Imiglucerase - Cerezyme; beta-Glucocerebrosidase, recombinant
Status - approved; marketed
Organizations involved:
Genzyme General – Manuf.; R&D; Tech.; World mark.
Genzyme Corp. – Parent
Sanofi S.A. – Parent
Hospira – Manuf. other
National Institute of Mental Health (NIHM) – Tech.
National Institutes of Health (NIH) – Parent
Columbia University – Tech.; Patent dispute
Hospira – Manuf. other
Cross ref.: See the entry for human-derived glucocerebrosidase (Ceredase), also from Genzyme, in the Enzymes section.
Description: Imiglucerase or Cerezyme is a lyophilized (freeze-dried) formulation of a recombinant mutein (altered form) of human beta-glucocerebrosidase glycoprotein enzyme with a single amino acid substitution produced by a transformed Chinese hamster ovary (CHO) cell line, with additional post-translation enzymatic processing to modify its glycosylation pattern. The amino acid sequence of imiglucerase differs from human placental beta-glucocerebrosidase by one amino acid at position 495, where histidine is substituted for arginine.
The CHO-expressed imiglucerase glycoprotein undergoes further processing during manufacture using enzymes to modify its glycosylation pattern (attached carbohydrate side chains). Genzyme modifies the glycosylation patterns of the CHO-expressed beta-glucocerebrosidase glycoprotein by sequentially reacting the molecule with neuraminidase to remove terminal sialic acid residues, galactosidase to remove galactose residues, and acetylglucosamidase to remove N-acetylglucosamine residues. This multiple enzymatic processing serves to expose more mannose residues at the non-reducing ends of the oligosaccharide chains of the glycoprotein, so that the side chains are predominantly terminated with mannose residues. The resulting carbohydrate structures of imiglucerase are somewhat different from those on native human placental glucocerebrosidase (e.g., Ceredase), providing a significantly longer in vivo half-life and higher affinity for mannose receptors on human cells. The mannose-terminated oligosaccharide chains are specifically recognized by endocytic carbohydrate receptors on macrophages, the cells that accumulate lipids in Gaucher disease.
Generally, post-translationally processed recombinant beta-glucocerebrosidase (imiglucerase) has at least two carbohydrate moieties, and sometimes three or four oligosaccharides, each having a Man3-->Man9 structure, with this representing at >50% of the recombinant beta-glucocerebrosidase in the final product. Purified imiglucerase is a monomeric glycoprotein of 497 amino acids, typically containing 4 N-linked glycosylation sites, with a molecular weight of 60,430 (60.43 kDa) and molecular formula of C2532H3843 N671O711S16.
Cerezyme is packaged in vials containing either 200 units or 400 units. The 200 unit vial contains 212 units of imiglucerase powder, providing a withdrawal dose of 200 units of imiglucerase; mannitol 155 mg; sodium citrates 70 mg (trisodium citrate 52 mg and disodium hydrogen citrate 18 mg); and polysorbate 80, NF (Tween 80) 0.53 mg. Citric acid and/or sodium hydroxide may be added to adjust pH. After reconstitution with 5.1 mL of Sterile Water for Injection, USP, the imiglucerase concentration is 40 U/mL in a final volume of 5.3 mL, which provides a withdrawal volume of 5.0 mL (200 enzyme units). Reconstituted solutions have a pH of approximately 6.1.
Some bovine source materials were used for cell bank establishment and used during cell culture. All of these materials are obtained from countries (e.g., U.S, New Zealand) considered free of BSE/TSE. Haemaccel (cross-linked bovine gelatin polypeptides) is used as a stabilizing agent during the manufacturing process and may also be present in very small amounts in the final product. The shelf life is 24 months when stored at 2-8˚C (refrigerated).
Note, Genzyme also manufactures and markets human female placenta-derived beta-glucocerebrosidase (Ceredase), although recombinant imiglucerase has almost totally replaced the human-derived product. Ceredase is difficult and expensive to harvest and purify from human tissues in the quantities needed to support the needs of the patient population.
Nomenclature: Glucocerebrosidase, rDNA/Genzyme [BIO]; Cerezyme [TR]; imiglucerase [FDA USAN INN BAN]; 495-L-Histidineglucosylceramidase (human placenta isoenzyme protein moiety) [CAS]; ceramidase, glucosyl ((human placenta isoenzyme protein moiety) 495-L-histidine- [CAS]; 154248-97-2 [CAS RN]
beta-D-glucosyl-N-acylsphingosine glucohydrolase [SY]; beta-glucocerebrosidase [SY]; glucocerebrosidase, beta- [SY]; E.C. 3.2.1.45 [EC]; NDC 58468-1983-1; NDC 58468-4663-1 [NDC]
Biological.: beta-Glucocerebrosidase (beta-D-glucosyl-N-acylsphingosine glucohydrolase; E.C. 3.2.1.45) is a lysosomal glycoprotein enzyme. It catalyzes the hydrolysis of the glycolipid glucocerebroside to glucose and ceramide, following the normal degradation pathway for membrane lipids. One beta-glucocerebrosidase enzyme unit (U) is defined as the amount of enzyme that catalyzes the hydrolysis of one micromole of the synthetic substrate para-nitrophenyl-beta-D-glucopyranoside (pNP-Glc) per minute at 37˚C.
There are generally four oligosaccharide moieties (carbohydrate side chains) present in native human placental glucocerebrosidase. However, the natural forms of beta-glucocerebrosidase enzyme lack exposed mannose residues in their oligosaccharide side chains, and have no therapeutic effect for Gaucher disease when injected into patients, because they do not get into the macrophage cells. Posttranslational enzymatically processed beta-glucocerebrosidase (imiglucerase) has up to nine moieties present in a Man3 –-> Man9 structure (referred to as Man3–GlcNAc2, etc.), has more terminal side chain mannose residues, and has greater affinity than native human enzyme for the mannose receptor on human cells, e.g., macrophages. The more exposed mannose residues per oligosaccharide moiety, and the more such oligosaccharide moieties, the greater the affinity for cellular mannose receptors.
See the Disease section below for information about Goucher disease.
Companies.: Cerezyme was developed and is nanufactured by Genzyme General, a subsidiary of Genzyme Corp., CBER/FDA est. no. 1596, now merged into Sanofi S.A.. Cerezyme is marketed by Genzyme in the U.S. and internationally by Genzyme or affiliates. Genzyme expended considerable expertise (and capital) to develop the large-scale, high-yield manufacturing system for Cerezyme, and currently manufactures imiglucerase at the 2,000 L bioreactor. Filling and finishing for the European market are performed at Genzyme facilities in Waterford, Ireland. In July 2006, Genzyme reported it was conducting manufacturing runs of Cerezyme to qualify for FDA approval of the facility. See the "Status" section for further discussion of Genzyme's manufacturing problems
In July 2010, a part of its consent decree, Genzyme concluded a new contract with Hospira for fill and finish operations for Cerezyme. Hospira had already been providing fill and finish services for Genzyme's recombinant proteins.
Manufacture: A Chinese hamster ovary (CHO) cell line was transformed with the gene for beta-glucocerebrosidase inserted along with the dihydrofolate reductase (DHFR) gene, enabling selection and amplification of transformed (with only transformed DHFR+ cells able to survive culture with methotrexate). The cDNA for the enzyme gene was obtained from Dr. Ernest Beutler, Scripps Research Institute, and isolated from a cDNA library derived from the W138 fetal human diploid cell line. Plasmids were constructed using plasmid pSV2 and used to transfect the CHO cells. Over 10,000 recombinant colonies were screened for production of beta-glucocerebrosidase. The top 100 producers were expanded into cell lines and the desired genes amplified by addition of methotrexate to the culture media. After six months of gene amplification, six candidate cell lines for manufacture were selected.
The anchorage-dependent CHO cells are initially cultured attached to microcarrier particles suspended in spinner flasks using serum-based media. After confluence is reached, cells are transferred to serum-free medium designed to maintain them in a non-growing state, with this protein-free medium greatly facilitating downstream purification. Efforts have been made to improve the medium formulation and manufacturing methods, but “expression of rGCR is only 10-20% of that achieved for other recombinant therapeutic proteins.” Despite this, recombinant CHO cell manufacture provides sufficient supplies of safe and effective enzyme. However, the low yield of enzyme surely contributes to the high cost of Cerezyme.
Another source reports the enzyme manufactured as Allston in 4 x 2,000 L bioreactors operating in perfusion mode using gravity settlers [Farid, S., Operational & Economic Evaluation of Integrated Continuous Biomanufacturing Strategies for Clinical & Commercial mAb Production, presented at ECI Integrated Continuous Biomanufacturing, Barcelona, Spain, 20-24 October 2013]
CBER class: Drug NDA
Approvals: Date = 19940523, first approval, NDA; orphan designation (granted 11/05/1991; expired 5/2001); Indication = for replacement therapy in patients with types I, II, and III Gaucher disease
Date = 19970531; NDA supplement; Indication = for upgrade from 160 liter scale manufacture to 340 liters
Date = 19991022; NDA supplement; Indication = for upgrade of scale of manufacture to two thousand liters
Date = 20060727; NDA supplement; Indication = approval of fill and finishing facilities in Waterford, Ireland
Indications: [full text of the "Indications AND USE” section of product insert/labeling]:
Cerezyme (imiglucerase for injection) is indicated for long-term enzyme replacement therapy for patients with a confirmed diagnosis of Type 1 Gaucher disease that results in one or more of the following conditions: anemia; thrombocytopenia; bone disease; hepatomegaly; or splenomegaly.
Status: Cerezyme as approved by FDA on May 23, 1994. This original filing received priority review and included orphan drug status, providing Cerezyme with market exclusivity in the U.S. through May 23, 2001. NDA supplements (sNDA) for manufacturing changes or additions were granted on 03/03/2005; 10/09/2002; 05/08/2001; 04/10/2000; 12/08/1999; 07/31/1997; 10/22/1996; 09/20/1996; 04/18/1996; 06/19/1995; and 02/07/1995.
The original approval was for manufacture at the 160 Liter scale. At this scale, Genzyme could only manufacture sufficient product for about 1,500 of the 5,000-10,000 persons worldwide with Gaucher disease. Subsequent approvals allowed for manufacture at the 340 and 2,000 Liter scales.
European Union (EU) Marketing Application Authorization (MAA) was granted on Nov. 17, 1997. This approval included “orphan” designation (although EU “orphan medicinal products” regulations had not been finalized at the time). On Sept. 15, 2003, EU approval was granted for an expanded indication, neuronopathic or Type 3 Gaucher disease.
On Feb. 27, 2009, FDA reported finding significant deviations from cGMP) in the manufacture of Cerezyme (and also Fabrazyme and Myozyme) at its Allston, MA, plant, and issued a form FDA 483. The problems noted involved CMC aspects of manufacture, including animal virus contamination by Vesivirus 2117, a porcine (pig) virus that is not pathogenic in humans. manufacture of Fabrazyme and Cerezyme at the Allston facility was halted due to viral contaimation in June 2009. In Nov. 2009, the company announced that stainless steel fragments, rubber and fiber-like materials had been found in some of its products due to aging machinery in the fill/finish area. This prompted the company to move some of those processes to its facility in Ireland and to outsource some to Hospira Inc.
On April 2010, Genzyme came under an FDA consent decreee allowing it to continue to operate. This included payment of an approximate $175 million fine attributed to unlawful profits. The consent decree essentially placed the plant under third-party control. Terms of the decree also require Genzyme to pay further fines and royalties if it failed to meet deadlines for bringing the plant into compliance with good manufacturing standards. The consent decree also required Genzyme to move fill and finish operations to a different facility for Cerezyme, Fabrazyme and Thyrogen, sold within the USA by November 28, 2010, and the deadline is August 31, 2011 for products sold abroad. Genzyme will have to pay 18.5% of sales of the products if fails to move the vial-filling and finishing process out of the plant by the set deadlines. If the company does not meet broader remediation goals by 2011 and 2012, it would be required to pay $15,000 per violation for each day it remained out of compliance.
In April 2010, with Genzyme coming under an FDA consent decreee allowing it to continue to operate, Genzyme continued to provide Fabrazyme patients in the U.S. with 30% of their usual dosage through the 3rd quarter of 2010.
In Jan. 2011, Genzyme finally reported, "that supply of Cerezyme is stable and there are no restrictions on dose or infusion frequency. We can now provide Cerezyme as prescribed for all patients currently receiving therapy and we have started to add new patients on Cerezyme therapy... When our new manufacturing plant in Framingham is approved by regulators, which we expect later this year, we will be able to devote more manufacturing capacity to Cerezyme and build the inventory we need."
Tech. transfer: It is commonly reported that Cerezyme has U.S. patents protecting its manufacturing method (until 2011) and its composition (until 2013). Other sources, e.g,. DataMonitor and ABN Amro, report U.S. patent coverage expires in 2001 (same year as Ceredase).
U.S. patents assigned to Genzyme include 6,451,600, U.S. patents assigned to Genzyme include 6,451,600 and 5,236,838, both entitled “Enzymatically active recombinant glucocerebrosidase.” The only claim for 6,451,600, expiring in 2019, states, “A CHO cell comprising nucleic acid encoding enzymatically active human glucocerebrosidase, said cell being transformed with any plasmid selected from the group pGB20, pGB37 and pGB42.” S and 5,236,838, both entitled “Enzymatically active recombinant glucocerebrosidase.” The only claim for 6,451,600 states, “A CHO cell comprising nucleic acid encoding enzymatically active human glucocerebrosidase, said cell being transformed with any plasmid selected from the group pGB20, pGB37 and pGB42.” See also WO 90-07573.
Genzyme Corp. co-exclusively licensed recombinant beta-glucocerebrosidase technology from the National Institute of Mental Health (NIHM), National Institutes of Health (NIH; Bethesda, MD) in the early 1990s. This included U.S. 5,879,680, “Cloned DNA for Synthesizing Unique Glucocerebrosidase beta-Glucocerebrosidase,” March 1999, concerning cloning and expression of recombinant glycosylated beta-glucocerebrosidase and its use for treatment of Goucher’s disease. NIH claims that previous methods for producing glucocerebrosidase by recombinant DNA technology yielded an enzyme with altered carbohydrate structure or only produced small amounts of enzyme. Enzon Corp. also co-licensed this technology from NIH, but did not develop a glucocerebrosidase product.
Genzyme was a licensee of Columbia University’s patents concerning cotransformation, a broadly-useful genetic engineering method allowing selection and isolation of transformed cells. The original patents and license expired in 2000, but Columbia received another patent in 2002 and was again seeking royalties, which Genzyme and other companies challenged in court. Recently, the University decided not to continue to press infringement suits and seek royalties, but the patent office is reexaming the relevant patent, and the university could against pursue infringement and royalties at a later date. See the “Tech. transfer” section of the Recombinant DNA Products entry (#100) for further information.
In Jan. 2005, Genzyme file a patent infringement suit in Israel alleging infringement of Israeli patent 100,715 against Transkaryotic Therapies, Inc. (TKT; becoming part Shire Pharmaceuticals Group plc), which is developing a beta-glucocerebrosidase enzyme replacement therapy, GA-CBC, using its human gene activation technology (see the EPO, rDNA/TKT or Dynepo entry). Genzyme claims that TKT is infringing patented purification processes, and is seeking seizure/destruction of TKT’s supply of enzyme being used in a Phase I/II open-label trial in Israel and halt of further development (in Israel).
On Feb. 27, 2009, FDA reported finding significant deviations from cGMP) in the manufacture of Fabrazyme (and also Cerezyme and Myozyme) at its Allston, MA, plant, and issued a form FDA 483. The problems noted involved CMC aspects of manufacture, including animal virus contamination. manufacture of Fabrazyme and Cerezyme at the Allston facility was halted due to viral contaimation in June 2009. In Nov. 2009, the company announced that stainless steel fragments, rubber and fiber-like materials had been found in some of its products due to aging machinery in the fill/finish area. This prompted the company to move some of those processes to its facility in Ireland and to outsource some to Hospira Inc.
On April 2010, Genzyme came under an FDA consent decreee allowing it to continue to operate. This included payment of an approximate $175 million fine. The consent decree essentially placed the plant under third-party control. Proposed terms of the decree would also require Genzyme to pay further fines and royalties if it failed to meet deadlines for bringing the plant into compliance with good manufacturing standards. The consent decree also required Genzyme to move fill and finish operations to a different facility. Genzyme would have to pay 18.5% of sales of the products if it failed to move the vial-filling and finishing process out of the plant by a set deadline. The FDA proposed to set deadlines by which time the company must complete that task, and also bring other aspects of the plant into manufacturing compliance. If the company did not meet broader remediation goals by 2011 and 2012, it would be required to pay $15,000 per violation for each day it remained out of compliance.
In March 2010, Genzyme reported finding one Cerezyme vial produced at its manufacturing facility in Waterford, Ireland, containing a contaminant, 2,4 dichlorobenzoic acid (2,4 DBCA), from silicone tubing. Genzyme stated, “Based on review of the medical literature and the Cerezyme safety database, any risk to patients from this impurity is considered to be remote," with the impurity at insigificant levels. This was not expected to affect plant recertification and reoppening.
In April 2010, Genzyme came under an FDA consent decreee allowing it to continue to operate, Genzyme continued to provide its replacement enzymes to patients in the U.S. with 50% of their usual dosage.
Trials: Clinical trials supporting original approval demonstrated efficacy primarily on the basis of surrogate markers – increases in hemoglobin levels, increases in platelet counts, and decreases in liver and spleen volume as assessed by MRI and CT. In clinical trials, Cerezyme improved anemia and thrombocytopenia, reduced spleen and liver size, and decreased cachexia to a degree similar to that observed with Ceredase. Studies supporting original approval used material manufactured at the 160 L scale.
Results from a trial in 342 patients with Type 1 Gaucher disease reported in the Jan. 2007 issue of the Journal of Bone and Mineral Research showed that long-term use of Cerezyme significantly improved bone mineral density in patients with Type 1 Gaucher disease in a dose-dependent manner. On average, patients receiving Cerezyme at 60 units/kg biweekly achieved scores that approached those in the general population, while untreated patients experienced no improvement or declining bone mineral density over the same period.
Medical: Gaucher disease is treated by enzyme replacement therapy (ERT) with enzyme formulations having beta-glucocerebrosidase activity, particularly enzymes (imiglucerase or Cerezyme, and alglucerase or Ceredase) having been post-translationally enzymatically modified to increase terminal mannose residues on the oligosaccharide (carbohydrate) side chains of the beta-glucocerebrosidase molecule. Exposure of terminal mannose-residues enables the enzyme to bind to cellular mannose receptors, particularly receptors on macrophages in the liver, spleen and bones, and enter the cells and their lysosomes.
Antibodies to imiglucerase form in about 15% of treated patients, but this does not have any adverse effects and does not affect efficacy. No serious adverse events have been reported with Cerezyme therapy, and there are no contraindications: to its use.
Due to the heterogeneity and multi-systemic nature of Gaucher disease, Cerezyme dosage is generally individualized for each patient. Dosages can range from 2.5 U/kg body weight three times weekly or 14 U/kg every two weeks to 60 U/kg every two weeks. Provision of between 10-500 mg per 70 kg patient per month provides the patient with between 0.25-3 grams of recombinant product over a one-year period.
Most Gaucher disease-treating physicians in the U.S. follow the recommended dosing regimen for Cerezyme (and Ceredase). This involves an initial dose of up to 60 units/kg body weight per infusion, usually once every two weeks (although this can vary to as often as daily or every other day or as infrequent as once every four weeks). Some physicians use higher starting doses for more rapid response in seriously ill patients. Outside the U.S., e.g., in Europe, low-dose/high-frequency regimens, e.g., 2.5 units/kg body weight or lower three times weekly, are more common.
In 2008, with costs being a significant concern, controversy persists about the proper dosing with Cerezyme. Some Gaucher specialists believe that Cerezyme can be used in many or some patients at much lower dosage, e.g., one-quarter the usual, and still retain sufficient efficacy.
Dr. Ernest Beutler, Scripps Research Institute, a noted critic of Genzyme's dosing recommendations has stated, "It is economic malpractice to give a much higher dose of an expensive drug than is required," Other Gaucher specialists argue otherwise, saying that skimping on the medicine could endanger patients.
Disease: Gaucher disease is one of a family of some 30 genetic (inherited) diseases known as lysosomal storage disorders (sphingolipidoses). Gaucher disease (glucosylceramide lipidosis; beta-glucocerebrosidase deficiency) is an autosomal recessive disorder characterized by deficiency in the lysosomal enzyme, glucocerebrosidase. Gaucher disease is the most severe of the lipid storage diseases. Gaucher disease is characterized by the accumulation of glucocerebroside in tissue macrophages, due to lack of beta-glucocerebrosidase enzyme to break down excess glucocerebroside. Accumulation of glucocerebroside in tissue macrophages results in the cells become engorged (termed Gaucher cells).
Clinical features of Gaucher disease include anemia and thrombocytopenia due to splenic sequestration and replacement of bone marrow by glucocerebroside-accumulating Gaucher cells. Gaucher cells are typically found in liver, spleen and bone marrow, and sometimes in the lung, kidney and intestine. Secondary hematologic sequelae of Gaucher disease include severe anemia and thrombocytopenia in addition to characteristic progressive hepatosplenomegaly. Skeletal complications are common and are often the disease’s most debilitating and disabling feature.
Gaucher disease includes three subtypes: a) type I - chronic, non-neuropathic form; b) type II - infantile neuropathic form; and c) type III - juvenile neuropathic form. Type I is the most frequent (although still rare) and type II is the least frequent. Type I Gaucher disease affects an estimated 20,000 patients worldwide (i.e., even on a worldwide basis, Gaucher disease therapeutics very much orphan products). Type I disease has an incidence of 1/40,000 to 1/60,000 individuals. A large percentage of affected patients are Jews of Eastern European (Ashkenazic) descent, with incidence as high as 1/450. Type I disease is extremely variable in signs, symptoms and course, even among those with the same genotype, with disease ranging from asymptomatic to life-threatening. Clinical onset can occur at any age, but it typically appears after infancy and sometimes not until adulthood.
Market: Total 2012 sales were $824.8 milion; $720 million in 2011 and 2010. 2009 worldwide sales of Cerezyme were $793 million, with Genzyme losing considerable sales due to halt of Cerezyme manufacture at the Allston facilities. Sales were $1.239 billion in 2009, $1.113 billion in 2008; $1.007 billion in 2006 (attaining blockbuster status); $933 in 2005; $839.4 million in 2004 (38% of total revenue); $739 million in 2003; $619.2 million in 2002, $570 million in 2001, $537 million in 2000 (71% of total revenue), $479 million in 1999, and $333 million in 1997. Cerezyme accounts for about 50% or more of Genzyme’s income. Generally, about one-half of Cerezyme sales are in the U.S. In 2005, more than 4,500 patients in over 80 countries were receiving Cerezyme.
The 2007 Average Wholesale Price (AWP) is $790/200 U vial, with a Direct Price (Manufacturer’s discount price) of $740.00; and $1,580.00/400 U vial, with a Direct Cost of $1,480.00 (Red Book, 2007). These prices are unchanged since at least 2005.
The typical cost for Cerezyme treatment is ~$175,000 per patient or more.
In the U.S., Cerezyme is reimbursed by Medicaid and nearly all health insurance providers. Genzyme provides the product at no cost for those patients not covered by insurance and/or otherwise unable to afford it. In Jan. 2003, about 40% of U.S. Cerezyme patients were receiving therapy at home.
In March 2003, the U.K. Office of Fair Trading (OFT; similar to the Federal Trade Commission/FTC) fined Genzyme £38.6 million, accusing the company of manipulating the price of Cerezyme, which costs the National Health Service (NHS) over £360,000/year/adult patient. Genzyme (or its contractor) was charging the NHS a flat-rate price including home administration, which OFT alleged prevented other companies from making a profit and competing for home delivery services. OFT ruled that Genzyme’s practice of bundling home delivery and home care services with sales of Cerezyme precluded fair competition, fined the company, and required Genzyme to offer Cerezyme to distributors. Genzyme appealed and replied that Cerezyme is used by fewer than 200 of the 250-300 Britons with Gaucher disease, with only about 30 receiving nursing care. In March 2004, the U.K. Competition Appeal Tribunal ruled on Genzyme’s appeal, reducing the fine to ~$5.5 million, allowed Genzyme to retain its list price for Cerezyme and continue delivery of home services, while also offering Cerezyme to distributors. In Sept., the Competition Appeal Tribunal, OFT, reiterated the finding of lack of competition (squeezing out of home care providers) and issued a final order requiring Genzyme to supply Cerezyme to any bona fide provider of homecare services at a discount from the prevailing NHS list price of at least 20 pence per unit (7.2% of the current NHS list price).
In June 2009, viral contamination at the Allston facility halted all manufacture of Cerezyme. Existing patients were allocated only 50% of their usual supplies. In Feb. 2010, Genzyme reported that 85% of its Cerezyme patients continued on Cerezyme treatment (at lower doses), and that supplies would be cut to 50% of usual. In April 2010, with Genzyme coming under an FDA consent decreee allowing it to continue to operate, Genzyme continued to provide Cerezyme patients in the U.S. with one-half of their usual dosage. Full supplies were expected to be restored in May 2010.
Competition: No other recombinant beta-glucocerebrosidase products are currently fully approved in the U.S. The other (human-derived) glucocerebrosidase product from Genzyme, Ceredase, is being phased out (patients switched to Cerezyme), and its sales are small. Cerezyme is expected to not have serious competition for at least several years.
In mid-2009, starting with the June closing of the Allston manufacturing facilities, many patients and physicians started losing faith and trust in Genzyme. Thus, many welcomed and began using comparable enzyme products from Protalix and Shire (see related entries).
Zavesca (miglustat), a glucosylceramide synthetase inhibitor drug, from Actellion Pharmaceuticals and Celltech Group received Europe Union approval in Nov. 2002 and approval from FDA on July 31, 2003 for treatment of mild to moderate type 1 Gaucher disease in patients for whom Cerezyme is unsuitable. Zavesca, as marketed in Europe by Actelion Ltd., costs about $97,000 per year.
Companies involvement:
Full monograph
167 Glucocerebrosidase, rDNA/Genzyme
Nomenclature:
Glucocerebrosidase, rDNA/Genzyme [BIO]
Cerezyme [TR]
Imiglucerase [FDA USAN INN BAN]
495-L-Histidineglucosylceramidase (human placenta isoenzyme protein moiety) [CAS]
Ceramidase, glucosyl ((human placenta isoenzyme protein moiety) 495-L-histidine- [CAS]
154248-97-2 [CAS RN]
beta-D-glucosyl-N-acylsphingosine glucohydrolase [SY]
beta-Glucocerebrosidase [SY]
Glucocerebrosidase, beta- [SY]
E.C. 3.2.1.45 [NUM EC]
NDC 58468-1983-1; NDC 58468-4663-1 [NDC]
molecular weight (kDa) = 60
FDA Class: Drug NDA
Year of approval (FDA) = 1994
Date of 1st FDA approval = 19940523
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2019, based on 6,451,600, as claimed by Genzyme, which also claims relevance for 5,236,838 which expired in 2010 and 5,549,892 which expires in 2013
IMS has reported expiration in 2013. Express Scripts reports Aug. 2013. PWC has reported 2001. Technology Catalysts Intl., affililated with Harvest Moon Pharm, has reported 2013.
ABN Ambro has reported 2010. |
U.S. Patent Expiration Year: | 2019 |
U.S. Biosimilars Data Exclusivity Expiration: | 2006 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2001 |
U.S. Biosimilars Launchability Year: | 2019 |
U.S. Biobetters Launchability Year: | 2019 |
Biosimilars/biobetters-related EU Patents: | 2019, based on EP 0401362) |
EU Patent Expiration Year: | 2019 |
EU Biosimilars Data Exclusivity Expiration: | 2007 |
EU Biosimilars Orphan Exclusivity Expiration: | 2007 |
EU Biosimilars Launchability Year: | 2019 |
EU Biobetters Launchability Year: | 2019 |
Index Terms:
biopharmaceutical products
blepharospasm
bovine materials used<!-- bovinesource -->
bovine materials used<!-- bovinesource -->
enzymes
exempt from CBER lot release requirements
hamster source materials
recombinant DNA
rodent source materials
Chinese hamster ovary (CHO) cells
glycosaminoglycans
mammalian cell culture
PedvaxHIB
petrolatum gauze
plasmid pDW27
porcine teeth
rodent cells <!-- rodentcells -->
vesicular stomatitis virus (VSV)
acetylglucosamidase
ceramide
citric acid
galactose
galactosidase
gelatin (bovine source)
glucose
glycosylation
glycosylation enzymes
Haemaccel
lyophilized (freeze-dried)
mannose-terminated oligosaccharides
N-acetyl glucosamine
neuraminidase
para-nitrophenyl-beta-D-glucopyranoside (pNP-Glc)
polysorbate 80 (Tween 80)
sialic acid derivatives
sodium citrate
sodium hydroxide
Sterile Water for Injection
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
orphan status
priority review status
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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