alglucosidase alfa - Lumizyme; alpha glucosidase (rhGAA), recombinant
Status: same or (bio)similar product approved (marketed as Myozyme; see related entry) in over 40 countries worldwide, including the EU; BLA approved in May 2010
Organizations involved:
Genzyme Corp. – Manuf.; R&D; Tech.; World mark.; Parent
Hospira – Manuf. other
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. – Former
Duke University – R&D; Tech
Erasmus University – R&D; Tech.
Cross ref.: See the Glucosidase, rDNA/Myozyme entry for further information about Lumizyme, which is substantially biosimilar or identical to Myozyme except for slight differences due to its manufacture at larger scale.
Note, this entry concerns alpha glucosidase manufactured at large scale, originally planned at Genzyme's Allston/Boston, MA, facilities, but with Genzyme experiencing manufacturing problems, including closing of Allston manufacturing facilities, Lumizyme as originally approved by FDA is being manufactured at Lumizyme is manufactured at Genzyme facilities in Allston/Boston, MA, facilities. The FDA considers this product different than that (Myozyme) produced by Genzyme at its other Framingham, MA, manufacturing facilty. Essentially every other country considers the enzyme manufactured at all Genzyme facilities to be the same (Myozyme). Lumizyme is only marketed (under this name in the U.S.), while the same product is marketed as Myozyme (all considered the same product) elsewhere.
Description: Lumizyme 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 using continuous perfusion culture. Lumizyme is substantially very (bio)similar or nearly identical to Myozyme, except for a different glycosylation profile of alpha glucosidase attributed to its manufacture at larger scale.
Alglucosidase alfa is a glycoprotein with a calculated mass of 99,377 daltons (99.4 kDa) for the polypeptide chain, and a total mass of 109,000 daltons (109.0 kDa), including carbohydrates. Alglucosidase alfa has a specific activity of 3 to 5 Units/mg (one unit is defined as that amount of activity that results in the hydrolysis of 1 micromole of synthetic substrate per minute under specified assay conditions).
Lumizyme 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. Myozyme contains no preservatives.
The product is stored at 2-8˚C (refrigerated). The dating period for Lumizyme is 24 months from the date of manufacture when stored at 2 to 8 ºC. The date of manufacture shall be defined as a date whose definition has been redacted (censored) by FDA in the product's approval letter. The dating period for the bulk drug substance is 4 weeks when stored at 6 to 10 ºC. Lumizyme is exempt from CBER, FDA, lot release requirements.
Nomenclature: Glucosidase, rDNA/Lumizyme [BIO]; Myozyme [TR in U.S.]; 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.: See the Glucosidase, rDNA/Myozyme entry.
Companies.: Genzyme Corp. developed, manufactures and has full marketing rights for Lumizyme. Note, this same product is marketed outside the U.S. as Myozyme (see related entry). Lumizyme/Myozyme (for ex-U.S. marketing) is primarily manufactured at Genzyme facilities in Ireland and Geel, Belgium, with two 4,000 L bioreactors. available for gluosidase alpha manufacture.
Genzyme had been manufacturing glucosidase alfa marketed worldwide as Myzozyme at its facilities in Framingham, MA, and Allston (Boston), MA. Myozyme manufactured at Framingham was used in U.S. clinical trials and received initial FDA approval (as Myzozyme). The Framingham facility operates on the scale of ~160 L (uses a 160 L bioreactor), but a larger supply is needed for U.S. commercial distribution, particularly with Myozyme having received U.S. approval. The new Allston manufacturing facility operates on a much larger scale with 2,000 L bioreactor(s), and product from this facility has received approval in over 40 countries as Myozyme (while FDA considered it different and required a new name, now Lumizyme, and new full approval). A BLA supplement for manufacture at 4,000 L scale at Allston had been planned in 2009, before Genzyme experienced multiple problems at the facility.
In Dec. 2009, after Genzyme halted production at its Allston facility due to animal virus (porcine vesivirus) contamination, and in Nov. 2009 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, including having to pay a fine of $175 million and operate its manufacturing facilities under third-party oversight/control. Manufacturing at Allston was halted. [This was independent of the problems Genzyme had showing comparability of glucosidase alfa manufactured ant the 160 and 2,000 liter scales]. Genyzme was then also installing a third 4,000 L bioreactor in Geel, Belgium, that may be used for Lumizyme manufacture.
In July 2010, as part of its consent decree with FDA allowing continued operation while manufacrturing facility problems are resolved, Genzyme concluded a new contract with Hospira for fill and finish operations, adding (now including) Lumizyme. Hospira had already been providing fill and finish services for Genzyme's recombinant proteins.
In Jan 2011, Genzyme reported it would be constructing a €250 million manufacturing plant in Geel, Belgium, for Myozyme and Lumizyme. The new plant, sited next to its existing manufacturing site for Myozyme and Lumizyme, will have a capacity of 8,000 liters, with room for expansion. Genzyme said it expected commercial approvals for the new site will start in late 2014.
In Jan. 2011, Genzyme also reported production capacity at its current plant at Geel was being increased to 12,000 liters, with the addition of a third bioreactor that scheduled for approval by the end of 2011. Genzyme separately continues to operates a 160 L production plant in the U.S. for Myozyme manufacture.
FDA class: Drug NDA
Approvals: Date = 20100525; BLA
Indications: [Full text of the "Indications and USAGE" section of the product insert/labeling]:
LUMIZYME (alglucosidase alfa) is a lysosomal glycogen-specific enzyme indicated for patients 8 years and older with late (non-infantile) onset Pompe disease (GAA deficiency) who do not have evidence of cardiac hypertrophy. The safety and efficacy of LUMIZYME have not been evaluated in controlled clinical trials in infantile-onset patients, or in late (non-infantile) onset patients less than 8 years of age.
Status: Genzyme has had problems manufacturing Myozyme for the U.S .market (Lumizyme) 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 and continues to supply the U.S. market (until Lumizyme approval by FDA).
On Feb. 27, 2009, FDA issued Genzyme a "complete response" letter concerning Lumizyme.
In June 2007, Genzyme submitted documentation to the FDA for the licensure, then a sBLA, for the 2,000 liter manufacturing process (Allston/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.
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. FDa concluded that available CMC, pharmacokinetic and clinical data did not establish the comparability of enzyme manufactured at 160 L (Framingham) and 2000 L (Allston/Boston) scales. Thus, a new BLA (not NDA) was 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, with these countries recognizing product manufactured at the 160 and 2000 Liter scales as being the same.
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 has 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.
The primary problem that delayed FDA approval of the new process/facilities was that Myozyme (now called Lumizyme for the U.S. market) manufactured at larger-scale (Allston/Boston) is not chemically identical to that manufactured at the Framingham facility, apparently due to differences in glycosylation. With Congress then considering follow-on biologics/biosimilar legislation, Genzyme's difficulties in manufacturing identical/similar product at larger scale was dragged into this debate. Many, particularly those seeking extensive clinical trials of follow-on biologics (generally those supporting innovator companies), pointed to Genzyme's difficulties to support their position. They noted 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 May 30, 2008, Genzyme submitted a new separate BLA for Lumizyme, with a PDUFA date of Nov. 29, 2008. Genzyme requested Myozyme be the U.S. trade name for 2,000 L product, but FDA later required a new trade name, now Lumizyme, with 160 L product retaining the Myozyme name.
On Oct. 21, 2008, the Endocrinologic and Metabolic Drugs Advisory Committee, FDA, affirmed by a 16 to 1 vote that the Late-Onset Treatment Study established effectiveness of the 2000 L-scale product for the treatment of Pompe disease. This recommendation was provided despite concerns that efficacy in the sole pivotal trial were moderate, at best, and there were statistical problems with this trial. A majority of the committee members supported Accelerated Approval (Subpart E). As part of the accelerated approval procedure, a verification trial would be required to demonstrate clinical benefit of the 2000 L-scale product during the post-marketing period. The panel recommended post-marketing studies in patients under 18 years of age, since few of these patients had been included in the pivotal trial.
In Nov. 2008, FDA reported it would grant the new BLA for Lumizyme Accelerated Approval status. The company and FDA need to agree on the design of a post-approval verification study and the FDA must complete its review of the Risk Evaluation and Mitigation Strategy (REMS) for the product. Genzyme submitted the REMS earlier in Nov 2008. The FDA class:ified this submission as a major amendment to the BLA for Myozyme produced at the 2000 L scale (Lumizyme), and extended the PDUFA date by 90 days to Feb. 28, 2009. Genzyme would be required to submit the final protocol for the verification study after approval.
In March 2009, FDA sent Genzyme a complete response letter regarding its BLA concerning the remaining items that need to be addressed before the application can be approved. Genzyme and the FDA must finalize agreement on the design of a post-approval verification study to demonstrate the clinical benefit of Lumizyme, as required under the Accelerated Approval process. In addition, Genzyme and FDA need to finalize the Risk Evaluation and Mitigation Strategy (REMS) for Lumizyme. Genzyme and FDA had been working closely and making progress toward these goals, but were not able to reach them by the oiginal PDUFA date. Genzyme asserted that needed information was readily available, and that it would provide this to FDA within a month. A satisfactory resolution of the FDA’s warning letter pertaining to manufacturing problems at the Allston facility is required before the agency will approve Lumizyme (see the Myozyme entry)
On May 25, 2010, FDA approved Lumizyme. This included a risk evaluation and mitigation strategy (REMS). Note, Lumizyme’s safety and effectiveness have not been evaluated in patients with infantile-onset Pompe disease or in patients ages 8 years and younger with late-onset disease, and these patients should be treated with Myozyme, not Lumizyme. With orphan status, Lumizyme is exempt from requirements to conduct pediatric clinical trials. Multiple post-approval safety-related were required to be conducted. A Risk Evaluation and Mitigation Strategy (REMS) was required.
Genzyme now has two enzymes approved in the U.S, Myozyme and Lumizyme. One (Myozyme ) is produced at the 160L scale and the other (Lumizyme at the 2000 L scale) was approved but is not being manufactured.
The Lumizyme product insert carries a Boxed Warning because of the risk of anaphylaxis, severe allergic reactions, and immune-mediated reactions. Lumizyme’s safety and effectiveness have not been evaluated in patients with infantile-onset Pompe disease or in patients ages 8 years and younger with late-onset disease. These patients should be treated with Myozyme, not Lumizyme.
Lumizyme was approved with a risk evaluation and mitigation strategy (REMS). It is only be available through a restricted distribution system called the Lumizyme ACE (Alglucosidase Alfa Control and Education) Program to ensure that it is used by the correct patient group.
In Nov. 2009, FDA issued Genzyme a complete response letter requiring resolution of deficiencies at the Allston Landing manufacturing plant prior to approval.
In Dec. 2009, Genzyme decided to avoid the problems, including viral contamination, at its Allston, MA, facility, where the company had been planning to manufacture glucosidase alpha using 2,000 L bioreactors. The company decided to apply for a full BLA for U.S. marketing of Lumizyme manufactured in 4,000 L bioreactor(s) at its facililties in Geel, Belgium. FDA is expected to compare the 4,000-liter version of Lumizyme with the 2,000-liter version to ensure there are no changes to the drug's properties, even though the 2,000-liter version has not been approved. Under its original plans for Lumizyme, Genzyme had hoped for FDA approval for the 2,000-liter version, and then would submit a supplemental application for approval of the 4,000-liter product. In the meantime, Genzyme has ceased making the 2,000-liter version at Allston (the plant remained closed), with Genzyme reporting enough capacity to supply the entire world patient population, including U.S. patients, with product from its two 4,000-liter bioreactors in Geel.
In Jan. 2010, Genzyme received a June 17, 2010 PDUFA date from the FDA for its ful BLA for Lumizyme produced at Geel at the 4000 L scale. The FDA class:ified the resubmission as a class 2 complete response, which carries a six-month review timeframe.
In Jan. 2011, Genyzme reported that 1,400 of the 10,000 or so Pompe disease patients worldwide were currently being treated with either Myozyme or Lumizyme [showing how severe the shortage had become].
Tech. transfer: See the Glucosidase, rDNA/Myozyme entry.
Trials: The new BLA includes data from the Late Onset Treatment Study (LOTS) trial in 90 patients under age 18 first experiencing Pompe disease after age 2. A 28 meter increase in walking distance was observed with Lumizyme vs. placebo.in the 6-minute walk test. FDA disagreed with Genzyme regarding the statistical significance of these findings. Interpretation was further complicated by changes in the study design and statistical analysis plan. There was a significant 3.4% improvement in forced vital capacity in favor of Lumizyme. However, FDA question this endpoint and noted that there was no data correlating a change in either force vital capacity of the 6-minute walk test with clinical improvements in Pompe disease. FDA reviewers also had safety concerns regarding anaphylaxis, immune-mediated adverse events and infuson-related reactions with Lumizyzyme.
Medical: The recommended dosage of Lumizyme is 20 mg/kg body weight administered every 2 weeks as an intravenous infusion. See the Glucosidase, rDNA/Myozyme entry.
Disease: See the Glucosidase, rDNA/Myozyme entry.
Market: See the Glucosidase, rDNA/Myozyme entry.
In Jan. 2011, Genzyme reported, "Full-year 2010 sales of Myozyme and Lumizyme increased 27% to $412 million."
In March 2009, Genzyme reported that 170 adult patients in the U.S. were receiving Lumizyme free through the MTAP program.
Companies involvement:
Full monograph
168.5 Glucosidase, rDNA/Lumizyme
Nomenclature:
Glucosidase, rDNA/Lumizyme [BIO]
Lumizyme [TR in U.S. only]
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 [SY]
acid alpha-glucosidase [SY]
acid maltase [SY]
alpha glucosidase [SY]
EC 3.2.1.20 [EC]
glucosidase alpha [SY]
rhGAA [SY]
NDC 58468-0160-1 [NDC]
molecular weight (kDa) = 109
FDA Class: Drug NDA
Year of approval (FDA) = 2010
Date of 1st FDA approval = 20100525
(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: | 2022 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2015 |
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
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
perfusion bioreactors
porcine teeth
vesicular stomatitis virus (VSV)
adw, hepatitis B virus subtype
Complement-Fixation Test
sucrose
accelerated approval (based on surrogate endpoints) (FDAapproved)
orphan status
ribose
EU000 Not yet/Never filed with EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
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