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Daniel G. Bichet - One of the best experts on this subject based on the ideXlab platform.

  • long term follow up of renal function in patients treated with Migalastat for fabry disease
    2021
    Co-Authors: Daniel G. Bichet, Roberto Giugliani, Derralynn Hughes, Raphael Schiffmann, Nina Skuban, Ulla Feldtrasmussen, Eva Krusinska, Roser Torra, Eric Wallace, Kathy Nicholls
    Abstract:

    The effect of Migalastat on long-term renal outcomes in enzyme replacement therapy (ERT)–naive and ERT-experienced patients with Fabry disease is not well defined. An integrated posthoc analysis of the phase 3 clinical trials and open-label extension studies was conducted to evaluate long-term changes in renal function in patients with Fabry disease and amenable GLA variants who were treated with Migalastat for ≥2 years during these studies. The analysis included ERT-naive (n = 36 [23 females]; mean age 45 years; mean baseline estimated glomerular filtration rate (eGFR), 91.4 mL/min/mL/1.73 m2) and ERT-experienced (n = 42 [24 females]; mean age, 50 years; mean baseline eGFR, 89.2 mL/min/1.73m2) patients with amenable variants who received Migalastat 123 mg every other day for ≥2 years. The annualized rate of change from baseline to last observation in estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI) was calculated by both simple linear regression and a random coefficient model. In ERT-naive patients, mean annualized rates of change from baseline in eGFRCKD-EPI were − 1.6 mL/min/1.73 m2 overall and − 1.8 mL/min/1.73 m2 and − 1.4 mL/min/1.73 m2 in male and female patients, respectively, as estimated by simple linear regression. In ERT-experienced patients, mean annualized rates of change from baseline in eGFRCKD-EPI were − 1.6 mL/min/1.73 m2 overall and − 2.6 mL/min/1.73 m2 and − 0.8 mL/min/1.73 m2 in male and female patients, respectively. Mean annualized rate of change in eGFRCKD-EPI in ERT-naive patients with the classic phenotype (defined by white blood cell alpha galactosidase A [α-Gal A] activity of <3% of normal and multiorgan system involvement) was −1.7 mL/min/1.73 m2. When calculated using the random coefficient model, which adjusted for sex, age, and baseline renal function, the annualized eGFRCKD-EPI change was minimal (mean: −0.1 and 0.1 mL/min/1.73 m2 in ERT-naive and ERT-experienced patients, respectively). In conclusion, patients with Fabry disease and amenable GLA variants receiving long-term Migalastat treatment (≤8.6 years) maintained renal function irrespective of treatment status, sex, or phenotype.

  • assessment of plasma lyso gb3 for clinical monitoring of treatment response in Migalastat treated patients with fabry disease
    2021
    Co-Authors: Daniel G. Bichet, Atul Mehta, Nina Skuban, Johannes M. Aerts, Hiroki Maruyama, Eva Krusinska, Christiane Aurayblais, Raphael Schiffmann
    Abstract:

    Purpose To assess the utility of globotriaosylsphingosine (lyso-Gb(3)) for clinical monitoring of treatment response in patients with Fabry disease receiving Migalastat. Methods A post hoc analysis evaluated data from 97 treatment-naive and enzyme replacement therapy (ERT)-experienced patients with Migalastat-amenableGLAvariants from FACETS (NCT00925301) and ATTRACT (NCT01218659) and subsequent open-label extension studies. The relationship between plasma lyso-Gb(3)and measures of Fabry disease progression (left ventricular mass index [LVMi], estimated glomerular filtration rate [eGFR], and pain) and the relationship between lyso-Gb(3)and incidence of Fabry-associated clinical events (FACEs) were assessed in both groups. The relationship between changes in lyso-Gb(3)and kidney interstitial capillary (KIC) globotriaosylceramide (Gb(3)) inclusions was assessed in treatment-naive patients. Results No significant correlations were identified between changes in lyso-Gb(3)and changes in LVMi, eGFR, or pain. Neither baseline lyso-Gb(3)levels nor the rate of change in lyso-Gb(3)levels during treatment predicted FACE occurrences in all patients or those receiving Migalastat for >= 24 months. Changes in lyso-Gb(3)correlated with changes in KIC Gb(3)inclusions in treatment-naive patients. Conclusions Although used as a pharmacodynamic biomarker in research and clinical studies, plasma lyso-Gb(3)may not be a suitable biomarker for monitoring treatment response in Migalastat-treated patients.

  • Assessment of plasma lyso-Gb_3 for clinical monitoring of treatment response in Migalastat-treated patients with Fabry disease
    2020
    Co-Authors: Daniel G. Bichet, Nina Skuban, Johannes M. Aerts, Christiane Auray-blais, Hiroki Maruyama, Atul B. Mehta, Eva Krusinska, Raphael Schiffmann
    Abstract:

    Purpose To assess the utility of globotriaosylsphingosine (lyso-Gb_3) for clinical monitoring of treatment response in patients with Fabry disease receiving Migalastat. Methods A post hoc analysis evaluated data from 97 treatment-naive and enzyme replacement therapy (ERT)–experienced patients with Migalastat- amenable GLA variants from FACETS (NCT00925301) and ATTRACT (NCT01218659) and subsequent open-label extension studies. The relationship between plasma lyso-Gb_3 and measures of Fabry disease progression (left ventricular mass index [LVMi], estimated glomerular filtration rate [eGFR], and pain) and the relationship between lyso-Gb_3 and incidence of Fabry-associated clinical events (FACEs) were assessed in both groups. The relationship between changes in lyso-Gb_3 and kidney interstitial capillary (KIC) globotriaosylceramide (Gb_3) inclusions was assessed in treatment-naive patients. Results No significant correlations were identified between changes in lyso-Gb_3 and changes in LVMi, eGFR, or pain. Neither baseline lyso-Gb_3 levels nor the rate of change in lyso-Gb_3 levels during treatment predicted FACE occurrences in all patients or those receiving Migalastat for ≥24 months. Changes in lyso-Gb_3 correlated with changes in KIC Gb_3 inclusions in treatment-naive patients. Conclusions Although used as a pharmacodynamic biomarker in research and clinical studies, plasma lyso-Gb_3 may not be a suitable biomarker for monitoring treatment response in Migalastat-treated patients.

  • Efficacy of the pharmacologic chaperone Migalastat in a subset of male patients with the classic phenotype of Fabry disease and Migalastat-amenable variants: data from the phase 3 randomized, multicenter, double-blind clinical trial and extension study
    2019
    Co-Authors: Dominique P Germain, Robert B. Colvin, Laura Barisoni, Roberto Giugliani, Kathy Nicholls, Daniel G. Bichet, Derralynn A. Hughes, Nina Skuban, J. Charles Jennette, Jeffrey P Castelli
    Abstract:

    Purpose Outcomes in patients with Fabry disease receiving Migalastat during the phase 3 FACETS trial (NCT00925301) were evaluated by phenotype. Methods Data were evaluated in two subgroups of patients with Migalastat-amenable GLA variants: “classic phenotype” ( n  = 14; males with residual peripheral blood mononuclear cell α-galactosidase A

  • efficacy of the pharmacologic chaperone Migalastat in a subset of male patients with the classic phenotype of fabry disease and Migalastat amenable variants data from the phase 3 randomized multicenter double blind clinical trial and extension study
    2019
    Co-Authors: Dominique P Germain, Robert B. Colvin, Laura Barisoni, Roberto Giugliani, Derralynn Hughes, Kathy Nicholls, Charles Jennette, Daniel G. Bichet, Nina Skuban, Jeffrey P Castelli
    Abstract:

    Outcomes in patients with Fabry disease receiving Migalastat during the phase 3 FACETS trial (NCT00925301) were evaluated by phenotype. Data were evaluated in two subgroups of patients with Migalastat-amenable GLA variants: “classic phenotype” (n = 14; males with residual peripheral blood mononuclear cell α-galactosidase A <3% normal and multiorgan system involvement) and “other patients” (n = 36; males not meeting classic phenotype criteria and all females). Endpoints included estimated glomerular filtration rate (eGFR), left ventricular mass index (LVMi), Gastrointestinal Symptoms Rating Scale diarrhea subscale (GSRS-D), renal peritubular capillary (PTC) globotriaosylceramide (GL-3) inclusions, and plasma globotriaosylsphingosine (lyso-Gb3). Baseline measures in the classic phenotype patients suggested a more severe phenotype. At month 24, mean (SD) annualized change in eGFRCKD-EPI with Migalastat was −0.3 (3.76) mL/min/1.73 m2 in the classic phenotype subgroup; changes in LVMi, GSRS-D, and lyso-Gb3 were −16.7 (18.64) g/m2, −0.9 (1.66), and −36.8 (35.78) nmol/L, respectively. At month 6, mean PTC GL-3 inclusions decreased with Migalastat (−0.8) and increased with placebo (0.3); switching from placebo to Migalastat, PTC inclusions decreased by −0.7. Numerically smaller changes in these endpoints were observed in the other patients. Migalastat provided clinical benefit to patients with Fabry disease and amenable variants, regardless of disease severity.

Jeffrey P Castelli - One of the best experts on this subject based on the ideXlab platform.

  • efficacy and safety of Migalastat in a japanese population a subgroup analysis of the attract study
    2020
    Co-Authors: Ichiei Narita, Jeffrey P Castelli, Toya Ohashi, Takashi Hamazaki, Norio Sakai, Nina Skuban, Hjalmar Lagast, Jay Barth
    Abstract:

    Fabry disease is a progressive X-linked lysosomal disorder. In this subgroup analysis of the global phase III ATTRACT study, the efficacy and safety of oral Migalastat, a pharmacologic chaperone, were investigated in Japanese patients with Fabry disease. Patients were randomly assigned to receive Migalastat (150 mg every other day) or to continue biweekly enzyme replacement therapy infusions (ERT; agalsidase alfa 0.2 mg/kg or agalsidase beta 1.0 mg/kg) for 18 months followed by a 12-month open-label extension during which all patients received Migalastat. End points included glomerular filtration rate (estimated and measured), left ventricular mass index (LVMi), composite clinical outcomes, leukocyte alpha-galactosidase A activity, plasma globotriaosylsphingosine (lyso-Gb3), and safety. Data from 7 Japanese patients (Migalastat, 5; ERT, 2), mean age 55 years, with high disease burden, were analyzed. All patients in the Migalastat group completed the open-label comparison and extension periods. At 18 months, efficacy in the Japanese patient population was similar to that in the overall ATTRACT population. Migalastat treatment increased leukocyte alpha-galactosidase A activity, stabilized renal function, and decreased LVMi. Plasma lyso-Gb3 levels remained low and stable. Additionally, the long-term extension study showed that efficacy of Migalastat was maintained for up to 48 months. Migalastat was safe and well tolerated in the Japanese patients, as in the overall ATTRACT population. Migalastat can be used to treat Japanese patients with Fabry disease with GLA mutations amenable to Migalastat according to the dosage and administration approved in other countries. ClinicalTrials.gov, NCT01218659 and NCT02194985.

  • Efficacy of the pharmacologic chaperone Migalastat in a subset of male patients with the classic phenotype of Fabry disease and Migalastat-amenable variants: data from the phase 3 randomized, multicenter, double-blind clinical trial and extension study
    2019
    Co-Authors: Dominique P Germain, Robert B. Colvin, Laura Barisoni, Roberto Giugliani, Kathy Nicholls, Daniel G. Bichet, Derralynn A. Hughes, Nina Skuban, J. Charles Jennette, Jeffrey P Castelli
    Abstract:

    Purpose Outcomes in patients with Fabry disease receiving Migalastat during the phase 3 FACETS trial (NCT00925301) were evaluated by phenotype. Methods Data were evaluated in two subgroups of patients with Migalastat-amenable GLA variants: “classic phenotype” ( n  = 14; males with residual peripheral blood mononuclear cell α-galactosidase A

  • efficacy of the pharmacologic chaperone Migalastat in a subset of male patients with the classic phenotype of fabry disease and Migalastat amenable variants data from the phase 3 randomized multicenter double blind clinical trial and extension study
    2019
    Co-Authors: Dominique P Germain, Robert B. Colvin, Laura Barisoni, Roberto Giugliani, Derralynn Hughes, Kathy Nicholls, Charles Jennette, Daniel G. Bichet, Nina Skuban, Jeffrey P Castelli
    Abstract:

    Outcomes in patients with Fabry disease receiving Migalastat during the phase 3 FACETS trial (NCT00925301) were evaluated by phenotype. Data were evaluated in two subgroups of patients with Migalastat-amenable GLA variants: “classic phenotype” (n = 14; males with residual peripheral blood mononuclear cell α-galactosidase A <3% normal and multiorgan system involvement) and “other patients” (n = 36; males not meeting classic phenotype criteria and all females). Endpoints included estimated glomerular filtration rate (eGFR), left ventricular mass index (LVMi), Gastrointestinal Symptoms Rating Scale diarrhea subscale (GSRS-D), renal peritubular capillary (PTC) globotriaosylceramide (GL-3) inclusions, and plasma globotriaosylsphingosine (lyso-Gb3). Baseline measures in the classic phenotype patients suggested a more severe phenotype. At month 24, mean (SD) annualized change in eGFRCKD-EPI with Migalastat was −0.3 (3.76) mL/min/1.73 m2 in the classic phenotype subgroup; changes in LVMi, GSRS-D, and lyso-Gb3 were −16.7 (18.64) g/m2, −0.9 (1.66), and −36.8 (35.78) nmol/L, respectively. At month 6, mean PTC GL-3 inclusions decreased with Migalastat (−0.8) and increased with placebo (0.3); switching from placebo to Migalastat, PTC inclusions decreased by −0.7. Numerically smaller changes in these endpoints were observed in the other patients. Migalastat provided clinical benefit to patients with Fabry disease and amenable variants, regardless of disease severity.

  • efficacy of the pharmacologic chaperone Migalastat in a subset of male patients with the classic phenotype of fabry disease and Migalastat amenable variants data from the phase 3 randomized multicenter double blind clinical trial and extension study
    2019
    Co-Authors: Dominique Germain, Robert B. Colvin, Laura Barisoni, Roberto Giugliani, Derralynn Hughes, Kathy Nicholls, Charles Jennette, Daniel G. Bichet, Nina Skuban, Jeffrey P Castelli
    Abstract:

    PURPOSE: Outcomes in patients with Fabry disease receiving Migalastat during the phase 3 FACETS trial (NCT00925301) were evaluated by phenotype. METHODS: Data were evaluated in two subgroups of patients with Migalastat-amenable GLA variants: "classic phenotype" (n = 14; males with residual peripheral blood mononuclear cell α-galactosidase A <3% normal and multiorgan system involvement) and "other patients" (n = 36; males not meeting classic phenotype criteria and all females). Endpoints included estimated glomerular filtration rate (eGFR), left ventricular mass index (LVMi), Gastrointestinal Symptoms Rating Scale diarrhea subscale (GSRS-D), renal peritubular capillary (PTC) globotriaosylceramide (GL-3) inclusions, and plasma globotriaosylsphingosine (lyso-Gb3). RESULTS: Baseline measures in the classic phenotype patients suggested a more severe phenotype. At month 24, mean (SD) annualized change in eGFRCKD-EPI with Migalastat was -0.3 (3.76) mL/min/1.73 m2 in the classic phenotype subgroup; changes in LVMi, GSRS-D, and lyso-Gb3 were -16.7 (18.64) g/m2, -0.9 (1.66), and -36.8 (35.78) nmol/L, respectively. At month 6, mean PTC GL-3 inclusions decreased with Migalastat (-0.8) and increased with placebo (0.3); switching from placebo to Migalastat, PTC inclusions decreased by -0.7. Numerically smaller changes in these endpoints were observed in the other patients. CONCLUSION: Migalastat provided clinical benefit to patients with Fabry disease and amenable variants, regardless of disease severity.

  • resultats cardiaques au long cours du traitement par Migalastat chez des patients atteints de la maladie de fabry resultats des essais cliniques de phase 3
    2018
    Co-Authors: Dominique P Germain, Raphael Schiffmann, Daniel G. Bichet, A Jovanovic, Ulla Feldtrasmussen, D Hugues, Jeffrey P Castelli
    Abstract:

    Introduction Evaluer les effets au long cours du Migalastat sur la morphologie et la fonction cardiaque (evaluees par lecture centralisee des echocardiographies) chez des patients atteints de la maladie de Fabry, porteurs de mutations sensibles du gene GLA selon le Migalastat Amenability Assay, et recrutes dans deux essais randomises de Phase 3 : FACETS et ATTRACT. Patients et methodes FACETS est un essai de phase 3 avec une 1re phase d’une duree de 6 mois randomisee, en double aveugle, controlee versus placebo, evaluant l’efficacite, la securite et la pharmacodynamie du Migalastat administre a la dose de 150 mg un jour sur deux, suivie d’une etude d’extension de 18 mois consistant en l’ administration en ouvert de Migalastat chez des patients naifs de traitement enzymatique de substitution (TES). Les patients ayant termine l’etude FACETS furent eligibles pour participer a une etude d’extension en ouvert (etude 041). ATTRACT est un essai de phase 3 randomise en ouvert, comparant l’efficacite et la securite du Migalastat et du TES sur une periode de 18 mois, suivie d’une phase d’extension en ouvert (12 mois) ou tous les patients etaient traites par Migalastat ; il fut conduit chez des patients prealablement traites par TES pendant au moins 12 mois. Resultats Etude FACETS et etude d’extension 041. A l’inclusion, la masse ventriculaire gauche indexee (MVGi) moyenne etait egale a 96,5 g/m2 (n = 44). Une reduction moyenne statistiquement significative de la MVGi a ete observee par rapport a la baseline apres 24 mois de traitement par le Migalastat. Celle-ci s’est maintenue a 48 mois (n = 18). La majorite des patients presentant une HVG a l’inclusion ont presente une reduction de la MVGi, avec normalisation dans la moitie des cas a 48 mois. Etude ATTRACT. A l’inclusion, la MVGi moyenne etait de 94,6 g/m2 (n = 30) chez les patients randomises dans le groupe Migalastat et 88,5 g/m2 (n = 13) chez les patients randomises dans le groupe TES. Une reduction statistiquement significative de la MVGi fut observee apres 18 mois de traitement par Migalastat mais pas dans le groupe TES. Cette reduction s’est maintenue pendant la phase en ouvert de 12 mois de traitement chez les patients sous Migalastat (Mois 30 ; −3,8 g/m2 [IC a 95 % −8,9, 1,3] ; n = 28). Parmi les patients presentant une HVG a baseline, la MVGi diminua significativement dans le groupe Migalastat mais pas dans le groupe TES. Conclusion Dans les etudes FACETS et ATTRACT, le traitement au long cours (48 mois) par Migalastat fut associe a une diminution de la MVG, avec regression de l’HVG. Ces effets benefiques a long terme sur la morphologie cardiaque suggerent que le Migalastat est potentiellement capable de reduire le risque de complications cardiaques associees a la maladie de Fabry.

Nina Skuban - One of the best experts on this subject based on the ideXlab platform.

  • long term follow up of renal function in patients treated with Migalastat for fabry disease
    2021
    Co-Authors: Daniel G. Bichet, Roberto Giugliani, Derralynn Hughes, Raphael Schiffmann, Nina Skuban, Ulla Feldtrasmussen, Eva Krusinska, Roser Torra, Eric Wallace, Kathy Nicholls
    Abstract:

    The effect of Migalastat on long-term renal outcomes in enzyme replacement therapy (ERT)–naive and ERT-experienced patients with Fabry disease is not well defined. An integrated posthoc analysis of the phase 3 clinical trials and open-label extension studies was conducted to evaluate long-term changes in renal function in patients with Fabry disease and amenable GLA variants who were treated with Migalastat for ≥2 years during these studies. The analysis included ERT-naive (n = 36 [23 females]; mean age 45 years; mean baseline estimated glomerular filtration rate (eGFR), 91.4 mL/min/mL/1.73 m2) and ERT-experienced (n = 42 [24 females]; mean age, 50 years; mean baseline eGFR, 89.2 mL/min/1.73m2) patients with amenable variants who received Migalastat 123 mg every other day for ≥2 years. The annualized rate of change from baseline to last observation in estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI) was calculated by both simple linear regression and a random coefficient model. In ERT-naive patients, mean annualized rates of change from baseline in eGFRCKD-EPI were − 1.6 mL/min/1.73 m2 overall and − 1.8 mL/min/1.73 m2 and − 1.4 mL/min/1.73 m2 in male and female patients, respectively, as estimated by simple linear regression. In ERT-experienced patients, mean annualized rates of change from baseline in eGFRCKD-EPI were − 1.6 mL/min/1.73 m2 overall and − 2.6 mL/min/1.73 m2 and − 0.8 mL/min/1.73 m2 in male and female patients, respectively. Mean annualized rate of change in eGFRCKD-EPI in ERT-naive patients with the classic phenotype (defined by white blood cell alpha galactosidase A [α-Gal A] activity of <3% of normal and multiorgan system involvement) was −1.7 mL/min/1.73 m2. When calculated using the random coefficient model, which adjusted for sex, age, and baseline renal function, the annualized eGFRCKD-EPI change was minimal (mean: −0.1 and 0.1 mL/min/1.73 m2 in ERT-naive and ERT-experienced patients, respectively). In conclusion, patients with Fabry disease and amenable GLA variants receiving long-term Migalastat treatment (≤8.6 years) maintained renal function irrespective of treatment status, sex, or phenotype.

  • assessment of plasma lyso gb3 for clinical monitoring of treatment response in Migalastat treated patients with fabry disease
    2021
    Co-Authors: Daniel G. Bichet, Atul Mehta, Nina Skuban, Johannes M. Aerts, Hiroki Maruyama, Eva Krusinska, Christiane Aurayblais, Raphael Schiffmann
    Abstract:

    Purpose To assess the utility of globotriaosylsphingosine (lyso-Gb(3)) for clinical monitoring of treatment response in patients with Fabry disease receiving Migalastat. Methods A post hoc analysis evaluated data from 97 treatment-naive and enzyme replacement therapy (ERT)-experienced patients with Migalastat-amenableGLAvariants from FACETS (NCT00925301) and ATTRACT (NCT01218659) and subsequent open-label extension studies. The relationship between plasma lyso-Gb(3)and measures of Fabry disease progression (left ventricular mass index [LVMi], estimated glomerular filtration rate [eGFR], and pain) and the relationship between lyso-Gb(3)and incidence of Fabry-associated clinical events (FACEs) were assessed in both groups. The relationship between changes in lyso-Gb(3)and kidney interstitial capillary (KIC) globotriaosylceramide (Gb(3)) inclusions was assessed in treatment-naive patients. Results No significant correlations were identified between changes in lyso-Gb(3)and changes in LVMi, eGFR, or pain. Neither baseline lyso-Gb(3)levels nor the rate of change in lyso-Gb(3)levels during treatment predicted FACE occurrences in all patients or those receiving Migalastat for >= 24 months. Changes in lyso-Gb(3)correlated with changes in KIC Gb(3)inclusions in treatment-naive patients. Conclusions Although used as a pharmacodynamic biomarker in research and clinical studies, plasma lyso-Gb(3)may not be a suitable biomarker for monitoring treatment response in Migalastat-treated patients.

  • Assessment of plasma lyso-Gb_3 for clinical monitoring of treatment response in Migalastat-treated patients with Fabry disease
    2020
    Co-Authors: Daniel G. Bichet, Nina Skuban, Johannes M. Aerts, Christiane Auray-blais, Hiroki Maruyama, Atul B. Mehta, Eva Krusinska, Raphael Schiffmann
    Abstract:

    Purpose To assess the utility of globotriaosylsphingosine (lyso-Gb_3) for clinical monitoring of treatment response in patients with Fabry disease receiving Migalastat. Methods A post hoc analysis evaluated data from 97 treatment-naive and enzyme replacement therapy (ERT)–experienced patients with Migalastat- amenable GLA variants from FACETS (NCT00925301) and ATTRACT (NCT01218659) and subsequent open-label extension studies. The relationship between plasma lyso-Gb_3 and measures of Fabry disease progression (left ventricular mass index [LVMi], estimated glomerular filtration rate [eGFR], and pain) and the relationship between lyso-Gb_3 and incidence of Fabry-associated clinical events (FACEs) were assessed in both groups. The relationship between changes in lyso-Gb_3 and kidney interstitial capillary (KIC) globotriaosylceramide (Gb_3) inclusions was assessed in treatment-naive patients. Results No significant correlations were identified between changes in lyso-Gb_3 and changes in LVMi, eGFR, or pain. Neither baseline lyso-Gb_3 levels nor the rate of change in lyso-Gb_3 levels during treatment predicted FACE occurrences in all patients or those receiving Migalastat for ≥24 months. Changes in lyso-Gb_3 correlated with changes in KIC Gb_3 inclusions in treatment-naive patients. Conclusions Although used as a pharmacodynamic biomarker in research and clinical studies, plasma lyso-Gb_3 may not be a suitable biomarker for monitoring treatment response in Migalastat-treated patients.

  • long term efficacy and safety of Migalastat treatment in fabry disease 30 month results from the open label extension of the randomized phase 3 attract study
    2020
    Co-Authors: Ulla Feldtrasmussen, Toya Ohashi, Derralynn Hughes, Suma P Shankar, Gere Sunderplassmann, Khan Nedd, Takashi Hamazaki, Iacopo Olivotto, Damara Ortiz, Nina Skuban
    Abstract:

    Results from the 18-month randomized treatment period of the phase 3 ATTRACT study demonstrated the efficacy and safety of oral Migalastat compared with enzyme replacement therapy (ERT) in patients with Fabry disease who previously received ERT. Here, we report data from the subsequent 12-month, Migalastat-only, open-label extension (OLE) period. ATTRACT (Study AT1001-012; NCT01218659) was a randomized, open-label, active-controlled study in patients aged 16-74 years with Fabry disease, an amenable GLA variant, and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. During the OLE, patients who received Migalastat 150 mg every other day (QOD) during the randomized period continued receiving Migalastat (Group 1 [MM]); patients who received ERT every other week discontinued ERT and started Migalastat treatment (Group 2 [EM]). Outcome measures included eGFR, left ventricular mass index (LVMi), composite clinical outcome (renal, cardiac or cerebrovascular events), and safety. Forty-six patients who completed the randomized treatment period continued into the OLE (Group 1 [MM], n = 31; Group 2 [EM], n = 15). eGFR remained stable in both treatment groups. LVMi decreased from baseline at month 30 in Group 1 (MM) in patients with left ventricular hypertrophy at baseline. Only 10% of patients experienced a new composite clinical event with Migalastat treatment during the OLE. No new safety concerns were reported. In conclusion, in patients with Fabry disease and amenable GLA variants, Migalastat 150 mg QOD was well tolerated and demonstrated durable, long-term stability of renal function and reduction in LVMi.

  • efficacy and safety of Migalastat in a japanese population a subgroup analysis of the attract study
    2020
    Co-Authors: Ichiei Narita, Jeffrey P Castelli, Toya Ohashi, Takashi Hamazaki, Norio Sakai, Nina Skuban, Hjalmar Lagast, Jay Barth
    Abstract:

    Fabry disease is a progressive X-linked lysosomal disorder. In this subgroup analysis of the global phase III ATTRACT study, the efficacy and safety of oral Migalastat, a pharmacologic chaperone, were investigated in Japanese patients with Fabry disease. Patients were randomly assigned to receive Migalastat (150 mg every other day) or to continue biweekly enzyme replacement therapy infusions (ERT; agalsidase alfa 0.2 mg/kg or agalsidase beta 1.0 mg/kg) for 18 months followed by a 12-month open-label extension during which all patients received Migalastat. End points included glomerular filtration rate (estimated and measured), left ventricular mass index (LVMi), composite clinical outcomes, leukocyte alpha-galactosidase A activity, plasma globotriaosylsphingosine (lyso-Gb3), and safety. Data from 7 Japanese patients (Migalastat, 5; ERT, 2), mean age 55 years, with high disease burden, were analyzed. All patients in the Migalastat group completed the open-label comparison and extension periods. At 18 months, efficacy in the Japanese patient population was similar to that in the overall ATTRACT population. Migalastat treatment increased leukocyte alpha-galactosidase A activity, stabilized renal function, and decreased LVMi. Plasma lyso-Gb3 levels remained low and stable. Additionally, the long-term extension study showed that efficacy of Migalastat was maintained for up to 48 months. Migalastat was safe and well tolerated in the Japanese patients, as in the overall ATTRACT population. Migalastat can be used to treat Japanese patients with Fabry disease with GLA mutations amenable to Migalastat according to the dosage and administration approved in other countries. ClinicalTrials.gov, NCT01218659 and NCT02194985.

Roberto Giugliani - One of the best experts on this subject based on the ideXlab platform.

  • long term follow up of renal function in patients treated with Migalastat for fabry disease
    2021
    Co-Authors: Daniel G. Bichet, Roberto Giugliani, Derralynn Hughes, Raphael Schiffmann, Nina Skuban, Ulla Feldtrasmussen, Eva Krusinska, Roser Torra, Eric Wallace, Kathy Nicholls
    Abstract:

    The effect of Migalastat on long-term renal outcomes in enzyme replacement therapy (ERT)–naive and ERT-experienced patients with Fabry disease is not well defined. An integrated posthoc analysis of the phase 3 clinical trials and open-label extension studies was conducted to evaluate long-term changes in renal function in patients with Fabry disease and amenable GLA variants who were treated with Migalastat for ≥2 years during these studies. The analysis included ERT-naive (n = 36 [23 females]; mean age 45 years; mean baseline estimated glomerular filtration rate (eGFR), 91.4 mL/min/mL/1.73 m2) and ERT-experienced (n = 42 [24 females]; mean age, 50 years; mean baseline eGFR, 89.2 mL/min/1.73m2) patients with amenable variants who received Migalastat 123 mg every other day for ≥2 years. The annualized rate of change from baseline to last observation in estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI) was calculated by both simple linear regression and a random coefficient model. In ERT-naive patients, mean annualized rates of change from baseline in eGFRCKD-EPI were − 1.6 mL/min/1.73 m2 overall and − 1.8 mL/min/1.73 m2 and − 1.4 mL/min/1.73 m2 in male and female patients, respectively, as estimated by simple linear regression. In ERT-experienced patients, mean annualized rates of change from baseline in eGFRCKD-EPI were − 1.6 mL/min/1.73 m2 overall and − 2.6 mL/min/1.73 m2 and − 0.8 mL/min/1.73 m2 in male and female patients, respectively. Mean annualized rate of change in eGFRCKD-EPI in ERT-naive patients with the classic phenotype (defined by white blood cell alpha galactosidase A [α-Gal A] activity of <3% of normal and multiorgan system involvement) was −1.7 mL/min/1.73 m2. When calculated using the random coefficient model, which adjusted for sex, age, and baseline renal function, the annualized eGFRCKD-EPI change was minimal (mean: −0.1 and 0.1 mL/min/1.73 m2 in ERT-naive and ERT-experienced patients, respectively). In conclusion, patients with Fabry disease and amenable GLA variants receiving long-term Migalastat treatment (≤8.6 years) maintained renal function irrespective of treatment status, sex, or phenotype.

  • Efficacy of the pharmacologic chaperone Migalastat in a subset of male patients with the classic phenotype of Fabry disease and Migalastat-amenable variants: data from the phase 3 randomized, multicenter, double-blind clinical trial and extension study
    2019
    Co-Authors: Dominique P Germain, Robert B. Colvin, Laura Barisoni, Roberto Giugliani, Kathy Nicholls, Daniel G. Bichet, Derralynn A. Hughes, Nina Skuban, J. Charles Jennette, Jeffrey P Castelli
    Abstract:

    Purpose Outcomes in patients with Fabry disease receiving Migalastat during the phase 3 FACETS trial (NCT00925301) were evaluated by phenotype. Methods Data were evaluated in two subgroups of patients with Migalastat-amenable GLA variants: “classic phenotype” ( n  = 14; males with residual peripheral blood mononuclear cell α-galactosidase A

  • efficacy of the pharmacologic chaperone Migalastat in a subset of male patients with the classic phenotype of fabry disease and Migalastat amenable variants data from the phase 3 randomized multicenter double blind clinical trial and extension study
    2019
    Co-Authors: Dominique P Germain, Robert B. Colvin, Laura Barisoni, Roberto Giugliani, Derralynn Hughes, Kathy Nicholls, Charles Jennette, Daniel G. Bichet, Nina Skuban, Jeffrey P Castelli
    Abstract:

    Outcomes in patients with Fabry disease receiving Migalastat during the phase 3 FACETS trial (NCT00925301) were evaluated by phenotype. Data were evaluated in two subgroups of patients with Migalastat-amenable GLA variants: “classic phenotype” (n = 14; males with residual peripheral blood mononuclear cell α-galactosidase A <3% normal and multiorgan system involvement) and “other patients” (n = 36; males not meeting classic phenotype criteria and all females). Endpoints included estimated glomerular filtration rate (eGFR), left ventricular mass index (LVMi), Gastrointestinal Symptoms Rating Scale diarrhea subscale (GSRS-D), renal peritubular capillary (PTC) globotriaosylceramide (GL-3) inclusions, and plasma globotriaosylsphingosine (lyso-Gb3). Baseline measures in the classic phenotype patients suggested a more severe phenotype. At month 24, mean (SD) annualized change in eGFRCKD-EPI with Migalastat was −0.3 (3.76) mL/min/1.73 m2 in the classic phenotype subgroup; changes in LVMi, GSRS-D, and lyso-Gb3 were −16.7 (18.64) g/m2, −0.9 (1.66), and −36.8 (35.78) nmol/L, respectively. At month 6, mean PTC GL-3 inclusions decreased with Migalastat (−0.8) and increased with placebo (0.3); switching from placebo to Migalastat, PTC inclusions decreased by −0.7. Numerically smaller changes in these endpoints were observed in the other patients. Migalastat provided clinical benefit to patients with Fabry disease and amenable variants, regardless of disease severity.

  • efficacy of the pharmacologic chaperone Migalastat in a subset of male patients with the classic phenotype of fabry disease and Migalastat amenable variants data from the phase 3 randomized multicenter double blind clinical trial and extension study
    2019
    Co-Authors: Dominique Germain, Robert B. Colvin, Laura Barisoni, Roberto Giugliani, Derralynn Hughes, Kathy Nicholls, Charles Jennette, Daniel G. Bichet, Nina Skuban, Jeffrey P Castelli
    Abstract:

    PURPOSE: Outcomes in patients with Fabry disease receiving Migalastat during the phase 3 FACETS trial (NCT00925301) were evaluated by phenotype. METHODS: Data were evaluated in two subgroups of patients with Migalastat-amenable GLA variants: "classic phenotype" (n = 14; males with residual peripheral blood mononuclear cell α-galactosidase A <3% normal and multiorgan system involvement) and "other patients" (n = 36; males not meeting classic phenotype criteria and all females). Endpoints included estimated glomerular filtration rate (eGFR), left ventricular mass index (LVMi), Gastrointestinal Symptoms Rating Scale diarrhea subscale (GSRS-D), renal peritubular capillary (PTC) globotriaosylceramide (GL-3) inclusions, and plasma globotriaosylsphingosine (lyso-Gb3). RESULTS: Baseline measures in the classic phenotype patients suggested a more severe phenotype. At month 24, mean (SD) annualized change in eGFRCKD-EPI with Migalastat was -0.3 (3.76) mL/min/1.73 m2 in the classic phenotype subgroup; changes in LVMi, GSRS-D, and lyso-Gb3 were -16.7 (18.64) g/m2, -0.9 (1.66), and -36.8 (35.78) nmol/L, respectively. At month 6, mean PTC GL-3 inclusions decreased with Migalastat (-0.8) and increased with placebo (0.3); switching from placebo to Migalastat, PTC inclusions decreased by -0.7. Numerically smaller changes in these endpoints were observed in the other patients. CONCLUSION: Migalastat provided clinical benefit to patients with Fabry disease and amenable variants, regardless of disease severity.

  • Migalastat improves diarrhea in patients with fabry disease clinical biomarker correlations from the phase 3 facets trial
    2018
    Co-Authors: Roberto Giugliani, Derralynn Hughes, Raphael Schiffmann, Suma P Shankar, Daniel G. Bichet, Ana Jovanovic, Ulla Feldtrasmussen, Laura Barisoni
    Abstract:

    Fabry disease is frequently characterized by gastrointestinal symptoms, including diarrhea. Migalastat is an orally-administered small molecule approved to treat the symptoms of Fabry disease in patients with amenable mutations. We evaluated minimal clinically important differences (MCID) in diarrhea based on the corresponding domain of the patient-reported Gastrointestinal Symptom Rating Scale (GSRS) in patients with Fabry disease and amenable mutations (N = 50) treated with Migalastat 150 mg every other day or placebo during the phase 3 FACETS trial (NCT00925301). After 6 months, significantly more patients receiving Migalastat versus placebo experienced improvement in diarrhea based on a MCID of 0.33 (43% vs 11%; p = .02), including the subset with baseline diarrhea (71% vs 20%; p = .02). A decline in kidney peritubular capillary globotriaosylceramide inclusions correlated with diarrhea improvement; patients with a reduction > 0.1 were 5.6 times more likely to have an improvement in diarrhea than those without (p = .031). Migalastat was associated with a clinically meaningful improvement in diarrhea in patients with Fabry disease and amenable mutations. Reductions in kidney globotriaosylceramide may be a useful surrogate endpoint to predict clinical benefit with Migalastat in patients with Fabry disease. NCT00925301 ; June 19, 2009.

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  • long term follow up of renal function in patients treated with Migalastat for fabry disease
    2021
    Co-Authors: Daniel G. Bichet, Roberto Giugliani, Derralynn Hughes, Raphael Schiffmann, Nina Skuban, Ulla Feldtrasmussen, Eva Krusinska, Roser Torra, Eric Wallace, Kathy Nicholls
    Abstract:

    The effect of Migalastat on long-term renal outcomes in enzyme replacement therapy (ERT)–naive and ERT-experienced patients with Fabry disease is not well defined. An integrated posthoc analysis of the phase 3 clinical trials and open-label extension studies was conducted to evaluate long-term changes in renal function in patients with Fabry disease and amenable GLA variants who were treated with Migalastat for ≥2 years during these studies. The analysis included ERT-naive (n = 36 [23 females]; mean age 45 years; mean baseline estimated glomerular filtration rate (eGFR), 91.4 mL/min/mL/1.73 m2) and ERT-experienced (n = 42 [24 females]; mean age, 50 years; mean baseline eGFR, 89.2 mL/min/1.73m2) patients with amenable variants who received Migalastat 123 mg every other day for ≥2 years. The annualized rate of change from baseline to last observation in estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI) was calculated by both simple linear regression and a random coefficient model. In ERT-naive patients, mean annualized rates of change from baseline in eGFRCKD-EPI were − 1.6 mL/min/1.73 m2 overall and − 1.8 mL/min/1.73 m2 and − 1.4 mL/min/1.73 m2 in male and female patients, respectively, as estimated by simple linear regression. In ERT-experienced patients, mean annualized rates of change from baseline in eGFRCKD-EPI were − 1.6 mL/min/1.73 m2 overall and − 2.6 mL/min/1.73 m2 and − 0.8 mL/min/1.73 m2 in male and female patients, respectively. Mean annualized rate of change in eGFRCKD-EPI in ERT-naive patients with the classic phenotype (defined by white blood cell alpha galactosidase A [α-Gal A] activity of <3% of normal and multiorgan system involvement) was −1.7 mL/min/1.73 m2. When calculated using the random coefficient model, which adjusted for sex, age, and baseline renal function, the annualized eGFRCKD-EPI change was minimal (mean: −0.1 and 0.1 mL/min/1.73 m2 in ERT-naive and ERT-experienced patients, respectively). In conclusion, patients with Fabry disease and amenable GLA variants receiving long-term Migalastat treatment (≤8.6 years) maintained renal function irrespective of treatment status, sex, or phenotype.

  • assessment of plasma lyso gb3 for clinical monitoring of treatment response in Migalastat treated patients with fabry disease
    2021
    Co-Authors: Daniel G. Bichet, Atul Mehta, Nina Skuban, Johannes M. Aerts, Hiroki Maruyama, Eva Krusinska, Christiane Aurayblais, Raphael Schiffmann
    Abstract:

    Purpose To assess the utility of globotriaosylsphingosine (lyso-Gb(3)) for clinical monitoring of treatment response in patients with Fabry disease receiving Migalastat. Methods A post hoc analysis evaluated data from 97 treatment-naive and enzyme replacement therapy (ERT)-experienced patients with Migalastat-amenableGLAvariants from FACETS (NCT00925301) and ATTRACT (NCT01218659) and subsequent open-label extension studies. The relationship between plasma lyso-Gb(3)and measures of Fabry disease progression (left ventricular mass index [LVMi], estimated glomerular filtration rate [eGFR], and pain) and the relationship between lyso-Gb(3)and incidence of Fabry-associated clinical events (FACEs) were assessed in both groups. The relationship between changes in lyso-Gb(3)and kidney interstitial capillary (KIC) globotriaosylceramide (Gb(3)) inclusions was assessed in treatment-naive patients. Results No significant correlations were identified between changes in lyso-Gb(3)and changes in LVMi, eGFR, or pain. Neither baseline lyso-Gb(3)levels nor the rate of change in lyso-Gb(3)levels during treatment predicted FACE occurrences in all patients or those receiving Migalastat for >= 24 months. Changes in lyso-Gb(3)correlated with changes in KIC Gb(3)inclusions in treatment-naive patients. Conclusions Although used as a pharmacodynamic biomarker in research and clinical studies, plasma lyso-Gb(3)may not be a suitable biomarker for monitoring treatment response in Migalastat-treated patients.

  • Assessment of plasma lyso-Gb_3 for clinical monitoring of treatment response in Migalastat-treated patients with Fabry disease
    2020
    Co-Authors: Daniel G. Bichet, Nina Skuban, Johannes M. Aerts, Christiane Auray-blais, Hiroki Maruyama, Atul B. Mehta, Eva Krusinska, Raphael Schiffmann
    Abstract:

    Purpose To assess the utility of globotriaosylsphingosine (lyso-Gb_3) for clinical monitoring of treatment response in patients with Fabry disease receiving Migalastat. Methods A post hoc analysis evaluated data from 97 treatment-naive and enzyme replacement therapy (ERT)–experienced patients with Migalastat- amenable GLA variants from FACETS (NCT00925301) and ATTRACT (NCT01218659) and subsequent open-label extension studies. The relationship between plasma lyso-Gb_3 and measures of Fabry disease progression (left ventricular mass index [LVMi], estimated glomerular filtration rate [eGFR], and pain) and the relationship between lyso-Gb_3 and incidence of Fabry-associated clinical events (FACEs) were assessed in both groups. The relationship between changes in lyso-Gb_3 and kidney interstitial capillary (KIC) globotriaosylceramide (Gb_3) inclusions was assessed in treatment-naive patients. Results No significant correlations were identified between changes in lyso-Gb_3 and changes in LVMi, eGFR, or pain. Neither baseline lyso-Gb_3 levels nor the rate of change in lyso-Gb_3 levels during treatment predicted FACE occurrences in all patients or those receiving Migalastat for ≥24 months. Changes in lyso-Gb_3 correlated with changes in KIC Gb_3 inclusions in treatment-naive patients. Conclusions Although used as a pharmacodynamic biomarker in research and clinical studies, plasma lyso-Gb_3 may not be a suitable biomarker for monitoring treatment response in Migalastat-treated patients.

  • resultats cardiaques au long cours du traitement par Migalastat chez des patients atteints de la maladie de fabry resultats des essais cliniques de phase 3
    2018
    Co-Authors: Dominique P Germain, Raphael Schiffmann, Daniel G. Bichet, A Jovanovic, Ulla Feldtrasmussen, D Hugues, Jeffrey P Castelli
    Abstract:

    Introduction Evaluer les effets au long cours du Migalastat sur la morphologie et la fonction cardiaque (evaluees par lecture centralisee des echocardiographies) chez des patients atteints de la maladie de Fabry, porteurs de mutations sensibles du gene GLA selon le Migalastat Amenability Assay, et recrutes dans deux essais randomises de Phase 3 : FACETS et ATTRACT. Patients et methodes FACETS est un essai de phase 3 avec une 1re phase d’une duree de 6 mois randomisee, en double aveugle, controlee versus placebo, evaluant l’efficacite, la securite et la pharmacodynamie du Migalastat administre a la dose de 150 mg un jour sur deux, suivie d’une etude d’extension de 18 mois consistant en l’ administration en ouvert de Migalastat chez des patients naifs de traitement enzymatique de substitution (TES). Les patients ayant termine l’etude FACETS furent eligibles pour participer a une etude d’extension en ouvert (etude 041). ATTRACT est un essai de phase 3 randomise en ouvert, comparant l’efficacite et la securite du Migalastat et du TES sur une periode de 18 mois, suivie d’une phase d’extension en ouvert (12 mois) ou tous les patients etaient traites par Migalastat ; il fut conduit chez des patients prealablement traites par TES pendant au moins 12 mois. Resultats Etude FACETS et etude d’extension 041. A l’inclusion, la masse ventriculaire gauche indexee (MVGi) moyenne etait egale a 96,5 g/m2 (n = 44). Une reduction moyenne statistiquement significative de la MVGi a ete observee par rapport a la baseline apres 24 mois de traitement par le Migalastat. Celle-ci s’est maintenue a 48 mois (n = 18). La majorite des patients presentant une HVG a l’inclusion ont presente une reduction de la MVGi, avec normalisation dans la moitie des cas a 48 mois. Etude ATTRACT. A l’inclusion, la MVGi moyenne etait de 94,6 g/m2 (n = 30) chez les patients randomises dans le groupe Migalastat et 88,5 g/m2 (n = 13) chez les patients randomises dans le groupe TES. Une reduction statistiquement significative de la MVGi fut observee apres 18 mois de traitement par Migalastat mais pas dans le groupe TES. Cette reduction s’est maintenue pendant la phase en ouvert de 12 mois de traitement chez les patients sous Migalastat (Mois 30 ; −3,8 g/m2 [IC a 95 % −8,9, 1,3] ; n = 28). Parmi les patients presentant une HVG a baseline, la MVGi diminua significativement dans le groupe Migalastat mais pas dans le groupe TES. Conclusion Dans les etudes FACETS et ATTRACT, le traitement au long cours (48 mois) par Migalastat fut associe a une diminution de la MVG, avec regression de l’HVG. Ces effets benefiques a long terme sur la morphologie cardiaque suggerent que le Migalastat est potentiellement capable de reduire le risque de complications cardiaques associees a la maladie de Fabry.

  • Migalastat for the treatment of fabry disease
    2018
    Co-Authors: Gere Sunderplassmann, Raphael Schiffmann, Kathleen Nicholls
    Abstract:

    Introduction: Fabry disease, a rare X-linked disorder of α-galactosidase A deficiency, leads to progressive multiorgan damage.Areas covered: Enzyme replacement therapy (ERT) is the current standard...