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Gregory A. Grabowski - One of the best experts on this subject based on the ideXlab platform.

  • Dose-response relationships for Enzyme replacement Therapy with imiglucerase/alglucerase in patients with Gaucher disease type 1
    Genetics in Medicine, 2009
    Co-Authors: Gregory A. Grabowski, Carla E. M. Hollak, Pramod K. Mistry, J. Alexander Cole, Katherine Kacena, Lin Zhang, Ari Zimran, Joel Charrow, Stephan Vom Dahl
    Abstract:

    Purpose: To determine whether Enzyme Therapy with imiglucerase/alglucerase demonstrates dose-response relationships with doses and disease parameters used in routine clinical practice for Gaucher disease type 1 patients. Methods: Analyses included all patients with Gaucher disease type 1 on Enzyme Therapy and with intact spleens in the large observational database of the International Collaborative Gaucher Group Gaucher Registry. Propensity scoring was used to match patients between Enzyme Therapy dose groups categorized as Group A (5 U to

  • Gaucher Disease: Progressive Mesenteric and Mediastinal Lymphadenopathy Despite Enzyme Therapy
    The Journal of Pediatrics, 2007
    Co-Authors: T. Andrew Burrow, Mitchell B. Cohen, Ronald E. Bokulic, Gail H. Deutsch, Arabinda K. Choudhary, Richard A. Falcone, Gregory A. Grabowski
    Abstract:

    A 5-year-old male with Gaucher's disease type 3 developed progressive mesenteric and mediastinal lymphadenopathy over 12 months, despite Enzyme replacement Therapy, contributing to the development of a protein-losing enteropathy. These complications are unique, indicating poorly accessible, differentially responsive compartments in patients with Gaucher's disease who are receiving Enzyme Therapy.

  • Gaucher Disease: alendronate disodium improves bone mineral density in adults receiving Enzyme Therapy
    Blood, 2004
    Co-Authors: Richard J. Wenstrup, Gregory A. Grabowski, Jay Moskovitz, Laurie Bailey, Alan E. Oestreich, Shumei Sun
    Abstract:

    Symptomatic patients with Gaucher disease (GD) (acid beta-glucosidase [Gcase] deficiency) are treated with injectable human recombinant GCase. Treatment results in significant decreases in lipid storage in liver, spleen, and bone marrow, but the generalized osteopenia and focal bone lesions present in many adult patients are refractory to treatment. A double-blind, 2-arm, placebo-controlled trial of alendronate (40 mg/d) was performed in adults with GD who had been treated with Enzyme for at least 24 months. Primary therapeutic endpoints were improvements in (1) bone mineral density (BMD) and content (BMC) at the lumbar spine, and (2) focal lesions in x-rays of long bones assessed by a blinded reviewer. There were 34 patients with GD type 1 (age range, 18-50 years) receiving Enzyme Therapy who were randomized for this study. After 18 months, DeltaBMD at the lumbar spine was 0.068 +/- 0.21 and 0.015 +/- 0.034 for alendronate and placebo groups, respectively (P =.001). Long-bone x-rays showed no change in focal lesions or bone deformities in any subject in either arm. Alendronate is a useful adjunctive Therapy in combination with Enzyme replacement Therapy (ERT) for the treatment of GD-related osteopenia in adults, but it cannot be expected to improve focal lesions.

  • Enzyme Therapy for lysosomal storage disease principles practice and prospects
    Annual Review of Genomics and Human Genetics, 2003
    Co-Authors: Gregory A. Grabowski, Robert J Hopkin
    Abstract:

    Over the past three decades, Enzyme Therapy for lysosomal storage diseases has moved from an academic pursuit to direct delivery of effective clinical care for affected patients and families. This success is based on understanding the complexities of lysosomal biogenesis, lysosomal hydrolase sorting and hydrolytic requirements, and the target sites of pathology of these diseases. This article reviews these concepts and their application to the treatment of affected patients with Gaucher disease, Fabry disease, and mucopolysaccharidosis I. The principles, progress, and practice in these diseases provide prototypes for expansion of Enzyme Therapy to a growing set of these diseases.

  • Enzyme Therapy of gaucher disease: clinical and biochemical changes during production of and tolerization for neutralizing antibodies
    Blood cells molecules & diseases, 2003
    Co-Authors: Huiquan Zhao, Laurie Bailey, Gregory A. Grabowski
    Abstract:

    The clinical impact of neutralizing antibodies directed against the therapeutic Enzyme was investigated in patients with Gaucher disease. Two patients with Gaucher disease type 1 were followed for their clinical progression during antibody development and clinical changes during tolerization. Patient 1 developed neutralizing antibodies to imiglucerase (GCase) at the 10th month of Enzyme Therapy. Tolerization was achieved within a 42-month period with a short course of cyclophosphamide and then higher dose Enzyme (60 IU/kg/week) alone. Patient 1 continues to improve up to 100 months of Enzyme Therapy despite the presence of low level in vitro neutralizing antibodies. Patient 2 developed neutralizing antibodies to GCase at the 29th month of Enzyme Therapy that correlated with clinical deterioration. Clinical stabilization has been observed with increased Enzyme Therapy (60 IU/kg/week) even in the presence of the neutralizing antibodies. Patient 2 is the first to develop neutralizing antibodies after 12 months of Enzyme Therapy. Plasma chitotriosidase activities were not well correlated with the clinical course in either patient. The presence of neutralizing antibodies should be suspected in Gaucher disease patients on Enzyme Therapy who experience diminished response or deterioration. The persistence of minimal amounts of in vitro neutralizing antibodies does not interfere with the therapeutic effectiveness. Chitotriosidase is not a sensitive marker for the severity of disease or disease progression.

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

  • Evaluation of miglustat as maintenance Therapy after Enzyme Therapy in adults with stable type 1 Gaucher disease: a prospective, open-label non-inferiority study.
    Orphanet journal of rare diseases, 2012
    Co-Authors: Timothy M. Cox, Dominick Amato, Cécile Luzy, Ruben Giorgino, Carla E. M. Hollak, M. Silkey, Robert D. Steiner
    Abstract:

    Background Previous studies have provided equivocal data on the use of miglustat as maintenance Therapy in Gaucher disease type 1. We report findings from a clinical trial evaluating the effects of miglustat treatment in patients with stable type 1 Gaucher disease after Enzyme Therapy.

  • Enzyme Therapy for the treatment of type 1 Gaucher disease: clinical outcomes and dose – response relationships
    Expert opinion on pharmacotherapy, 2009
    Co-Authors: Carla E. M. Hollak, Maaike De Fost, Laura Van Dussen, Stephan Vom Dahl, Johannes M F G Aerts
    Abstract:

    Background: Enzyme Therapy for Gaucher disease has improved the lives of many patients, by reducing the burden of their disease. Several studies have sought to determine to what extent optimal clinical outcomes are a function of the prescribed Enzyme dose and its resultant costs. Objective: Issues concerning dose – response relationships during initial and maintenance treatment phases and currently applied treatment goals have been addressed. Methods: All studies that aimed to describe the efficacy of different doses of treatment and approaches for maintenance, such as lowering the dose or changing to less frequent infusions and the effects of drug interruptions, were reviewed. Results/conclusion: Dose – response relationships do exist, but doses between 30 and 60 U/kg per month may be sufficient in a large majority of patients. Goals of treatment should include important clinical end points, such as enhanced quality of life and decreased risk for malignancies and other morbidities. The relationship betwe...

  • Dose-response relationships for Enzyme replacement Therapy with imiglucerase/alglucerase in patients with Gaucher disease type 1
    Genetics in Medicine, 2009
    Co-Authors: Gregory A. Grabowski, Carla E. M. Hollak, Pramod K. Mistry, J. Alexander Cole, Katherine Kacena, Lin Zhang, Ari Zimran, Joel Charrow, Stephan Vom Dahl
    Abstract:

    Purpose: To determine whether Enzyme Therapy with imiglucerase/alglucerase demonstrates dose-response relationships with doses and disease parameters used in routine clinical practice for Gaucher disease type 1 patients. Methods: Analyses included all patients with Gaucher disease type 1 on Enzyme Therapy and with intact spleens in the large observational database of the International Collaborative Gaucher Group Gaucher Registry. Propensity scoring was used to match patients between Enzyme Therapy dose groups categorized as Group A (5 U to

  • Enzyme Therapy for fabry disease neutralizing antibodies toward agalsidase alpha and beta
    Kidney International, 2004
    Co-Authors: Gabor E Linthorst, Carla E. M. Hollak, Wilma E Donkerkoopman, Anneke Strijland, Johannes M F G Aerts
    Abstract:

    Enzyme Therapy for Fabry disease: Neutralizing antibodies toward agalsidase alpha and beta. Background Fabry disease is an X-linked inherited disorder that is caused by excessive lysosomal globotriaosylceramide (CTH) storage due to a deficiency in α-galactosidase A (α-Gal A). Two recombinant Enzyme preparations have been approved as treatment modality. We studied emergence and properties of α-Gal A antibodies in treated patients. Methods During the first 6 to 12 months of intravenous administration of recombinant Enzymes (rh-α-Gal A) formation of antibodies was studied in 18 adult Fabry patients (two females). Results The female patients did not develop detectable amounts of antibodies following Enzyme Therapy. After 6 months of treatment with either agalsidase alpha or beta, 11/16 male patients showed high titers of immunoglobulin G (IgG) antibodies that cross-react in vitro similarly with both recombinant Enzymes. The anti–rh-α-Gal A IgG neutralizes rh-α-Gal A activity in vitro for 65% to 95%. During infusion with rh-α-Gal A, circulating Enzyme-antibody complexes are formed and these complexes are taken up by leukocytes in the peripheral blood. After 6 months of treatment all IgG-negative patients showed a significant ( P Conclusion Emergence of antibodies with in vivo neutralizing capacities is frequently encountered in treated Fabry disease patients. Complete cross-reactivity of these antibodies suggests that it is unlikely that switching from one to the other recombinant protein prevents the immune response and related effects. Further studies on the clinical implications of α-Gal A antibodies are essential.

Robert D. Steiner - One of the best experts on this subject based on the ideXlab platform.

Timothy M. Cox - One of the best experts on this subject based on the ideXlab platform.

  • eliglustat maintains long term clinical stability in patients with gaucher disease type 1 stabilized on Enzyme Therapy
    Blood, 2017
    Co-Authors: Timothy M. Cox, Guillermo Drelichman, Renata Cravo, Manisha Balwani, Thomas A Burrow, Ana Maria Martins, Elena Lukina, Barry E Rosenbloom, Ozlem Gokeralpan, Nora Watman
    Abstract:

    In the phase 3 Study of Eliglustat Tartrate (Genz-112638) in Patients With Gaucher Disease Who Have Reached Therapeutic Goals With Enzyme Replacement Therapy (ENCORE), at 1 year, eliglustat was noninferior to imiglucerase Enzyme Therapy in maintaining stable platelet counts, hemoglobin concentrations, and spleen and liver volumes. After this primary analysis period, patients entered a long-term extension phase in which all received eliglustat. Duration on eliglustat ranged from 2 to 5 years, depending on timing of enrollment (which spanned 2 years), treatment group to which patients were randomized, and whether they lived in the United States when commercial eliglustat became available. Here we report long-term safety and efficacy of eliglustat for 157 patients who received eliglustat in the ENCORE trial; data are available for 46 patients who received eliglustat for 4 years. Mean hemoglobin concentration, platelet count, and spleen and liver volumes remained stable for up to 4 years. Year to year, all 4 measures remained collectively stable (composite end point relative to baseline values) in ≥85% of patients as well as individually in ≥92%. Mean bone mineral density z scores (lumbar spine and femur) remained stable and were maintained in the healthy reference range throughout. Eliglustat was well tolerated over 4 years; 4 (2.5%) patients withdrew because of adverse events that were considered related to the study drug. No new or long-term safety concerns were identified. Clinical stability assessed by composite and individual measures was maintained in adults with Gaucher disease type 1 treated with eliglustat who remained in the ENCORE trial for up to 4 years. This trial was registered at www.clinicaltrials.gov as #NCT00943111.

  • Evaluation of miglustat as maintenance Therapy after Enzyme Therapy in adults with stable type 1 Gaucher disease: a prospective, open-label non-inferiority study.
    Orphanet journal of rare diseases, 2012
    Co-Authors: Timothy M. Cox, Dominick Amato, Cécile Luzy, Ruben Giorgino, Carla E. M. Hollak, M. Silkey, Robert D. Steiner
    Abstract:

    Background Previous studies have provided equivocal data on the use of miglustat as maintenance Therapy in Gaucher disease type 1. We report findings from a clinical trial evaluating the effects of miglustat treatment in patients with stable type 1 Gaucher disease after Enzyme Therapy.

Johannes M F G Aerts - One of the best experts on this subject based on the ideXlab platform.

  • Enzyme Therapy for the treatment of type 1 Gaucher disease: clinical outcomes and dose – response relationships
    Expert opinion on pharmacotherapy, 2009
    Co-Authors: Carla E. M. Hollak, Maaike De Fost, Laura Van Dussen, Stephan Vom Dahl, Johannes M F G Aerts
    Abstract:

    Background: Enzyme Therapy for Gaucher disease has improved the lives of many patients, by reducing the burden of their disease. Several studies have sought to determine to what extent optimal clinical outcomes are a function of the prescribed Enzyme dose and its resultant costs. Objective: Issues concerning dose – response relationships during initial and maintenance treatment phases and currently applied treatment goals have been addressed. Methods: All studies that aimed to describe the efficacy of different doses of treatment and approaches for maintenance, such as lowering the dose or changing to less frequent infusions and the effects of drug interruptions, were reviewed. Results/conclusion: Dose – response relationships do exist, but doses between 30 and 60 U/kg per month may be sufficient in a large majority of patients. Goals of treatment should include important clinical end points, such as enhanced quality of life and decreased risk for malignancies and other morbidities. The relationship betwe...

  • Enzyme Therapy for fabry disease neutralizing antibodies toward agalsidase alpha and beta
    Kidney International, 2004
    Co-Authors: Gabor E Linthorst, Carla E. M. Hollak, Wilma E Donkerkoopman, Anneke Strijland, Johannes M F G Aerts
    Abstract:

    Enzyme Therapy for Fabry disease: Neutralizing antibodies toward agalsidase alpha and beta. Background Fabry disease is an X-linked inherited disorder that is caused by excessive lysosomal globotriaosylceramide (CTH) storage due to a deficiency in α-galactosidase A (α-Gal A). Two recombinant Enzyme preparations have been approved as treatment modality. We studied emergence and properties of α-Gal A antibodies in treated patients. Methods During the first 6 to 12 months of intravenous administration of recombinant Enzymes (rh-α-Gal A) formation of antibodies was studied in 18 adult Fabry patients (two females). Results The female patients did not develop detectable amounts of antibodies following Enzyme Therapy. After 6 months of treatment with either agalsidase alpha or beta, 11/16 male patients showed high titers of immunoglobulin G (IgG) antibodies that cross-react in vitro similarly with both recombinant Enzymes. The anti–rh-α-Gal A IgG neutralizes rh-α-Gal A activity in vitro for 65% to 95%. During infusion with rh-α-Gal A, circulating Enzyme-antibody complexes are formed and these complexes are taken up by leukocytes in the peripheral blood. After 6 months of treatment all IgG-negative patients showed a significant ( P Conclusion Emergence of antibodies with in vivo neutralizing capacities is frequently encountered in treated Fabry disease patients. Complete cross-reactivity of these antibodies suggests that it is unlikely that switching from one to the other recombinant protein prevents the immune response and related effects. Further studies on the clinical implications of α-Gal A antibodies are essential.