, Judy Kempf, Robin H Lachmann, Ronald C ScottAbstract:Background Fabry disease results from deficient α-galactosidase A activity and globotriaosylceramide accumulation causing renal insufficiency, strokes, hypertrophic cardiomyopathy and early demise. We assessed the 10-year outcome of recombinant α-galactosidase A therapy. Methods The outcomes (severe clinical events, renal function, cardiac structure) of 52/58 patients with classic Fabry disease from the phase 3 clinical trial and extension study, and the Fabry Registry were evaluated. Disease progression rates for patients with low renal involvement (LRI, n=32) or high renal involvement (HRI, n=20) at baseline were assessed. Results 81% of patients (42/52) did not experience any severe clinical event during the treatment interval and 94% (49/52) were alive at the end of the study period. Ten patients reported a total of 16 events. Patients classified as LRI started therapy 13 years younger than HRI (mean 25 years vs 38 years). Mean slopes for estimated glomerular filtration rate for LRI and HRI were −1.89 mL/min/1.73 m 2 /year and −6.82 mL/min/1.73 m 2 /year, respectively. Overall, the mean left ventricular posterior wall thickness and interventricular septum thickness remained unchanged and normal. Patients who initiated treatment at age ≥40 years exhibited significant increase in left ventricular posterior wall thickness and interventricular septum thickness. Mean plasma globotriaosylceramide normalised within 6 months. Conclusions This 10-year study documents the effectiveness of Agalsidase Beta (1 mg/kg/2 weeks) in patients with Fabry disease. Most patients remained alive and event-free. Patients who initiated treatment at a younger age and with less kidney involvement benefited the most from therapy. Patients who initiated treatment at older ages and/or had advanced renal disease experienced disease progression.
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recommendations on reintroduction of Agalsidase Beta for patients with fabry disease in europe following a period of shortage
JIMD reports, 2012Co-Authors: Gabor E Linthorst, A Burlina, Franco Cecchi, Janice M Fletcher, Ulla Feldtrasmussen, Roberto Giugliani, Carla E M Hollak, Gunnar Houge, Derralynn Hughes, Iikka KantolaAbstract: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.
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anti α galactosidase a antibody response to Agalsidase Beta treatment data from the fabry registry
Molecular Genetics and Metabolism, 2012Co-Authors: William R Wilcox, Stephen Waldek, Gabor E Linthorst, Dominique P Germain, Ulla Feldtrasmussen, Susan Richards, Dana Beitnerjohnson, Marta Cizmarik, Alexander J ColeAbstract:Abstract Agalsidase Beta, a form of recombinant human α-galactosidase A (αGAL), is approved for use as enzyme replacement therapy (ERT) for Fabry disease. An immunogenic response against a therapeutic protein could potentially impact its efficacy or safety. The development of anti-αGAL IgG antibodies was evaluated in 571 men and 251 women from the Fabry Registry who were treated with Agalsidase Beta. Most men developed antibodies (416 of 571, 73%), whereas most women did not (31 of 251, 12%). Women were also significantly more likely to tolerize than men; whereas 18 of 31 women tolerized (58%, 95%CI: 52%–64%), only 47 of 416 men tolerized during the observation period (11%, 95% CI: 8%–15%). Patients who eventually tolerized had lower median peak anti-αGAL IgG antibody titers than patients who remained seropositive at their most recent assessment (400 versus 3200 in men, 200 versus 400 in women, respectively). Patients with nonsense mutations in the GLA gene were more likely to develop anti-αGAL IgG antibodies than patients with missense mutations. Approximately 26% of men (151 of 571) reported infusion-associated reactions (IARs), compared to 11% of women (27 of 251). Men who developed anti-αGAL IgG antibodies were more likely to experience IARs compared to those who remained seronegative. Nine percent of seronegative men and women (34 of 375) reported IARs. The majority of IARs occurred during the first 6 to 12 months of Agalsidase Beta treatment and decreased over time, in both seroconverted and seronegative patients.
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renal outcomes of Agalsidase Beta treatment for fabry disease role of proteinuria and timing of treatment initiation
Nephrology Dialysis Transplantation, 2012Co-Authors: David G Warnock, Gabor E Linthorst, Bojan Vujkovac, Alberto Ortiz, Michael Mauer, Renzo Mignani, Joao Paulo Oliveira, Andreas L Serra, Laszlo Marodi, Dana BeitnerjohnsonAbstract:Background. The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with Agalsidase Beta. Methods. Renal function was evaluated in 151 men and 62 women from the Fabry Registry who received Agalsidase Beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression. Results. Men within the first quartile had a mean eGFR slope of -0.1 mL/min/1.73m(2)/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of -6.7 mL/min/1.73m(2)/year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) >= 1 g/g (odds ratio 112, 95% confidence interval (95% CI) 4-3109, P = 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95% CI 2-184, P = 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope -4.4 mL/min/1.73m(2)/year). Conclusions. Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is >= 1 g/g. Men with little urinary protein excretion and those who began receiving Agalsidase Beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcomes
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Enzyme Replacement Therapy and Fabry Kidney Disease
Clinical Therapeutics, 2020Co-Authors: David G WarnockAbstract:for Agalsidase alfa is 0.2 mg/kg and for Agalsidase Beta it is 1.0 mg/kg body weight. Approval for both agents was based on Orphan Drug provisions with the use of surrogate end points, 8 such as clearing of vascular endothelial deposits, 11 and symptomatic improvement of pain scores. 12 Furthermore, when ERT was initiated in patients with relatively mild disease, there appeared to be favorable responses in terms of slowing or preventing serious organ dysfunction. 12,13 Less favorable results have been reported in open-label, longitudinal studies in patients with more advanced kidney disease, particularly with overt proteinuria. 14,15 These concerns are echoed by the recently published results of a Phase IV, randomized, prospective, placebo-controlled trial, in which 82 patients with initial glomerular filtration rate (GFR) values 55 mL/min/1.73 m 2 did quite well compared with their placebo control group, but those with more severe disease and proteinuria were not as clearly benefited by ERT. 16 Interpretation of this study is complicated by a baseline imbalance in the urine protein excretion between the placebo group and the Agalsidase Beta group, 16 and the relatively small number of patients included in what was designed to be an outcome study. 17 Proteinuria has emerged as an important risk factor for progression of kidney involvement in a number of kidney diseases, 18 including Fabry disease. 13 The significance of proteinuria in patients with Fabry disease and the limitations of ERT in addressing this issue have recently been examined. A common thread in all of the published outcome studies with Agalsidase alfa 15,19 and Agalsidase Beta 11,13,14,16,20 is that ERT at the currently approved doses simply does not impact urinary protein excretion. The association between pathologic changes (eg, focal and global glomerular sclerosis, tubular atrophy, interstitial fibrosis) and proteinuria is not surprising. 20,21 To date, however, there has been no systematic attempt to reduce the proteinuria and slow the progression of kidney GFR decline in Fabry disease with antiproteinuric therapy, as has been so successful in type 1 and type 2 diabetes mellitus and other forms of proteinuric kidney disease. 22,23 A number of patients in the various trials 11,13‐16,19,20 were treated with angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs), but in none of these studies was systematic reduction of urinary protein excretion identified as a primary or secondary objective. 16 Post hoc analysis of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study would stongly support the primary goal of reducing urinary protein and albumin excretion to a target level, perhaps even more importantly than achieving a fixed goal for systolic
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Agalsidase Beta therapy for advanced fabry disease
Annals of Internal Medicine, 2020Co-Authors: Maryam Banikazemi, William R Wilcox, Stephen Waldek, Jan Bultas, Chester B Whitley, Marie Mcdonald, Richard S Finkel, Seymour Packman, Daniel G Bichet, David G WarnockAbstract:Fabry disease is a rare, X-linked lysosomal storage disorder that can cause early death from renal, cardiac, and cerebrovascular involvement. In this double-blind multicenter trial, 82 adults with ...
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antiproteinuric therapy and fabry nephropathy factors associated with preserved kidney function during Agalsidase Beta therapy
Journal of Medical Genetics, 2015Co-Authors: David G Warnock, William R Wilcox, Christie P Thomas, Bojan Vujkovac, Ruth C Campbell, Joel Charrow, Dawn Laney, Leslie L Jackson, Christoph WannerAbstract:Background Nephropathy is an important feature of classical Fabry disease, which results in alpha-galactosidase A deficiency and cellular globotriaosylceramide accumulation. We report the safety and efficacy of antiproteinuric therapy with ACE inhibitors or angiotensin II receptor blockers (ARBs) in a study of classical Fabry patients receiving recombinant Agalsidase-Beta therapy. Methods and design The goal was maintenance of urine protein to creatinine ratio (UPCR) <0.5 g/g or a 50% reduction in baseline UPCR for 24 patients at eight study sites. The change in estimated glomerular filtration rate (eGFR) was assessed over 21 months of treatment. Results 18 out of 24 patients achieved the UPCR goal with eGFR slopes that were significantly better than six patients who did not achieve the UPCR goal (−3.6 (−4.8 to −1.1) versus −7.0 (−9.0 to −5.6) mL/min/1.73 m2/year, respectively, p=0.018). Despite achieving the UPCR goal, 67% (12/18 patients) still progressed with an eGFR slope <−2 mL/min/1.73 m2/year. Regression analysis showed that increased age at initiation of Agalsidase-Beta therapy was significantly associated with worsened kidney outcome. Hypotension and hyperkalaemia occurred in seven and eight patients, respectively, which required modification of antiproteinuric therapy but was not associated with serious adverse events. Conclusions This study documents the effectiveness of Agalsidase-Beta (1 mg/kg/2 weeks) and antiproteinuric therapy with ACE inhibitors and/or ARB in patients with severe Fabry nephropathy. Patients had preservation of kidney function if Agalsidase-Beta treatment was initiated at a younger age, and UPCR maintained at or below 0.5 g/g with antiproteinuric therapy. Trial registration number NCT00446862.
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Antiproteinuric therapy and Fabry nephropathy: factors associated with preserved kidney function during Agalsidase-Beta therapy.
Journal of Medical Genetics, 2015Co-Authors: David G Warnock, William R Wilcox, Christie P Thomas, Bojan Vujkovac, Ruth C Campbell, Joel Charrow, Dawn Laney, Leslie L Jackson, Christoph WannerAbstract:Background Nephropathy is an important feature of classical Fabry disease, which results in alpha-galactosidase A deficiency and cellular globotriaosylceramide accumulation. We report the safety and efficacy of antiproteinuric therapy with ACE inhibitors or angiotensin II receptor blockers (ARBs) in a study of classical Fabry patients receiving recombinant Agalsidase-Beta therapy. Methods and design The goal was maintenance of urine protein to creatinine ratio (UPCR)
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Cardiomyopathy and response to enzyme replacement therapy in a male mouse model for Fabry disease.
PLOS ONE, 2012Co-Authors: Brigitte Escoubet, David G Warnock, Vincent Agrapart, Violaine Griol-charhbili, Trenton R. Schoeb, Wenguang Feng, Edgar A. Jaimes, Frederic JaisserAbstract:Fabry disease is an X-linked disorder of glycosphingolipid metabolism that results in progressive accumulation of neutral glycosphingolipids, (predominately globotriaosylceramide; GL-3) in lysosomes, as well as other cellular compartments and the extracellular space. Our aim was to characterize the cardiac phenotype of male knock-out mice that are deficient in alpha-galactosidase A activity, as a model for Fabry disease and test the efficacy of Enzyme Replacement Therapy with Agalsidase-Beta. Male mice (3–4 months of age) were characterized with awake blood pressure and heart rate measurements, cardiac echocardiography and electrocardiography measurements under light anesthesia, histological studies and molecular studies with real-time polymerase chain reaction. The Fabry knock-out mouse has bradycardia and lower blood pressure than control wild type (CB7BL/6J) mice. In Fabry knock-out mice, the cardiomyopathy associated mild hypertrophy at echography with normal systolic LV function and mild diastolic dysfunction. Premature atrial contractions were more frequent in without conduction defect. Heart weight normalized to tibial length was increased in Fabry knock-out mice. Ascending aorta dilatation was observed. Molecular studies were consistent with early stages of cardiac remodeling. A single dose of Agalsidase-Beta (3 mg/kg) did not affect the LV hypertrophy, function or heart rate, but did improve the mRNA signals of early cardiac remodeling. In conclusion, the alpha-galactosidase A deficient mice at 3 to 4 months of age have cardiac and vascular alterations similar to that described in early clinical stage of Fabry disease in children and adolescents. Enzyme replacement therapy affects cardiac molecular remodeling after a single dose.
