02 novembre 2009
Mutation du gène de la Glucocerebrosidase (maladie de Gaucher) et la maladie de Parkinson chez les Ashkénazes
Article classé dans la catégorie "Parkinson et Gaucher". Les patients atteints de maladie de Gaucher sont suceptibles d'être atteints par la maladie de Parkinson. Il a été constaté que certaines personnes hétérozygotes avec la mutation S370 sont atteints de la maladie de Parkinson. Liens utiles à la fin des catégoriesGhislaine SURREL
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Background A clinical association has been reported between type 1 Gaucher's disease, which is caused by a glucocerebrosidase deficiency owing to mutations in the glucocerebrosidase gene (GBA), and parkinsonism. We examined whether mutations in the GBA gene are relevant to idiopathic Parkinson's disease. Methods A clinic-based case series of 99 Ashkenazi patients with idiopathic Parkinson's disease, 74 Ashkenazi patients with Alzheimer's disease, and 1543 healthy Ashkenazi Jews who underwent testing to identify heterozygosity for certain recessive diseases were screened for the six GBA mutations (N370S, L444P, 84GG, IVS+1, V394L, and R496H) that are most common among Ashkenazi Jews. Results Thirty-one patients with Parkinson's disease (31.3 percent; 95 percent confidence interval, 22.2 to 40.4 percent) had one or two mutant GBA alleles: 23 were heterozygous for N370S, 4 were heterozygous for 84GG, 3 were homozygous for N370S, and 1 was heterozygous for R496H. Among the 74 patients with Alzheimer's disease, 3 were identified as carriers of Gaucher's disease (4.1 percent; 95 percent confidence interval, 0.0 to 8.5 percent): 2 were heterozygous for N370S, and 1 was heterozygous for 84GG. Ninety-five carriers of Gaucher's disease were identified among the 1543 control subjects (6.2 percent; 95 percent confidence interval, 5.0 to 7.4 percent): 92 were heterozygous for N370S, and 3 were heterozygous for 84GG. Patients with Parkinson's disease had significantly greater odds of being carriers of Gaucher's disease than did patients with Alzheimer's disease (odds ratio, 10.8; 95 percent confidence interval, 3.0 to 46.6; P<0.001) or control subjects (odds ratio, 7.0; 95 percent confidence interval, 4.2 to 11.4; P<0.001). Among the patients with Parkinson's disease, patients who were carriers of Gaucher's disease were younger than those who were not carriers (mean [±SD] age at onset, 60.0±14.2 years vs. 64.2±11.7 years; P=0.04). Conclusions Our results suggest that heterozygosity for a GBA mutation may predispose Ashkenazi Jews to Parkinson's disease. Gaucher's disease, the most prevalent, recessively inherited disorder of glycolipid storage,13 is caused by a deficiency of the lysosomal enzyme glucocerebrosidase, which normally hydrolyzes glucocerebroside to glucose and ceramide, leading to the accumulation of glucocerebroside in macrophages and resulting in multiorgan involvement.13 Three phenotypes have been described that are denoted by the absence (type 1) or presence of neurologic involvement during childhood (type 2) or adolescence (type 3).13 Type 1 Gaucher's disease is panethnic, but is especially prevalentamong persons of Ashkenazi Jewish descent, with a carrier rate of 1 in 17 Ashkenazi Jews.14 The N370S and 84GG mutations are the most frequent mutations in the glucocerebrosidase gene (GBA) among Ashkenazi Jews, with rates of 1 in 17.5 for N370S and 1 in 400 for 84GG in the general healthy Ashkenazi population, and are associated with mild and severe Gaucher's disease, respectively. The 84GG mutation occurs almost exclusively among Ashkenazi Jews.14 Other rare GBA variants identified in patients of Ashkenazi descent with Gaucher's disease include L444P, IVS2+1G In an attempt to establish whether there is an association between Parkinson's disease and Gaucher's disease, we determined the prevalence of mutations in the GBA gene in 99 Ashkenazi patients with idiopathic Parkinson's disease, who had no signs or symptoms of Gaucher's disease, and compared the rate with that among Ashkenazi patients with Alzheimer's disease and among healthy Ashkenazi controls. Methods Population Ninety-nine Ashkenazi patients with idiopathic Parkinson's disease (55 men and 44 women) were sequentially recruited from the Cognitive and Movement Disorder Unit at the Rambam Medical Center, Haifa, Israel, on their arrival at the clinic for follow-up or treatment over a period of 28 months (from February 21, 2002, to April 30, 2004). None had a history of neurologic or psychiatric conditions other than Parkinson's disease. Seventy-four patients with Alzheimer's disease (42 men and 32 women) were similarly recruited from the same clinic to serve as a comparison group. The clinic serves as a secondary and tertiary referral center for patients with Alzheimer's disease and Parkinson's disease from the northern part of Israel. Parkinson's disease was diagnosed according to the United Kingdom brain-bank criteria.15 Patients with Alzheimer's disease met the criteria for dementia of the Alzheimer's type of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition,16 and the criteria for probable Alzheimer's disease of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association.17 Information on family history, demographic characteristics, and clinical data were obtained in a uniform manner with the use of structured questionnaires. Patients underwent a physical, neurobehavioral, and neurologic examination that incorporated the Unified Parkinson's Disease Rating Scale.18Patients or their guardians were asked to provide written informed consent, and patients were asked to provide a blood sample. All patients were informed regarding the results of the analysis. The study was approved by the hospital's institutional review board. A control group of 1543 healthy Ashkenazi Jews from the same geographic area who were undergoing testing to identify heterozygosity for certain recessive diseases and who provided written informed consent allowing the use of their DNA for research purposes was used to determine the frequency of GBA mutations in ourgeneral population. Detection of Mutations DNA samples were subjected to a polymerase-chain-reaction (PCR) assay to identify six GBA mutations (N370S, L444P, 84GG, IVS2+1G When the mutation is present (lanes 1, 4, and 7), the enzyme (XhoI) digests a 105-bp PCR product, producing two fragments of 89 and 16 bp. The wild-type PCR product remains uncut (lanes 2, 3, 5, and 6). M denotes a 50-bp marker. The arrows show the position of the mutation. Differences in carrier rates among groups were analyzed by means of the chi-square test. Differences in clinical characteristics were compared between carriers and noncarriers by means of an independent-sample t-test for age and a chi-square test for family history. Results Among the 99 Ashkenazi patients with Parkinson's disease, 31 (31.3 percent; 95 percent confidence interval, 22.2 to 40.4 percent) had a mutant GBA allele (Table 2): 23 were heterozygous for N370S, 3 were homozygous for N370S, 1 was heterozygous for R496H, and 4 were heterozygous for 84GG. Among the 74 patients with Alzheimer's disease, 3 were carriers of Gaucher's disease (4.1 percent; 95 percent confidence interval, 0.0 to 8.5 percent); 2 were heterozygous for N370S, and 1 was heterozygous for 84GG. Among the 1543 control subjects, 95 were carriers of Gaucher's disease (6.2 percent; 95 percent confidence interval, 5.0 to 7.4 percent); 92 were heterozygous for N370S, and 3 were heterozygous for 84GG, findings consistent with a carrier rate of 1 in 16.7 for the N370S variant and 1 in 514 for 84GG. Patients with Parkinson's disease had significantly greater odds of being carriers of Gaucher's disease than did patients with Alzheimer's disease (odds ratio, 10.8; 95 percent confidence interval, 3.0 to 46.6; P<0.001) or control subjects (odds ratio, 7.0; 95 percent confidence interval, 4.2 to 11.4; P<0.001). The rate of carriage of Gaucher's disease among patients with Alzheimer's disease did not differ significantly from that among controls (odds ratio, 0.6; 95 percent confidence interval, 0.2 to 2.2; P=0.62). Discussion Because parkinsonism has occasionally been described in patients with Gaucher's disease, we evaluated the effect of GBA mutations on idiopathic Parkinson's disease. In our population of patients with Parkinson's disease, the frequency of a mutant N370S GBA allele was 5 times that among our healthy Ashkenazi control subjects, and the frequency of a mutant 84GG GBA allele was 21 times that among controls (P<0.001 for both comparisons). In addition, three patients with Parkinson's disease were found to be homozygous for nonpenetrant Gaucher's disease (N370S/N370S), as compared with none of the 1543 control subjects. Since N370S causes a mild phenotype, N370S/N370S homozygotes may remain symptom-free, and their Gaucher's disease may escape detection. The prevalence of GBA mutations in our population of Ashkenazi patients with Parkinson's disease by far outweighs the reported prevalence of mutations in other susceptibility genes for Parkinson's disease, such as parkin and synuclein.20 Mutations in the GBA gene thus emerge as strong genetic determinants predisposing people to Parkinson's disease. The nature of the association between Parkinson's disease and Gaucher's disease remains elusive. In recent years, two hypotheses regarding the pathogenesis of Parkinson's disease have been suggested. The first posits that misfolding and aggregation of proteins are instrumental in the death of dopaminergic neurons, and the other proposes that the culprit is oxidative stress resulting from mitochondrial dysfunction, which may also increase the amount of misfolded proteins.21 The aggregation of proteins may lead to cell dysfunction by inhibiting the ubiquitin–proteasome system,22,23 a finding that has been implicated in the causation of both familial and sporadic Parkinson's disease.24 We speculate that the pathogenic mechanism leading to Parkinson's disease in carriers of mutant GBA alleles may be related to the faulty processing of toxic, unwanted proteins, aggravated by the relative decrease in glucocerebrosidase activity and accumulation of glucocerebroside. Indeed, studies demonstrate that the inhibition of glucocerebrosidase and accumulation of glucocerebroside induce apoptosis in cultured neurons by increasing the mobilization of calcium ions from intracellular stores25 and that neurons with elevated levels of glucocerebroside show enhanced sensitivity to agents that induce cell death by potentiating calcium ions.26 Moreover, mesencephalic cells, including dopaminergic neurons, can undergo apoptosis after ceramide-induced damage,27 suggesting that dysfunctional metabolism of sphyngolipids may induce the death of dopaminergic cells. However, since brain glucocerebroside levels were not consistently elevated in patients with type 1 Gaucher's disease,28 the pathogenetic relevance of these findings remains unclear. Recent findings indicate that Gaucher's disease and Parkinson's disease share pathophysiological features. Unique pathological findings, such as neuronal loss, astrogliosis, and the presence of intraneuronal Lewy-body–like synuclein inclusions specifically targeting the hippocampal CA2–3 region were recently described in both diseases.29 Synuclein is a neuronal protein. Mutations in the gene encoding Carriage of type 1 Gaucher's disease is common in the Ashkenazi population. Taking into account the frequency of GBA mutations in the general Ashkenazi population and the general prevalence of parkinsonism,30 we can extrapolate that the majority of carriers of mutant GBA alleles, in whom Parkinson's disease does not develop, are equipped with an efficient genetic mechanism that either prevents the deposition and accumulation of glucocerebroside in dopaminergic neurons or adequately degrades the glucocerebroside that is deposited. Alternatively, the occurrence of Parkinson'sdisease in carriers of Gaucher's disease may be accounted for by genetic variance in another gene. In conclusion, our data indicate that some GBA mutations are genetic susceptibility factors for Parkinson's disease. We have also found that, in contrast to previous suggestions, heterozygosity for a non-neuropathic GBA mutation is not an absolutely asymptomatic state. Additional studies are needed to replicate our findings, to perform further analyses of the correlation between genotype and phenotype, and to identify the pathogenetic mechanisms that render some carriers of Gaucher's disease vulnerable to Parkinson's disease. The clinical implications of our findings and those of other studies that are soon to be completed should affect the treatment options available to patients with Parkinson's disease. We are indebted to Gerald Brook, Hadas Shoshani, and Adi Sela-Goldberg for their contributions. From the Department of Neurology and the Cognitive Neurology Unit (J.A.-P.) and the Departments of Hematology and Bone Marrow Transplantation (H.R.) and Human Genetics (R.G.-B.), Rambam Medical Center; and the Bruce Rappaport Faculty of Medicine, Technion–Israel Institute of Technology (J.A.-P., H.R., R.G.-B.) — both in Haifa, Israel. Address reprint requests to Dr. Gershoni-Baruch at the Department of Medical Genetics, Rambam Medical Center, Haifa 31096, Israel, or at rgershoni@rambam.health.gov.il. References Related Letters: The Glucocerebrosidase Gene and Parkinson's Disease in Ashkenazi Jews This article has been cited by other articles: HOME | SUBSCRIBE | SEARCH | CURRENT ISSUE | PAST ISSUES | COLLECTIONS | PRIVACY | TERMS OF USE | HELP | beta.nejm.org Comments and questions? Please contact us. The New England Journal of Medicine is owned, published, and copyrighted © 2009 Massachusetts Medical Society. All rights reserved.
Volume 351:1972-1977 November 4, 2004 Number 19
ABSTRACT 
Parkinson's disease is a common neurodegenerative condition, with an estimated prevalence of approximately 1 in 100 persons.1 Parkinson's disease is characterized by resting tremor, akinesia, rigidity, and postural instability, caused by selective degeneration of dopaminergic neurons within the substantia nigra pars compacta and consequent depletion of dopamine in their striatal projections.1 Most cases of Parkinson's disease are sporadic, and familial cases are rare.2,3 Data from twin and family studies,4 the mapping and cloning of PARK genes, and analysis of potential susceptibility genes have provided increasing evidence to indicate a causative role for genetic factors in the disease.5,6 There is also evidence indicating that environmental factors play a role in the causation of Parkinson's disease.7 The association of parkinsonism with type 1 Gaucher's disease has been reported.8,9,10,11,12 The simultaneous occurrence of Parkinson's disease and Gaucher's disease is marked by atypical parkinsonism generally presenting by the fourth through sixth decades of life. The combination progresses inexorably and is refractory to conventional antiparkinson therapy.11
A, V394L, and R496H.A, V394L, and R496H). PCR amplification was followed by digestion with appropriate enzymes (Table 1), to distinguish the wild-type allele from the mutant allele.19 Six primer pairs were used separately to amplify the genomic segments flanking each mutation. The PCR primers, annealing temperatures, restriction enzymes, and length of the PCR products before and after cleavage are listed in Table 1. The L444P and R496H mutations create cleavage sites with the use of the NciI and HphI restriction enzymes, respectively. The IVS2+1GA mutation abolishes a native restriction site for HphI. A mismatch introduced in either the forward or reverse primer is used to create a restriction site in either the mutant PCR product (N370S and 84GG) or the normal PCR product (V394L) with the use of XhoI for N370S, BsabI for 84GG, and BanI for V394L. All mutant-allele profiles were confirmed by means of sequence analysis in an independent PCR assay, with the use of an automated ABI Prism 310 Genetic Analyzer (Perkin–Elmer Applied Biosystems). No discrepancies were detected between the results of cleavage analyses and the results of sequencing (Figure 1 and Figure 2).View this table:
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Table 1. Primers and Variables Used for the Detection of Mutations in the GBA Gene. 
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Figure 1. PCR Analysis of the A1226G (N370S) Mutation in Patients with Parkinson's Disease. 
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Figure 2. Electropherogram of the Normal Sequence and the A1226G (N370S) Mutation in the GBA Gene.
Statistical AnalysisView this table:
[in a new window]
Table 2. Rates of Carriage of Gaucher's Disease among Patients with Parkinson's Disease, Patients with Alzheimer's Disease, and Control Subjects.
All patients with Parkinson's disease had an initially favorable response to dopaminergic agonists or levodopa. Among the patients with Parkinson's disease, those who were also carriers of Gaucher's disease were significantly younger than those who were not carriers (mean [±SD] age at onset, 60.0±14.2 years vs. 64.2±11.7 years; P=0.04). Carriers of Gaucher's disease did not differ significantly from noncarriers with regard to the presence of a family history of Parkinson's disease in a first- or second-degree relative, initial motor manifestations, or initial response to levodopa or dopaminergic agonists.
-synuclein appear to be responsible for Parkinson's disease in rare familial cases, and the aggregated protein is a major component of Lewy bodies, the pathological hallmark of sporadic Parkinson's disease.5 Thus, the presence of intraneuronal Lewy-body–like synuclein inclusions in patients with both type 1 and neuronopathic Gaucher's disease points to a selective vulnerability and cytotoxicity, specifically targeting the CA2–3 region that appears to characterize idiopathic Parkinson's disease, diffuse Lewy-body dementia, and according to recent reports, Gaucher's disease.
Source Information
Eblan M. J., Walker J. M., Sidransky E., Zimran A., Neudorfer O., Elstein D., Schlossmacher M. G., Cullen V., Müthing J., Gershoni-Baruch R., Aharon-Peretz J., Rosenbaum H.
Extract | Full Text | PDF
N Engl J Med 2005; 352:728-731, Feb 17, 2005. Correspondence
22 septembre 2009
ACTELION, lettre du 08/09 relatif à la prescription de ZAVESCA suite à la pénurie de CEREZYME ( VESIVIRUS 2117)
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Ghislaine SURREL
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ACTELION
AUGUST 2009
Dear Healthcare Professional:
In June 2009, Genzyme Corporation issued a press release announcing the detection of a virus in its recombinant cell cultures that produce the enzyme replacement therapy (ERT), imiglucerase. The contamination of cell cultures resulted in the immediate interruption of drug production and the subsequent supply shortage of Cerezyme® (imiglucerase) for some patients for a period of time. Since the announcement, Actelion has received direct requests from Healthcare Professionals for information regarding Zavesca® (miglustat) as an immediate option for patients who may not have access to imiglucerase treatment during the shortage.
Actelion would like to inform physicians that Zavesca® is indicated for the treatment of adult patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (e.g. due to constraints such as allergy, hypersensitivity or poor venous access). Zavesca® was approved and has been marketed in the United States since 2003. The decision to prescribe Zavesca® to patients is at the discretion of the treating physician. The physician should assess the risks and benefits of therapy for the individual patient.
Clinical studies where patients were switched from Cerezyme® to Zavesca® monotherapy have been conducted. One of these studies is described as follows:
The Study OGT 918-004 was a prospective, open-label, randomized clinical study over 24 months in which type 1 Gaucher patients were switched from ERT to Zavesca® monotherapy in one treatment arm. There were no significant differences for mean absolute changes in liver, spleen volume and hemoglobin concentration between the groups of patients switched to Zavesca® monotherapy and the Cerezyme® group. However, in adult type 1 Gaucher disease patients who had been treated with enzyme replacement therapy for at least 2 years, switching to Zavesca® as monotherapy was associated with decreases in platelet counts after discontinuation of enzyme replacement therapy. Platelet counts also declined after discontinuation of enzyme replacement therapy in patients originally randomized to combination therapy. [USPI; Elstein et al, Blood, 2007, 110(7):2296-2301] Important Safety Information for Zavesca®
§ Gastrointestinal disturbances (GI) such as diarrhea, flatulence and abdominal pain are the most common adverse side reactions associated with Zavesca® therapy.
— Diarrhea due to Zavesca® therapy usually responds to the introduction of a lactose-free and low carbohydrate diet and/or loperamide treatment.
§ Peripheral neuropathy has been reported in patients receiving Zavesca®.
— Patients should undergo neurological examination at the start of treatment and every 6 months thereafter; Zavesca® should be reassessed in patients who develop symptoms of peripheral neuropathy.
§ Zavesca® may cause fetal harm if administered to a pregnant woman.
— Pregnancy category X; Zavesca® is contraindicated in women who are or who may become pregnant; patients should be appraised of the potential hazard to a fetus.
§ There is a risk of impaired fertility in men.
— Men should maintain reliable contraceptive methods and not plan to conceive while taking Zavesca® and for 3 months after discontinuing treatment.
§ There is no experience with the use of Zavesca® in type 1 Gaucher disease patients under the age of 18 years.
Please consult the enclosed Zavesca® package insert for complete prescribing information. If you have additional questions or require additional information, please contact the Medical Information Department at usmedinfo@actelion.com or call toll-free (866) 228-3546 and follow the prompts for Medical Information.
Sincerely,
Kirk Taylor, MD Stefan Kolb, MD
Senior Vice President, US Medical Global Medical Leader, Zavesca®
Enclosure: Zavesca USPI 2008
Actelion Pharmaceuticals US, Inc.
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25 août 2009
SHIRE : Résultat de l'essai clinique de Phase III du Velaglucerase alfa pour la maladie de Gaucher de Type I
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Registered in Jersey, No. 99854, 22 Grenville Street, St Helier, Jersey JE4 8PX
Shire Reports Positive Results from First of Three Phase III Trials of velaglucerase alfa for Type 1 Gaucher Disease and Provides Important Updates on Interactions with FDA
Treatment Protocol Accepted and Rolling Submission of New Drug Application Initiated
Lexington, Massachusetts, US – August 3, 2009 – Shire plc (LSE: SHP, NASDAQ: SHPGY), the global specialty biopharmaceutical company, today reported positive results from the first of three Phase III studies of velaglucerase alfa, its enzyme replacement therapy in development for the treatment of Type 1 Gaucher disease. The Company also announced that the U.S. Food and Drug Administration (FDA) has accepted its treatment protocol for velaglucerase alfa and that Shire has begun its rolling submission of the New Drug Application (NDA) for velaglucerase alfa allowed under the Fast Track process.
“We are very pleased with the progress of the velaglucerase alfa program from both a clinical and regulatory perspective,” said Sylvie Grégoire, President of Shire Human Genetic Therapies. “This data are consistent with those previously reported from the Phase I/II and extension studies. We will continue to work diligently with the FDA and other regulatory agencies to make velaglucerase alfa available as soon as possible to help meet the needs of the Gaucher community.”
Shire’s velaglucerase alfa program is the largest and most comprehensive set of Phase III clinical trials conducted to date for Gaucher disease. Over 100 patients at 24 sites in 10 countries around the world have participated in the clinical studies.
Velaglucerase alfa is made using Shire’s proprietary technology, in a human cell line. The enzyme produced has the exact human amino acid sequence and carries a human glycosylation pattern.
Phase III Study Overview and Results
The first trial in the Phase III program to be completed was a multicenter, randomized, double-blind, two dose study of velaglucerase alfa in patients with Type 1 Gaucher disease.
The primary goal of this study was to evaluate the safety and efficacy of velaglucerase alfa in 25 patients with Type 1 Gaucher disease.
Patients aged two years and older who were treatment naïve were eligible to participate in the study if they presented with disease-related anemia and had at least one of the following clinical manifestations of Gaucher disease: thrombocytopenia, moderate splenomegaly or a readily palpable enlarged liver. Patients were randomized to receive velaglucerase alfa at either 45 U/ kg or 60 U/ kg for a duration of 12 months.
In the trial, the primary endpoint was reached with patients benefiting from a clinically important and statistically significant (p<0.0001) increase in mean hemoglobin concentration compared with baseline after receiving velaglucerase alfa at 60 U/kg IV every other week for 12 months. Statistically significant improvements compared with baselines were also observed in platelet and spleen sizes, and nominally significant improvements were observed in liver size at this dose. Results were clinically important as defined by standard criteria and consistent with the previously published Phase I/II data.
At the 45 U/kg IV dose, statistically significant improvements in hemoglobin, platelet count, and spleen volume were also demonstrated. The magnitude of changes in the 45U/kg dose was also clinically important, and a trend in liver volume reduction was observed. The 60U/kg dose performed numerically as well or better than 45U/kg across all measured clinical endpoints.
The specific data from this trial will be presented at a scientific meeting later this year.
Velaglucerase alfa was found to be generally well tolerated with no drug-related serious adverse events reported in the trial. No patients withdrew from the trial due to an adverse event.
Most of the drug-related adverse events were reported in association with velaglucerase alfa infusions, all of which were mild and resolved without sequelae.
“These findings are very encouraging. They illustrate important potential benefits that velaglucerase alfa may provide to patients who are affected by Type 1 Gaucher disease,” said Dr. Atul Mehta, Clinical Director of the Lysosomal Storage Disorders Unit, Royal Free Hospital, London. “Velaglucerase alfa appears to be an excellent choice for Type 1 Gaucher patients. The prospect of having another treatment option available to help patients achieve therapeutic goals is very important and is welcomed by both the physicians and patients.”
Regulatory Updates
With regard to ongoing interactions with the FDA, Shire provided the following important updates:
- The FDA has accepted Shire’s treatment protocol for velaglucerase alfa. The acceptance of the treatment protocol by the FDA will enable physicians to treat Gaucher patients with velaglucerase alfa prior to commercialization. Shire will initially provide velaglucerase alfa free of charge to patients who are enrolled in the protocol.
- Shire has begun a rolling submission of a New Drug Application (NDA) to the FDA for velaglucerase alfa to treat patients with Type 1 Gaucher disease. The submission was initiated on July 30, 2009, three weeks after Shire received Fast Track designation. Fast Track designation allows a company to file the sections of the NDA as they become available and enables the agency to commence its review on a rolling basis. The company expects to complete the NDA submission by the end of this quarter.
Gaucher disease is an autosomal recessive disease and the most prevalent Lysosomal Storage Disorder (LSD), with an incidence of about 1 in 20,000 live births. Despite the fact that Gaucher Disease consists of a phenotype, with varying degrees of severity, it has been sub-divided in three subtypes according to the presence or absence of neurological involvement. It is also the most common genetic disease affecting Ashkenazi Jewish people Eastern, Central and Northern European ancestry), with a carrier frequency of 1 in 10 (Dr. John Barranger and Dr. Ed Ginns 1989). This panethnic disease involves many organ systems, such as liver, spleen, lungs, brain, metabolism and bone marrow.
Gaucher Disease results from a specific enzyme deficiency in the body, caused by a genetic mutation received from both parents. The disease course is quite variable, ranging from no outward symptoms to severe disability and death. Carrier status can be detected through blood or saliva to identify potential carriers of the Gaucher gene. Gaucher Disease can be diagnosed early through a blood test.
Worldwide the diagnosed population of Gaucher Disease patients is approximately 7,000.
Based on incidence, the estimated total world population is likely to be between 10,000 and 15,000 patients.
For further information please contact:
Investor Relations Cléa Rosenfeld (Rest of the World) +44 1256 894 160
Eric Rojas (North America) +1 617 551 9715
Media Jessica Mann (Rest of the World) +44 1256 894 280
Jessica Cotrone (North America) +1 617 613 4640
Notes to editors
SHIRE PLC
Shire’s strategic goal is to become the leading specialty biopharmaceutical company that focuses on meeting the needs of the specialist physician. Shire focuses its business on attention deficit hyperactivity disorder (ADHD), human genetic therapies (HGT) and gastrointestinal (GI) diseases as well as opportunities in other therapeutic areas to the extent they arise through acquisitions. Shire’s in-licensing, merger and acquisition efforts are focused on products in specialist markets with strong intellectual property protection and global rights. Shire believes that a carefully selected and balanced portfolio of products with strategically aligned and relatively small-scale sales forces will deliver strong results.
For further information on Shire, please visit the Company’s website: www.shire.com.
"SAFE HARBOR" STATEMENT UNDER THE PRIVATE SECURITIES LITIGATION REFORM ACT
OF 1995
Statements included herein that are not historical facts are forward-looking statements. Such forward-looking statements involve a number of risks and uncertainties and are subject to change at any time. In the event such risks or uncertainties materialize, the Company’s results could be materially adversely affected. The risks and uncertainties include, but are not limited to, risks associated with: the inherent uncertainty of research, development, approval, reimbursement, manufacturing and commercialization of the Company’s Specialty Pharmaceutical and Human Genetic Therapies products, as well as the ability to secure and integrate new products for commercialization and/or development; government regulation of the Company’s products; the
Company’s ability to manufacture its products in sufficient quantities to meet demand; the impact of competitive therapies on the Company’s products; the Company’s ability to register, maintain and enforce patents and other intellectual property rights relating to its products; the Company’s ability to obtain and maintain government and other third-party reimbursement for its products; and other risks and uncertainties detailed from time to time in the Company’s filings with the Securities and Exchange Commission.
Press Release
www.shire.com
Protalix : FDA approuve le "treatment protocol" pour le prGCD
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Subject: Protalix - press
release: U.S. Food and Drug Administration Approves Protalix's Treatment
Protocol for prGCD
CARMIEL, Israel--(BUSINESS WIRE)--Protalix BioTherapeutics, Inc.
(NYSE-Amex:PLX), announced today that the U.S. Food and Drug Administration
(FDA) has approved the Company’s treatment protocol for prGCD, the Company’s
proprietary plant-cell expressed recombinant form of glucocerebrosidase (GCD)
for the treatment of Gaucher disease. The treatment protocol allows physicians
and other care-providers to treat patients of Gaucher disease with prGCD in the
United States and additional countries world-wide while studies of prGCD
continue as part of the Company’s ongoing pivotal Phase III clinical trial.
Prior to accepting the protocol, the FDA reviewed available data from the
Company’s on-going Phase III clinical development programs.
The treatment protocol is a multicenter, open-label trial designed to
allow physicians and other care-providers to treat patients of Gaucher disease
with prGCD during the expected shortage of Cerezyme® and thereafter. Cerezyme®
is a mammalian cell expressed version of glucocerebrosidase and the only enzyme
replacement therapy currently approved for Gaucher disease. The treatment
protocol allows patients enrolled in the protocol to continue being treated
with prGCD until its anticipated marketing approval from the FDA. The Company
will provide the drug free of charge to patients enrolled in the protocol.
"We appreciate the guidance and vote of confidence provided by the
FDA in establishing a treatment protocol for prGCD and are working closely with
physicians and patient advocacy groups to allow Gaucher disease patients to
gain access to our drug," commented Dr. David Aviezer, the Company’s
President and Chief Executive Officer. "We expect to conclude our phase
III pivotal study next month and are looking forward to announcing top-line
results from this study in October. We anticipate filing an NDA with the FDA by
the end of this year.”
About Protalix BioTherapeutics
Protalix is a biopharmaceutical company. Its goal is to become a fully
integrated biopharmaceutical company focused on the development and
commercialization of proprietary recombinant therapeutic proteins to be
expressed through its proprietary plant cell based expression system.
Protalix’s ProCellEx(TM) presents a proprietary method for the expression of
recombinant proteins that Protalix believes will allow for the cost-effective,
industrial-scale production of recombinant therapeutic proteins in an
environment free of mammalian components and viruses. Protalix is conducting a
Phase III pivotal study for its lead product candidate, prGCD, to be used in
enzyme replacement therapy for Gaucher disease, a rare and serious lysosomal
storage disorder in humans with severe and debilitating symptoms. Protalix and
the U.S. Food and Drug Administration agreed on the final design of the pivotal
Phase III clinical trial through the FDA’s Special Protocol Assessment (SPA)
process. Protalix has completed enrollment for this study and is treating
patients in the study in North America, South America, Israel, Europe and South
Africa. The study is monitored by an independent Data Monitoring Committee,
including experts in the field, who monitor the on-going safety data, which has
recently held their last scheduled meeting before the end of the trial. No
serious adverse events have been reported in the study. Protalix is also
advancing additional recombinant biopharmaceutical drug development programs
EMEA 14-08-09 : PQuestions et réponses sur les manques de Cerezyme et Fabrazyme (virus Vesivirus 2117)
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Ghislaine SURREL
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European Medicines Agency
7 Westferry Circus, Canary Wharf, London E14 4HB, UK
Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 84 16
E-mail: mail@emea.europa.eu http://www.emea.europa.eu
European Medicines Agency, 2009. Reproduction is authorised provided the source is acknowledged.
London, 14 August 2009
Doc. Ref. EMEA/510766/2009
Questions and answers on the shortages of Cerezyme and Fabrazyme
The European Medicines Agency has reviewed treatment recommendations from June 2009 on which
patients should receive Cerezyme and Fabrazyme as a priority during the shortage of these two
medicines over the next few months. The shortage, which is expected to last until the end of the year,
is happening because of a problem in a factory where the active substances for the medicines are
made.
The company has informed the Agency that the supply shortage of Cerezyme is more severe than it
previously thought. Because of this, the Agency is now recommending the following:
• for Cerezyme, only patients at greatest need of treatment will receive Cerezyme but at a reduced
dosage;
• for Fabrazyme, the recommendations given in June 2009 remain the same. They are ensuring that
patients at greatest need of treatment continue to receive this medicine until the shortage is
resolved.
What are Cerezyme and Fabrazyme?
Cerezyme and Fabrazyme are medicines that are used in two rare, inherited, life-threatening diseases
in which patients have a lack of an enzyme involved in the breakdown of fatty substances in the body:
• Cerezyme is used in patients with Gaucher disease, a disease in which patients do not have enough
of an enzyme called alglucerase. Cerezyme contains imiglucerase, which is a copy of the natural
enzyme;
• Fabrazyme is used in patients with Fabry disease, a disease in which patients do not have enough of
an enzyme called alpha-galactosidase A. Fabrazyme contains agalsidase beta, which is a copy of
the natural enzyme.
In both medicines, the replacement enzyme is made by a method known as ‘recombinant DNA
technology’: the enzymes are made by cells that have received genes (DNA) that makes them able to
produce the enzymes. The cells are grown in special tanks called ‘bioreactors’ over a three- to
four-month process, and the enzyme is extracted from the culture at regular intervals during the
process.
Cerezyme has been authorised since November 1997 and Fabrazyme since August 2001. Both
medicines are marketed in all Member States of the European Union.
What is the problem with Cerezyme and Fabrazyme?
Earlier this year, Genzyme, the company that makes Cerezyme and Fabrazyme, became aware of
reduced yields from the bioreactors used to produce Cerezyme and Fabrazyme at their production site
in Allston Landing in the United States of America. The company found out that the bioreactors were
contaminated with a virus (a calicivirus of the type Vesivirus 2117). This virus is not known to cause
disease in humans, but it can attack the cells used to produce these medicines. The contamination has
an impact on cell growth, affecting the quantity, but not the quality, of the enzymes produced by the
cells.
In June 2009, in order to sanitise the production facilities and conduct an investigation to prevent the
contamination from re-occurring, the company had to stop the production of new batches of Cerezyme
and Fabrazyme for an extended period of time. As a result of the supply shortage of both medicines,
the company, in agreement with the Agency, recommended some temporary changes to the way
Cerezyme and Fabrazyme were prescribed and used.
Although manufacturing is resuming, Genzyme has now informed the European Medicines Agency
that the stocks of Cerezyme are lower than it said they were in June. Therefore the recommendations
on the use of Cerezyme have had to be revised. These changes should be implemented immediately.
What are the recommendations while the shortages are ongoing?
Revised recommendations for Cerezyme
For Cerezyme, priority is given to infants, children and adolescents, and adults with severe, life-
threatening disease progression:
• infants, children and adolescents should receive Cerezyme at a reduced dose or at a reduced
infusion frequency. However, no patient should be treated at a dose lower than 15 units per
kilogram body weight every two weeks, or alternative treatment should be considered.
• adult patients with severe, life-threatening disease progression should receive Cerezyme at a
reduced dose or at a reduced infusion frequency. However, no patient should be treated at a dose
lower than 15 U/kg every four weeks, or alternative treatment should be considered.
In adult patients without severe, life-threatening disease progression, alternative treatment such as
miglustat should be considered or treatment should be interrupted. Adults who demonstrate
progression to severe, life-threatening disease should re-initiate treatment with Cerezyme.
Recommendations for Fabrazyme
For Fabrazyme, as in June 2009, priority is given to children and adolescents, and adult male
patients, who should continue to receive Fabrazyme as one infusion every two weeks.
However, adult female patients, in whom the disease is less severe, may receive Fabrazyme at a
reduced dose.
All patients will be closely monitored while treatment is suspended or while they are receiving
reduced doses of Cerezyme or Fabrazyme. Reporting of side effects will continue as normal, with
doctors recording the batch numbers of the medicines in each patient’s records.
These changes will need to continue until end of 2009 when the shortages are to be resolved.
What are the recommendations for prescribers?
• Doctors who look after patients with Gaucher or Fabry disease should be aware of the shortages,
and should consider which patients should be switched to the reduced dose or other treatment.
What are the recommendations for patients with Gaucher disease who receive Cerezyme?
• Young patients with the disease (infants, children and adolescents) and adult patients with severe,
life-threatening disease progression should be contacted by their doctor to discuss their treatment
options. While the shortages are ongoing, they may be treated at a different frequency and with a
reduced dose.
• Adult patients without severe, life-threatening disease progression should be contacted by their
doctor to discuss the possibility of switching to alternative treatments (e.g. miglustat) or suspending
treatment.
• Patients who have any questions should speak to their doctor or pharmacist.
What are the recommendations for patients with Fabry disease who receive Fabrazyme?
• There are no consequences for young patients with the disease (infants, children and adolescents)
or for adult male patients.
• Adult female patients with Fabry disease should be contacted by their doctor to discuss their
treatment options. While the shortages are ongoing, they may be treated at the same frequency
(every two weeks) but with a reduced dose.
• Patients who have any questions should speak to their doctor or pharmacist.
What will happen next?
Genzyme is sending specific communications to all Cerezyme prescribers on how to select patients for
dose reduction, switch to alternative treatment or suspension of treatment, according to the new
recommendations. Genzyme has informed the Agency that no changes to the June recommendations
are required for Fabrazyme.
Genzyme has also informed the Agency that these stock-sparing measures will have no impact on the
supplies to ongoing clinical trials.
The European Medicines Agency will update this document as new information becomes available.
22 août 2009
Production de l'enzyme recombinant GCD exprimé dans des cellules de carrots
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Plant Biotechnol J. 2007 Sep;5(5):579-90. Epub 2007 May 24.
-
Production of glucocerebrosidase with terminal mannose glycans for enzyme replacement therapy of Gaucher's disease using a plant cell system.
Shaaltiel Y, Bartfeld D, Hashmueli S, Baum G, Brill-Almon E, Galili G, Dym O, Boldin-Adamsky SA, Silman I, Sussman JL, Futerman AH, Aviezer D.
Protalix Biotherapeutics, 2 Snunit Street, Science Park, Carmiel 20100, Israel.Gaucher's disease, a lysosomal storage disorder caused by mutations in the gene encoding glucocerebrosidase (GCD), is currently treated by enzyme replacement therapy using recombinant GCD (Cerezyme) expressed in Chinese hamster ovary (CHO) cells. As complex glycans in mammalian cells do not terminate in mannose residues, which are essential for the biological uptake of GCD via macrophage mannose receptors in human patients with Gaucher's disease, an in vitro glycan modification is required in order to expose the mannose residues on the glycans of Cerezyme. In this report, the production of a recombinant human GCD in a carrot cell suspension culture is described. The recombinant plant-derived GCD (prGCD) is targeted to the storage vacuoles, using a plant-specific C-terminal sorting signal. Notably, the recombinant human GCD expressed in the carrot cells naturally contains terminal mannose residues on its complex glycans, apparently as a result of the activity of a special vacuolar enzyme that modifies complex glycans. Hence, the plant-produced recombinant human GCD does not require exposure of mannose residues in vitro, which is a requirement for the production of Cerezyme. prGCD also displays a level of biological activity similar to that of Cerezyme produced in CHO cells, as well as a highly homologous high-resolution three-dimensional structure, determined by X-ray crystallography. A single-dose toxicity study with prGCD in mice demonstrated the absence of treatment-related adverse reactions or clinical findings, indicating the potential safety of prGCD. prGCD is currently undergoing clinical studies, and may offer a new and alternative therapeutic option for Gaucher's disease.
Publication Types:
PMID: 17524049 [PubMed - indexed for MEDLINE]
FDA : traitement SHIRE et PROTALIX
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Ghislaine SURREL
maladies-lysosomales-subscribe@yahoogroupes.fr
Current Drug
Shortages
|
Drug Name |
Company |
|
Drug Name |
|
Cerezyme (imiglucerase)
Injection Updated 8/21/2009 |
Genzyme Corporation For inquiries contact
Genzyme Medical Information: medinfo@genzyme.com or 1-800-745-4447, option 2 |
Manufacturing delays |
Please see Dear Doctor
letter, Dear Patient letter, and Request Form also visit the Website: Genzyme
supply update for additional information. Please
see the following link Treatment Protocol of Velaglucerase Alfa (this is a
treatment protocol available under IND) Please see the following
link: Expanded Access Trial of Plant Expressed Recombinant Glucocerebrosidase
(prGCD) in Patients With Gaucher Disease for information about prGCD, also
called Taliglucerase Alfa (this is a treatment protocol available under IND |
http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm050792.htm#cerezyme
PROTALIX : Accés étendu à l'essai de Glucocerebrosidase (prGCD) Recombinant dans la maladie de Gaucher
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Expanded Access Trial of Plant Expressed Recombinant Glucocerebrosidase (prGCD) in Patients With Gaucher Disease
Expanded access is currently available for this treatment.
Verified by Protalix, August 2009
First Received: August 18, 2009 No Changes Posted
| Sponsored by: |
Protalix |
|---|---|
| Information provided by: | Protalix |
| ClinicalTrials.gov Identifier: | NCT00962260 |
Purpose
This is an open-label expanded access trial of prGCD in patients with Gaucher disease who require enzyme replacement therapy (ERT) and who have been treated with imiglucerase but for whom the dose has been reduced or discontinued due to shortage of the product.
| Condition | Intervention |
|---|---|
|
Gaucher Disease |
Drug: Plant cell expressed recombinant glucocerebrosidase (prGCD) |
| Study Type: | Expanded Access |
| Official Title: | An Open-label Expanded Access Trial of Plant Cell Expressed Recombinant Human Glucocerebrosidase (prGCD) in Patients With Gaucher Disease Who Require Enzyme Replacement Therapy |
Resource links provided by NLM:
Genetics Home Reference related topics: Chanarin-Dorfman syndrome cholesteryl ester storage disease Farber lipogranulomatosis Gaucher disease primary carnitine deficiency succinic semialdehyde dehydrogenase deficiency
MedlinePlus related topics: Gaucher's Disease
Drug Information available for: Alglucerase Imiglucerase
Further study details as provided by Protalix:
Intervention Details:Drug: Plant cell expressed recombinant glucocerebrosidase (prGCD)
Intravenous infusion every two weeks at the dose level equal to each patient's previous imiglucerase dose before reduction or discontinuation due to shortage
Detailed Description:
Gaucher disease, the most prevalent lysosomal storage disorder, is caused by mutations in the human glucocerebrosidase gene (GCD), which have been mapped to chromosome 1 q21-q31, leading to reduced activity of the lysosomal enzyme glucocerebrosidase and thereby to the accumulation of substrate glucocerebroside (GlcCer) in the cells of the monocyte-macrophage system. This accumulation leads to the visceral manifestations of hepatosplenomegaly, anemia and thrombocytopenia, as well as to the skeletal features and less frequently also to lung involvement.
prGCD is a plant cell expressed recombinant glucocerebrosidase enzyme for the treatment of Gaucher disease.
Expression of proteins in plant cell culture is highly efficient, does not require post-expression modification of the protein, and is not susceptible to contamination by agents such as viruses that are pathological to humans.
prGCD safety will be observed in this treatment protocol of patients with non-neuronopathic Gaucher disease who require enzyme replacement therapy. Eligible patients will receive intravenous (IV) infusions of prGCD every two weeks. The dose of prGCD will be equal to each patient's previous imiglucerase dose before reduction or discontinuation due to shortage. The infusions will be administered at the selected medical center.
Eligibility
| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Bot |
Criteria
Inclusion Criteria:
- Males and females, 18 years or older
- Diagnosis of Gaucher disease treated historically with imiglucerase
- Able to provide written informed consent
Exclusion Criteria:
- Currently taking another experimental drug for any condition
- History of allergy to carrots
- Presence of anti-glucocerebrosidase (GCD) antibodies
- Previous infusion reaction suspected to be allergic in nature to Cerezyme® or Ceredase® or receiving premedication to prevent infusion reactions
- Allergy to beta-lactam antibiotics
- Presence of any medical, emotional, behavioral or psychological condition that in the judgment of the Investigator would interfere with the patient's compliance with the requirements of the study.
Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00962260
Contacts
| Contact: Raul Chertkoff, MD | +972 (4) 988-9488 | raul@protalix.com |
Protalix
More Information
Publications:
| Responsible Party: | Protalix Ltd ( Einat Brill Almon, PhD ) |
| Study ID Numbers: | PB-06-004 |
| Study First Received: | August 18, 2009 |
| Last Updated: | August 18, 2009 |
| ClinicalTrials.gov Identifier: | NCT00962260 History of Changes |
| Health Authority: | United States: Food and Drug Administration; Israel: Ministry of Health |
Keywords provided by Protalix:
|
glucocerebrosidase enzyme replacement therapy Gaucher disease plant cell culture |
splenomegaly hepatomegaly anemia thrombocytopenia |
Study placed in the following topic categories:
|
Lipid Metabolism, Inborn Errors Sphingolipidoses Metabolic Diseases Lysosomal Storage Diseases Anemia Sphingolipidosis Central Nervous System Diseases Brain Diseases Lymphatic Diseases Metabolism, Inborn Errors |
Thrombocytopenia Genetic Diseases, Inborn Splenomegaly Lipidoses Brain Diseases, Metabolic, Inborn Gaucher Disease Metabolic Disorder Hepatomegaly Lipid Metabolism Disorders Brain Diseases, Metabolic |
Additional relevant MeSH terms:
|
Lipid Metabolism, Inborn Errors Sphingolipidoses Metabolic Diseases Reticuloendotheliosis Lysosomal Storage Diseases, Nervous System Lysosomal Storage Diseases Nervous System Diseases Central Nervous System Diseases Brain Diseases |
Lymphatic Diseases Metabolism, Inborn Errors Genetic Diseases, Inborn Brain Diseases, Metabolic, Inborn Lipidoses Gaucher Disease Lipid Metabolism Disorders Brain Diseases, Metabolic |
Contact Help Desk
Lister Hill National Center for Biomedical Communications,
U.S. National Library of Medicine,
U.S. National Institutes of Health,
U.S. Department of Health & Human Services,
USA.gov,
Copyright,
Privacy,
Accessibility,
Freedom of Information Act
http://www.clinicaltrials.gov/ct2/show/NCT00962260?term=prgcd
19 août 2009
Treatment Protocol of Velaglucerase Alfa for Patients With Type 1 Gaucher Disease
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Treatment Protocol of Velaglucerase Alfa for Patients With Type 1 Gaucher Disease
Expanded access is currently available for this treatment.
Verified by Shire Human Genetic Therapies, Inc., August 2009
First Received: August 5, 2009 Last Updated: August 6, 2009 History of Changes
| Sponsored by: | Shire Human Genetic Therapies, Inc. |
|---|---|
| Information provided by: | Shire Human Genetic Therapies, Inc. |
| ClinicalTrials.gov Identifier: | NCT00954460 |
Purpose
Gaucher disease is a rare lysosomal storage disorder caused by the deficiency of the enzyme glucocerebrosidase (GCB). Due to the deficiency of functional GCB, glucocerebroside accumulates within macrophages leading to cellular engorgement, organomegaly, and organ system dysfunction. The purpose of this treatment protocol is to observe the safety of velaglucerase alfa in patients with type 1 Gaucher disease who are either treatment naive (newly diagnosed) or who are currently being treated with the Enzyme Replacement Therapy (ERT) imiglucerase.
| Condition | Intervention |
|---|---|
| Gaucher Disease, Type 1 | Drug: velaglucerase alfa |
Multicenter Open-Label Treatment Protocol to Observe the Safety of Gene-Activated™ Human Glucocerebrosidase (GA-GCB, Velaglucerase Alfa) ERT in Newly Diagnosed or Previously Treated (With Imiglucerase) Patients With Type 1 Gaucher DiseaseStudy Type:
Expanded Access Official Title:
Resource links provided by NLM:
Genetics Home Reference related topics: Chanarin-Dorfman syndrome cholesteryl ester storage disease Farber lipogranulomatosis Gaucher disease primary carnitine deficiency succinic semialdehyde dehydrogenase deficiency
MedlinePlus related topics: Gaucher's Disease
Drug Information available for: Alglucerase Imiglucerase
Further study details as provided by Shire Human Genetic Therapies, Inc.:
Intervention Details:
Drug: velaglucerase alfa
up to 60 U/kg, every other week via intravenous infusion
Type 1 Gaucher disease, the most common form, accounts for more than 90% of all cases of Gaucher disease and does not involve the CNS. Typical manifestations of type 1 Gaucher disease include hepatomegaly, splenomegaly, thrombocytopenia, bleeding tendencies, anemia, hypermetabolism, skeletal pathology, growth retardation, pulmonary disease, and decreased quality of life. Velaglucerase alfa (Gene-Activated™ human glucocerebrosidase;GA-GCB) is produced in a continuous human cell line using proprietary gene-activation technology and has an identical amino acid sequence to the naturally occurring human enzyme. Velaglucerase alfa contains terminal mannose residues that target the enzyme to the macrophages-the primary target cells in Gaucher disease. This treatment protocol will observe the safety of velaglucerase alfa in patients with type 1 Gaucher disease who are either treatment naive (newly diagnosed) or who are currently being treated with the Enzyme Replacement Therapy (ERT) imiglucerase.
Patients currently being treated with ERT for their Gaucher disease will receive the same number of units of velaglucerase alfa per month as their imiglucerase dose for doses between 30-120 U/kg/month. For patients who experienced dose reductions in their imiglucerase treatment due to supply constraints the pre-reduction monthly dose may be used to determine the monthly dose of velaglucerase alfa.
Eligibility
| Ages Eligible for Study: | 3 Years and older |
| Genders Eligible for Study: | Both |
Criteria
Inclusion Criteria:
- The patient has a documented diagnosis of type 1 Gaucher disease
- The patient is > 2 years of age
- The patient has NOT previously experienced an anaphylactic or anaphylactoid reaction to another ERT including imiglucerase
- Women of child-bearing potential must agree to use a medically acceptable method of contraception at all times during the study; and must have a negative result to a pregnancy test as required throughout their participation in the study. Male patients must use a medically acceptable method of birth control throughout their participation in the study and must report their partner's pregnancy.
- The patient is sufficiently cooperative to participate in this treatment plan as judged by the Investigator
If the patient is naïve or new to treatment, the patient has one or more of the following (in absence of the following criteria, please call the sponsor for treatment justification):
- Gaucher disease-related anemia
- Moderate splenomegaly (2 to 3 cm below the left costal margin), by palpation
- Gaucher disease-related thrombocytopenia
- Gaucher disease-related palpable enlarged liver
Exclusion Criteria: None
Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00954460
Contacts
| Contact: Dan Madden (One Path) | 1-866-888-0660 |
Sponsors and Collaborators
Shire Human Genetic Therapies, Inc.
More Information
No publications provided
| Responsible Party: | Shire Human Genetic Therapies, Inc. ( Gabriel M. Cohn, M.D., MBA, FACMG, FACOG ) |
| Study ID Numbers: | HGT-GCB-058 |
| Study First Received: | August 5, 2009 |
| Last Updated: | August 6, 2009 |
| ClinicalTrials.gov Identifier: | NCT00954460 History of Changes |
| Health Authority: | United States: Food and Drug Administration |
Keywords provided by Shire Human Genetic Therapies, Inc.:
| Enzyme Replacement Therapy Gaucher disease glucocerebrosidase beta-glucocerebrosidase Acid beta-glucocerebrosidase |
glucosylceramidase D-glucosyl-N-acylsphingosine glucohydrolase gene activation human |
Study placed in the following topic categories:
| Lipid Metabolism, Inborn Errors Sphingolipidoses Metabolic Diseases Lysosomal Storage Diseases Sphingolipidosis Central Nervous System Diseases Brain Diseases Lymphatic Diseases |
Metabolism, Inborn Errors Genetic Diseases, Inborn Brain Diseases, Metabolic, Inborn Lipidoses Gaucher Disease Metabolic Disorder Lipid Metabolism Disorders Brain Diseases, Metabolic |
Additional relevant MeSH terms:
| Lipid Metabolism, Inborn Errors Sphingolipidoses Metabolic Diseases Reticuloendotheliosis Lysosomal Storage Diseases, Nervous System Lysosomal Storage Diseases Nervous System Diseases Central Nervous System Diseases Brain Diseases |
Lymphatic Diseases Metabolism, Inborn Errors Genetic Diseases, Inborn Brain Diseases, Metabolic, Inborn Lipidoses Gaucher Disease Lipid Metabolism Disorders Brain Diseases, Metabolic |
ClinicalTrials.gov processed this record on August 18, 2009
Lettre de Genzyme du 3/08/09 aux US docteurs sur la gestion du stock et attente de la la FDA concernant la GENZ-112638
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Genzyme Corporation
500 Kendall Street
Cambridge, MA 02142
Tel 617-252-7500
August 3, 2009
RE: Revised Cerezyme® (imiglucerase for injection) Supply Management plan effective August 3, 2009
Dear Doctor:
As we previously informed you, we are in a period of temporary shortage of Cerezyme while we interrupt production to remediate a viral contamination of our manufacturing facility in Allston, Massachusetts.
Throughout this period, our overarching objective has been to protect the most vulnerable Gaucher patients.
On June 22, Genzyme convened a Cerezyme Stakeholders Working Group (including physicians and patient advocacy leaders) to develop a set of recommendations (a “Guidance”) for patient management designed to conserve supply for the most vulnerable patients. Across the U.S., physicians have begun to implement these recommendations. However, due to the complexities and time required to make these changes, we have not yet seen an adequate reduction in the usage of Cerezyme.
The projected levels of Cerezyme inventory are at a point where there is a high risk of not maintaining supply sufficient to protect the most vulnerable patients in August. The Cerezyme Stakeholders Working Group and FDA have been updated regarding this situation. As a result we have decided to begin more actively managing Cerezyme supply in order to preserve supply for the most vulnerable patients.
As of Monday August 3, 2009, Genzyme will implement a revised supply management plan which has been reviewed by the CSWG and which continues to have as its main objective conservation of Cerezyme supply for the most vulnerable patients.
The most vulnerable Gaucher patients will be defined as: infants, children and adolescents (≤18 years old) and patients with type 2 or 3 Gaucher disease. These patients should continue receiving Cerezyme according to their current dose and frequency, without any interruptions, and shipments will continue to these patients.
In addition, Genzyme will implement a Cerezyme Emergency Access Program (CEAP) which is designed to enable physicians to request Cerezyme for a limited number of other adult patients with life- threatening clinical situations defined as one or more of the following:
Platelet count ≤20,000/uL and/or documented bleeding diathesis Impending emergency non-elective surgery (e.g., splenectomy) Documented history of rapid and life-threatening disease progression following dose-reduction or treatment interruption.
Other life-threatening clinical situation which requires Cerezyme
The number of qualifying patients who will be able to receive Cerezyme through CEAP will depend on inventory levels. The CEAP form with instructions regarding the process is enclosed.
Other adult patients (>18 years old) will not receive shipments of Cerezyme as of August 3rd, in order to conserve supply for the most vulnerable patients defined above.
This revised supply management plan will be in effect through the month of August. At that point, the situation will be reassessed in consultation with the Cerezyme Stakeholders Working Group and the FDA, and we will inform the Gaucher community about any changes to the plan.
We anticipate having additional information to share with the community at that time regarding the availability of additional inventory of Cerezyme that is not currently approved for finishing and release by FDA. In addition, Genzyme has submitted a treatment IND for our investigational oral small molecule to treat Gaucher disease, GENZ-112638, and we anticipate a response from FDA regarding that treatment protocol by the end of August. In the meantime, if you need any further information, please contact Genzyme Medical Information (medinfo@genzyme.com or 800-745-4447, option 2). A copy of the Cerezyme US Prescribing Information is included with this letter.
We acknowledge that this has been a challenging period for the entire Gaucher community. As of today, the sanitization of the Allston facility has been completed, and the process of restarting production of Cerezyme has already begun. Throughout this time, thank you for working together with us to protect the most vulnerable patients until the supply of Cerezyme is fully restored.
Sincerely,
John Yee, MD, MPH
VP, Global Medical Affairs
Genzyme Corporation
Fabrazyme® (agalsidase beta) Update: Initial adoption of the Fabry Stakeholders Working Group Guidance appears to be strong, with many indications that physicians and patients have chosen to alter their treatment plans by missing a dose, reducing their dose, or changing the frequency of infusions. At this time, there is not a need to revise this Guidance. However, during this period of supply constraint, there continues to be a need for physicians to make the appropriate clinical decisions for each Fabry patient in consideration of the Fabry Stakeholders Working Group Guidance until the Fabrazyme supply is fully restored.
CZ-US-P067-08-09
