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Neal J. Weinreb - One of the best experts on this subject based on the ideXlab platform.
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the international collaborative gaucher group graf gaucher risk assessment for fracture score a composite risk score for assessing adult fracture risk in Imiglucerase treated gaucher disease type 1 patients
Orphanet Journal of Rare Diseases, 2021Co-Authors: Patrick Deegan, Aneal Khan, Julie L Batista, Jose Simon Camelo, Neal J. WeinrebAbstract:Fractures in Gaucher disease type 1 (GD1) patients cause significant morbidity. Fracture risk may be decreased by enzyme replacement therapy (ERT) but not eliminated. When considering initiation of treatment, it is useful to know to what extent fixed patient-specific factors determine risk for future fractures beyond standard risk factors that change with time and treatment, such as decreased bone mineral density. We developed a tool called the GRAF score (Gaucher Risk Assessment for Fracture) that applies 5 widely available characteristics (sex, age at treatment initiation [ATI], time interval between diagnosis and treatment initiation, splenectomy status, history of pre-treatment bone crisis) and provides a practical method to assess future fracture risk when Imiglucerase ERT is initiated. Inclusion criteria: GD1 patients in the International Collaborative Gaucher Group Gaucher Registry as of September 2019 initially treated with alglucerase/Imiglucerase; known splenectomy status; at least one skeletal assessment on treatment (3216 of 6422 patients). Data were analyzed by ATI group (< 18, ≥ 18 to < 50, or ≥ 50 years of age) using Cox proportional hazards regression with all 5 risk factors included in the multivariable model. A composite risk score was calculated by summing the contribution of each parameter weighted by the strength of its association (regression coefficient) with fracture risk. Patients were followed from the date of treatment initiation (or age 18 years for patients if treatment started earlier) to the date of first adult fracture (n = 288 first fracture endpoints), death, or end of follow-up. The GRAF score for each ATI group was associated with a 2.7-fold increased risk of adult fracture for each one-point increase (p < 0.02 for < 18 ATI, p < 0.0001 for ≥ 18 to < 50 ATI and ≥ 50 ATI). The GRAF score is a tool to be used with bone density and other modifiable, non-GD-specific risk factors (e.g. smoking, alcohol intake, frailty) to inform physicians and previously untreated GD1 patients about risk for a future fracture after starting Imiglucerase regardless of whether there is an eventual switch to an alternative ERT or to substrate reduction therapy. GRAF can also help predict the extent that fracture risk increases if initiation of treatment is further delayed.
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gaucher disease type 1 patients from the icgg gaucher registry sustain initial clinical improvements during twenty years of Imiglucerase treatment
Molecular Genetics and Metabolism, 2021Co-Authors: Neal J. Weinreb, Pramod K. Mistry, Joel Charrow, Jose Simon Camelo, Monica R Mcclain, Nadia BelmatougAbstract:Abstract Background Alglucerase enzyme replacement therapy was approved for Gaucher disease (GD) in the United States in 1991; Imiglucerase in 1994. We report hematologic, visceral, bone pain, bone crisis, height, weight, and Body Mass Index (BMI) outcomes in patients treated for 20 (±3) years with subset analyses based on pre-treatment severity, genotype, and age at treatment initiation. Methods GD type 1 (GD1) patients in the ICGG Gaucher Registry with complete sets of baseline, 10-year, and 20-year data are included (N = 475). Ten-year and 20-year data are compared to pre-treatment baseline, stratified by splenectomy status. Results Non-splenectomized patients: Improvements observed at 10 years were maintained at 20 years for most outcomes. Mean changes from baseline at 10 and 20 years, respectively, were: spleen volume: 18.2 multiples of normal (MN) to 5.1 MN and 4.2 MN; liver volume: 1.8 MN to 1.0 MN and 1.0 MN; hemoglobin: 11.4 g/dL to 13.7 g/dL and 13.8 g/dL; platelet count: 91.6 × 109/L to 168.0 × 109/L and 169.1 × 109/L; without bone crisis: 85.0% to 98.2% and 96.5%; without bone pain: 52.5% to 72.0% at 10 years, no significant change at 20 years (58.5%). Splenectomized patients: significant changes were observed in liver volume: 2.3 MN to 1.1 MN and 1.0 MN; hemoglobin: 11.7 g/dL to 13.3 g/dL and 13.4 g/dL; platelet count: 229.1 × 109/L to 288.1 × 109/L and 257.0 × 109/L; without bone crisis: 52.2% to 91.3% and 100%; without bone pain: 16.3% to 30.6% (not significant) and 46.9%. Similar results were found in each of the subset analyses. Patients who start treatment during childhood have normal weight and height in young adulthood. Many treated adult patients are overweight or obese; however, this is consistent with BMI trends observed in the general population. After 1–2 years, the average biweekly Imiglucerase dose is ~40 units/kg body weight. Conclusion Imiglucerase is an effective, long-term treatment for GD1. In a long-term observational setting, improvements seen during early treatment years are sustained by continuing treatment for 20 years, except for bone pain in non-splenectomized patients. These results are consistent when analyzed by different patient subsets, including by disease severity.
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ORIGINAL ARTICLE Long-term clinical outcomes in type 1 Gaucher disease following 10 years of Imiglucerase treatment
2016Co-Authors: Neal J. Weinreb, Carla E M Hollak, Jack Goldblatt, Joel Charrow, Stephan Vom Dahl, Jacobo Villalobos, J. Alex, Er Cole, Marcelo Kerstenetzky, N. J. WeinrebAbstract:Objective We studied the effect of long-term alglucerase/ Imiglucerase (Ceredase®/Cerezyme®, Genzyme, a Sanofi company, Cambridge, MA, USA) treatment on hematolog-ical, visceral, and bone manifestations of Gaucher disease type 1 (GD1). Methods The International Collaborative Gaucher Group (ICGG) Gaucher Registry identified GD1 patients treated with alglucerase/Imiglucerase who had dose and clinical data at first infusion and after 10 years of follow-up. Data for hemoglobin, platelet count, organ volumes, bone pain, and bone crisis were analyzed. Tests of the null hypothesis (no change from first infusion to 10 years) were performed using t tests for within-patient absolute change in continu-ous measurements and McNemar/chi-square tests fo
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Imiglucerase treatment associated with reduction of bone claims in gaucher patients analysis of us claims data
Blood, 2014Co-Authors: L Nalysnyk, Martin Selzer, Alaa Hamed, Neal J. WeinrebAbstract:BACKGROUND: Gaucher disease type 1 (GD1) is a rare, genetic, multisystemic disorder caused by a deficiency of acid s-glucosidase and characterized by an accumulation of lipid glucosylceramide in organs such as the spleen, liver and bone marrow. The key clinical features include anemia, thrombocytopenia, hepatosplenomegaly, and skeletal disease. Bone involvement is one of the most frequent, debilitating complications of GD1 that can have significant negative impact on patients’ quality of life due to pain, disability, and need for orthopedic intervention. Several studies have shown that treatment with Imiglucerase improves bone density, decreases the occurrence of bone crisis, and ameliorates bone pain. OBJECTIVE: To examine the impact of treatment with Imiglucerase on bone claims in Gaucher patients before and after initiation of treatment using US administrative claims data. METHODS: A retrospective study of medical claims data was conducted using Optum’s Clinformatics Data Mart database. Gaucher patients treated with Imiglucerase between January 1, 1997 and June 30, 2013 were identified. Adult and pediatric patients were eligible for this study and were required to have at least 3 months continuous insurance coverage prior to their first treatment with Imiglucerase (index date), at least 3 months follow-up post-index date, and at least 4 Imiglucerase administrations within the first 3 months. The number of claims associated with bone disease and number of patients reporting these claims before and after treatment initiation with Imiglucerase were assessed. The percentage of patients with bone claims and the average bone claims per patient were used to compare pre- and post-treatment data. Bone claims with the following treatment diagnoses were included: osteoporosis, pathological fracture, joint pain, necrosis, and unspecified bone problems. RESULTS: A total of 107 GD patients were evaluated in the pre-treatment period; 59 (55%) were male and 48 (45%) were female; there were 85 (79%) adults (18 years and older) and 22 (21%) pediatric patients. Among the 107 GD patients, 31 patients (29%) reported bone claims within 3 months prior to treatment initiation with Imiglucerase. During the first year of post-treatment initiation, a significant reduction in the number of patients with bone claims was observed in all 3-month intervals when compared to the pre-treatment period. The same results were observed for the average bone claims per patient, except it did not reach statistical significance for the 6-9 month period. Results for all patients are presented in the Table below. | Time interval | N evaluated | N (%) of patients with bone claims | Total # of bone claims | Average # of bone claims per patient (SD) | | ------------------------------------ | ----------- | ---------------------------------- | ---------------------- | ----------------------------------------- | | Baseline/3 months prior to treatment | 107 | 31 (29%) | 99 | 0.93 (1.922) | | 0-3 months after treatment | 105 | 10 (9.5%*) | 32* | 0.3 (1.161)* | | 3-6 months after treatment | 98 | 12 (12.2%)* | 30* | 0.31 (1.04)* | | 6-9 months after treatment | 80 | 7 (8.8%)* | 49* | 0.61 (2.447) | | 9-12 months after treatment | 72 | 7 (9.7%)* | 14* | 0.19 (0.685)* | Table: Bone Claims Before and After Treatment Initiation with Imiglucerase N = Number of patients * Statistically significant compared to baseline at a cumulative probability level > 0.95. Note: Statistical significance for % of patients is evaluated as a difference in proportions. Data has been adjusted for outliers. When data were analyzed separately for adult and pediatric populations, similar trends were observed with more pronounced results among pediatric patients. For pediatric patients, 5 patients reported bone claims prior to initiation of treatment and no bone claims in the first 6 months after treatment initiation. CONCLUSION: A reduction in the number of bone claims and number of patients with bone claims was observed after initiation of treatment with Imiglucerase in Gaucher patients in the US. These results suggest that Imiglucerase treatment is associated with a reduction of bone complaints in both adult and pediatric patients. Differences in bone claim frequencies between adult and pediatric patients after treatment initiation with Imiglucerase also suggest that early treatment can mitigate the development of chronic bone disease and can result in a reduction of associated medical claims. Disclosures Nalysnyk: Genzyme, a Sanofi Company: Employment. Selzer: Genzyme, a Sanofi Company: Employment. Hamed: Genzyme, a Sanofi Company: Employment. Weinreb: Genzyme, A Sanofi Company: Consultancy, Honoraria, Speakers Bureau.
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position statement national gaucher foundation medical advisory board january 7 2014
American Journal of Hematology, 2014Co-Authors: John A Barranger, Pramod K. Mistry, Gregory A Grabowski, Roscoe O Brady, Henry J Mankin, Neal J. WeinrebAbstract:Patients and physicians have contacted the National Gaucher Foundation regarding recent discussions and decisions by US insurance carriers and specifically United Health Care to establish a preferred status category for one of the three enzyme replacement therapies currently approved by FDA for treatment of patients with Gaucher disease. The position of the National Gaucher Foundation and its Medical Advisory Board is as follows: Imiglucerase, velaglucerase alfa, and taliglucerase alfa are bio-similar products that are not bio-identical. They are all highly purified pharmacologic recombinant human glucocerebrosidase glycoproteins produced using different technologies and derived from different cell lines: Imiglucerase (Chinese hamster ovary cell line); Velaglucerase alfa (human fibroblasts derived from a fibrosarcoma cell line); Taliglucerase (carrot root cell line). Although the conformational crystal structures of all three appear to be similar, there are minor differences in primary amino acid structure and more significant differences in glycosylation [1,2]. Globally since 1994, more than 5,000 phenotypically and genotypically diverse Gaucher disease patients have been treated with Imiglucerase with an extensive observational record of efficacy and safety. Since 2010, other enzyme therapies for Gaucher disease, velaglucerase alfa, and taliglucerase, were also approved by the FDA. Randomized and observational clinical trials comprising a few hundred treatment-na€ive and “switch” patients suggest that during the initial 1–3 years of treatment, velaglucerase alfa and taliglucerase are arguably safe and of comparable efficacy to Imiglucerase for reversing disease manifestations such as anemia, thrombocytopenia, and hepatosplenomegaly, for reduction of biomarkers and, in the case of velaglucerase alfa, for maintaining therapeutic gains in patients previously treated with Imiglucerase [3–14]. Velaglucerase alfa and taliglucerase appear to reduce bone marrow Gaucher cell infiltration measured indirectly with quantitative chemical shift MRI imaging similarly to Imiglucerase [8,15,16]. Compared to Imiglucerase, currently published clinical trial and post-marketing data for velaglucerase alfa and taliglucerase with respect to patient-centered outcomes, such as osteopenia, osteonecrosis, fractures, need for hospitalization for splenectomy, and health-related quality of life are rudimentary [17–23]. Although taliglucerase is currently authorized for use only in adults, Imiglucerase and velaglucerase alfa are approved for pediatric use. However, published data showing that enzyme replacement therapy (ERT) reverses Gaucher disease-associated growth and development retardation in pre-pubertal children are only available for Imiglucerase [24,25]. Finally, in stable patients during the “maintenance” phase of treatment, the safety and efficacy of infusion schedules less frequent than every two weeks is supported by clinical trial evidence only for Imiglucerase [26]. Before endorsing a position that Imiglucerase, velaglucerase alfa, and taliglucerase are interchangeable or that one ERT should be granted preferential status over the others, we believe further study and clinical experience is warranted and advisable. Differences in antigenicity and seroconversion (apparently less likely with velaglucerase compared with Imiglucerase and taliglucerase) to date appear to have little overall effect on safety and efficacy although some severe adverse reactions have been reported [6,7,9–13,27]. The long-term effect of antigenic variation, if any, is not known. Differences in safety profiles not directly related to the recombinant enzymes themselves but rather to some other aspect of the variant manufacturing process are also possible and may explain atypical late-onset severe adverse events that are beginning to appear in the literature [28]. Because Imiglucerase has had much longer “exposure time” than either velaglucerase or taliglucerase, the reports of late onset events are largely confined to that product. That pattern may not necessarily hold up in the future. In vitro and animal studies of differential cellular uptake of the three ERTs have been inconsistent although most studies were not done using Gaucher monocytes or macrophages or in Gaucher animal models [1,2,29,30]. In the D409V/null Gaucher mouse model, “significant differential molecular responses were observed in direct transcriptome (the set of all RNA molecules, including mRNA, rRNA, tRNA, and other non-coding RNA) comparisons from Imigluceraseand velaglucerase-treated tissues” [31]. Whether these cellular differences may ultimately relate to different long-term clinical outcomes including late onset complications of Gaucher disease such as cancers and Parkinson disease is also currently unknown. We understand that the United Health Care decision to assign preferential status to a single ERT was heavily, if not entirely, based on important and legitimate financial considerations. We strongly endorse efforts to reduce personal and societal costs of health care, including therapies for rare, orphan diseases such as Gaucher disease. However, should each insurance company have a preferential and exclusive ERT, patients may have to switch treatments every time a new negotiation is concluded and every time they change from one health insurance company to another, possibly with a
Joel Charrow - One of the best experts on this subject based on the ideXlab platform.
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gaucher disease type 1 patients from the icgg gaucher registry sustain initial clinical improvements during twenty years of Imiglucerase treatment
Molecular Genetics and Metabolism, 2021Co-Authors: Neal J. Weinreb, Pramod K. Mistry, Joel Charrow, Jose Simon Camelo, Monica R Mcclain, Nadia BelmatougAbstract:Abstract Background Alglucerase enzyme replacement therapy was approved for Gaucher disease (GD) in the United States in 1991; Imiglucerase in 1994. We report hematologic, visceral, bone pain, bone crisis, height, weight, and Body Mass Index (BMI) outcomes in patients treated for 20 (±3) years with subset analyses based on pre-treatment severity, genotype, and age at treatment initiation. Methods GD type 1 (GD1) patients in the ICGG Gaucher Registry with complete sets of baseline, 10-year, and 20-year data are included (N = 475). Ten-year and 20-year data are compared to pre-treatment baseline, stratified by splenectomy status. Results Non-splenectomized patients: Improvements observed at 10 years were maintained at 20 years for most outcomes. Mean changes from baseline at 10 and 20 years, respectively, were: spleen volume: 18.2 multiples of normal (MN) to 5.1 MN and 4.2 MN; liver volume: 1.8 MN to 1.0 MN and 1.0 MN; hemoglobin: 11.4 g/dL to 13.7 g/dL and 13.8 g/dL; platelet count: 91.6 × 109/L to 168.0 × 109/L and 169.1 × 109/L; without bone crisis: 85.0% to 98.2% and 96.5%; without bone pain: 52.5% to 72.0% at 10 years, no significant change at 20 years (58.5%). Splenectomized patients: significant changes were observed in liver volume: 2.3 MN to 1.1 MN and 1.0 MN; hemoglobin: 11.7 g/dL to 13.3 g/dL and 13.4 g/dL; platelet count: 229.1 × 109/L to 288.1 × 109/L and 257.0 × 109/L; without bone crisis: 52.2% to 91.3% and 100%; without bone pain: 16.3% to 30.6% (not significant) and 46.9%. Similar results were found in each of the subset analyses. Patients who start treatment during childhood have normal weight and height in young adulthood. Many treated adult patients are overweight or obese; however, this is consistent with BMI trends observed in the general population. After 1–2 years, the average biweekly Imiglucerase dose is ~40 units/kg body weight. Conclusion Imiglucerase is an effective, long-term treatment for GD1. In a long-term observational setting, improvements seen during early treatment years are sustained by continuing treatment for 20 years, except for bone pain in non-splenectomized patients. These results are consistent when analyzed by different patient subsets, including by disease severity.
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transformation in pretreatment manifestations of gaucher disease type 1 during two decades of alglucerase Imiglucerase enzyme replacement therapy in the international collaborative gaucher group icgg gaucher registry
American Journal of Hematology, 2017Co-Authors: Pramod K. Mistry, Hans C Andersson, Paige Kaplan, Joel Charrow, Julie L Batista, Manisha Balwani, Thomas A Burrow, Aneal Khan, Priya S Kishnani, Edwin H KolodnyAbstract:This study tests the hypothesis that the prevalence of severe clinical manifestations in Gaucher disease type 1 (GD1) patients at the time of treatment initiation has changed since alglucerase/Imiglucerase enzyme replacement therapy (ERT) was approved in the United States (US) in 1991. US alglucerase/Imiglucerase-treated GD1 patients from the International Collaborative Gaucher Group Gaucher Registry were stratified by age at ERT initiation (<18, 18 to <50, ≥50 years), era of ERT initiation (1991-1995, 1996-2000, 2001-2005, 2006-2009), and splenectomy status pre-ERT. Prevalence of splenectomy decreased dramatically across the eras among all age groups. Bone manifestations were more prevalent in splenectomized patients than non-splenectomized patients in all age groups. Prevalence of bone manifestations differed across eras in certain age groups: non-splenectomized patients had a lower prevalence of ischemic bone events (pediatric patients) and bone crisis (pediatric patients and adults 18 to <50 years) in later eras; splenectomized adult (18 to <50 years) patients had a lower prevalence of ischemic bone events and bone crisis in later eras. Over two decades after the introduction of ERT, the prevalence of splenectomy and associated skeletal complications has declined dramatically. Concomitantly, the interval between diagnosis and initiation of ERT has decreased, most strikingly in pediatric patients who have the most severe disease. Together, these findings suggest that since the introduction of Imiglucerase ERT, optimal standard of care has become established in the US to prevent destructive complications of GD1. This article is protected by copyright. All rights reserved.
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transformation in pretreatment manifestations of gaucher disease type 1 during two decades of alglucerase Imiglucerase enzyme replacement therapy in the international collaborative gaucher group icgg gaucher registry
American Journal of Hematology, 2017Co-Authors: Pramod K. Mistry, Hans C Andersson, Paige Kaplan, Joel Charrow, Julie L Batista, Manisha Balwani, Thomas A Burrow, Aneal Khan, Priya S Kishnani, Edwin H KolodnyAbstract:This study tests the hypothesis that the prevalence of severe clinical manifestations in Gaucher disease type 1 (GD1) patients at the time of treatment initiation has changed since alglucerase/Imiglucerase enzyme replacement therapy (ERT) was approved in the United States (US) in 1991. US alglucerase/Imiglucerase-treated GD1 patients from the International Collaborative Gaucher Group Gaucher Registry clinicaltrials.gov NCT00358943 were stratified by age at ERT initiation (<18, 18 to <50, ≥50 years), era of ERT initiation (1991-1995, 1996-2000, 2001-2005, 2006-2009), and splenectomy status pre-ERT. Prevalence of splenectomy decreased dramatically across the eras among all age groups. Bone manifestations were more prevalent in splenectomized patients than non-splenectomized patients in all age groups. Prevalence of bone manifestations differed across eras in certain age groups: non-splenectomized patients had a lower prevalence of ischemic bone events (pediatric patients) and bone crisis (pediatric patients and adults 18 to <50 years) in later eras; splenectomized adult (18 to <50 years) patients had a lower prevalence of ischemic bone events and bone crisis in later eras. Over two decades after the introduction of ERT, the prevalence of splenectomy and associated skeletal complications has declined dramatically. Concomitantly, the interval between diagnosis and initiation of ERT has decreased, most strikingly in pediatric patients who have the most severe disease. Together, these findings suggest that since the introduction of alglucerase/Imiglucerase ERT, optimal standard of care has become established in the US to prevent destructive complications of GD1.
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ORIGINAL ARTICLE Long-term clinical outcomes in type 1 Gaucher disease following 10 years of Imiglucerase treatment
2016Co-Authors: Neal J. Weinreb, Carla E M Hollak, Jack Goldblatt, Joel Charrow, Stephan Vom Dahl, Jacobo Villalobos, J. Alex, Er Cole, Marcelo Kerstenetzky, N. J. WeinrebAbstract:Objective We studied the effect of long-term alglucerase/ Imiglucerase (Ceredase®/Cerezyme®, Genzyme, a Sanofi company, Cambridge, MA, USA) treatment on hematolog-ical, visceral, and bone manifestations of Gaucher disease type 1 (GD1). Methods The International Collaborative Gaucher Group (ICGG) Gaucher Registry identified GD1 patients treated with alglucerase/Imiglucerase who had dose and clinical data at first infusion and after 10 years of follow-up. Data for hemoglobin, platelet count, organ volumes, bone pain, and bone crisis were analyzed. Tests of the null hypothesis (no change from first infusion to 10 years) were performed using t tests for within-patient absolute change in continu-ous measurements and McNemar/chi-square tests fo
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long term velaglucerase alfa treatment in children with gaucher disease type 1 naive to enzyme replacement therapy or previously treated with Imiglucerase
Molecular Genetics and Metabolism, 2016Co-Authors: Laurie D Smith, Joel Charrow, Ashish Bavdekar, Rebecca Mardach, Nicola Longo, William J Rhead, Suma P Shankar, Paul Harmatz, Thomas N. HangartnerAbstract:Abstract Background Gaucher Disease type 1 (GD1) often manifests in childhood. Early treatment with enzyme replacement therapy (ERT) may prevent disease complications. We report the assessment of velaglucerase alfa ERT in pediatric GD1 patients who participated in a long-term extension study (HGT-GCB-044, ClinicalTrials.gov Identifier NCT00635427). Methods Safety and efficacy were evaluated in pediatric patients receiving velaglucerase alfa 30–60U/kg by intravenous infusion every other week. In addition to key hematological and visceral efficacy assessments, exploratory assessments conducted specifically in pediatric patients included evaluation of height, bone age, bone marrow burden, and Tanner stage of puberty. Results The study included 24 pediatric patients. Fifteen patients were naive to ERT on entry into the preceding trials TKT032 (12-month trial) or HGT-GCB-039 (9-month trial): in the preceding trials, ten of these 15 patients received velaglucerase alfa and five patients received Imiglucerase ERT. Nine patients in the study were previously treated with Imiglucerase for >30months and were switched to velaglucerase alfa in the preceding trial TKT034 (12-month trial). Cumulative ERT exposure in the clinical studies ranged from 2.0 to 5.8years. Three serious adverse events, including a fatal convulsion, were reported; none were deemed related to velaglucerase alfa. One patient tested positive for anti-velaglucerase alfa antibodies. An efficacy assessment at 24months showed that velaglucerase alfa had positive effects on primary hematological and visceral parameters in treatment-naive patients, which were maintained with longer-term treatment. Disease parameters were stable in patients switched from long-term Imiglucerase ERT. Exploratory results may suggest benefits of early treatment to enable normal growth in pediatric patients. Conclusion The safety profile and clinical response seen in pediatric patients are consistent with results reported in adults.
Pramod K. Mistry - One of the best experts on this subject based on the ideXlab platform.
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gaucher disease type 1 patients from the icgg gaucher registry sustain initial clinical improvements during twenty years of Imiglucerase treatment
Molecular Genetics and Metabolism, 2021Co-Authors: Neal J. Weinreb, Pramod K. Mistry, Joel Charrow, Jose Simon Camelo, Monica R Mcclain, Nadia BelmatougAbstract:Abstract Background Alglucerase enzyme replacement therapy was approved for Gaucher disease (GD) in the United States in 1991; Imiglucerase in 1994. We report hematologic, visceral, bone pain, bone crisis, height, weight, and Body Mass Index (BMI) outcomes in patients treated for 20 (±3) years with subset analyses based on pre-treatment severity, genotype, and age at treatment initiation. Methods GD type 1 (GD1) patients in the ICGG Gaucher Registry with complete sets of baseline, 10-year, and 20-year data are included (N = 475). Ten-year and 20-year data are compared to pre-treatment baseline, stratified by splenectomy status. Results Non-splenectomized patients: Improvements observed at 10 years were maintained at 20 years for most outcomes. Mean changes from baseline at 10 and 20 years, respectively, were: spleen volume: 18.2 multiples of normal (MN) to 5.1 MN and 4.2 MN; liver volume: 1.8 MN to 1.0 MN and 1.0 MN; hemoglobin: 11.4 g/dL to 13.7 g/dL and 13.8 g/dL; platelet count: 91.6 × 109/L to 168.0 × 109/L and 169.1 × 109/L; without bone crisis: 85.0% to 98.2% and 96.5%; without bone pain: 52.5% to 72.0% at 10 years, no significant change at 20 years (58.5%). Splenectomized patients: significant changes were observed in liver volume: 2.3 MN to 1.1 MN and 1.0 MN; hemoglobin: 11.7 g/dL to 13.3 g/dL and 13.4 g/dL; platelet count: 229.1 × 109/L to 288.1 × 109/L and 257.0 × 109/L; without bone crisis: 52.2% to 91.3% and 100%; without bone pain: 16.3% to 30.6% (not significant) and 46.9%. Similar results were found in each of the subset analyses. Patients who start treatment during childhood have normal weight and height in young adulthood. Many treated adult patients are overweight or obese; however, this is consistent with BMI trends observed in the general population. After 1–2 years, the average biweekly Imiglucerase dose is ~40 units/kg body weight. Conclusion Imiglucerase is an effective, long-term treatment for GD1. In a long-term observational setting, improvements seen during early treatment years are sustained by continuing treatment for 20 years, except for bone pain in non-splenectomized patients. These results are consistent when analyzed by different patient subsets, including by disease severity.
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Reversal of life-threatening hepatopulmonary syndrome in Gaucher disease by Imiglucerase enzyme replacement therapy.
Molecular Genetics and Metabolism Reports, 2019Co-Authors: Amal El Beshlawy, Vagishwari Murugesan, Pramod K. Mistry, Khaled EidAbstract:Abstract Advanced liver disease complicated by hepatopulmonary syndrome is a recognized complication of Gaucher disease. Macrophage-targeted, recombinant enzyme replacement therapy is effective in reversing clinical manifestations attributed to the accumulation of glycolipid-laden macrophages but it is not known whether advanced fibrotic features of the disease can be ameliorated. We describe a splenectomized patient with Gaucher disease who developed massive hepatomegaly, cirrhosis of the liver and life-threatening hepatopulmonary syndrome. Treatment with Imiglucerase enzyme replacement therapy resulted in dramatic reversal of hepatopulmonary syndrome and liver disease. Our report suggests that Gaucher disease pathology involving advanced fibrosis and life-threatening complications can be reversed by Imiglucerase enzyme therapy. Synopsis Effect of Imiglucerase enzyme replacement therapy on Hepatopulmonary Syndrome in Gaucher Disease.
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transformation in pretreatment manifestations of gaucher disease type 1 during two decades of alglucerase Imiglucerase enzyme replacement therapy in the international collaborative gaucher group icgg gaucher registry
American Journal of Hematology, 2017Co-Authors: Pramod K. Mistry, Hans C Andersson, Paige Kaplan, Joel Charrow, Julie L Batista, Manisha Balwani, Thomas A Burrow, Aneal Khan, Priya S Kishnani, Edwin H KolodnyAbstract:This study tests the hypothesis that the prevalence of severe clinical manifestations in Gaucher disease type 1 (GD1) patients at the time of treatment initiation has changed since alglucerase/Imiglucerase enzyme replacement therapy (ERT) was approved in the United States (US) in 1991. US alglucerase/Imiglucerase-treated GD1 patients from the International Collaborative Gaucher Group Gaucher Registry were stratified by age at ERT initiation (<18, 18 to <50, ≥50 years), era of ERT initiation (1991-1995, 1996-2000, 2001-2005, 2006-2009), and splenectomy status pre-ERT. Prevalence of splenectomy decreased dramatically across the eras among all age groups. Bone manifestations were more prevalent in splenectomized patients than non-splenectomized patients in all age groups. Prevalence of bone manifestations differed across eras in certain age groups: non-splenectomized patients had a lower prevalence of ischemic bone events (pediatric patients) and bone crisis (pediatric patients and adults 18 to <50 years) in later eras; splenectomized adult (18 to <50 years) patients had a lower prevalence of ischemic bone events and bone crisis in later eras. Over two decades after the introduction of ERT, the prevalence of splenectomy and associated skeletal complications has declined dramatically. Concomitantly, the interval between diagnosis and initiation of ERT has decreased, most strikingly in pediatric patients who have the most severe disease. Together, these findings suggest that since the introduction of Imiglucerase ERT, optimal standard of care has become established in the US to prevent destructive complications of GD1. This article is protected by copyright. All rights reserved.
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transformation in pretreatment manifestations of gaucher disease type 1 during two decades of alglucerase Imiglucerase enzyme replacement therapy in the international collaborative gaucher group icgg gaucher registry
American Journal of Hematology, 2017Co-Authors: Pramod K. Mistry, Hans C Andersson, Paige Kaplan, Joel Charrow, Julie L Batista, Manisha Balwani, Thomas A Burrow, Aneal Khan, Priya S Kishnani, Edwin H KolodnyAbstract:This study tests the hypothesis that the prevalence of severe clinical manifestations in Gaucher disease type 1 (GD1) patients at the time of treatment initiation has changed since alglucerase/Imiglucerase enzyme replacement therapy (ERT) was approved in the United States (US) in 1991. US alglucerase/Imiglucerase-treated GD1 patients from the International Collaborative Gaucher Group Gaucher Registry clinicaltrials.gov NCT00358943 were stratified by age at ERT initiation (<18, 18 to <50, ≥50 years), era of ERT initiation (1991-1995, 1996-2000, 2001-2005, 2006-2009), and splenectomy status pre-ERT. Prevalence of splenectomy decreased dramatically across the eras among all age groups. Bone manifestations were more prevalent in splenectomized patients than non-splenectomized patients in all age groups. Prevalence of bone manifestations differed across eras in certain age groups: non-splenectomized patients had a lower prevalence of ischemic bone events (pediatric patients) and bone crisis (pediatric patients and adults 18 to <50 years) in later eras; splenectomized adult (18 to <50 years) patients had a lower prevalence of ischemic bone events and bone crisis in later eras. Over two decades after the introduction of ERT, the prevalence of splenectomy and associated skeletal complications has declined dramatically. Concomitantly, the interval between diagnosis and initiation of ERT has decreased, most strikingly in pediatric patients who have the most severe disease. Together, these findings suggest that since the introduction of alglucerase/Imiglucerase ERT, optimal standard of care has become established in the US to prevent destructive complications of GD1.
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long term hematological visceral and growth outcomes in children with gaucher disease type 3 treated with Imiglucerase in the international collaborative gaucher group gaucher registry
Molecular Genetics and Metabolism, 2017Co-Authors: Amal Elbeshlawy, Nadia Belmatoug, Gregory A Grabowski, Julie L Batista, Edwin H Kolodny, Anna Tylkiszymanska, Ashok Vellodi, Gerald F Cox, Pramod K. MistryAbstract:In Gaucher disease (GD), deficiency of lysosomal acid β-glucosidase results in a broad phenotypic spectrum that is classified into three types based on the absence (type 1 [GD1]) or presence and severity of primary central nervous system involvement (type 2 [GD2], the fulminant neuronopathic form, and type 3 [GD3], the milder chronic neuronopathic form). Enzyme replacement therapy (ERT) with Imiglucerase ameliorates and prevents hematological and visceral manifestations in GD1, but data in GD3 are limited to small, single-center series. The effects of Imiglucerase ERT on hematological, visceral and growth outcomes (note: ERT is not expected to directly impact neurologic outcomes) were evaluated during the first 5years of treatment in 253 children and adolescents (<18years of age) with GD3 enrolled in the International Collaborative Gaucher Group (ICGG) Gaucher Registry. The vast majority of GBA mutations in this diverse global population consisted of only 2 mutations: L444P (77%) and D409H (7%). At baseline, GD3 patients exhibited early onset of severe hematological and visceral disease and growth failure. During the first year of Imiglucerase treatment, hemoglobin levels and platelet counts increased and liver and spleen volumes decreased, leading to marked decreases in the number of patients with moderate or severe anemia, thrombocytopenia, and hepatosplenomegaly. These improvements were maintained through Year 5. There was also acceleration in linear growth as evidenced by increasing height Z-scores. Despite devastating disease at baseline, the probability of surviving for at least 5years after starting Imiglucerase was 92%. In this large, multinational cohort of pediatric GD3 patients, Imiglucerase ERT provided a life-saving and life-prolonging benefit for patients with GD3, suggesting that, with proper treatment, many such severely affected patients can lead productive lives and contribute to society.
Paige Kaplan - One of the best experts on this subject based on the ideXlab platform.
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transformation in pretreatment manifestations of gaucher disease type 1 during two decades of alglucerase Imiglucerase enzyme replacement therapy in the international collaborative gaucher group icgg gaucher registry
American Journal of Hematology, 2017Co-Authors: Pramod K. Mistry, Hans C Andersson, Paige Kaplan, Joel Charrow, Julie L Batista, Manisha Balwani, Thomas A Burrow, Aneal Khan, Priya S Kishnani, Edwin H KolodnyAbstract:This study tests the hypothesis that the prevalence of severe clinical manifestations in Gaucher disease type 1 (GD1) patients at the time of treatment initiation has changed since alglucerase/Imiglucerase enzyme replacement therapy (ERT) was approved in the United States (US) in 1991. US alglucerase/Imiglucerase-treated GD1 patients from the International Collaborative Gaucher Group Gaucher Registry clinicaltrials.gov NCT00358943 were stratified by age at ERT initiation (<18, 18 to <50, ≥50 years), era of ERT initiation (1991-1995, 1996-2000, 2001-2005, 2006-2009), and splenectomy status pre-ERT. Prevalence of splenectomy decreased dramatically across the eras among all age groups. Bone manifestations were more prevalent in splenectomized patients than non-splenectomized patients in all age groups. Prevalence of bone manifestations differed across eras in certain age groups: non-splenectomized patients had a lower prevalence of ischemic bone events (pediatric patients) and bone crisis (pediatric patients and adults 18 to <50 years) in later eras; splenectomized adult (18 to <50 years) patients had a lower prevalence of ischemic bone events and bone crisis in later eras. Over two decades after the introduction of ERT, the prevalence of splenectomy and associated skeletal complications has declined dramatically. Concomitantly, the interval between diagnosis and initiation of ERT has decreased, most strikingly in pediatric patients who have the most severe disease. Together, these findings suggest that since the introduction of alglucerase/Imiglucerase ERT, optimal standard of care has become established in the US to prevent destructive complications of GD1.
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transformation in pretreatment manifestations of gaucher disease type 1 during two decades of alglucerase Imiglucerase enzyme replacement therapy in the international collaborative gaucher group icgg gaucher registry
American Journal of Hematology, 2017Co-Authors: Pramod K. Mistry, Hans C Andersson, Paige Kaplan, Joel Charrow, Julie L Batista, Manisha Balwani, Thomas A Burrow, Aneal Khan, Priya S Kishnani, Edwin H KolodnyAbstract:This study tests the hypothesis that the prevalence of severe clinical manifestations in Gaucher disease type 1 (GD1) patients at the time of treatment initiation has changed since alglucerase/Imiglucerase enzyme replacement therapy (ERT) was approved in the United States (US) in 1991. US alglucerase/Imiglucerase-treated GD1 patients from the International Collaborative Gaucher Group Gaucher Registry were stratified by age at ERT initiation (<18, 18 to <50, ≥50 years), era of ERT initiation (1991-1995, 1996-2000, 2001-2005, 2006-2009), and splenectomy status pre-ERT. Prevalence of splenectomy decreased dramatically across the eras among all age groups. Bone manifestations were more prevalent in splenectomized patients than non-splenectomized patients in all age groups. Prevalence of bone manifestations differed across eras in certain age groups: non-splenectomized patients had a lower prevalence of ischemic bone events (pediatric patients) and bone crisis (pediatric patients and adults 18 to <50 years) in later eras; splenectomized adult (18 to <50 years) patients had a lower prevalence of ischemic bone events and bone crisis in later eras. Over two decades after the introduction of ERT, the prevalence of splenectomy and associated skeletal complications has declined dramatically. Concomitantly, the interval between diagnosis and initiation of ERT has decreased, most strikingly in pediatric patients who have the most severe disease. Together, these findings suggest that since the introduction of Imiglucerase ERT, optimal standard of care has become established in the US to prevent destructive complications of GD1. This article is protected by copyright. All rights reserved.
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Osteopenia in Gaucher disease develops early in life: Response to Imiglucerase enzyme therapy in children, adolescents and adults
Blood cells molecules & diseases, 2010Co-Authors: Pramod K. Mistry, Paige Kaplan, Neal J. Weinreb, J. Alexander Cole, A. R. Gwosdow, Thomas N. HangartnerAbstract:Background In Gaucher disease (GD), acid-β-glucosidase (GBA1) gene mutations result in defective glucocerebrosidase and variable combinations of hematological, visceral, and diverse bone disease. Osteopenia is highly prevalent, but its age of onset during the natural course of GD is not known. It is also unclear if the degree of improvement in osteopenia, secondary to Imiglucerase enzyme therapy, differs by the age of the patient.
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the female gaucher patient the impact of enzyme replacement therapy around key reproductive events menstruation pregnancy and menopause
Blood Cells Molecules and Diseases, 2009Co-Authors: Ari Zimran, Paige Kaplan, Nadia Belmatoug, Elizabeth Morris, Eugen Mengel, Derralynn Hughes, Vera Malinova, Rene Heitner, Elisa Sobreira, Mirando MrsicAbstract:Abstract Background The principal manifestations of type 1 Gaucher disease (GD) (increased risk of bleeding, anaemia, splenomegaly, hepatomegaly and bone disease) are likely to affect females during reproductive events such as menarche and menstruation; fertility, pregnancy, parity, delivery and lactation; and menopause. In order to determine the optimal management of female Gaucher patients based on available data, we examine reproductive events and GD in untreated and alglucerase and/or Imiglucerase-treated females. Methods A panel of international clinicians experienced in the management of GD reviewed and presented evidence from peer-reviewed literature, a pharmacovigilance database on Imiglucerase, and their own clinical experience to support discussions and recommendations. Nine panel members completed a 130-item-questionnaire on the outcomes of the management of female patients in their clinical practice. Results, covering menarche (137 females), menstruation (261 reports), fertility (295 females), pregnancy (416 pregnancies in 247 women) and menopause (45 women) were analysed. Data from a recent Canadian survey on 50 patients with 39 pregnancies, the Imiglucerase pharmacovigilance database (100 pregnancies), and relevant literature (56 items covering 398 pregnancies in 205 women) were also reviewed. Key results Menarche : May be delayed in girls with GD. Menorrhagia : Appears to be more common in GD than in the non-Gaucher population and may be ameliorated by alglucerase and/or Imiglucerase treatment (menorrhagia in 67/133 (50.4%) untreated females compared with 37/128 (28.9%) treated; Mann–Whitney U test: p = 0.001). Fertility : There is no evidence of decreased fertility in GD. Pregnancy : Pregnancy in GD may be complicated by haematological disease, organomegaly and bone involvement. GD diagnosis occurs frequently during pregnancy. Questionnaire results demonstrate: a reduced risk of spontaneous abortion in women treated with alglucerase and/or Imiglucerase (untreated: 26/189 (13.8%); treated 1/58 (1.7%) χ 2 p = 0.010); reduced risk of Gaucher-related complications during delivery (untreated 43/109 (39.4%); treated 3/46 (6.5%) χ 2 p χ 2 p = 0.014). There is no evidence to date of any untoward effect of alglucerase and/or Imiglucerase on the fetus, or on infants breast fed by mothers receiving alglucerase and/or Imiglucerase. Menopause : The impact of GD on menopause requires further study especially in relation to bone pathology. Conclusions On the basis of this review, GD may have an impact on reproductive events in affected women. Enzyme therapy may have benefits in reducing menorrhagia, spontaneous abortions and complications associated with delivery and the postpartum period.
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a randomized trial comparing the efficacy and safety of Imiglucerase cerezyme infusions every 4 weeks versus every 2 weeks in the maintenance therapy of adult patients with gaucher disease type 1
Molecular Genetics and Metabolism, 2009Co-Authors: Priya S Kishnani, Paige Kaplan, Sharon Smith, Atul Mehta, Ana Cristina Puga, M Dirocco, G M Pastores, Roberta Lemay, Neal J. WeinrebAbstract:Imiglucerase (Cerezyme) has been the standard of care for treatment of Gaucher disease, a lysosomal storage disorder resulting from deficiency of glucocerebrosidase, since its approval in 1994. Infusions are typically given once every 2 weeks. However, many patients have expressed a desire for less frequent infusions as a matter of convenience. This clinical study assessed the safety and efficacy of intravenous Imiglucerase infused once every 4 weeks (Q4) compared to once every 2 weeks (Q2) at the same total monthly dose in adult patients with clinically stable Gaucher disease type 1 (GD1). This was a 24-month, open-label, randomized, Phase 4, dose-frequency study conducted in 25 centers worldwide. Patients receiving Imiglucerase were randomized to receive their monthly dose biweekly (n=33) or every 4 weeks (n=62). Changes from baseline in hemoglobin, platelets, liver and spleen volumes, bone crisis, and bone disease comprised a predefined composite endpoint; achievement or maintenance of established Gaucher disease therapeutic goals comprised a secondary endpoint. Sixty-three percent of Q4- and 81% of Q2-treated patients met the composite endpoint at Month 24; 89% of Q4- and 100% of Q2-treated patients met the therapeutic goals-based endpoint. The frequency of related adverse events was comparable between treatment groups. This study suggests that with comprehensive monitoring, a Q4 Imiglucerase infusion regimen may be a safe and effective treatment option for the majority of clinically stable adult patients with GD1 but may not be appropriate for all GD1 patients. Continued monitoring in patients treated with Q4 dosing is required to assess long-term effectiveness.
Ari Zimran - One of the best experts on this subject based on the ideXlab platform.
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open label expanded access study of taliglucerase alfa in patients with gaucher disease requiring enzyme replacement therapy
Blood Cells Molecules and Diseases, 2020Co-Authors: David J Kuter, Raul Chertkoff, Betina Hernandez, Michael P Wajnrajch, Rong Wang, Ari ZimranAbstract:Abstract A multicenter, open-label, expanded-access study followed the safety of taliglucerase alfa, a plant cell–expressed recombinant enzyme replacement therapy (ERT), in adults with Gaucher disease previously treated with Imiglucerase. Patients received taliglucerase alfa every 2 weeks for 9 months at a dose equivalent to their previous Imiglucerase dose (Part A); patients were offered treatment for up to 33 months (Part B), and a later amendment allowed treatment-naive patients. Fifty-eight patients received taliglucerase alfa (55.2% male; mean age, 46.1 years; mean bi-weekly dose, 35.2 U/kg; mean duration, 17.8 months); 51 patients previously received ERT, seven were treatment-naive, and 36 completed the study. Most adverse events were mild or moderate; treatment-related adverse events were mild and transient. In previously treated patients, increases from baseline to last follow-up were observed for mean ± SE hemoglobin concentration (13.0 ± 0.3 g/dL to 13.4 ± 0.2 g/dL) and platelet count (179,242 ± 15,344/mm3 to 215,242 ± 17,867/mm3). Findings were similar in treatment-naive patients (mean ± SE hemoglobin concentration and platelet count, 12.8 ± 0.3 g/dL to 13.5 ± 0.2 g/dL and 168,821 ± 14,368/mm3 to 204,641 ± 16,071/mm3, respectively). Taliglucerase alfa was well-tolerated for up to 33 months and demonstrated a durable therapeutic effect.
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long term safety and efficacy of taliglucerase alfa in pediatric gaucher disease patients who were treatment naive or previously treated with Imiglucerase
Blood Cells Molecules and Diseases, 2018Co-Authors: Ari Zimran, Pilar Giraldo, Milan Petakov, Ee Shien Tan, Derlis Emilio Gonzalezrodriguez, Aya Abrahamov, Peter A Cooper, Sheeba Varughese, Raul ChertkoffAbstract:Taliglucerase alfa is an enzyme replacement therapy approved for treatment of Gaucher disease (GD) in children and adults in several countries. This multicenter extension study assessed the efficacy and safety of taliglucerase alfa in pediatric patients with GD who were treatment-naive (n=10) or switched from Imiglucerase (n=5). Patients received taliglucerase alfa 30 or 60U/kg (treatment-naive) or the same dose as previously treated with Imiglucerase every other week. In treatment-naive patients, taliglucerase alfa 30 and 60U/kg, respectively, reduced mean spleen volume (-18.6 multiples of normal [MN] and -26.0MN), liver volume (-0.8MN and -0.9MN), and chitotriosidase activity (-72.7% and -84.4%), and increased mean Hb concentration (+2.0g/dL and +2.3g/dL) and mean platelet count (+38,200/mm3 and +138,250/mm3) from baseline through 36 total months of treatment. In patients previously treated with Imiglucerase, these disease parameters remained stable through 33 total months of treatment with taliglucerase alfa. Most adverse events were mild/moderate; treatment was well tolerated. These findings extend the taliglucerase alfa safety and efficacy profile and demonstrate long-term clinical improvement in treatment-naive children receiving taliglucerase alfa and maintenance of disease stability in children switched to taliglucerase alfa. Treatment was well-tolerated, with no new safety signals. This study is registered at www.clinicaltrials.gov as NCT01411228.
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Taliglucerase alfa: safety and efficacy across 6 clinical studies in adults and children with Gaucher disease
'Springer Science and Business Media LLC', 2018Co-Authors: Ari Zimran, Michael Wajnrajch, Betina Hernandez, Gregory M PastoresAbstract:Abstract Taliglucerase alfa is an enzyme replacement therapy (ERT) approved for treatment of adult and paediatric patients with Type 1 Gaucher disease (GD) in several countries and the first plant cell–expressed recombinant therapeutic protein approved by the US Food and Drug Administration for humans. Here, we review the findings across six key taliglucerase alfa clinical studies. A total of 33 treatment-naïve adult patients were randomized to taliglucerase alfa 30 U/kg or 60 U/kg in a 9-month, multicentre, randomized, double-blind, parallel-group, dose-comparison pivotal study, after which eligible patients continued into two consecutive extension studies; 17 treatment-naïve adult patients completed 5 total years of treatment with taliglucerase alfa. In the only ERT study focused on exclusively paediatric patients with GD, 11 treatment-naïve children were randomized to taliglucerase alfa 30 U/kg or 60 U/kg in a 12-month, multicentre, double-blind study; nine completed 3 total years of treatment in a dedicated paediatric extension study. The effect of switching patients from Imiglucerase to taliglucerase alfa was also investigated in a separate 9-month study that included 26 adults and five children; 10 adults completed a total of 3 years and two children completed a total of 2.75 years of taliglucerase alfa treatment in the extension studies. All studies evaluated safety and spleen volume, liver volume, platelet count, haemoglobin concentration, and biomarkers as measures of efficacy. Detailed results from baseline through the end of these studies are presented. Taliglucerase alfa was well tolerated, and adverse events were generally mild/moderate in severity and transient. Treatment with taliglucerase alfa resulted in improvements (treatment-naïve patients) or stability (patients switched from Imiglucerase) in visceral, haematologic, and biomarker parameters. Together, this comprehensive data set supports the treatment of adult and paediatric patients with GD who are naïve to ERT or who have previously been treated with Imiglucerase
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achievement of therapeutic goals with low dose Imiglucerase in gaucher disease a single center experience
Advances in Hematology, 2013Co-Authors: Irina Tukan, Deborah Elstein, Irith Hadashalpern, Gheona Altarescu, Ayala Abrahamov, Ari ZimranAbstract:Gaucher disease, a lysosomal storage disorder, is a multisystem disorder with variable and unpredictable onset and severity. Disease-specific enzyme replacement therapy (ERT) has been shown to reverse or ameliorate disease-specific hepatosplenomegaly and anemia and thrombocytopenia. ERT also impacts bone manifestations, including bone crises, bone pain, and appearance of new osteonecrosis, and improves bone mineral density to varying degrees. The objective of this study was to assess achievement of predefined therapeutic goals based on international registry outcomes for Israeli patients with Gaucher disease receiving Imiglucerase for four consecutive years on a low-dose regimen followed in a single center. All data were taken from patient files. The therapeutic goals were taken from standards published in the literature for disease-specific clinical parameters. Among 164 patients at baseline, values for spleen and liver volumes, hemoglobin and platelet counts, and Z-scores for lumbar spine and femoral were significantly different from the goal. After four years ERT, there was a significant improvement (P = 0.000) in each of the therapeutic goal parameters from baseline. 15.2% of these patients achieved all hematology-visceral goals. In children, there was achievement of linear growth and puberty. This survey highlights the good overall response in symptomatic patients receiving low-dose ERT with Imiglucerase in Israel.
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velaglucerase alfa enzyme replacement therapy compared with Imiglucerase in patients with gaucher disease
American Journal of Hematology, 2013Co-Authors: Hadhami Ben Turkia, Pilar Giraldo, Ari Zimran, Derlis E Gonzalez, Norman W Barton, Madhulika Kabra, Elena Lukina, Isaac Kisinovsky, Ashish Bavdekar, Mariefrancoise Ben DridiAbstract:Enzyme replacement therapy for Gaucher disease (GD) has been available since 1991. This study compared the efficacy and safety of velaglucerase alfa with Imiglucerase, the previous standard of care. A 9-month, global, randomized, double-blind, non-inferiority study compared velaglucerase alfa with Imiglucerase (60 U/kg every other week) in treatment-naive patients aged 3-73 years with anemia and either thrombocytopenia or organomegaly. The primary endpoint was the difference between groups in mean change from baseline to 9 months in hemoglobin concentration. 35 patients were randomized: 34 received study drug (intent-to-treat: 17 per arm), 20 were splenectomized. Baseline characteristics were similar in the two groups. The per-protocol population included 15 patients per arm. The mean treatment difference for hemoglobin concentration from baseline to 9 months (velaglucerase alfa minus Imiglucerase) was 0.14 and 0.16 g/dL in the intent-to-treat and per-protocol populations, respectively. The lower bound of the 97.5% one-sided confidence interval in both populations lay within the pre-defined non-inferiority margin of -1.0 g/dL, confirming that velaglucerase alfa is non-inferior to Imiglucerase. There were no statistically significant differences in the secondary endpoints. Most adverse events were mild to moderate. No patient receiving velaglucerase alfa developed antibodies to either drug, whereas four patients (23.5%) receiving Imiglucerase developed IgG antibodies to Imiglucerase, which were cross-reactive with velaglucerase alfa in one patient. This study demonstrates the efficacy and safety of velaglucerase alfa compared with Imiglucerase in adult and pediatric patients with GD clinically characterized as Type 1. Differences in immunogenicity were also observed.
