alglucosidase alfa - Myozyme; Pompase; alpha glucosidase (rhGAA), recombinant
Cross ref.: See the Glucosidase, rDNA/Lumizyme entry for a (bio)similar or the same product marketed in the U.S.
Status: approved in U.S. and EU; forced off U.S. market while manufacturing issues are resolved
Organizations involved:
Genzyme Corp. – Manuf.; R&D; Tech.; World mark.; Parent
Sanofi S.A. – Parent
Synpac (NC), Inc. – R&D; Tech.
Synpac Pharmaceuticals Ltd. – Parent
China Synthetic Rubber Corp. – Parent
Koos Group – Parent
Genzyme Transgenics Corp. – Former
Pharming B.V. – Manuf.; R&D; Tech.; Former
Hospira – Manuf. other
Duke University – R&D; Tech
Erasmus University – R&D; Tech.
Hospira – Manuf. other
Description: Myozyme is a lyophilized (freeze-dried) formulation of recombinant glycosylated alpha glucosidase (EC 3.2.1.20) enzyme, an enzyme that degrades glycogen, as encoded by the most predominant of nine observed haplotypes of the human gene, expressed by a transformed Chinese hamster ovary (CHO) cell line. Myozyme was the first treatment available for patients with Pompe disease, a lysosomal storage disease involving accumulation of incompletely-degraded glycogen in the lysosomes of cells. The protein has a calculated mass of 99,377 daltons (99.377 kDa) for the polypeptide chain, and a total mass of ~109,000 daltons, including attached carbohydrates. Alglucosidase alfa has a specific activity of 3 to 5 U/mg, with one unit is defined as that amount of activity that results in the hydrolysis of 1 µmole of synthetic substrate per minute under the specified assay conditions).
Myozyme is packaged in 50 mg single-use vials containing 52.5 mg glucosidase alfa, 210 mg mannitol, 0.5 mg polysorbate 80 (Tween 80), 9.9 mg sodium phosphate dibasic heptahydrate, 31.2 mg sodium phosphate monobasic monohydrate. Following reconstitution with Sterile Water for Dilution, each vial contains 10.5 mL reconstituted solution and a total extractable volume of 10 mL at 5.0 mg/mL. The product is stored at 2-8˚C (refrigerated). Myozyme contains no preservatives.
The enzyme in Myozyme is expressed conventionally in CHO cells. Genzyme Transgenics Corp., a subsidiary of Genzyme Corp., and Pharming B.V., now rEVO Biologics, a subsidiary of LFB, had previously worked to develop recombinant alpha-glucosidase expressed in the milk of transgenic rabbits, with the formulated product having the trade name Pompase. This has resulted in much confusion regarding Myozyme, e.g., with some sources reporting Myozyme as a transgenic product, mixing up which product was in development at certain times, etc..
Nomenclature: Glucosidase, rDNA/Myozyme [BIO]; Myozyme [TR]; Pompase [TR former]; glucosidase alfa [USAN INN]; glucosidase, prepro-alpha-[199-arginine,223-histidine] (human) [CAS]; [199-Arginine,223-histidine]prepro-alpha-glucosidase (human) [CAS]; 420794-05-0 [CAS RN]; alpha glucosidase [SY]; rhGAA [SY]; glucosidase alpha [TR]; acid alpha-glucosidase [TR]; 1,4-alpha-D-glucan glucohydrolase [SY]; acid maltase [SY]; acid alpha-glucosidase [SY]; EC 3.2.1.20 [EC]; NDC 58468-0150-1 [NDC]
Biological.: Lysosomal acid alpha-glucosidase is an exo-1,4-alpha-D-glucosidase enzyme that hydrolyzes both the alpha-1,4 and alpha-1,6 linkages of oligosaccharides, particularly glycogen, resulting in release of glucose. The enzyme catalyzes the complete degradation of susceptible oligosaccharides to glucose, with slowing at branching points. Alpha-glucosidase is targeted to lysosomes and taken into cells via the mannose-6-phosphate receptors.
The 28-kb alpha-glucosidase gene on chromosome 17 encodes a 3.6 kb mRNA, translation of which results in a 951 amino acid polypeptide, followed by cotranslational N-linked glycosylation in the endoplasmic reticulum. This results in a 110 kDa precursor form of the enzyme, which matures by extensive modification of its glycosylation, phosphorylation, and proteolytic processing through a 90 kDa endosomal intermediate into the final active lysosomal 76 kDa and 67 kDa forms. Since the final forms have poor pharmacokinetics, the 110 kDa precursor form is used for therapeutically.
Because of interspecies immunogenicity, only human alpha glucosidase may be used therapeutically. Levels of alpha glucosidase in human urine are too low for cost-effective manufacture of the enzyme from this source. Recombinant alpha glucosidase expressed by bacteria is inactive (no glycosylation). Baculovirus expressed enzyme is active in vitro but not taken up by human fibroblasts. Mammalian expression is required for the post-translational modifications required for enzyme uptake and activity. CHO (and transgenic goat) expressed recombinant enzyme has been shown to be taken up by cultured human fibroblasts and skeletal muscle cells from Pompe patients, endocytosed GAA was localized to the lysosome, and to correct mutant lysosomal storage phenotype (model for Pompe disease).
Glycogenosis type II (GSD II, Pompe disease) is an inherited (genetic) autosomal recessive lysosomal storage disease that results from a deficiency of alpha glucosidase. Patients with this disorder are unable to break down lysosomal glycogen, which consequently accumulates in cellular lysosomes. Enzyme replacement therapy (ERT) for Pompe disease relies on parenterally administered enzyme being targeted to lysosomes of affected cells either by fluid-phase or receptor-mediated endocytosis. After M6P receptor-mediated endocytosis of the 110 kDa precursor enzyme, the precursor is processed by proteases to the primary mature 76 kDa form. Once inside the lysosome, fully active exogenous enzyme can supplement the defective native enzyme and restore full enzymatic activity. This in turn leads to the clearance of lysosomal storage and the restoration of normal cellular homeostasis.
Three natural animal models of Pompe disease have been developed – two in cattle one in Japanese quail. A genetically engineered model in knockout mice has also been developed. Cattle are too large for experimentation with scarce and expensive recombinant enzyme, so quail and mouse models have been used primarily. The disease in enzyme-deficient quail resembles the juvenile and adult forms of human Pompe disease and related histological changes in affected muscles. Quail have a second alpha glucosidase gene, resulting in residual enzyme activity and milder disease. Knockout mice lacking the gene for the enzyme experience a progressive skeletal muscle myopathy with cardiac involvement, with this mimicking the human infantile form of Pompe disease. In animal studies, recombinant CHO-expressed enzyme (Myozyme) was taken up into muscle tissue, decreased glycogen storage, and improved histopathological findings in a dose-dependent fashion. Glycogen reductions were most pronounced in the liver and heart.
Companies.: Genzyme Corp., CBER/FDA est. no. 1596, has developed, manufactures and markets Myozyme. Genzyme has reported spending over $500 million over eight years for development of Myozyme.
Genzyme (5/2009) manufactures Myozyme at its facilities in Framingham, MA. Myozyme manufactured at Framingham was used in U.S. clinical trials and has received FDA approval. This facility operates on the scale of ~160 L. However, a larger supply was need for commercial distribution, particularly since Myozyme received U.S. approval, with Lumizyme now replacing Myozyme.
A new manufacturing facility in Allston (Boston), MA, was constructed to manufacture Myozyme at much larger scale (with this product now Lumizyme). This site uses 2,000 L bioreactor(s). Myozyme (later renamed Lumizyme for the U.S. market) from this facility has received approval in 29 countries, and this plant supplies the international market. However, as discussed in the Glucosidase, rDNA/Lumizyme entry, this facility has not received FDA approval (as of 5/2009) for Myzoyme (Lumizyme) manufacture, with FDA requiring Genzyme submit a new BLA for alpha glucosidase (Lumizyme) manufactured at this facility, due to enzyme manufactured at larger scale at this facility having a slightly different glycosylation pattern. This delay in FDA approval of expanded alpha glucosidease manufacturing facilities has caused supply disruptions, even before Genzyme experienced major manufacturing problems that resulted in closing of its Allston facility (see below and the Myozyme entry).
Genzyme has also scaled-up bulk glucosidase alfa manufacture using a 4,000 Liter bioreactor at its new protein manufacturing facility in Geel, Belgium. These are the facilities that received FDA approval for Lumizyme manufacture for the U.S. market. Fill and finish facilities for Myozyme for European distribution are based in Waterford, Ireland.
Genzyme exclusively licensed worldwide rights to recombinant CHO-expressed alpha-glucosidase from Synpac (NC), Inc., a subsidiary of Synpac Pharmaceuticals (UK; best known as manufacturers of bulk penicillin), a subsidiary of China Synthetic Rubber Corp., owned by the Koos group, the fourth largest business conglomerate of Taiwan (Republic of China). In Oct. 2006, Synpac concluded a royalty agreement with Genzyme, and is expected to receive $423-$821 million over 15 years.
Researchers from Erasmus University (Rotterdam, NL) reported the cloning of the monkey alpha-glucosidase gene in 1984 (Biochem. & Biophys. Res. Comm., 119(1), p. 252-8, Feb. 29, 1984). By 1990, after promising animal studies with recombinant enzyme, Erasmus Univ. researchers began a collaboration with Dr. Y.T. Chen and coworkers, Duke University Medical Center, for development of a human therapeutic, including providing the human alpha-glucosidase gene to Dr. Chen, who first tried expressing it in insect cells and later CHO cells. Dr. J. Hopwood and coworkers, Women’s and Children’s Hospital (North Adelaide, Australia), also referred to as Adelaide Children’s Hospital, later joined the collaboration and contributed to the development of CHO expression.
In 1993, Synpac Pharmaceuticals became involved in alpha-glucosidase for Pompe disease through its support of Dr. Chen, Duke University This was successful and in 1996 Synpac (NC), Inc. was formed to acquire the technology developed by Dr. Chen and to initiate a program to manufacture the recombinant human alpha glucosidase for clinical trials and commercial use. Synpac used unspecified contractors for manufacture of CHO-expressed enzyme. Synpac researchers developed their own cGMP CHO cells lines adapted for large-scale suspension culture in serum-free medium at low pH, purification methods, and a formulation buffer that was needed to prevent aggregation and precipitation. Synpac’s preclinical studies for Pompe disease therapy were funded in part by the North Carolina Biotechnology Center, affiliated with the State of North Carolina. In June 1999, Synpac began clinical trials at Duke in three infants with Pompe’s disease.
In Oct. 1998, Genzyme formed a joint venture with Pharming B.V. for development of transgenic alpha-glucosidase for Pompe disease. In late 1999, Pharming completed a 36-week Phase II clinical trial with transgenic enzyme at the Sophia Children’s Hospital in Rotterdam, the Netherlands. The joint venture’s work was conducted in parallel/competition with that of Synpac. In March 2000, Pharming caused considerable controversy in the scientific/medical community when, under financial pressure (to maintain stock price, comply with SEC regulations regarding need to make significant disclosures; etc.), it released promising results from a clinical trial with Pompase prior to its publication in a peer reviewed journal and without permission of the study’s Erasmus Univ. investigators. This was compounded by false information circulated in the press that the results had not been as promising as expected. [Note, different sources attribute transgenic-based manufacture of enzyme for Pompase to Genzyme and/or Pharming].
In April 2000, the Genzyme/Pharming joint venture exclusively licensed Synpac’s technologies and preclinical clinical data. Synpac received an initial payment of $19.5 million and will receive unspecified royalties on sales. Development included Genzyme Transgenics in collaboration with Pharming B.V. developing transgenic rabbit alpha-glucosidase, which was tested in early-phase clinical trials. In 2000, Genzyme and Pharming shifted their development focus to enzyme produced in CHO cell culture (for reasons discussed in the Manufacturing section below). Pharming went into receivership (bankrupt) in 2001, leaving Genzyme developing alpha-glucosidase. Genzyme continued to fully fund production of the transgenic product until patients in its trials could be transitioned to CHO-expressed product, which was used for all subsequent testing and development.
In 2001, due to concerns about large scale manufacture using the Synpac CHO cell line, Genzyme initiated development of its own transformed CHO cell line to increase manufacturing capacity for larger trials and eventual commercialization. Genzyme was successful, and subsequently decided that it CHO cell line, rather than transgenic rabbits or the Synpac CHO cell line, was a more viable expression system for commercialization. CHO cell-based manufacture would be more cost-effective and provided a much clearer regulatory path. At the time (and still), no transgenic animal-expressed therapeutic had ever received FDA approval. In 2003, Genzyme initiated two clinical studies with its CHO-expressed alpha-galactosidase (Myozyme) for the infantile-onset form of Pompe disease.
Genzyme has been sponsoring four major manufacturing capacity expansion projects in Europe, including a new plant in Geel, Belgium, to meet increased demand for Myozyme after U.S. and EU approvals. Myozyme manufactured at Geel was planned to supplement that manufactured in Allston (Boston), MA. Fill and finish facilities for Myozyme (and other European-Manufactured Genzyme products and products for the European market) are based in Waterford, Ireland. EU approval for manufacture of Myozyme at Geel was granted in Feb. 2009.
It has been reported that Duke Univ. could receive $8-$10 million in annual royalty income from Myozyme sales, based on sales of $300 million to $400 million per year. This indicates a royalty rate of about $3.33%.
In Dec. 2009, after Genzyme halted production at its Allston facility due to animal virus (porcine vesivirus) contamination, and in Nov. 2009 has reported contamination in fill and finish operations at the same facility. See the Cerezyme entry for further discussion of Genzyme's manufacturing problems and its operating under a consent decree.
In July 2010, a part of its consent decree with FDA, Genzyme concluded a new contract with Hospira for fill and finish operations for Myozyme.
In Jan. 2011, Genzyme announced it would build a second production facility in Geel, Belgium, for manufacture of Myozyme costing about $336 million. The facility will have 8,000 L capacity and is expected to be completed and online in 2014. Meanwhile, production capacity at its current plant at Geel was also being increased to 12,000 liters, with the addition of a third bioreactor scheduled for approval by the end of 2011.
Manufacture: During early development Genzyme manufactured preclinical and clinical trial materials at the 30L/60L scales using CHO cells cultivated in microcarrier-based continuous perfusion process bioreactors. alpha-Glucosidase was later produced in CHO cells cultivated in a microcarrier-based continuous perfusion process bioreactor, at two larger bioreactor scales at different sites (most likely Boston, MA and Geel, Belgium). Genzyme’s European Union application requested marketing authorization for both the 160 L and 2,000 L production scales. Initial EU approval was only granted to product manufactured at 2,000 L scale (Boston). There were major EU concerns regarding the potential levels of process impurities (host cell proteins and DNA) and possible immunogenicity of CHO cell impurities for the 160L scale. EMEU/European Union (EPAR document) also reported, “Five biological reagents have been used in the production of Myozyme: donor bovine serum, foetal bovine serum, porcine derived trypsine/EDTA, salmon derived protamine sulfate and salmon derived 2-deoxycytidine. Questions raised to confirm the TSE [transmissible spongiform encephalitis, a type of prion] status of these materials have been satisfactorily addressed.”
As described in patents (which may not fully reflect actual manufacture), alpha-glucosidase human cDNA is expressed in Chinese hamster ovary (CHO) K1 cells utilizing a vector that places the cDNA under the transcriptional control of the human polypeptide chain elongation factor 1 alpha gene promoter. A clonal cell line was isolated that secreted precursor recombinant enzyme precursor at approximately 18 mg/L/day-1. During culture, the 76- and 90-kDa forms of the enzyme predominate within the CHO cells, while the 110 kDa precursor form accumulates in the culture medium.
Genzyme/Pharming Phase I and II studies of alpha-glucosidase enzyme replacement therapy in Pompe disease patients used recombinant enzyme purified from the milk of transgenic rabbits (Pompase) developed by the companies, and manufactured by Pharming. This method of manufacture was not feasible economically for supply of enzyme on a global basis and seeking approval for transgenic enzyme, for which there still are not precedents, would have further delayed commercialization. Also, CHO-expressed enzyme is taken up more and is more active than transgenic animal-expressed enzyme. This is apparently due to a greater number of exposed mannose-6-phosphate (M6P) ligands. CHO enzyme was more effective than transgenic enzyme in murine models of Pompe disease. Genzyme switched to CHO expressed enzyme (Myozyme) for further development and commercialization.
Duke Univ. investigators reported that use of a CMV promoter-drive expression vector with geneticin (antibiotic) selection and dihyrofolate reductase (DHFR) amplification enabled the development of a high-production cell clone, particularly using a medium of high-glucose Iscove’s medium with butyrate (butyric acid), providing yields up to 91.4 µg/mL in the medium, up to 13% of cellular protein. They also developed purification methods using concanavalin A affinity chromatography, hydrophobic interaction chromatography, affinity chromatography on Superdex, and anion exchange chromatography. Presumably, some of these aspects have been retained in Genzyme’s large-scale manufacturing process.
alpha-Glucosidase has been reported to be manufactured using 3 x 4,000 L bioreactors at Geel, Belgium, and 3 at Cork, Ireland, 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].
FDA class: Drug NDA
Approvals: Date = 20060428; NDA 125141
Indications: [Full text of the "INDICATIONS AND USAGE” section of product insert/labeling]:
MYOZYME (alglucosidase alfa) is indicated for use in patients with Pompe disease (GAA deficiency). MYOZYME has been shown to improve ventilator-free survival in patients with infantile-onset Pompe disease as compared to an untreated historical control, whereas use of MYOZYME in patients with other forms of Pompe disease has not been adequately studied to assure safety and efficacy (see CLINICAL STUDIES).
Status: The NDA was filed in Dec. 2005 with priority review. On Jan. 17, 2006, Genzyme reported that FDA had extended its review of the NDA by three months, with a decision/PDUFA date of April 28, 2006. The NDA was approved on April 28, 2006 with orphan status (originally granted in Sept. 1997).
In May 2007, to ensure that severely affected adults with Pompe disease in the U.S. have access to treatment, Genzyme, in collaboration with the FDA, created the Myozyme Temporary Access Program (MTAP). Through this program, Genzyme provides Myozyme produced at the 2000L scale free of charge to ~140 patients. Thus, due to manufacturing problems, Genzyme has effectively lost all revenue from Myozyme sales to adults. Infants and children with Pompe disease in the U.S. continue to receive commercially approved Myozyme produced at the 160L scale at the Allston facility.
Genzyme has had problems manufacturing Myozyme at large scale at its Boston facilities sufficiently identical (or biosimilar/biogeneric) to that manufactured in smaller scale at its Framingham facility, which manufactured Myozyme used in U.S. clinical trials. In June 2007, Genzyme submitted documentation to the FDA for the licensure of the 2,000 liter manufacturing process (Boston facilities). However, in late July 2007, FDA requested further information. Genzyme formally responded to FDA information requests, but noted that "Unfortunately, this will extend the timeline for approval and we now anticipate an FDA decision in the first quarter of 2008 at the earliest." In the meantime, the foreign market continued to be supplied with Myozyme manufactured at the Boston facilities. However, as discussed in the Glucosidase, rDNA/Lumizyme entry, enzyme manufactured at larger scale in the Boston facility has a different glycosylation pattern than that of product manufactured at smaller scale in Allston facilities, and FDA required Genzyme submit a new BLA (not NDA) for enzyme manufactured for the U.S. market at large scale in its Boston facilities, with this product given the U.S. trade name Lumizyme.
Until the new plant receives FDA approval for Lumizyme manufacture, the enzyme will be in short supply in the U.S., since it must come from the 160 L Allston plant. Pompe patients in the U.S. are being enrolled in the Myozyme Temporary Access Program (MTAP), making them eligible to receive Myozyme from clinical supplies manufactured at Framingham at no cost. These patients are being warned until Lumizyme approal supplies will be very short supply. Genzyme planned to enroll all adult U.S. Pompe patients (desiring Myozyme) in MTAP by early October 2007 "to effectively manage the commercial supply of Myozyme in the U.S." (which could involve a triage-type system for distributing the product to adults).
The primary problem delaying FDA approval of the new process/facilities is that Myozyme (now called Lumizyme for the U.S. market) manufactured at larger-scale (Boston) is not chemically identical to that manufactured at the Framingham facility, apparently due to differences in glycosylation. With Congress considering follow-on biologics/biosimilar legislation in summer 2007, Genzyme's difficulties in manufacturing identical/similar product at larger scale has been dragged into this debate. Many, particularly those seeking extensive clinical trials of follow-on biologics (generally those supporting innovator companies), have pointing to Genzyme's difficulties to support their position. They note that, if Genzyme, with its world-class manufacturing expertise, including large-scale CHO cell culture and controlled glycosylation, cannot manufacture sufficiently comparable product for FDA approval in its own facilities, how could another (biogeneric) manufacturer ever be expected to manufacture a comparable or biosimilar product Others have noted that innovator companies, i.e., those now generally large and well-established companies that originally develop biopharmaceuticals becoming targets for biogeneric development, want to have it both ways, as exemplified by Genzyme -- wanting FDA to approve their product despite obvious manufacturing-related chemical differences, while seeking to require follow-on/biosimilar products to receive extensive clinical testing to show comparability/biosimilarity.
On April 21, 2008, FDA informed Genzyme of its opinion that alglucosidase alfa produced at the 160L bioreactor scale and that produced at the 2000L scale should be classified as two different products because of differences in the carbohydrate structures of the molecules. Thus, a new BLA will be required for the product, Lumizyme, manufactured at 2000 L scale. At the time, production at of Myozyme at larger scale and in the new facilities had already been approved in more than 40 countries.
Genzyme anticipates that its new BLA for Lumizyme will culminate in the availability of two commercial versions of its alglucosidase alfa, Myozyme and Lumizyme, in the U.S,: one (Myozyme ) produced at the 160L scale and the other (Lumizyme) produced at the 2000L scale. The company had expected to begin providing U.S. patients with commercial 2000L Lumizyme during the first quarter of 2009.
On Dec. 20, 2004, Genzyme filed an MAA for European Union (EU) approval for Myozyme use as a long-term enzyme replacement therapy for all patients with a confirmed diagnosis of Pompe disease, defined as alpha-glucosidase deficiency. The MAA was approved in early April 2006. Myozyme has orphan medicinal product designation in the EU, which applies to treatments for diseases that affect fewer than 5 in 10,000 people in the EU.
The MAA contained results from several clinical trials, including interim data from the ongoing study AGLU-01702, which is evaluating the use of Myozyme in severely affected children between 6 months and 3 years of age. One-year results from AGLU-01702 became available during the application-review process, along with interim data from the ongoing study AGLU-01602 (interim results discussed below; being added to the EU application), which is fully enrolled and includes children younger than 6 months of age with the classical infantile-onset form of Pompe disease. Patients in the AGLU-01602 trial are younger and less advanced than in AGLU-01702. Waiting for more final results from ongoing trials may be among the reasons for Genzyme’ delay in filing with FDA.
In May 2007, to ensure that severely affected adults with Pompe disease in the U.S. (with priority given to supplying those under 18) have access to treatment, Genzyme created the Myozyme Temporary Access Program (MTAP) in collaboration with the FDA. This involved providing Lumizyme free of charge to approximately 170 patients on a regular dosing regimen through this program until approval of Lumizyme.
On Feb. 27, 2009, FDA reported finding significant deviations from cGMP in the manufacture of Fabrazyme, Cerezyme and Myozyme at its Allston, MA, plant, and issued a form FDA 483. These issues relate to aspects of microbiological monitoring and controls, production equipment maintenance and certain process controls. Genzyme had earlier responded to the FDA concerns on October 31, 2008, with a detailed plan and timeline to address all of the agency’s prior observations. The company provided a progress update in Feb. 2009, confirming that all corrective actions had either been completed or were on schedule to be completed by the original commitment date of March 31, 2009. Given the substantial progress that Genzyme claims it made toward addressing the inspection observations, this warning letter was unexpected.
On Feb. 26, 2009, the EU approved the production of Myozyme (Lumizyme in the U.S.) at the 4000 liter bioreactor scale at Genzyme's manufacturing facility in Geel, Belgium, with orphan status designation. With this approval, the availability of product supply enabled adult patients internationally (ex-U.S.) to resume regular infusion schedules, and new patients are being allowed to initiate therapy.
On May 24, 2010, FDA approved the BLA for Lumizyme (made at 4,000 L scale in Geel, Belgium). The final formulated product will be manufactured, filled, and packaged at Genzyme Ireland in Waterford, Ireland.
In the meatime in U.S. with Myozyme only produced at smaller scale being available, use was restricted to patients under 18, with adults requested to delay or minimize Myozyme use.
Genzyme plans to submit a supplemental BLA filing for 4000 L-scale production to the FDA during the first half of 2009. This was originally planned for the first half of 2009.
Tech. transfer: Duke University has received WO-00205841 (also WO-09705771 and WO-09705771), but not U.S. patents, concerning use of alpha-glucosidase and methods for treatment of GSD II (Pompe disease) and CHO expression of the precursor enzyme. A comparable U.S. application 2002110551 is pending. As discussed in the Company section, Duke Univ. patents were licensed to Synpac, which later transferred these to Genzyme.
Genzyme has received patents concerning transgenic alpha-glucosidase including U.S., 6,858,425, “Human acid alpha glucosidase gene and bovine alpha-S1 casein gene sequences,” This primarily concerns expression in recombinant animals, with broad use claims concerning any recombinant alpha glucosidase for parenteral therapeutic uses.
Pharming B.V. has also received patents concerning transgenic alpha-glucosidase including U.S. 6,118,045, “Lysosomal proteins produced in the milk of transgenic animals,” coassigned to Pharming B.V.; Academic Hospital (Rotterdam, NL); and Eramus Universiteit. Other patents shared by these three organizations include EP1262191 claiming CHO-expressed phosphorylated alpha-glucosidase, formulations and use for treatment of Pompe disease.
Presumably, Genzyme has licensed patents and/or materials (e.g., clones, cell lines) from Duke Univ., Erasmus Univ. and perhaps other organizations involved in alpha-glucosidase development, whether directly or through Synpac. However, having developed its own CHO cell line, these other organizations may receive no or minimal royalties.
Trials: The NDA and MAA were primarily supported by two separate clinical trials in 39 infantile-onset patients with Pompe disease ranging in age from 1 month to 3.5 years at the time of the first infusion. Patient survival without needing invasive ventilatory support was substantially greater in the Myozyme-treated infants than would be expected compared to the known high mortality of untreated patients of similar age and disease severity. The drug’s safety and effectiveness in other forms of Pompe disease have not been adequately studied. The most serious adverse reactions reported with Myozyme were heart and lung failure and allergic shock. Most common reactions included pneumonia, respiratory failure and distress, infections and fever. A boxed warning is included in the Myozyme label to warn about the possibility of life-threatening allergic reactions.
Phase I and II studies of alpha glucosidase enzyme replacement therapy in Pompe disease patients used recombinant enzyme purified from the milk of transgenic rabbits (Pompase). This showed promise in its early trials. However, subsequent trials used CHO-expressed product (Myozyme). Development of enzyme-specific antibodies has been reported in some patients in clinical trials. However, these patients still respond adequately to therapy.
Results from Synpac’s Phase I/II, open-label, single-dose study of CHO-expressed enzyme infused intravenously twice weekly in three infants with GSD-II were reported in Genetics in Medicine. 3(2):132-138, March/April 2001. Cardiac and skeletal muscle functions improvements were observed.
Genzyme expanded its clinical program by initiating open-label studies with older patients with the late-onset form of the disease. The Late-Onset Prospective Observational study began in 2004. This observational study will provide information needed to design the Late-Onset Treatment Study planned to start in mid-2005. These studies are intended to support approval for all patients with Pompe disease (i.e., those with other than early onset disease).
In April 2005, Genzyme reported interim analysis from its pivotal Phase III trial (AGLU-01602) of Myozyme for the treatment of Pompe disease. The ongoing trial already met one of its key secondary efficacy endpoints, and there is a high probability the study will meet its primary efficacy endpoint upon completion. This is expected to allow BLA submission in mid-2005. AGLU-01602 includes 18 patients with infantile-onset Pompe disease who began receiving Myozyme by 6 months of age. Because of the rapidly progressive and fatal nature of infantile-onset Pompe disease, outcomes for these patients were compared with a matched historical cohort rather than a placebo cohort. The study’s primary endpoint is the proportion of patients treated with Myozyme who are alive and free of invasive ventilator support at 18 months of age, compared with the proportion of patients who were alive at 18 months of age in the historical cohort (2%). By 12 months of age, 89% of patients treated with Myozyme (16/18) were alive and free of invasive ventilator support compared with 17% of patients who were alive at 12 months of age in the historical cohort. This met a secondary efficacy endpoint, and indicates the trial will very likely meet its primary endpoint. The interim analysis also showed that all patients treated with Myozyme had a reversal in cardiomyopathy; 72% of patients treated with Myozyme showed gains in motor development as measured by the Alberta Infant Motor Scale; all patients evaluated showed gains in cognitive, language and personal/social skills from baseline; and 83% of patients developed antibodies to Myozyme and 44% experienced infusion associated reactions. Results from AGLU-01602 were being included in the pending MAA for European Union approval.
In April 2006, Genzyme completed enrollment in a placebo-controlled Phase III trial with Myozyme in 90 late-stage Pompe disease patients in the U.S. and Europe to determine whether Myozyme improves endurance on a six-minute walk test and respiratory muscle weakness. The trial is designed to provide additional support for Myozyme’s use. Participants will receive intravenous infusions of either Myozyme at a dose of 20 mg/kg or placebo every other week for 52 weeks. The study has two primary efficacy endpoints: the effect of Myozyme on functional endurance as measured by the Six-Minute Walk Test; and the effect of Myozyme on respiratory muscle weakness as measured by Forced Vital Capacity. These endpoints are the same as those used in the pivotal clinical trial of Aldurazyme (laronidase; see related entry), which was approved for the treatment of MPS I disease in 2003.
As of April 2006, more than 280 patients in 30 countries were receiving Myozyme through clinical trials, expanded access programs, or pre-approval regulatory mechanisms.
In Dec. 2007, Genzyme announced that its post-marketing Late-Onset Treatment Study of Myozyme met its co-primary endpoints, confirming the benefit of the product for patients across the spectrum of Pompe disease. Myozyme used in the LOTS study was produced at Genzyme's Allston Landing facility using the larger scale manufacturing process (2000L). This study was performed as part of post-approval studies agreed upon with FDA, and its expected to be used to support approval of Myozyme manufactured at 2000 Liter sacle.. The randomized, double-blind, placebo-controlled study enrolled 90 patients at 8 primary sites in the U.S. and Europe. Participants received either Myozyme or a placebo every other week for 18 months. The primary efficacy endpoints sought to determine the effect of Myozyme on functional endurance as measured by the six-minute walk test and to determine the effect of Myozyme on pulmonary function as measured by percent predicted forced vital capacity. At 18 months, patients treated with Myozyme increased their distance walked in six minutes by an average of approximately 30 meters as compared with the placebo group (p=0.0283; Wilcoxon test). The placebo group did not show any improvement from baseline. The average baseline distance walked in six minutes in both groups was approximately 325 meters. Percent predicted forced vital capacity in those treated with Myozyme increased by 1% at 18 months, and declided ~3% in the placebo group (p=0.0026; Wilcoxon test). The average baseline percent predicted forced vital capacity in both groups was ~53 percent. The results for both efficacy endpoints were consistent across various prospectively defined subgroups. The preservation of pulmonary function was important, because respiratory failure is the major cause of mortality in Pompe disease.
Medical: The recommended dosage regimen is 20 mg/kg body weight administered every two weeks as an intravenous infusion. The total volume of infusion is determined by the patient’s body weight and should be administered over ~4 hours.
Enzyme replacement therapy with Myozyme is administered by infusion to restore glycogen levels in muscle tissue to normal. Correction of Pompe disease requires supplementing alpha-glucosidase to normal levels. This treatment is required for the remainder of a patient’s life. The doses of alpha glucosidase needed to treat patients with Pompe disease (remove glycogen stored in skeletal muscle) are an order of magnitude greater than those used for some other lysosomal storage disorders. For example, alpha-glucosidase dosing is 20–40 times that of Fabrazyme (beta-glucosidase from Genzyme) for treatment of Fabry’s disease. Most other lysosomal storage diseases can be treated with small proportions of normal enzyme activity. This need for large amounts of enzyme helps explain Genzyme’s concerns about selecting/developing optimal expression and manufacturing methods.
The U.S. product insert/label includes a boxed warning with information on the potential risk of hypersensitivity reactions associated with Myozyme. The boxed warning states that “Life-threatening anaphylactic reactions, including anaphylactic shock, have been observed in patients during Myozyme infusion. Because of the potential for severe infusion reactions, appropriate medical support measures should be available when Myozyme is administered.” Of the 280 patients who received Myozyme in clinical studies or through expanded access, eight patients (3%) experienced severe or significant hypersensitivity reactions.
Disease: Glycogen storage disease type II (GSD II; Pompe disease; acid maltase deficiency) is rare inherited muscle disease. Three clinical forms are distinguished: infantile, juvenile and adult. The infant onset disease affects about one child in 100,000. Severe disease, which usually results in death from respiratory failure, is rapidly fatal in newborn babies. The less severe, but still life-threatening adult form of Pompe disease has an overall incidence in the region of 1 in 40,000. Pompe’s disease is estimated to afflicts between 5,000–10,000 patients worldwide. There is a good correlation between the severity of the disease and the residual alpha-glucosidase activity, the activity being 10-20% of normal in late onset and less than 2% in early onset forms of the disease. There is currently no treatment for Pompe disease.
Pompe disease manifests as a broad spectrum of clinical symptoms with varying rates of disease progression. Infantile-onset patients present in the first months of life with an enlarged heart and skeletal and respiratory muscle weakness. Most of these patients die from cardiac or respiratory complications by one year of age. The disease is usually less severe when symptoms first appear later in childhood (or early adulthood), but life expectancy extends only into the second or third decade in these cases. These late-onset patients may present with muscle or respiratory weakness anytime during childhood or adulthood, and disease progression is less rapid. In these patients, cardiac involvement is less pronounced and shortened life-span (mortality) is due to progressive respiratory failure. Late-onset patients often require mechanical ventilation for breathing assistance and mobility aids such as canes, walkers or wheelchairs. Late-onset patients have a shortened lifespan due to progressive respiratory failure. To prevent further damage, Pompe disease should be treated as soon as it is identified.
Market: Worldwide sales of Myozyme were $324 million in 2009 and $296 million in 2008. Total 2007 worldwide sales of Myozyme were $201 million, and $59 million in 2006. In Nov. 2008, Myozyme was being used by over 750 patients outside of the U.S. The 2009 sales were driven by strong growth in Europe, where the label for Myozyme was expanded in Dec. 2008 to include data from the Late Onset Treatment Study of the therapy in adult patients. Expansion continues worldwide, and the majority of markets have transitioned to the 4000 L product.
The 2007 Average Wholesale Price (AWP) is $720/vial, with a Direct Price (Manufacturer’s discount price) of $600 (Red Book, 2007).
With a potential 5,000-10,000 patients worldwide, Pompe disease presents a larger market than many other lysosomal disease enzyme replacement therapies. This may contribute to economies-of-scale in manufacture, but the high levels of enzyme required for Pompe disease treatment (see the Medical section above) mean that much more enzyme will be needed by each patient. Thus, Myozyme treatment costs at least as much as other lysosomal disease enzyme replacements.
Myozyme may well become another orphan product with major sales (presuming manufacturing issues are resolved). For example, presuming 4,000 patients receive Myozyme at $200,000/year (which may be a low estimate for average cost) this provides $800 million in sales. The product could even become a blockbuster (sales over $1 billion/year).
Myozyme treatment, where marketed, has been reported to cost more than $300,000/year for adult patients. Perhaps, the cost will come down once the Boston and Geel large-scale manufacturing facilites come online and receive approvals.
In 2007, demand for U.S. approved product (Myozyme manufactured at 160 L) exceeded supply. Genzyme begain supplying product (Lumizyme) manufactured at 2000 L scale at Allston/Boston facilities on a case-by-case basis to adults over age 18 in the U.S. through its Myozyme Treatment Access Program (MTAP), with available Myozyme (160 L product) going to patients under age 18. In Nov. 2008, MTAP was providing Myozyme to 168 patients, and the program was closed to new patients, with over 50 newly-diagnosed patients on a waiting list.
Ongoing: Genzyme is developing a diagnostic to screen all children for Pompe disease at birth. Besides being a useful diagnostic, this will likely provide more candidates for treatment with Myozyme.
Companies involvement:
Full monograph
168 Glucosidase, rDNA/Myozyme
Nomenclature:
Glucosidase, rDNA/Myozyme [BIO]
Myozyme [TR]
alglucosidase alfa [USAN INN]
[199-Arginine,223-histidine]prepro-a-glucosidase (human) [CAS]
glucosidase, prepro-a-[199-arginine,223-histidine] (human) [CAS]
420794-05-0 [CAS RN]
1,4-alpha-D-glucan glucohydrolase [SY]
acid alpha-glucosidase [TR]
acid alpha-glucosidase [SY]
acid maltase [SY]
alpha glucosidase [SY]
glucosidase alpha [TR]
rhGAA [SY]
Pompase [TR former assigned to Synpac]
EC 3.2.1.20 [EC]
molecular weight (kDa) = 109
FDA Class: biologic BLA
Year of approval (FDA) = 2006
Date of 1st FDA approval = 20060428
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2023, based on 7,056,712 use patent (exclusively licensed), as claimed by Genzyme
other patents for which Genzyme claims coverage include 6,118,045 (2018), 7,351,410 (2020) and 7,655,226 (2019)
Tech. Catalysts Intl., affiliated with Harvest Moon Pharm., has reported 2016 |
U.S. Patent Expiration Year: | 2023 |
U.S. Biosimilars Data Exclusivity Expiration: | 2018 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2013 |
U.S. Biosimilars Launchability Year: | 2023 |
U.S. Biobetters Launchability Year: | 2023 |
Biosimilars/biobetters-related EU Patents: | 2021, based on EP 1301201 use patent
Tech. Catalysts Intl., affiliated with Harvest Moon Pharm., has reported SPC extent to 2016. |
EU Patent Expiration Year: | 2021 |
EU Biosimilars Data Exclusivity Expiration: | 2016 |
EU Biosimilars Orphan Exclusivity Expiration: | 2016 |
EU Biosimilars Launchability Year: | 2021 |
EU Biobetters Launchability Year: | 2021 |
Index Terms:
biopharmaceutical products
enzymes
exempt from CBER lot release requirements
exempt from CBER lot release requirements
hamster source materials
RA 27/3 Wistar Inst. strain, rubella virus
recombinant DNA
rodent source materials
butanol, 2-methyl-2-
Chinese hamster ovary (CHO) cells, CHO-K1
cytomegalovirus (CMV) promoter
digoxin-albumin conjugate
ellagic acid
glycogen
glycosaminoglycans
iron ammonium citrate
K-12, Escherichia coli (E. coli)
mannose
RA 27/3 Wistar Inst. strain, rubella virus
transgenic goats
adw, hepatitis B virus subtype
Complement-Fixation Test
sucrose
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
orphan 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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