The Experts below are selected from a list of 237 Experts worldwide ranked by ideXlab platform

Elena Lukina - One of the best experts on this subject based on the ideXlab platform.

  • pregnancy outcome in women with gaucher disease type 1 who had unplanned pregnancies during Eliglustat clinical trials
    JIMD reports, 2021
    Co-Authors: Elena Lukina, Nora Watman, Derralynn Hughes, Nadia Belmatoug, Manisha Balwani, Sebastiaan J M Gaemers, Meredith C Foster, Grace Lewis, Judith M Peterschmitt
    Abstract:

    Gaucher disease type 1 (GD1) is an inherited lysosomal storage disorder caused by deficient enzymatic activity of acid β-glucosidase, resulting in accumulation of its substrate glucosylceramide, leading to debilitating visceral, hematologic, and skeletal manifestations. Women with GD1 are at increased risk for complications during pregnancy, delivery, and postpartum. Treatment with enzyme replacement therapy is generally recommended before and during pregnancy to reduce risks. Eliglustat, an oral substrate-reduction therapy, is a first-line treatment for adults with GD1 adults who have extensive, intermediate, or poor CYP2D6-metabolizer phenotypes (>90% of patients). We report on pregnancy outcomes among women in Eliglustat trials who had unplanned pregnancies and female partners of men in the trials. In four phase 2 and 3 Eliglustat trials of 393 adults with GD1, women of childbearing potential were required to use contraception, have monthly pregnancy tests, and discontinue Eliglustat promptly if pregnant. In phase 2 and 3 trials, 18 women had 19 pregnancies, resulting in 14 healthy infants from 13 pregnancies (one set of twins), three elective terminations, one ectopic pregnancy, one spontaneous abortion, and one in utero death. Median estimated Eliglustat exposure duration during pregnancy was 38 days. In phase 1 trials (non-GD1 subjects), one woman had a spontaneous abortion. Partners of 16 Eliglustat-treated men with GD1 had 18 pregnancies, all resulting in healthy infants. Eliglustat is not approved during pregnancy due to limited data. Guidelines for clinicians and patients with GD that address use of Eliglustat in women of childbearing potential are needed.

  • outcomes after 18 months of Eliglustat therapy in treatment naive adults with gaucher disease type 1 the phase 3 engage trial
    American Journal of Hematology, 2017
    Co-Authors: Pramod K. Mistry, Elena Lukina, Gregory M. Pastores, Hadhami Ben Turkia, Suma P Shankar, Hagit N Baris, Marwan Ghosn, Atul Mehta, Seymour Packman, Milan Petakov
    Abstract:

    Eliglustat, an oral substrate reduction therapy, is a first-line treatment for adults with Gaucher disease type 1 (GD1) who are poor, intermediate, or extensive CYP2D6 metabolizers (>90% of patients). In the primary analysis of the Phase 3 ENGAGE trial (NCT00891202), Eliglustat treatment for 9 months resulted in significant reductions in spleen and liver volumes and increases in hemoglobin concentration and platelet count compared with placebo. We report 18-month outcomes of patients who entered the trial extension period, in which all patients received Eliglustat. Of 40 trial patients, 39 entered the extension period, and 38 completed 18 months. Absolute values and percent change over time were determined for spleen and liver volume, hemoglobin concentration, platelet count, bone mineral density, bone marrow burden, and Gaucher disease biomarkers. For patients randomized to Eliglustat in the double-blind period, continuing treatment with Eliglustat for 9 more months resulted in incremental improvement of all disease parameters. For patients randomized to placebo in the double-blind period, Eliglustat treatment during the 9-month, open-label period resulted in significant decrease of spleen and liver volumes and significant increase of hemoglobin and platelets, with a similar rate of change to patients who had received Eliglustat in the double-blind period. Eliglustat treatment was also associated with improvement in bone marrow burden score, bone mineral density, and established biomarkers of Gaucher disease, including reduction of the bioactive lipid, glucosylsphingosine. These findings underscore the efficacy of Eliglustat in treatment-naive patients. Eliglustat was well-tolerated, and there were no new safety concerns with longer-term exposure.

  • Eliglustat maintains long term clinical stability in patients with gaucher disease type 1 stabilized on enzyme therapy
    Blood, 2017
    Co-Authors: Timothy M. Cox, Elena Lukina, Guillermo Drelichman, Renata Cravo, Manisha Balwani, Thomas A Burrow, Ana Maria Martins, 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.

  • SCIENTIFIC ARTICLE Skeletal improvement in patients with Gaucher disease type
    2016
    Co-Authors: Andrea M. Norfleet, Nora Watman, Elsa Avila Arreguin, Marta Dragosky, Ravi S. Kamath, Elena Lukina, Gregory M. Pastores, Daniel I Rosenthal, H. Rosenbaum, Ari Zimran
    Abstract:

    Objective Eliglustat is an investigational oral substrate reduc-tion therapy for Gaucher disease type 1 (GD1). Its skeletal effects were evaluated by prospective monitoring of bone mineral density (BMD), fractures, marrow infiltration by Gaucher cells, focal bone lesions, and infarcts during an open-label, multi-site, single-arm phase 2 trial (NCT00358150). Materials and methods Institutional review board approval and patient informed consent were obtained. Eliglustat (50 or 100 mg) was self-administered by mouth twice daily; 19 patients completed 4 years of treatment. All were skeletally mature (age range, 18–55 years). DXA and MRI assessments were conducted at baseline and annually thereafter. X-rays were obtained annually until month 24, and then every other year. Results Lumbar spine BMD increased significantly (p=0.02; n=15) by a mean (SD) of 9.9 % (14.2%) from baseline to year 4; corresponding T-scores increased significantly (p=0.01) from a mean (SD) of −1.6 (1.1) to −0.9 (1.3). Mean femur T-score remained normal through 4 years. Femur MRI showed that 10/18 (56 %) patients had decreased Gaucher cell infiltration compared to baseline; one patient with early im-provement had transient worsening at year 4. There were n

  • Management and monitoring recommendations for the use of Eliglustat in adults with type 1 Gaucher disease in Europe.
    European Journal of Internal Medicine, 2016
    Co-Authors: Nadia Belmatoug, Cristina Fraga, Elena Lukina, Martin Merkel, Derralynn Hughes, Pierre Maison-blanche, Claus Niederau, Pilar Giraldo, Maja Di Rocco, Ursula Plӧckinger
    Abstract:

    Abstract Purpose In Gaucher disease, diminished activity of the lysosomal enzyme, acid β-glucosidase, leads to accumulation of glucosylceramides and related substrates, primarily in the spleen, liver, and bone marrow. Eliglustat is an oral substrate reduction therapy approved in the European Union and the United States as a first-line treatment for adults with type 1 Gaucher disease who have compatible CYP2D6 metabolism phenotypes. A European Advisory Council of experts in Gaucher disease describes the characteristics of Eliglustat that are distinct from enzyme augmentation therapy (the standard of care) and miglustat (the other approved substrate reduction therapy) and recommends investigations and monitoring for patients on Eliglustat therapy within the context of current recommendations for Gaucher disease management. Results Eliglustat is a selective, potent inhibitor of glucosylceramide synthase, the enzyme responsible for biosynthesis of glucosylceramides which accumulate in Gaucher disease. Extensive metabolism of Eliglustat by CYP2D6, and, to a lesser extent, CYP3A of the cytochrome P450 pathway, necessitates careful consideration of the patient's CYP2D6 metaboliser status and use of concomitant medications which share metabolism by these pathways. Guidance on specific assessments and monitoring required for Eliglustat therapy, including an algorithm to determine eligibility for Eliglustat, are provided. Conclusions As a first-line therapy for type 1 Gaucher disease, Eliglustat offers eligible patients a daily oral therapy alternative to biweekly infusions of enzyme therapy. Physicians will need to carefully assess individual Gaucher patients to determine their appropriateness for Eliglustat therapy. The therapeutic response to Eliglustat and use of concomitant medications will require long-term monitoring.

Gregory M. Pastores - One of the best experts on this subject based on the ideXlab platform.

  • outcomes after 18 months of Eliglustat therapy in treatment naive adults with gaucher disease type 1 the phase 3 engage trial
    American Journal of Hematology, 2017
    Co-Authors: Pramod K. Mistry, Elena Lukina, Gregory M. Pastores, Hadhami Ben Turkia, Suma P Shankar, Hagit N Baris, Marwan Ghosn, Atul Mehta, Seymour Packman, Milan Petakov
    Abstract:

    Eliglustat, an oral substrate reduction therapy, is a first-line treatment for adults with Gaucher disease type 1 (GD1) who are poor, intermediate, or extensive CYP2D6 metabolizers (>90% of patients). In the primary analysis of the Phase 3 ENGAGE trial (NCT00891202), Eliglustat treatment for 9 months resulted in significant reductions in spleen and liver volumes and increases in hemoglobin concentration and platelet count compared with placebo. We report 18-month outcomes of patients who entered the trial extension period, in which all patients received Eliglustat. Of 40 trial patients, 39 entered the extension period, and 38 completed 18 months. Absolute values and percent change over time were determined for spleen and liver volume, hemoglobin concentration, platelet count, bone mineral density, bone marrow burden, and Gaucher disease biomarkers. For patients randomized to Eliglustat in the double-blind period, continuing treatment with Eliglustat for 9 more months resulted in incremental improvement of all disease parameters. For patients randomized to placebo in the double-blind period, Eliglustat treatment during the 9-month, open-label period resulted in significant decrease of spleen and liver volumes and significant increase of hemoglobin and platelets, with a similar rate of change to patients who had received Eliglustat in the double-blind period. Eliglustat treatment was also associated with improvement in bone marrow burden score, bone mineral density, and established biomarkers of Gaucher disease, including reduction of the bioactive lipid, glucosylsphingosine. These findings underscore the efficacy of Eliglustat in treatment-naive patients. Eliglustat was well-tolerated, and there were no new safety concerns with longer-term exposure.

  • SCIENTIFIC ARTICLE Skeletal improvement in patients with Gaucher disease type
    2016
    Co-Authors: Andrea M. Norfleet, Nora Watman, Elsa Avila Arreguin, Marta Dragosky, Ravi S. Kamath, Elena Lukina, Gregory M. Pastores, Daniel I Rosenthal, H. Rosenbaum, Ari Zimran
    Abstract:

    Objective Eliglustat is an investigational oral substrate reduc-tion therapy for Gaucher disease type 1 (GD1). Its skeletal effects were evaluated by prospective monitoring of bone mineral density (BMD), fractures, marrow infiltration by Gaucher cells, focal bone lesions, and infarcts during an open-label, multi-site, single-arm phase 2 trial (NCT00358150). Materials and methods Institutional review board approval and patient informed consent were obtained. Eliglustat (50 or 100 mg) was self-administered by mouth twice daily; 19 patients completed 4 years of treatment. All were skeletally mature (age range, 18–55 years). DXA and MRI assessments were conducted at baseline and annually thereafter. X-rays were obtained annually until month 24, and then every other year. Results Lumbar spine BMD increased significantly (p=0.02; n=15) by a mean (SD) of 9.9 % (14.2%) from baseline to year 4; corresponding T-scores increased significantly (p=0.01) from a mean (SD) of −1.6 (1.1) to −0.9 (1.3). Mean femur T-score remained normal through 4 years. Femur MRI showed that 10/18 (56 %) patients had decreased Gaucher cell infiltration compared to baseline; one patient with early im-provement had transient worsening at year 4. There were n

  • glucosylsphingosine is a key biomarker of gaucher disease
    American Journal of Hematology, 2016
    Co-Authors: Vagishwari Murugesan, Gregory M. Pastores, Wei-lien Chuang, Haiqun Lin, Jun Liu, Andrew Lischuk, Katherine Kacena, Ruhua Yang, Joan Keutzer, Kate Zhang
    Abstract:

    Gaucher disease (GD) involves the accumulation of glucosylceramide (GL1) and its deacylated lysolipid, glucosylsphingosine (lyso-GL1) which is implicated in mediating immune dysregulation and skeletal disease. The aim of our study was to assess plasma Lyso-GL1 as a biomarker of GD and its response to therapy. Plasma lyso-GL1 in 169 patients with GD type 1 (GD1) was measured by LC-MS/MS. Significant predictors of plasma LGL1 were assessed by Pearson's correlation coefficient, Wilcoxon Mann Whitney test and multiple linear regression. Propensity scores were used to match patients on treatment mode: Enzyme Replacement Therapy (ERT) vs. Eliglustat Tartrate SRT (ELI-SRT). Plasma Lyso-GL1 levels in healthy controls averaged 1.5 ng/ml (1.3–1.7; 95% CI). In untreated GD patients, the levels were massively elevated (180.9 ng/ml: 95% CI, 145.4–216.5) and imiglucerase ERT resulted in marked reduction (89 ng/ml: 95% CI, 69.2–129.4) (P < 0.001). Lyso-GL1 correlated with chitotriosidase (r = 0.59 P < 0.001), CCL18 (r = 0.62 P <0.001), hepatomegaly (r = 0.28 P < 0.001), splenomegaly (r = 0.27 P = 0.003), splenectomy (P = 0.01) and treatment mode (P < 0.001). By multiple linear regression, the strongest predictors of lyso-GL1 were age (P < 0.001), splenectomy (P = 0.02), Chitotriosidase (P < 0.001) and CCL18 levels (P = 0.001). After propensity score matching to obtain comparable groups of patients on ERT vs ELI-SRT, lyso-GL1 levels were lower among patients receiving ELI-SRT by 113 ng/ml (95% CI: 136–90.3 ng/ml P < 0.001). Plasma lyso-GL1 is a key biomarker of GD. ERT reduced lyso-GL1 levels. By propensity scoring, ELI-SRT resulted in greater reduction of lyso-GL1 than ERT. Am. J. Hematol. 91:1082–1089, 2016. © 2016 Wiley Periodicals, Inc.

  • effect of oral Eliglustat on splenomegaly in patients with gaucher disease type 1 the engage randomized clinical trial
    JAMA, 2015
    Co-Authors: Pramod K. Mistry, Elena Lukina, Hadhami Ben Turkia, Hagit N Baris, Marwan Ghosn, Atul Mehta, Seymour Packman, Dominick Amato, Majed Dasouki, Gregory M. Pastores
    Abstract:

    Importance Gaucher disease type 1 is characterized by hepatosplenomegaly, anemia, thrombocytopenia, and skeletal disease. A safe, effective oral therapy is needed. Objective To determine whether Eliglustat, a novel oral substrate reduction therapy, safely reverses clinical manifestations in untreated adults with Gaucher disease type 1. Design, Setting, and Participants Phase 3, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 12 countries from November 2009 to July 2012 among eligible patients with splenomegaly plus thrombocytopenia and/or anemia. Of 72 patients screened, 40 were enrolled. Interventions Patients were stratified by spleen volume and randomized 1:1 to receive Eliglustat (50 or 100 mg twice daily; n = 20) or placebo (n = 20) for 9 months. Main Outcomes and Measures The primary efficacy end point was percentage change in spleen volume in multiples of normal from baseline to 9 months; secondary efficacy end points were change in hemoglobin level and percentage changes in liver volume and platelet count. Results All patients had baseline splenomegaly and thrombocytopenia (mostly moderate or severe), most had mild or moderate hepatomegaly, and 20% had mild anemia. Least-square mean spleen volume decreased by 27.77% (95% CI, −32.57% to −22.97%) in the Eliglustat group (from 13.89 to 10.17 multiples of normal) vs an increase of 2.26% (95% CI, −2.54% to 7.06%) in the placebo group (from 12.50 to 12.84 multiples of normal) for an absolute treatment difference of −30.03% (95% CI, −36.82% to −23.24%; P P P  = .007), and 41.06% increase in platelet count (95% CI, 23.95%-58.17%; P Conclusions and Relevance Among previously untreated adults with Gaucher disease type 1, treatment with Eliglustat compared with placebo for 9 months resulted in significant improvements in spleen volume, hemoglobin level, liver volume, and platelet count. The clinical significance of these findings is uncertain, and more definitive conclusions about clinical efficacy and utility will require comparison with the standard treatment of enzyme replacement therapy as well as longer-term follow-up. Trial Registration clinicaltrials.gov Identifier:NCT00891202

  • Eliglustat an investigational oral therapy for gaucher disease type 1 phase 2 trial results after 4 years of treatment
    Blood Cells Molecules and Diseases, 2014
    Co-Authors: Elena Lukina, Nora Watman, Elsa Avila Arreguin, Marta Dragosky, Hanna Rosenbaum, Leorah Ross, Gregory M. Pastores, Ari Zimran, Jennifer Angell, Ana Cristina Puga
    Abstract:

    Eliglustat is an investigational, oral substrate reduction therapy for Gaucher disease type 1 (GD1). Nineteen treatment-naive patients have now completed 4years of an open-label study (NCT00358150). Mean hemoglobin level and platelet count increased by 2.3±1.5g/dL (baseline: 11.3±1.5g/dL) and 95% (baseline: 68,700±21,200/mm(3)), respectively. Mean spleen and liver volumes (multiples of normal, MN) decreased by 63% (baseline: 17.3±9.5 MN) and 28% (baseline: 1.7±0.4 MN), respectively. Median chitotriosidase and CCL-18 each decreased by 82%; plasma glucosylceramide and GM3 normalized. Mean bone mineral density T-score for the lumbar spine increased by 0.8 (60%) (baseline: -1.6±1.1). Femur dark marrow, a reflection of Gaucher cell infiltration into bone marrow, was reduced or stable in 17/18 patients. There were no bone crises. Most adverse events were mild and unrelated to treatment. These results extend the safety and efficacy of Eliglustat reported at 1 and 2 years to 4 years.

Nora Watman - One of the best experts on this subject based on the ideXlab platform.

  • pregnancy outcome in women with gaucher disease type 1 who had unplanned pregnancies during Eliglustat clinical trials
    JIMD reports, 2021
    Co-Authors: Elena Lukina, Nora Watman, Derralynn Hughes, Nadia Belmatoug, Manisha Balwani, Sebastiaan J M Gaemers, Meredith C Foster, Grace Lewis, Judith M Peterschmitt
    Abstract:

    Gaucher disease type 1 (GD1) is an inherited lysosomal storage disorder caused by deficient enzymatic activity of acid β-glucosidase, resulting in accumulation of its substrate glucosylceramide, leading to debilitating visceral, hematologic, and skeletal manifestations. Women with GD1 are at increased risk for complications during pregnancy, delivery, and postpartum. Treatment with enzyme replacement therapy is generally recommended before and during pregnancy to reduce risks. Eliglustat, an oral substrate-reduction therapy, is a first-line treatment for adults with GD1 adults who have extensive, intermediate, or poor CYP2D6-metabolizer phenotypes (>90% of patients). We report on pregnancy outcomes among women in Eliglustat trials who had unplanned pregnancies and female partners of men in the trials. In four phase 2 and 3 Eliglustat trials of 393 adults with GD1, women of childbearing potential were required to use contraception, have monthly pregnancy tests, and discontinue Eliglustat promptly if pregnant. In phase 2 and 3 trials, 18 women had 19 pregnancies, resulting in 14 healthy infants from 13 pregnancies (one set of twins), three elective terminations, one ectopic pregnancy, one spontaneous abortion, and one in utero death. Median estimated Eliglustat exposure duration during pregnancy was 38 days. In phase 1 trials (non-GD1 subjects), one woman had a spontaneous abortion. Partners of 16 Eliglustat-treated men with GD1 had 18 pregnancies, all resulting in healthy infants. Eliglustat is not approved during pregnancy due to limited data. Guidelines for clinicians and patients with GD that address use of Eliglustat in women of childbearing potential are needed.

  • Eliglustat maintains long term clinical stability in patients with gaucher disease type 1 stabilized on enzyme therapy
    Blood, 2017
    Co-Authors: Timothy M. Cox, Elena Lukina, Guillermo Drelichman, Renata Cravo, Manisha Balwani, Thomas A Burrow, Ana Maria Martins, 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.

  • SCIENTIFIC ARTICLE Skeletal improvement in patients with Gaucher disease type
    2016
    Co-Authors: Andrea M. Norfleet, Nora Watman, Elsa Avila Arreguin, Marta Dragosky, Ravi S. Kamath, Elena Lukina, Gregory M. Pastores, Daniel I Rosenthal, H. Rosenbaum, Ari Zimran
    Abstract:

    Objective Eliglustat is an investigational oral substrate reduc-tion therapy for Gaucher disease type 1 (GD1). Its skeletal effects were evaluated by prospective monitoring of bone mineral density (BMD), fractures, marrow infiltration by Gaucher cells, focal bone lesions, and infarcts during an open-label, multi-site, single-arm phase 2 trial (NCT00358150). Materials and methods Institutional review board approval and patient informed consent were obtained. Eliglustat (50 or 100 mg) was self-administered by mouth twice daily; 19 patients completed 4 years of treatment. All were skeletally mature (age range, 18–55 years). DXA and MRI assessments were conducted at baseline and annually thereafter. X-rays were obtained annually until month 24, and then every other year. Results Lumbar spine BMD increased significantly (p=0.02; n=15) by a mean (SD) of 9.9 % (14.2%) from baseline to year 4; corresponding T-scores increased significantly (p=0.01) from a mean (SD) of −1.6 (1.1) to −0.9 (1.3). Mean femur T-score remained normal through 4 years. Femur MRI showed that 10/18 (56 %) patients had decreased Gaucher cell infiltration compared to baseline; one patient with early im-provement had transient worsening at year 4. There were n

  • Eliglustat an investigational oral therapy for gaucher disease type 1 phase 2 trial results after 4 years of treatment
    Blood Cells Molecules and Diseases, 2014
    Co-Authors: Elena Lukina, Nora Watman, Elsa Avila Arreguin, Marta Dragosky, Hanna Rosenbaum, Leorah Ross, Gregory M. Pastores, Ari Zimran, Jennifer Angell, Ana Cristina Puga
    Abstract:

    Eliglustat is an investigational, oral substrate reduction therapy for Gaucher disease type 1 (GD1). Nineteen treatment-naive patients have now completed 4years of an open-label study (NCT00358150). Mean hemoglobin level and platelet count increased by 2.3±1.5g/dL (baseline: 11.3±1.5g/dL) and 95% (baseline: 68,700±21,200/mm(3)), respectively. Mean spleen and liver volumes (multiples of normal, MN) decreased by 63% (baseline: 17.3±9.5 MN) and 28% (baseline: 1.7±0.4 MN), respectively. Median chitotriosidase and CCL-18 each decreased by 82%; plasma glucosylceramide and GM3 normalized. Mean bone mineral density T-score for the lumbar spine increased by 0.8 (60%) (baseline: -1.6±1.1). Femur dark marrow, a reflection of Gaucher cell infiltration into bone marrow, was reduced or stable in 17/18 patients. There were no bone crises. Most adverse events were mild and unrelated to treatment. These results extend the safety and efficacy of Eliglustat reported at 1 and 2 years to 4 years.

  • Skeletal improvement in patients with Gaucher disease type 1: a phase 2 trial of oral Eliglustat
    Skeletal Radiology, 2014
    Co-Authors: Ravi S. Kamath, Nora Watman, Elsa Avila Arreguin, Marta Dragosky, Hanna Rosenbaum, Rasha Aguzzi, Elena Lukina, Gregory M. Pastores, Ari Zimran, Ana Cristina Puga
    Abstract:

    Objective Eliglustat is an investigational oral substrate reduction therapy for Gaucher disease type 1 (GD1). Its skeletal effects were evaluated by prospective monitoring of bone mineral density (BMD), fractures, marrow infiltration by Gaucher cells, focal bone lesions, and infarcts during an open-label, multi-site, single-arm phase 2 trial (NCT00358150). Materials and methods Institutional review board approval and patient informed consent were obtained. Eliglustat (50 or 100 mg) was self-administered by mouth twice daily; 19 patients completed 4 years of treatment. All were skeletally mature (age range, 18–55 years). DXA and MRI assessments were conducted at baseline and annually thereafter. X-rays were obtained annually until month 24, and then every other year. Results Lumbar spine BMD increased significantly ( p  = 0.02; n  = 15) by a mean (SD) of 9.9 % (14.2 %) from baseline to year 4; corresponding T-scores increased significantly ( p  = 0.01) from a mean (SD) of −1.6 (1.1) to −0.9 (1.3). Mean femur T-score remained normal through 4 years. Femur MRI showed that 10/18 (56 %) patients had decreased Gaucher cell infiltration compared to baseline; one patient with early improvement had transient worsening at year 4. There were no lumbar spine or femoral fractures and no reported bone crises during the study. At baseline, 8/19 (42 %) patients had focal bone lesions, which remained stable, and 7/19 (37 %) patients had bone infarctions, which improved in one patient by year 2. At year 4, one new asymptomatic, indeterminate bone lesion was discovered that subsequently resolved. Conclusions Eliglustat may be a therapeutic option for treating the skeletal manifestations of GD1.

Hanna Rosenbaum - One of the best experts on this subject based on the ideXlab platform.

  • Eliglustat an investigational oral therapy for gaucher disease type 1 phase 2 trial results after 4 years of treatment
    Blood Cells Molecules and Diseases, 2014
    Co-Authors: Elena Lukina, Nora Watman, Elsa Avila Arreguin, Marta Dragosky, Hanna Rosenbaum, Leorah Ross, Gregory M. Pastores, Ari Zimran, Jennifer Angell, Ana Cristina Puga
    Abstract:

    Eliglustat is an investigational, oral substrate reduction therapy for Gaucher disease type 1 (GD1). Nineteen treatment-naive patients have now completed 4years of an open-label study (NCT00358150). Mean hemoglobin level and platelet count increased by 2.3±1.5g/dL (baseline: 11.3±1.5g/dL) and 95% (baseline: 68,700±21,200/mm(3)), respectively. Mean spleen and liver volumes (multiples of normal, MN) decreased by 63% (baseline: 17.3±9.5 MN) and 28% (baseline: 1.7±0.4 MN), respectively. Median chitotriosidase and CCL-18 each decreased by 82%; plasma glucosylceramide and GM3 normalized. Mean bone mineral density T-score for the lumbar spine increased by 0.8 (60%) (baseline: -1.6±1.1). Femur dark marrow, a reflection of Gaucher cell infiltration into bone marrow, was reduced or stable in 17/18 patients. There were no bone crises. Most adverse events were mild and unrelated to treatment. These results extend the safety and efficacy of Eliglustat reported at 1 and 2 years to 4 years.

  • Skeletal improvement in patients with Gaucher disease type 1: a phase 2 trial of oral Eliglustat
    Skeletal Radiology, 2014
    Co-Authors: Ravi S. Kamath, Nora Watman, Elsa Avila Arreguin, Marta Dragosky, Hanna Rosenbaum, Rasha Aguzzi, Elena Lukina, Gregory M. Pastores, Ari Zimran, Ana Cristina Puga
    Abstract:

    Objective Eliglustat is an investigational oral substrate reduction therapy for Gaucher disease type 1 (GD1). Its skeletal effects were evaluated by prospective monitoring of bone mineral density (BMD), fractures, marrow infiltration by Gaucher cells, focal bone lesions, and infarcts during an open-label, multi-site, single-arm phase 2 trial (NCT00358150). Materials and methods Institutional review board approval and patient informed consent were obtained. Eliglustat (50 or 100 mg) was self-administered by mouth twice daily; 19 patients completed 4 years of treatment. All were skeletally mature (age range, 18–55 years). DXA and MRI assessments were conducted at baseline and annually thereafter. X-rays were obtained annually until month 24, and then every other year. Results Lumbar spine BMD increased significantly ( p  = 0.02; n  = 15) by a mean (SD) of 9.9 % (14.2 %) from baseline to year 4; corresponding T-scores increased significantly ( p  = 0.01) from a mean (SD) of −1.6 (1.1) to −0.9 (1.3). Mean femur T-score remained normal through 4 years. Femur MRI showed that 10/18 (56 %) patients had decreased Gaucher cell infiltration compared to baseline; one patient with early improvement had transient worsening at year 4. There were no lumbar spine or femoral fractures and no reported bone crises during the study. At baseline, 8/19 (42 %) patients had focal bone lesions, which remained stable, and 7/19 (37 %) patients had bone infarctions, which improved in one patient by year 2. At year 4, one new asymptomatic, indeterminate bone lesion was discovered that subsequently resolved. Conclusions Eliglustat may be a therapeutic option for treating the skeletal manifestations of GD1.

  • Skeletal improvement in patients with Gaucher disease type 1: a phase 2 trial of oral Eliglustat
    Skeletal Radiology, 2014
    Co-Authors: Ravi S. Kamath, Nora Watman, Elsa Avila Arreguin, Marta Dragosky, Hanna Rosenbaum, Rasha Aguzzi, Elena Lukina, Gregory M. Pastores, Ari Zimran, Ana Cristina Puga
    Abstract:

    Objective Eliglustat is an investigational oral substrate reduction therapy for Gaucher disease type 1 (GD1). Its skeletal effects were evaluated by prospective monitoring of bone mineral density (BMD), fractures, marrow infiltration by Gaucher cells, focal bone lesions, and infarcts during an open-label, multi-site, single-arm phase 2 trial (NCT00358150).

  • Eliglustat tartrate a novel investigational oral substrate reduction therapy for gaucher disease type 1 updated phase 2 results
    Blood, 2010
    Co-Authors: Elena Lukina, Nora Watman, Elsa Avila Arreguin, Marta Dragosky, Marcelo Iastrebner, Hanna Rosenbaum, Mici Phillips, Judith Peterschmitt, Gregory M. Pastores, Mathilde Kaper
    Abstract:

    Abstract 3791 Background: Gaucher disease type 1 (GD1), an inherited lysosomal storage disorder, is characterized by a deficiency of acid β-glucosidase and accumulation of glucosylceramide in lysosomes causing organomegaly, thrombocytopenia, anemia, and bone disease. Eliglustat tartrate (formerly Genz-112638) is a novel, specific inhibitor of glucosylceramide synthase under development as an oral substrate reduction therapy for the treatment of GD1. Purpose: To report updated efficacy and safety observations in GD1 patients after 2 years of treatment with Eliglustat tartrate in an ongoing Phase 2 clinical trial. Methods: This is an open-label, uncontrolled, multicenter, Phase 2 clinical trial of Eliglustat tartrate (50 or 100 mg bid, depending on trough plasma level of drug) in 26 previously untreated adults with GD1. Entry criteria required that patients have splenomegaly with thrombocytopenia (platelet count: 45,000 to 100,000 mm3) and/or anemia (hemoglobin: 8.0–10 g/dL, females; 8.0–11 g/dL, males). Efficacy results included changes from baseline in hemoglobin and platelet levels, spleen and liver volumes, biomarkers, bone mineral density (BMD), and other skeletal findings. Hematologic and visceral parameters were assessed centrally every 3 to 6 months; MRI, DXA, and X-rays were performed yearly and reviewed centrally. Achievement of Gaucher disease therapeutic goals for hemoglobin, platelet counts, and organ volume also was assessed at 2 years. Results: Thirty-month hematologic, organ volume, and biomarker data will be available for presentation. Six of the 26 enrolled patients discontinued the Phase 2 study. Results (mean changes from baseline ± SD) are currently available in up to 20 patients who completed 2 years of treatment with Eliglustat tartrate. For these patients, hemoglobin level increased by 2.1±1.5 g/dL (11.2±1.6 to 13.3±1.5 g/dL), and platelet count increased by 81.5±56.0% (67,900±20,900/mm3 to 119,200±42,400/mm3). Spleen volume (as multiples of normal, MN) decreased by 52.4±10.7% (17.95 MN to 8.14 MN), and liver volume decreased by 23.9±12.8% (1.69 MN to 1.24 MN). Mean chitotriosidase and CCL18 decreased by 75.4% and 75.2%, respectively. Through 2 years, no bone crises or reductions in mobility were reported. Femur MRI showed improvement of the dark marrow signal in 8/18 patients, indicating reduction of the infiltration of the bone marrow by Gaucher cells; the rest of the patients remained stable (10/18 patients). In addition, there were no new lytic lesions or bone infarcts; existing lytic lesions remained stable, and of 7 existing infarcts, 1 improved and 6 remained stable. Mean lumbar spine BMD increased by 7.8±10.6% (P=0.010), DXA T-Score by 0.6±0.8 (P=0.012), and DXA Z-Score by 0.6±0.7 (P=0.003), with major gains among osteoporotic/osteopenic patients. After 2 years, most patients met short-term therapeutic goals published by Pastores et al (Semin Hematol 2004;41[suppl 5]:4–14); more patients met goals for hemoglobin (95%), liver volume (95%), and spleen volume (90%) than for platelet count (60%). Overall, 85% (17/20) of patients met established therapeutic goals for ≥3 of 4 parameters after 2 years. Eliglustat tartrate was well tolerated in this trial up to 2 years. Most adverse events (AEs) were mild and unrelated to treatment. The most common AEs reported during 2 years were viral infections (6 patients), and urinary tract infections, increased blood pressure, and abdominal pain (3 patients each). Eight drug-related AEs, all mild, occurred in 6 patients. Summary/Conclusions: In this Phase 2 study, Eliglustat tartrate has shown promising efficacy as a potential oral substrate reduction therapy for GD1. After 2 years, patients with GD1 treated with Eliglustat tartrate continued to show improvements in hematologic, organ volume, and bone parameters with a safety profile that supports ongoing treatment. Three controlled Phase 3 studies are underway: one in untreated patients (ENGAGE), one in patients switching from enzyme replacement therapy (ENCORE), and another that compares different dose regimens of Eliglustat (EDGE). Disclosures: Lukina:Genzyme Corporation: Honoraria. Peterschmitt:Genzyme Corporation: Employment. Pastores:Amicus: Research Funding; Actelion: Research Funding; Biomarin: Research Funding; Genzyme Corporation: Research Funding; Shire HGT: Research Funding; Protalix: Research Funding. Kaper:Genzyme Corporation: Employment. Haque:Genzyme Corporation: Employment. Puga:Genzyme Corporation: Employment.

  • improvement in hematological visceral and skeletal manifestations of gaucher disease type 1 with oral Eliglustat tartrate genz 112638 treatment 2 year results of a phase 2 study
    Blood, 2010
    Co-Authors: Elena Lukina, Nora Watman, Elsa Avila Arreguin, Marta Dragosky, Marcelo Iastrebner, Hanna Rosenbaum, Mici Phillips, Ravi S. Kamath, Gregory M. Pastores, Daniel I Rosenthal
    Abstract:

    Eliglustat tartrate is an investigational oral substrate reduction therapy for Gaucher disease type 1 that is pharmacologically distinct from intravenous enzyme replacement therapy. Eliglustat tartrate improved clinical manifestations in patients who received 50 or 100 mg BID for one year during an open-label Phase 2 study [Blood 116(6):893-899, 2010]. We report further improvements after two years of treatment in 20 patients (11F/9M; mean age=33) with baseline splenomegaly and thrombocytopenia and/or anemia. Statistically significant (p<0.001) percent improvements from baseline (mean±stdev) occurred in platelet count (+81±56%), hemoglobin level (+20±15%), spleen volume (-52±11%), and liver volume (-24±13%). Mean platelet count increased ~50,000/mm3. Mean hemoglobin level increased 2.1 g/dL overall and 3.1 g/dL in 10 patients with baseline anemia. Organ volume reductions were greatest in patients with severe baseline organomegaly. Seventeen (85%) patients met established therapeutic goals for ≥3 of the 4 parameters. Lumbar spine bone mineral density increased 7.8±10.6% (p=0.010) and T-Score 0.6±0.8 (p=0.012), with major gains in osteoporotic and osteopenic patients. MRI assessment showed decreased (8/18 patients) or stable (10/18 patients) bone marrow infiltration by Gaucher cells. No safety-related trends emerged during 2 years of treatment. This multi-site, open-label, single-arm Phase 2 study is registered as [NCT00358150][1] at www.clinicaltrials.gov. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00358150&atom=%2Fbloodjournal%2Fearly%2F2010%2F08%2F16%2Fblood-2010-06-293902.atom

Elsa Avila Arreguin - One of the best experts on this subject based on the ideXlab platform.

  • SCIENTIFIC ARTICLE Skeletal improvement in patients with Gaucher disease type
    2016
    Co-Authors: Andrea M. Norfleet, Nora Watman, Elsa Avila Arreguin, Marta Dragosky, Ravi S. Kamath, Elena Lukina, Gregory M. Pastores, Daniel I Rosenthal, H. Rosenbaum, Ari Zimran
    Abstract:

    Objective Eliglustat is an investigational oral substrate reduc-tion therapy for Gaucher disease type 1 (GD1). Its skeletal effects were evaluated by prospective monitoring of bone mineral density (BMD), fractures, marrow infiltration by Gaucher cells, focal bone lesions, and infarcts during an open-label, multi-site, single-arm phase 2 trial (NCT00358150). Materials and methods Institutional review board approval and patient informed consent were obtained. Eliglustat (50 or 100 mg) was self-administered by mouth twice daily; 19 patients completed 4 years of treatment. All were skeletally mature (age range, 18–55 years). DXA and MRI assessments were conducted at baseline and annually thereafter. X-rays were obtained annually until month 24, and then every other year. Results Lumbar spine BMD increased significantly (p=0.02; n=15) by a mean (SD) of 9.9 % (14.2%) from baseline to year 4; corresponding T-scores increased significantly (p=0.01) from a mean (SD) of −1.6 (1.1) to −0.9 (1.3). Mean femur T-score remained normal through 4 years. Femur MRI showed that 10/18 (56 %) patients had decreased Gaucher cell infiltration compared to baseline; one patient with early im-provement had transient worsening at year 4. There were n

  • Eliglustat an investigational oral therapy for gaucher disease type 1 phase 2 trial results after 4 years of treatment
    Blood Cells Molecules and Diseases, 2014
    Co-Authors: Elena Lukina, Nora Watman, Elsa Avila Arreguin, Marta Dragosky, Hanna Rosenbaum, Leorah Ross, Gregory M. Pastores, Ari Zimran, Jennifer Angell, Ana Cristina Puga
    Abstract:

    Eliglustat is an investigational, oral substrate reduction therapy for Gaucher disease type 1 (GD1). Nineteen treatment-naive patients have now completed 4years of an open-label study (NCT00358150). Mean hemoglobin level and platelet count increased by 2.3±1.5g/dL (baseline: 11.3±1.5g/dL) and 95% (baseline: 68,700±21,200/mm(3)), respectively. Mean spleen and liver volumes (multiples of normal, MN) decreased by 63% (baseline: 17.3±9.5 MN) and 28% (baseline: 1.7±0.4 MN), respectively. Median chitotriosidase and CCL-18 each decreased by 82%; plasma glucosylceramide and GM3 normalized. Mean bone mineral density T-score for the lumbar spine increased by 0.8 (60%) (baseline: -1.6±1.1). Femur dark marrow, a reflection of Gaucher cell infiltration into bone marrow, was reduced or stable in 17/18 patients. There were no bone crises. Most adverse events were mild and unrelated to treatment. These results extend the safety and efficacy of Eliglustat reported at 1 and 2 years to 4 years.

  • Skeletal improvement in patients with Gaucher disease type 1: a phase 2 trial of oral Eliglustat
    Skeletal Radiology, 2014
    Co-Authors: Ravi S. Kamath, Nora Watman, Elsa Avila Arreguin, Marta Dragosky, Hanna Rosenbaum, Rasha Aguzzi, Elena Lukina, Gregory M. Pastores, Ari Zimran, Ana Cristina Puga
    Abstract:

    Objective Eliglustat is an investigational oral substrate reduction therapy for Gaucher disease type 1 (GD1). Its skeletal effects were evaluated by prospective monitoring of bone mineral density (BMD), fractures, marrow infiltration by Gaucher cells, focal bone lesions, and infarcts during an open-label, multi-site, single-arm phase 2 trial (NCT00358150). Materials and methods Institutional review board approval and patient informed consent were obtained. Eliglustat (50 or 100 mg) was self-administered by mouth twice daily; 19 patients completed 4 years of treatment. All were skeletally mature (age range, 18–55 years). DXA and MRI assessments were conducted at baseline and annually thereafter. X-rays were obtained annually until month 24, and then every other year. Results Lumbar spine BMD increased significantly ( p  = 0.02; n  = 15) by a mean (SD) of 9.9 % (14.2 %) from baseline to year 4; corresponding T-scores increased significantly ( p  = 0.01) from a mean (SD) of −1.6 (1.1) to −0.9 (1.3). Mean femur T-score remained normal through 4 years. Femur MRI showed that 10/18 (56 %) patients had decreased Gaucher cell infiltration compared to baseline; one patient with early improvement had transient worsening at year 4. There were no lumbar spine or femoral fractures and no reported bone crises during the study. At baseline, 8/19 (42 %) patients had focal bone lesions, which remained stable, and 7/19 (37 %) patients had bone infarctions, which improved in one patient by year 2. At year 4, one new asymptomatic, indeterminate bone lesion was discovered that subsequently resolved. Conclusions Eliglustat may be a therapeutic option for treating the skeletal manifestations of GD1.

  • Skeletal improvement in patients with Gaucher disease type 1: a phase 2 trial of oral Eliglustat
    Skeletal Radiology, 2014
    Co-Authors: Ravi S. Kamath, Nora Watman, Elsa Avila Arreguin, Marta Dragosky, Hanna Rosenbaum, Rasha Aguzzi, Elena Lukina, Gregory M. Pastores, Ari Zimran, Ana Cristina Puga
    Abstract:

    Objective Eliglustat is an investigational oral substrate reduction therapy for Gaucher disease type 1 (GD1). Its skeletal effects were evaluated by prospective monitoring of bone mineral density (BMD), fractures, marrow infiltration by Gaucher cells, focal bone lesions, and infarcts during an open-label, multi-site, single-arm phase 2 trial (NCT00358150).

  • Eliglustat tartrate a novel investigational oral substrate reduction therapy for gaucher disease type 1 updated phase 2 results
    Blood, 2010
    Co-Authors: Elena Lukina, Nora Watman, Elsa Avila Arreguin, Marta Dragosky, Marcelo Iastrebner, Hanna Rosenbaum, Mici Phillips, Judith Peterschmitt, Gregory M. Pastores, Mathilde Kaper
    Abstract:

    Abstract 3791 Background: Gaucher disease type 1 (GD1), an inherited lysosomal storage disorder, is characterized by a deficiency of acid β-glucosidase and accumulation of glucosylceramide in lysosomes causing organomegaly, thrombocytopenia, anemia, and bone disease. Eliglustat tartrate (formerly Genz-112638) is a novel, specific inhibitor of glucosylceramide synthase under development as an oral substrate reduction therapy for the treatment of GD1. Purpose: To report updated efficacy and safety observations in GD1 patients after 2 years of treatment with Eliglustat tartrate in an ongoing Phase 2 clinical trial. Methods: This is an open-label, uncontrolled, multicenter, Phase 2 clinical trial of Eliglustat tartrate (50 or 100 mg bid, depending on trough plasma level of drug) in 26 previously untreated adults with GD1. Entry criteria required that patients have splenomegaly with thrombocytopenia (platelet count: 45,000 to 100,000 mm3) and/or anemia (hemoglobin: 8.0–10 g/dL, females; 8.0–11 g/dL, males). Efficacy results included changes from baseline in hemoglobin and platelet levels, spleen and liver volumes, biomarkers, bone mineral density (BMD), and other skeletal findings. Hematologic and visceral parameters were assessed centrally every 3 to 6 months; MRI, DXA, and X-rays were performed yearly and reviewed centrally. Achievement of Gaucher disease therapeutic goals for hemoglobin, platelet counts, and organ volume also was assessed at 2 years. Results: Thirty-month hematologic, organ volume, and biomarker data will be available for presentation. Six of the 26 enrolled patients discontinued the Phase 2 study. Results (mean changes from baseline ± SD) are currently available in up to 20 patients who completed 2 years of treatment with Eliglustat tartrate. For these patients, hemoglobin level increased by 2.1±1.5 g/dL (11.2±1.6 to 13.3±1.5 g/dL), and platelet count increased by 81.5±56.0% (67,900±20,900/mm3 to 119,200±42,400/mm3). Spleen volume (as multiples of normal, MN) decreased by 52.4±10.7% (17.95 MN to 8.14 MN), and liver volume decreased by 23.9±12.8% (1.69 MN to 1.24 MN). Mean chitotriosidase and CCL18 decreased by 75.4% and 75.2%, respectively. Through 2 years, no bone crises or reductions in mobility were reported. Femur MRI showed improvement of the dark marrow signal in 8/18 patients, indicating reduction of the infiltration of the bone marrow by Gaucher cells; the rest of the patients remained stable (10/18 patients). In addition, there were no new lytic lesions or bone infarcts; existing lytic lesions remained stable, and of 7 existing infarcts, 1 improved and 6 remained stable. Mean lumbar spine BMD increased by 7.8±10.6% (P=0.010), DXA T-Score by 0.6±0.8 (P=0.012), and DXA Z-Score by 0.6±0.7 (P=0.003), with major gains among osteoporotic/osteopenic patients. After 2 years, most patients met short-term therapeutic goals published by Pastores et al (Semin Hematol 2004;41[suppl 5]:4–14); more patients met goals for hemoglobin (95%), liver volume (95%), and spleen volume (90%) than for platelet count (60%). Overall, 85% (17/20) of patients met established therapeutic goals for ≥3 of 4 parameters after 2 years. Eliglustat tartrate was well tolerated in this trial up to 2 years. Most adverse events (AEs) were mild and unrelated to treatment. The most common AEs reported during 2 years were viral infections (6 patients), and urinary tract infections, increased blood pressure, and abdominal pain (3 patients each). Eight drug-related AEs, all mild, occurred in 6 patients. Summary/Conclusions: In this Phase 2 study, Eliglustat tartrate has shown promising efficacy as a potential oral substrate reduction therapy for GD1. After 2 years, patients with GD1 treated with Eliglustat tartrate continued to show improvements in hematologic, organ volume, and bone parameters with a safety profile that supports ongoing treatment. Three controlled Phase 3 studies are underway: one in untreated patients (ENGAGE), one in patients switching from enzyme replacement therapy (ENCORE), and another that compares different dose regimens of Eliglustat (EDGE). Disclosures: Lukina:Genzyme Corporation: Honoraria. Peterschmitt:Genzyme Corporation: Employment. Pastores:Amicus: Research Funding; Actelion: Research Funding; Biomarin: Research Funding; Genzyme Corporation: Research Funding; Shire HGT: Research Funding; Protalix: Research Funding. Kaper:Genzyme Corporation: Employment. Haque:Genzyme Corporation: Employment. Puga:Genzyme Corporation: Employment.