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Carla E M Hollak - One of the best experts on this subject based on the ideXlab platform.
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enzyme replacement and substrate reduction therapy for gaucher disease
Cochrane Database of Systematic Reviews, 2015Co-Authors: Elad Shemesh, Laura Deroma, Bruno Bembi, Carla E M Hollak, Patrick Deegan, Neal J. WeinrebAbstract:Background Gaucher disease, a rare disorder, is caused by inherited deficiency of the enzyme glucocerebrosidase. It is unique among the ultra-orphan disorders in that four treatments are currently approved by various regulatory authorities for use in routine clinical practice. Hitherto, because of the relatively few people affected worldwide, many of whom started therapy during a prolonged period when there were essentially no alternatives to imiglucerase, these treatments have not been systematically evaluated in studies such as randomized controlled trials now considered necessary to generate the highest level of clinical evidence. Objectives To summarize all available randomized controlled study data on the efficacy and safety of enzyme replacement therapies and substrate reduction therapy for treating Gaucher disease. Search methods We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register. Additional searches were conducted on ClinicalTrials.gov for any ongoing studies with potential interim results, and through PubMed. We also searched the reference lists of relevant articles and reviews. Date of last search: 07 August 2014. Selection criteria All randomized and quasi-randomized controlled studies (including open-label studies and cross-over studies) assessing enzyme replacement therapy or substrate reduction therapy, or both, in all types of Gaucher disease were included. Data collection and analysis Two authors independently assessed the risk of bias in the included studies, and extracted relevant data. Main results Of the 488 studies retrieved by the electronic searches, eight met the inclusion criteria and were analysed (300 participants). Response parameters were restricted to haemoglobin concentration, platelet count, spleen and liver volume and serum biomarkers (chitotriosidase and CCL18). Only one publication reported a 'low risk of bias' score in all parameters assessed, and all studies included were randomized. Four studies reported the responses to enzyme replacement therapy of previously untreated individuals with type 1 Gaucher disease. Two studies investigated maintenance enzyme replacement therapy in people with stable type 1 Gaucher disease previously treated for at least two years. One study compared substrate reduction therapy, enzyme replacement therapy and a combination thereof as maintenance therapy in people with type 1 Gaucher disease previously treated with enzyme replacement therapy. One study examined substrate reduction therapy in people with chronic neuronopathic (type 3) Gaucher disease who continued to receive enzyme replacement therapy. Treatment-naive participants had similar increases in haemoglobin when comparing those receiving imiglucerase or Alglucerase at 60 units/kg, imiglucerase or velaglucerase alfa at 60 U/kg, taliglucerase alfa at 30 units/kg or 60 units/kg, and velaglucerase alfa at 45 units/g or 60 units/kg. For platelet count response in participants with intact spleens, a benefit for imiglucerase over velaglucerase alfa at 60 units/kg was observed, mean difference -79.87 (95% confidence interval -137.57 to -22.17). There were no other significant differences in platelet count response when comparing different doses of velaglucerase alfa and of taliglucerase alfa, and when comparing imiglucerase to Alglucerase. Spleen and liver volume reductions were not significantly different in any enzyme replacement therapy product or dose comparison study. Although a dose effect on serum biomarkers was not seen after nine months, a significantly greater reduction with higher dose was reported after 12 months in the velaglucerase study, mean difference 16.70 (95% confidence intervaI 1.51 to 31.89). In the two enzyme replacement therapy maintenance studies comparing infusions every two weeks and every four weeks, there were no significant differences in haemoglobin concentration, platelet count, and spleen and liver volumes over a 6 to 12 month period when participants were treated with the same cumulative dose. A total of 25 serious adverse events were reported, nearly all deemed unrelated to treatment. There are, as yet, no randomized trials of substrate reduction therapy in treatment-naive patients that can be evaluated. Miglustat monotherapy appeared as effective as continued enzyme replacement therapy for maintenance of hematological, organ and biomarker responses in people with type 1 Gaucher disease previously treated with imiglucerase for at least two years. In those with neuronopathic Gaucher disease, no significant improvements in haemoglobin concentration, platelet count or organ volumes occurred when enzyme replacement therapy was augmented with miglustat. One randomized controlled study assessing substrate reduction therapy was published immediately prior to producing the final version of this review, and this, along with a further ongoing study (expected to be published in the near future), will be assessed for eligibility in a future update of the review. Authors' conclusions The results reflect the limitations of analysing evidence restricted to prospective randomized controlled trials, especially when dealing with chronic rare diseases. This analysis suggests that, during the first year of treatment, different recombinant glucocerebrosidases are bio-similar and non-inferior in safety and efficacy for surrogate biological response parameters. Enzyme replacement therapy given at 30 to 45 units/kg body weight every two to four weeks was generally as effective as the 60 unit/kg dose for the assessed clinical outcomes. The analysis emphasise the need to determine whether it is realistic to carry out multi-decade prospective clinical trials for rare diseases such as type 1 Gaucher disease. With large treatment effects on the classical manifestations of the disorder, therapeutic investigations in Gaucher disease mandate innovative trial designs and methodology to secure decisive data concerning long-term efficacy and safety – with the realization that knowledge about disease-modifying actions that are sustained are of crucial importance to people with this chronic condition.
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dose response relationships for enzyme replacement therapy with imiglucerase Alglucerase in patients with gaucher disease type 1
Genetics in Medicine, 2009Co-Authors: Gregory A Grabowski, Carla E M Hollak, Katherine Kacena, Ari Zimran, Alexander J Cole, Lin Zhang, John Yee, Pramod K Mistry, Joel Charrow, Stephan Vom DahlAbstract:Purpose: To determine whether enzyme therapy with imiglucerase/Alglucerase demonstrates dose-response relationships with doses and disease parameters used in routine clinical practice for Gaucher disease type 1 patients. Methods: Analyses included all patients with Gaucher disease type 1 on enzyme therapy and with intact spleens in the large observational database of the International Collaborative Gaucher Group Gaucher Registry. Propensity scoring was used to match patients between enzyme therapy dose groups categorized as Group A (5 U to <29 U/kg/2 weeks), Group B (29 U to <48 U/kg/2 weeks), Group C (48 U to <75 U/kg/2 weeks). Hemoglobin concentration, platelet count, and hepatic and splenic volumes were assessed after initiation of enzyme therapy using nonlinear mixed effects models. The maximal effect (Emax) and half-time to Emax (T50) of enzyme therapy for each parameter were compared across dosing groups. Results: Propensity score matching resulted in three comparable groups of 122 patients each (enzyme therapy in Groups A, B, and C). Dose-response relationships were found with regard to Emax and T50 over 96 months for each disease parameter. Conclusions: Enzyme therapy with imiglucerase/Alglucerase displays a dose-dependent improvement in hematological and visceral parameters in Gaucher disease type 1 patients. Group C displayed greater treatment effects than Groups A or B. Propensity score matching and nonlinear mixed effects model analyses provide a prototype for assessment of treatment outcomes based on observational data from international rare disease registries.
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dose response relationships for enzyme replacement therapy with imiglucerase Alglucerase in patients with gaucher disease type 1
Genetics in Medicine, 2009Co-Authors: Gregory A Grabowski, Carla E M Hollak, Katherine Kacena, Ari Zimran, Alexander J Cole, Lin Zhang, John Yee, Pramod K Mistry, Joel Charrow, Stephan Vom DahlAbstract:Gaucher disease (GD) is a lysosomal storage disorder that results from insufficient clearance of cellular glucosylceramide, the substrate for the lysosomal enzyme, acid β-glucosidase (EC 3.2.1.45; glucocerebrosidase). The pathologic accumulations of glucosylceramide in lysosomes of tissue macrophages results in splenomegaly, hepatomegaly, anemia, thrombocytopenia, and multiple forms of skeletal pathology.1–5 In the Western world, GD type 1 (GD1) is the most prevalent variant (94%) and is classically differentiated from types 2 (1%) and 3 (5%) by the absence of primary central nervous system involvement.1,6 GD1 is an ultraorphan disease, with an estimated worldwide prevalence of 1 in 60,000.7 The current standard of care for the treatment of GD1 is enzyme replacement (or more appropriately, reconstitution) therapy with imiglucerase, a recombinant form of glucocerebrosidase. Alglucerase, derived from placental tissue, was used before the availability of imiglucerase. A randomized clinical trial comparing Alglucerase and imiglucerase found these enzymes to be therapeutically equivalent in safety and efficacy.8 Whether enzyme therapy has dose-dependent treatment effects has been a subject of debate since the first clinical trial of Alglucerase was published in 1991.9 In 1995, a panel convened by the National Institutes of Health highlighted the importance of determining whether enzyme therapy has dose-dependent treatment effects.10 Dosing practices for enzyme therapy have varied around the world because, in part, of the lack of clear evidence of dose-response relationships.9,11–15 For patients with bone disease or other severe manifestations of GD, the recommendation has been to use higher doses.16,17 Given the high cost of therapy and the great phenotypic heterogeneity between patients with GD1, the goal of treatment has been to identify individualized dosing regimens that can achieve optimal long-term outcomes for each patient.18 Ideally, dose-response relationships would be evaluated by conducting a randomized clinical trial with multiple arms. For rare diseases, such as GD1, this study design would not be practical or feasible because of the large number of subjects and length of follow-up needed to achieve adequate statistical power. As an alternative, analyses of observational data from a large international disease registry using standard epidemiologic matching and modeling methods may offer a feasible and methodologically sound approach. In the present analyses, data from the International Collaborative Gaucher Group (ICGG) Gaucher Registry were analyzed using propensity scoring methods to match patients between dosing groups19–22 to approximate conditions under a randomized trial. Nonlinear mixed effects modeling of these matched data sets was used to assess dose-response relationships across disease parameters.
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Alglucerase practical guidance on appropriate dosage and administration in patients with gaucher disease
BioDrugs, 1998Co-Authors: Carla E M Hollak, Johannes M F G Aerts, Van M H J OersAbstract:Gaucher disease is caused by a deficiency of glucocerebrosidase. It is the first lysosomal storage disorder for which effective enzyme-supplementation therapy has become available. The enzyme, Alglucerase, is glucocerebrosidase derived from human placental tissue; its oligosaccharide chain has been modified to expose terminal mannose residues, facilitating uptake in macrophages. Many patients have been shown to benefit from treatment with the enzyme. Spleen and liver volumes decrease and cytopenia improves. Over a longer period of time, bone involvement can also be diminished, although severe pre-existing bone abnormalities do not change. The safety profile of Alglucerase seems excellent, with only few adverse events and approximately 12% of patients developing antibodies. Because long term safety is unknown and the enzyme is very expensive, studies have focused on the determination of the optimum individual dosage. Different dosages have shown to be effective, but so far the identification of patients who need a high or a low dosage is unclear. Other issues that deserve attention are the selection criteria for the initiation of treatment and the place of prophylactic treatment. Diversity in the course of the disease, which in many cases cannot be predicted by genotyping, hampers the establishment of strict rules. Multicentre studies, in which comparison of data is made possible by the use of standardised measurements of disease manifestations, may be needed to solve these issues.
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home treatment with intravenous enzyme replacement therapy for gaucher disease an international collaborative study of 33 patients
Blood, 1993Co-Authors: Ari Zimran, Carla E M Hollak, Ayala Abrahamov, M H Van Oers, M Kelly, E BeutlerAbstract:Intravenous enzyme replacement therapy (Alglucerase; Ceredase; Genzyme Corp, Boston, MA) is an effective and safe treatment for patients with type 1 Gaucher disease. In an attempt to reduce its high cost, a "low-dose high-frequency" protocol (30 U/kg/mo, 3 times a week) was introduced and found to be as effective as the original high-dose protocol (60 U/kg every 2 weeks). Because receiving frequent infusions creates a burden for many patients, we have implemented a program of home treatment for our patients. We now report the safety and feasibility of low-dose/high-frequency home intravenous enzyme-replacement therapy in 33 patients with Gaucher disease. The chronic nature of the treatment, its safety, lack of adverse effects, the stable condition of most patients, and the need to reduce the high cost make enzyme replacement for Gaucher disease a good candidate for intravenous home therapy.
Ari Zimran - One of the best experts on this subject based on the ideXlab platform.
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determinants of persisting thrombocytopenia in patients with type 1 gaucher disease treated with Alglucerase imiglucerase for 4 5 years
Blood, 2010Co-Authors: Maria Domenica Cappellini, Patrick Deegan, Neal J. Weinreb, Barry E Rosenbloom, Nadia Belmatoug, Stephan Vom Dahl, Alexander G Cole, Jack Goldblatt, Anna Tylkiszymanska, Ari ZimranAbstract:Abstract 4719 Introduction: Thrombocytopenia in type 1 Gaucher disease (GD) may result in surgical, obstetrical and spontaneous bleeding. Treatment with Alglucerase/imiglucerase generally results in rapid improvement in platelet count but, in rare cases, the platelet response to therapy is slow or lacking. The factors underlying persisting thrombocytopenia despite treatment are poorly understood. Aim: To identify patient characteristics associated with (and potentially predictive of) persisting thrombocytopenia despite therapy by retrospective analysis of ICGG Gaucher Registry data. Methods: 1,016 type 1 GD patients with an intact spleen, date of diagnosis and therapy initiation, no treatment breaks 4–5 years after therapy initiation, and known platelet counts, were classified into four groups by last platelet count 4–5 years after therapy initiation: >120 × 109/l (n = 772); >100 to 80 to <100 × 109/l (n = 80); and <80 × 109/l (n = 70, of which 20 had <60 × 109/platelets/l). Patients were characterized by demographics, BMI; platelet count; anemia; biomarkers; hepatomegaly; splenomegaly; and skeletal assessments at baseline (therapy initiation) and after 4–5 years of therapy. Initial enzyme dose and cumulative average dose were noted. Possible associations with persisting thrombocytopenia were tested using a multivariate analysis calculating odds ratios adjusted for age at diagnosis and therapy initiation, genotype, sex, year of diagnosis, and year of therapy initiation. Results: Of the 1,016 patients in this study, 20 (2%) had platelet counts <60 × 109/platelets/l after 4–5 years of therapy. These patients all had severe splenomegaly at baseline. Associations between persisting thrombocytopenia were found between baseline low platelet count (<80 × 109/l), splenomegaly and anemia (p <0.0001). After 4–5 years, persisting thrombocytopenia was associated with anemia (p <0.0001), reduced WBC (p = 0.049), splenomegaly (p <0.0001), hepatomegaly (p = 0.006), bone pain (p = 0.035) and cumulative enzyme dose (dose range 18.6–55.5 U/kg/2weeks; doses <25th percentile: p = 0.043). Too few data prevented reliable analysis of other bone parameters and biomarkers. Discussion and conclusion: Persisting thrombocytopenia despite therapy is rare (2% of patients with platelets <60 × 109/l). The strong association between splenomegaly, anemia and thrombocytopenia at therapy initiation and persisting thrombocytopenia after 4–5 years of treatment suggests that in a minority of cases extensive spleen involvement, possibly with fibrosis, may be predictive of thrombocytopenia that is refractory to treatment. Findings underline the importance of initiating treatment before irreversible complications have developed. Disclosures: Cole: Genzyme Corp: Employment.
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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, Elizabeth Morris, Eugen Mengel, Nadia Belmatoug, 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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dose response relationships for enzyme replacement therapy with imiglucerase Alglucerase in patients with gaucher disease type 1
Genetics in Medicine, 2009Co-Authors: Gregory A Grabowski, Carla E M Hollak, Katherine Kacena, Ari Zimran, Alexander J Cole, Lin Zhang, John Yee, Pramod K Mistry, Joel Charrow, Stephan Vom DahlAbstract:Purpose: To determine whether enzyme therapy with imiglucerase/Alglucerase demonstrates dose-response relationships with doses and disease parameters used in routine clinical practice for Gaucher disease type 1 patients. Methods: Analyses included all patients with Gaucher disease type 1 on enzyme therapy and with intact spleens in the large observational database of the International Collaborative Gaucher Group Gaucher Registry. Propensity scoring was used to match patients between enzyme therapy dose groups categorized as Group A (5 U to <29 U/kg/2 weeks), Group B (29 U to <48 U/kg/2 weeks), Group C (48 U to <75 U/kg/2 weeks). Hemoglobin concentration, platelet count, and hepatic and splenic volumes were assessed after initiation of enzyme therapy using nonlinear mixed effects models. The maximal effect (Emax) and half-time to Emax (T50) of enzyme therapy for each parameter were compared across dosing groups. Results: Propensity score matching resulted in three comparable groups of 122 patients each (enzyme therapy in Groups A, B, and C). Dose-response relationships were found with regard to Emax and T50 over 96 months for each disease parameter. Conclusions: Enzyme therapy with imiglucerase/Alglucerase displays a dose-dependent improvement in hematological and visceral parameters in Gaucher disease type 1 patients. Group C displayed greater treatment effects than Groups A or B. Propensity score matching and nonlinear mixed effects model analyses provide a prototype for assessment of treatment outcomes based on observational data from international rare disease registries.
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dose response relationships for enzyme replacement therapy with imiglucerase Alglucerase in patients with gaucher disease type 1
Genetics in Medicine, 2009Co-Authors: Gregory A Grabowski, Carla E M Hollak, Katherine Kacena, Ari Zimran, Alexander J Cole, Lin Zhang, John Yee, Pramod K Mistry, Joel Charrow, Stephan Vom DahlAbstract:Gaucher disease (GD) is a lysosomal storage disorder that results from insufficient clearance of cellular glucosylceramide, the substrate for the lysosomal enzyme, acid β-glucosidase (EC 3.2.1.45; glucocerebrosidase). The pathologic accumulations of glucosylceramide in lysosomes of tissue macrophages results in splenomegaly, hepatomegaly, anemia, thrombocytopenia, and multiple forms of skeletal pathology.1–5 In the Western world, GD type 1 (GD1) is the most prevalent variant (94%) and is classically differentiated from types 2 (1%) and 3 (5%) by the absence of primary central nervous system involvement.1,6 GD1 is an ultraorphan disease, with an estimated worldwide prevalence of 1 in 60,000.7 The current standard of care for the treatment of GD1 is enzyme replacement (or more appropriately, reconstitution) therapy with imiglucerase, a recombinant form of glucocerebrosidase. Alglucerase, derived from placental tissue, was used before the availability of imiglucerase. A randomized clinical trial comparing Alglucerase and imiglucerase found these enzymes to be therapeutically equivalent in safety and efficacy.8 Whether enzyme therapy has dose-dependent treatment effects has been a subject of debate since the first clinical trial of Alglucerase was published in 1991.9 In 1995, a panel convened by the National Institutes of Health highlighted the importance of determining whether enzyme therapy has dose-dependent treatment effects.10 Dosing practices for enzyme therapy have varied around the world because, in part, of the lack of clear evidence of dose-response relationships.9,11–15 For patients with bone disease or other severe manifestations of GD, the recommendation has been to use higher doses.16,17 Given the high cost of therapy and the great phenotypic heterogeneity between patients with GD1, the goal of treatment has been to identify individualized dosing regimens that can achieve optimal long-term outcomes for each patient.18 Ideally, dose-response relationships would be evaluated by conducting a randomized clinical trial with multiple arms. For rare diseases, such as GD1, this study design would not be practical or feasible because of the large number of subjects and length of follow-up needed to achieve adequate statistical power. As an alternative, analyses of observational data from a large international disease registry using standard epidemiologic matching and modeling methods may offer a feasible and methodologically sound approach. In the present analyses, data from the International Collaborative Gaucher Group (ICGG) Gaucher Registry were analyzed using propensity scoring methods to match patients between dosing groups19–22 to approximate conditions under a randomized trial. Nonlinear mixed effects modeling of these matched data sets was used to assess dose-response relationships across disease parameters.
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hcg contamination of Alglucerase clinical implications in low dose regimen
American Journal of Hematology, 1994Co-Authors: Yael Cohen, Deborah Elstein, A Abrahamov, Harry J Hirsch, Ari ZimranAbstract:Alglucerase (Ceredase) is currently the treatment of choice for patients with symptomatic Gaucher disease. The contamination of this placental enzyme with human chorionic gonadotropin (hCG) has raised concern regarding possible endocrinological complications. We examined 32 patients treated with low-dose Alglucerase and 27 untreated patients as controls, and found no significant clinical differences between the two groups: no prepubertal children were affected, no menstrual irregularities were reported, and all hCG levels were well within normal range. Conversely, our finding of a statistically significant difference between the groups underscores the importance of initiating parallel studies of hCG contamination in patients receiving high-dose protocol.
Neal J. Weinreb - One of the best experts on this subject based on the ideXlab platform.
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enzyme replacement and substrate reduction therapy for gaucher disease
Cochrane Database of Systematic Reviews, 2015Co-Authors: Elad Shemesh, Laura Deroma, Bruno Bembi, Carla E M Hollak, Patrick Deegan, Neal J. WeinrebAbstract:Background Gaucher disease, a rare disorder, is caused by inherited deficiency of the enzyme glucocerebrosidase. It is unique among the ultra-orphan disorders in that four treatments are currently approved by various regulatory authorities for use in routine clinical practice. Hitherto, because of the relatively few people affected worldwide, many of whom started therapy during a prolonged period when there were essentially no alternatives to imiglucerase, these treatments have not been systematically evaluated in studies such as randomized controlled trials now considered necessary to generate the highest level of clinical evidence. Objectives To summarize all available randomized controlled study data on the efficacy and safety of enzyme replacement therapies and substrate reduction therapy for treating Gaucher disease. Search methods We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register. Additional searches were conducted on ClinicalTrials.gov for any ongoing studies with potential interim results, and through PubMed. We also searched the reference lists of relevant articles and reviews. Date of last search: 07 August 2014. Selection criteria All randomized and quasi-randomized controlled studies (including open-label studies and cross-over studies) assessing enzyme replacement therapy or substrate reduction therapy, or both, in all types of Gaucher disease were included. Data collection and analysis Two authors independently assessed the risk of bias in the included studies, and extracted relevant data. Main results Of the 488 studies retrieved by the electronic searches, eight met the inclusion criteria and were analysed (300 participants). Response parameters were restricted to haemoglobin concentration, platelet count, spleen and liver volume and serum biomarkers (chitotriosidase and CCL18). Only one publication reported a 'low risk of bias' score in all parameters assessed, and all studies included were randomized. Four studies reported the responses to enzyme replacement therapy of previously untreated individuals with type 1 Gaucher disease. Two studies investigated maintenance enzyme replacement therapy in people with stable type 1 Gaucher disease previously treated for at least two years. One study compared substrate reduction therapy, enzyme replacement therapy and a combination thereof as maintenance therapy in people with type 1 Gaucher disease previously treated with enzyme replacement therapy. One study examined substrate reduction therapy in people with chronic neuronopathic (type 3) Gaucher disease who continued to receive enzyme replacement therapy. Treatment-naive participants had similar increases in haemoglobin when comparing those receiving imiglucerase or Alglucerase at 60 units/kg, imiglucerase or velaglucerase alfa at 60 U/kg, taliglucerase alfa at 30 units/kg or 60 units/kg, and velaglucerase alfa at 45 units/g or 60 units/kg. For platelet count response in participants with intact spleens, a benefit for imiglucerase over velaglucerase alfa at 60 units/kg was observed, mean difference -79.87 (95% confidence interval -137.57 to -22.17). There were no other significant differences in platelet count response when comparing different doses of velaglucerase alfa and of taliglucerase alfa, and when comparing imiglucerase to Alglucerase. Spleen and liver volume reductions were not significantly different in any enzyme replacement therapy product or dose comparison study. Although a dose effect on serum biomarkers was not seen after nine months, a significantly greater reduction with higher dose was reported after 12 months in the velaglucerase study, mean difference 16.70 (95% confidence intervaI 1.51 to 31.89). In the two enzyme replacement therapy maintenance studies comparing infusions every two weeks and every four weeks, there were no significant differences in haemoglobin concentration, platelet count, and spleen and liver volumes over a 6 to 12 month period when participants were treated with the same cumulative dose. A total of 25 serious adverse events were reported, nearly all deemed unrelated to treatment. There are, as yet, no randomized trials of substrate reduction therapy in treatment-naive patients that can be evaluated. Miglustat monotherapy appeared as effective as continued enzyme replacement therapy for maintenance of hematological, organ and biomarker responses in people with type 1 Gaucher disease previously treated with imiglucerase for at least two years. In those with neuronopathic Gaucher disease, no significant improvements in haemoglobin concentration, platelet count or organ volumes occurred when enzyme replacement therapy was augmented with miglustat. One randomized controlled study assessing substrate reduction therapy was published immediately prior to producing the final version of this review, and this, along with a further ongoing study (expected to be published in the near future), will be assessed for eligibility in a future update of the review. Authors' conclusions The results reflect the limitations of analysing evidence restricted to prospective randomized controlled trials, especially when dealing with chronic rare diseases. This analysis suggests that, during the first year of treatment, different recombinant glucocerebrosidases are bio-similar and non-inferior in safety and efficacy for surrogate biological response parameters. Enzyme replacement therapy given at 30 to 45 units/kg body weight every two to four weeks was generally as effective as the 60 unit/kg dose for the assessed clinical outcomes. The analysis emphasise the need to determine whether it is realistic to carry out multi-decade prospective clinical trials for rare diseases such as type 1 Gaucher disease. With large treatment effects on the classical manifestations of the disorder, therapeutic investigations in Gaucher disease mandate innovative trial designs and methodology to secure decisive data concerning long-term efficacy and safety – with the realization that knowledge about disease-modifying actions that are sustained are of crucial importance to people with this chronic condition.
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determinants of persisting thrombocytopenia in patients with type 1 gaucher disease treated with Alglucerase imiglucerase for 4 5 years
Blood, 2010Co-Authors: Maria Domenica Cappellini, Patrick Deegan, Neal J. Weinreb, Barry E Rosenbloom, Nadia Belmatoug, Stephan Vom Dahl, Alexander G Cole, Jack Goldblatt, Anna Tylkiszymanska, Ari ZimranAbstract:Abstract 4719 Introduction: Thrombocytopenia in type 1 Gaucher disease (GD) may result in surgical, obstetrical and spontaneous bleeding. Treatment with Alglucerase/imiglucerase generally results in rapid improvement in platelet count but, in rare cases, the platelet response to therapy is slow or lacking. The factors underlying persisting thrombocytopenia despite treatment are poorly understood. Aim: To identify patient characteristics associated with (and potentially predictive of) persisting thrombocytopenia despite therapy by retrospective analysis of ICGG Gaucher Registry data. Methods: 1,016 type 1 GD patients with an intact spleen, date of diagnosis and therapy initiation, no treatment breaks 4–5 years after therapy initiation, and known platelet counts, were classified into four groups by last platelet count 4–5 years after therapy initiation: >120 × 109/l (n = 772); >100 to 80 to <100 × 109/l (n = 80); and <80 × 109/l (n = 70, of which 20 had <60 × 109/platelets/l). Patients were characterized by demographics, BMI; platelet count; anemia; biomarkers; hepatomegaly; splenomegaly; and skeletal assessments at baseline (therapy initiation) and after 4–5 years of therapy. Initial enzyme dose and cumulative average dose were noted. Possible associations with persisting thrombocytopenia were tested using a multivariate analysis calculating odds ratios adjusted for age at diagnosis and therapy initiation, genotype, sex, year of diagnosis, and year of therapy initiation. Results: Of the 1,016 patients in this study, 20 (2%) had platelet counts <60 × 109/platelets/l after 4–5 years of therapy. These patients all had severe splenomegaly at baseline. Associations between persisting thrombocytopenia were found between baseline low platelet count (<80 × 109/l), splenomegaly and anemia (p <0.0001). After 4–5 years, persisting thrombocytopenia was associated with anemia (p <0.0001), reduced WBC (p = 0.049), splenomegaly (p <0.0001), hepatomegaly (p = 0.006), bone pain (p = 0.035) and cumulative enzyme dose (dose range 18.6–55.5 U/kg/2weeks; doses <25th percentile: p = 0.043). Too few data prevented reliable analysis of other bone parameters and biomarkers. Discussion and conclusion: Persisting thrombocytopenia despite therapy is rare (2% of patients with platelets <60 × 109/l). The strong association between splenomegaly, anemia and thrombocytopenia at therapy initiation and persisting thrombocytopenia after 4–5 years of treatment suggests that in a minority of cases extensive spleen involvement, possibly with fibrosis, may be predictive of thrombocytopenia that is refractory to treatment. Findings underline the importance of initiating treatment before irreversible complications have developed. Disclosures: Cole: Genzyme Corp: Employment.
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acceleration of retarded growth in children with gaucher disease after treatment with Alglucerase
The Journal of Pediatrics, 1996Co-Authors: Paige Kaplan, Joel Charrow, Alice T Mazur, Orly Manor, Joan A Esplin, John T Gribble, Rebecca S Wappner, Jeffrey S Wisch, Neal J. WeinrebAbstract:Abstract OBJECTIVES: The incidence and severity of growth retardation in children with type 1 Gaucher disease and the response to enzyme replacement therapy with Alglucerase were studied. STUDY DESIGN: A retrospective analysis of growth in 99 children and adolescents with type 1 Gaucher disease before treatment, and in 54 of those subjects during treatment, was done. Growth was compared with gender, age, and dosage of replacement enzyme. RESULTS: Linear growth was normal in the first 1 to 2 years of life and then decelerated. Height was at or below the 5th percentile in 50% of all subjects immediately before treatment. The mean z score was -1.49 (95% confidence interval, -1.83 to -1.16), corresponding to the 6.8th percentile for height. Seventy-two percent were below the 50th percentile and 50% were at or below the 5th percentile for mid-parental height ( p z score for all subjects was -1.01, which corresponds to the 16th percentile for height. Normal growth was achieved within 4 to 30 months in eight of nine subjects who were at or below the 5th percentile. It occurred only in those receiving higher doses (60 to 120 U/kg per 4-week period) of Alglucerase. There was a significant association between z scores for height before treatment and liver enlargement ( r = 0.57; p CONCLUSIONS: Half of the subjects who manifest type 1 Gaucher disease in childhood have growth retardation. Treatment with adequate amounts of modified enzyme replacement was effective in normalizing linear growth. (J PEDIATR 1996;129:149-53)
Gregory A Grabowski - One of the best experts on this subject based on the ideXlab platform.
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dose response relationships for enzyme replacement therapy with imiglucerase Alglucerase in patients with gaucher disease type 1
Genetics in Medicine, 2009Co-Authors: Gregory A Grabowski, Carla E M Hollak, Katherine Kacena, Ari Zimran, Alexander J Cole, Lin Zhang, John Yee, Pramod K Mistry, Joel Charrow, Stephan Vom DahlAbstract:Purpose: To determine whether enzyme therapy with imiglucerase/Alglucerase demonstrates dose-response relationships with doses and disease parameters used in routine clinical practice for Gaucher disease type 1 patients. Methods: Analyses included all patients with Gaucher disease type 1 on enzyme therapy and with intact spleens in the large observational database of the International Collaborative Gaucher Group Gaucher Registry. Propensity scoring was used to match patients between enzyme therapy dose groups categorized as Group A (5 U to <29 U/kg/2 weeks), Group B (29 U to <48 U/kg/2 weeks), Group C (48 U to <75 U/kg/2 weeks). Hemoglobin concentration, platelet count, and hepatic and splenic volumes were assessed after initiation of enzyme therapy using nonlinear mixed effects models. The maximal effect (Emax) and half-time to Emax (T50) of enzyme therapy for each parameter were compared across dosing groups. Results: Propensity score matching resulted in three comparable groups of 122 patients each (enzyme therapy in Groups A, B, and C). Dose-response relationships were found with regard to Emax and T50 over 96 months for each disease parameter. Conclusions: Enzyme therapy with imiglucerase/Alglucerase displays a dose-dependent improvement in hematological and visceral parameters in Gaucher disease type 1 patients. Group C displayed greater treatment effects than Groups A or B. Propensity score matching and nonlinear mixed effects model analyses provide a prototype for assessment of treatment outcomes based on observational data from international rare disease registries.
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dose response relationships for enzyme replacement therapy with imiglucerase Alglucerase in patients with gaucher disease type 1
Genetics in Medicine, 2009Co-Authors: Gregory A Grabowski, Carla E M Hollak, Katherine Kacena, Ari Zimran, Alexander J Cole, Lin Zhang, John Yee, Pramod K Mistry, Joel Charrow, Stephan Vom DahlAbstract:Gaucher disease (GD) is a lysosomal storage disorder that results from insufficient clearance of cellular glucosylceramide, the substrate for the lysosomal enzyme, acid β-glucosidase (EC 3.2.1.45; glucocerebrosidase). The pathologic accumulations of glucosylceramide in lysosomes of tissue macrophages results in splenomegaly, hepatomegaly, anemia, thrombocytopenia, and multiple forms of skeletal pathology.1–5 In the Western world, GD type 1 (GD1) is the most prevalent variant (94%) and is classically differentiated from types 2 (1%) and 3 (5%) by the absence of primary central nervous system involvement.1,6 GD1 is an ultraorphan disease, with an estimated worldwide prevalence of 1 in 60,000.7 The current standard of care for the treatment of GD1 is enzyme replacement (or more appropriately, reconstitution) therapy with imiglucerase, a recombinant form of glucocerebrosidase. Alglucerase, derived from placental tissue, was used before the availability of imiglucerase. A randomized clinical trial comparing Alglucerase and imiglucerase found these enzymes to be therapeutically equivalent in safety and efficacy.8 Whether enzyme therapy has dose-dependent treatment effects has been a subject of debate since the first clinical trial of Alglucerase was published in 1991.9 In 1995, a panel convened by the National Institutes of Health highlighted the importance of determining whether enzyme therapy has dose-dependent treatment effects.10 Dosing practices for enzyme therapy have varied around the world because, in part, of the lack of clear evidence of dose-response relationships.9,11–15 For patients with bone disease or other severe manifestations of GD, the recommendation has been to use higher doses.16,17 Given the high cost of therapy and the great phenotypic heterogeneity between patients with GD1, the goal of treatment has been to identify individualized dosing regimens that can achieve optimal long-term outcomes for each patient.18 Ideally, dose-response relationships would be evaluated by conducting a randomized clinical trial with multiple arms. For rare diseases, such as GD1, this study design would not be practical or feasible because of the large number of subjects and length of follow-up needed to achieve adequate statistical power. As an alternative, analyses of observational data from a large international disease registry using standard epidemiologic matching and modeling methods may offer a feasible and methodologically sound approach. In the present analyses, data from the International Collaborative Gaucher Group (ICGG) Gaucher Registry were analyzed using propensity scoring methods to match patients between dosing groups19–22 to approximate conditions under a randomized trial. Nonlinear mixed effects modeling of these matched data sets was used to assess dose-response relationships across disease parameters.
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enzyme therapy in type 1 gaucher disease comparative efficacy of mannose terminated glucocerebrosidase from natural and recombinant sources
Annals of Internal Medicine, 1995Co-Authors: Gregory A Grabowski, Norman W Barton, Gregory M Pastores, James M Dambrosia, Tapas K Banerjee, Mary Ann Mckee, Colette C Parker, Raphael Schiffmann, Suvimol Hill, Roscoe O BradyAbstract:Objective To compare the efficacy of mannose-terminated glucocerbrosidase prepared from natural (Alglucerase; Ceredase, Genzyme Corp., Cambridge, Massachusetts) and recombinant (imiglucerase; Cerezyme, Genzyme Corp.) sources in treating type 1 Gaucher disease. Design Double-blind, randomized, parallel trial. Setting University medical center and clinical research hospital. Patients 15 patients (4 children and 11 adults) randomly assigned to receive Ceredase and 15 patients (3 children and 12 adults) assigned to receive Cerezyme. Intervention Ceredase and Cerezyme were infused every 2 weeks for 9 months at a dose of 60 U/kg body weight. Outcome measures Hemoglobin levels, platelet counts, and serum acid phosphatase and angiotensin-converting enzyme activities were monitored every 2 weeks during the trial. Hepatic and splenic volumes were assessed at the time of randomization and after 6 and 9 months of enzyme infusion. Formation of IgG antibodies to Ceredase or Cerezyme was monitored every 3 months by radioimmunoprecipitation assay. Results No significant differences were found in the rate or extent of improvement in hemoglobin levels, platelet counts, serum acid phosphatase or angiotensin-converting enzyme activities, or hepatic or splenic volumes between either treatment group. The incidence of IgG antibody formation was greater in the Ceredase group (40%) than in the Cerezyme group (20%). No major immunologic adverse events occurred in either group. Conclusions Our study shows the therapeutic similarity of Ceredase and Cerezyme. Cerezyme has the advantage of being theoretically unlimited in supply and free of potential pathogenic contaminants.
Stephan Vom Dahl - One of the best experts on this subject based on the ideXlab platform.
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determinants of persisting thrombocytopenia in patients with type 1 gaucher disease treated with Alglucerase imiglucerase for 4 5 years
Blood, 2010Co-Authors: Maria Domenica Cappellini, Patrick Deegan, Neal J. Weinreb, Barry E Rosenbloom, Nadia Belmatoug, Stephan Vom Dahl, Alexander G Cole, Jack Goldblatt, Anna Tylkiszymanska, Ari ZimranAbstract:Abstract 4719 Introduction: Thrombocytopenia in type 1 Gaucher disease (GD) may result in surgical, obstetrical and spontaneous bleeding. Treatment with Alglucerase/imiglucerase generally results in rapid improvement in platelet count but, in rare cases, the platelet response to therapy is slow or lacking. The factors underlying persisting thrombocytopenia despite treatment are poorly understood. Aim: To identify patient characteristics associated with (and potentially predictive of) persisting thrombocytopenia despite therapy by retrospective analysis of ICGG Gaucher Registry data. Methods: 1,016 type 1 GD patients with an intact spleen, date of diagnosis and therapy initiation, no treatment breaks 4–5 years after therapy initiation, and known platelet counts, were classified into four groups by last platelet count 4–5 years after therapy initiation: >120 × 109/l (n = 772); >100 to 80 to <100 × 109/l (n = 80); and <80 × 109/l (n = 70, of which 20 had <60 × 109/platelets/l). Patients were characterized by demographics, BMI; platelet count; anemia; biomarkers; hepatomegaly; splenomegaly; and skeletal assessments at baseline (therapy initiation) and after 4–5 years of therapy. Initial enzyme dose and cumulative average dose were noted. Possible associations with persisting thrombocytopenia were tested using a multivariate analysis calculating odds ratios adjusted for age at diagnosis and therapy initiation, genotype, sex, year of diagnosis, and year of therapy initiation. Results: Of the 1,016 patients in this study, 20 (2%) had platelet counts <60 × 109/platelets/l after 4–5 years of therapy. These patients all had severe splenomegaly at baseline. Associations between persisting thrombocytopenia were found between baseline low platelet count (<80 × 109/l), splenomegaly and anemia (p <0.0001). After 4–5 years, persisting thrombocytopenia was associated with anemia (p <0.0001), reduced WBC (p = 0.049), splenomegaly (p <0.0001), hepatomegaly (p = 0.006), bone pain (p = 0.035) and cumulative enzyme dose (dose range 18.6–55.5 U/kg/2weeks; doses <25th percentile: p = 0.043). Too few data prevented reliable analysis of other bone parameters and biomarkers. Discussion and conclusion: Persisting thrombocytopenia despite therapy is rare (2% of patients with platelets <60 × 109/l). The strong association between splenomegaly, anemia and thrombocytopenia at therapy initiation and persisting thrombocytopenia after 4–5 years of treatment suggests that in a minority of cases extensive spleen involvement, possibly with fibrosis, may be predictive of thrombocytopenia that is refractory to treatment. Findings underline the importance of initiating treatment before irreversible complications have developed. Disclosures: Cole: Genzyme Corp: Employment.
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dose response relationships for enzyme replacement therapy with imiglucerase Alglucerase in patients with gaucher disease type 1
Genetics in Medicine, 2009Co-Authors: Gregory A Grabowski, Carla E M Hollak, Katherine Kacena, Ari Zimran, Alexander J Cole, Lin Zhang, John Yee, Pramod K Mistry, Joel Charrow, Stephan Vom DahlAbstract:Purpose: To determine whether enzyme therapy with imiglucerase/Alglucerase demonstrates dose-response relationships with doses and disease parameters used in routine clinical practice for Gaucher disease type 1 patients. Methods: Analyses included all patients with Gaucher disease type 1 on enzyme therapy and with intact spleens in the large observational database of the International Collaborative Gaucher Group Gaucher Registry. Propensity scoring was used to match patients between enzyme therapy dose groups categorized as Group A (5 U to <29 U/kg/2 weeks), Group B (29 U to <48 U/kg/2 weeks), Group C (48 U to <75 U/kg/2 weeks). Hemoglobin concentration, platelet count, and hepatic and splenic volumes were assessed after initiation of enzyme therapy using nonlinear mixed effects models. The maximal effect (Emax) and half-time to Emax (T50) of enzyme therapy for each parameter were compared across dosing groups. Results: Propensity score matching resulted in three comparable groups of 122 patients each (enzyme therapy in Groups A, B, and C). Dose-response relationships were found with regard to Emax and T50 over 96 months for each disease parameter. Conclusions: Enzyme therapy with imiglucerase/Alglucerase displays a dose-dependent improvement in hematological and visceral parameters in Gaucher disease type 1 patients. Group C displayed greater treatment effects than Groups A or B. Propensity score matching and nonlinear mixed effects model analyses provide a prototype for assessment of treatment outcomes based on observational data from international rare disease registries.
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dose response relationships for enzyme replacement therapy with imiglucerase Alglucerase in patients with gaucher disease type 1
Genetics in Medicine, 2009Co-Authors: Gregory A Grabowski, Carla E M Hollak, Katherine Kacena, Ari Zimran, Alexander J Cole, Lin Zhang, John Yee, Pramod K Mistry, Joel Charrow, Stephan Vom DahlAbstract:Gaucher disease (GD) is a lysosomal storage disorder that results from insufficient clearance of cellular glucosylceramide, the substrate for the lysosomal enzyme, acid β-glucosidase (EC 3.2.1.45; glucocerebrosidase). The pathologic accumulations of glucosylceramide in lysosomes of tissue macrophages results in splenomegaly, hepatomegaly, anemia, thrombocytopenia, and multiple forms of skeletal pathology.1–5 In the Western world, GD type 1 (GD1) is the most prevalent variant (94%) and is classically differentiated from types 2 (1%) and 3 (5%) by the absence of primary central nervous system involvement.1,6 GD1 is an ultraorphan disease, with an estimated worldwide prevalence of 1 in 60,000.7 The current standard of care for the treatment of GD1 is enzyme replacement (or more appropriately, reconstitution) therapy with imiglucerase, a recombinant form of glucocerebrosidase. Alglucerase, derived from placental tissue, was used before the availability of imiglucerase. A randomized clinical trial comparing Alglucerase and imiglucerase found these enzymes to be therapeutically equivalent in safety and efficacy.8 Whether enzyme therapy has dose-dependent treatment effects has been a subject of debate since the first clinical trial of Alglucerase was published in 1991.9 In 1995, a panel convened by the National Institutes of Health highlighted the importance of determining whether enzyme therapy has dose-dependent treatment effects.10 Dosing practices for enzyme therapy have varied around the world because, in part, of the lack of clear evidence of dose-response relationships.9,11–15 For patients with bone disease or other severe manifestations of GD, the recommendation has been to use higher doses.16,17 Given the high cost of therapy and the great phenotypic heterogeneity between patients with GD1, the goal of treatment has been to identify individualized dosing regimens that can achieve optimal long-term outcomes for each patient.18 Ideally, dose-response relationships would be evaluated by conducting a randomized clinical trial with multiple arms. For rare diseases, such as GD1, this study design would not be practical or feasible because of the large number of subjects and length of follow-up needed to achieve adequate statistical power. As an alternative, analyses of observational data from a large international disease registry using standard epidemiologic matching and modeling methods may offer a feasible and methodologically sound approach. In the present analyses, data from the International Collaborative Gaucher Group (ICGG) Gaucher Registry were analyzed using propensity scoring methods to match patients between dosing groups19–22 to approximate conditions under a randomized trial. Nonlinear mixed effects modeling of these matched data sets was used to assess dose-response relationships across disease parameters.