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Dominique P Germain – 1st expert on this subject based on the ideXlab platform
MO035HISTORICAL CONTROL ANALYSIS DEMONSTRATES SUPERIOR REDUCTION OF PLASMA GLOBOTRIAOSYLCERAMIDE BY VENGLUSTAT COMPARED WITH PLACEBO OR Agalsidase Beta IN CLASSIC FABRY DISEASE PATIENTSNephrology Dialysis Transplantation, 2020Co-Authors: Dominique P Germain, William Wilcox, Patrick Deegan, Eric Hailman, Alberto Ortiz, Vijay ModurAbstract:
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.
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.
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).
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.
cardiomyopathy and kidney function in Agalsidase Beta treated female fabry patients a pre treatment vs post treatment analysisEsc 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.
Cardiomyopathy and kidney function in Agalsidase Beta‐treated female Fabry patients: a pre‐treatment vs. post‐treatment analysisEsc 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
Robert J Hopkin – 2nd expert on this subject based on the ideXlab platform
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.
significant abdominal and acute pain improvements in young patients with fabry disease initiated on Agalsidase Beta treatment before age 30 a fabry registry analysisMolecular Genetics and Metabolism, 2019Co-Authors: Robert J Hopkin, Dominique P Germain, Nathalie Guffon, Ulla Feldtrasmussen, John L Jefferies, Ana Jovanovic, Eva Brand, 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.
renal and cardiac outcomes of young male patients with fabry disease initiated on Agalsidase Beta treatment before age 30 a fabry registry analysisMolecular Genetics and Metabolism, 2019Co-Authors: Robert J Hopkin, Dominique P Germain, Nathalie Guffon, Ulla Feldtrasmussen, John L Jefferies, Ana Jovanovic, Eva Brand, 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
William R Wilcox – 3rd expert on this subject based on the ideXlab platform
Agalsidase Beta therapy for advanced fabry diseaseAnnals 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 …
improvement of fabry disease related gastrointestinal symptoms in a significant proportion of female patients treated with Agalsidase Beta data from the fabry registryJIMD 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.
antiproteinuric therapy and fabry nephropathy factors associated with preserved kidney function during Agalsidase Beta therapyJournal 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.