Glyko Biomedical Ltd.'s 30.6%-owned affiliate, BioMarin Completes Important Milestone in the Manufacturing of Aldurazyme.
NOVATO, Calif.--(BW HealthWire)--April 24, 2001
BioMarin Senior Management Provides Comprehensive
Glyko Biomedical Ltd.'s (OTCBB: GLYK; TSE: GBL; BVD-Berlin: GLY) 30.6%-owned affiliate, BioMarin Pharmaceutical Inc. (Nasdaq and Swiss SWX New Market: BMRN) announced today that it has completed the last major manufacturing milestone for Aldurazyme(TM) prior to the submission of a Biologics License Application (BLA) in the U.S. and Marketing Authorization Application (MAA) in Europe. This key step involved the manufacture of the five required process qualification lots of Aldurazyme. Three process qualification lots are required for the submission of a BLA to the U.S. FDA, and five lots are required for the submission of an MAA to the European regulatory authorities.
Aldurazyme, recombinant human alpha-L-iduronidase, is being tested in a Phase III pivotal trial with BioMarin's joint venture partner Genzyme General (Nasdaq: GENZ) as enzyme replacement therapy for patients with MPS-I, a debilitating, life-threatening genetic disease.
Raymond W. (Bill) Anderson, BioMarin's Chief Operating and Chief Financial Officer, said, "Progress at our cGMP commercial manufacturing facility has exceeded our expectations with regard to the amount, quality, and reduced cost of formulated bulk enzyme produced for the Aldurazyme development program. With improvements developed by our Process Development group, we increased productivity by a factor greater than four and reduced costs proportionately. At the same time, we have completed validation studies that, combined with a rigorous quality system, help ensure product and process quality. As a result, we are confident that we will be able to meet the commercial demand for Aldurazyme."
John L. Jost, Ph.D., BioMarin's Vice President, Manufacturing, added, "We have developed an efficient manufacturing process in which the enzyme is properly glycosylated and phosphorylated. This enables us to produce Aldurazyme that has therapeutic effects (as reported by the New England Journal of Medicine, January 18, 2001) at a dose of only 0.7 mg per kg of patient weight per week - approximately one and a quarter grams per average patient per year. The reason for this low dose is that the enzyme produced by our Chinese Hamster Ovary (CHO) cell line has the proper structure of mannose-6-phosphate (M-6-P) ligand needed to ensure efficient uptake by the M-6-P receptors that are present on all of each patient's cells. Our CHO cells directly produce recombinant human alpha-L-iduronidase without the complexities inherent in additional manufacturing steps to remodel the enzyme."
Frequently Asked Questions About Manufacturing at BioMarin
"As a relatively young company, members of the investment community frequently ask us about our manufacturing capabilities," Mr. Anderson said. "In order to provide comprehensive information to all investors, we are taking this opportunity to present 13 of the most commonly asked manufacturing questions with answers provided by me, John L. Jost, Ph.D., Vice President, Manufacturing, and Robert A. Baffi, Ph.D., Vice President, Quality Assurance and Quality Control on the following five pages."
Glyko Biomedical Ltd.'s principal asset is a 30.6% ownership in the capital stock of BioMarin Pharmaceutical Inc.
BioMarin specializes in the development and commercialization of therapeutic enzyme products. Since inception in 1997, BioMarin has applied its proprietary enzyme technology to develop products for lysosomal storage diseases and for the treatment of serious burns. Glyko, Inc., a BioMarin subsidiary, provides analytical and diagnostic products and services in the area of carbohydrate biology.
This press release contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc., including the following potential future products: Aldurazyme for MPS-I and rhASB for MPS-VI. Results may differ materially depending on the progress of BioMarin's product programs, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market and developments by competitors, and those factors detailed in BioMarin's filings with the Securities and Exchange Commission such as 10Q, 10K and 8K reports.
Aldurazyme(TM) is a trademark of BioMarin/Genzyme LLC, which was formed in 1998 to develop and commercialize Aldurazyme throughout the world.
BioMarin's releases and other information on the Company and its products and technologies are available on the World Wide Web at: http://www.BioMarinPharm.com.
Biographies of Mr. Anderson, Dr. Jost, and Dr. Baffi can be found on the World Wide Web at: http://www.BioMarinPharm.com/about/management.html.
BioMarin Pharmaceutical Inc. Frequently Asked Manufacturing Questions and Answers 1) Q - Where will BioMarin manufacture commercial lots of Aldurazyme, the Company's enzyme product being developed for patients with MPS-I? A - Mr. Anderson -"BioMarin's manufacturing facility for commercial production is its `Galli Drive' facility located in Novato, California. The facility is designed for the commercial production of Aldurazyme (alpha-L-iduronidase) for use in enzyme replacement therapy for MPS-I. It produced the bulk enzyme for our pivotal Phase III trial that will be concluded later this year. The production technology used is recombinant CHO cell culture using a perfusion process. The Galli drive facility currently has approximately 900 liters of bioreactor cell culture capacity. The plant has protein purification capacity utilizing column chromatographic methods widely used in the biotechnology industry. The plant produces formulated bulk enzyme. The bulk enzyme is then shipped to our partner Genzyme or to an experienced contract manufacturer where it is filled into vials, labeled, and packaged for distribution." 2) Q - What is the physical size of the Galli Drive facility and what is the investment necessary to support Aldurazyme commercial production? A - Mr. Anderson - "The current configuration of the manufacturing operations (including related quality assurance and quality control functions) occupies approximately 51,800 square feet. Of this total floor space, the developed areas include 12,500 square feet of cGMP (current Good Manufacturing Practice) process manufacturing areas, 2,200 square feet of quality control laboratories, 8,000 square feet of materials and warehouse and 29,100 square feet of utilities support area and manufacturing-related administrative areas. When current facility modifications are completed in Q4 2001, BioMarin will have invested $28 to $30 million in the manufacturing areas of the facility." 3) Q - What is the capacity of the Galli Drive facility in terms of Aldurazyme market requirements? A - Mr. Anderson - "Based on our current production experience (without future process improvements), the facility can produce bulk enzyme sufficient for the treatment of approximately 2,400 patients per year. This capacity represents 70% of the 3,400 patients estimated to be available in the economically developed world, which is the primary market for Aldurazyme. At this level of output, the facility would be sufficient to satisfy the expected market demand for several years post approval." 4) Q - What manufacturing regulatory steps are necessary prior to launch of Aldurazyme? A - Dr. Baffi - "The Galli Drive facility was constructed in 1999, and full effort on the preparation and start-up of cGMP operations began in January 2000. The facility was licensed for the production of product for use in clinical trials by the California Food and Drug Branch in June 2000. Under cGMP procedures and disciplines, we completed production of clinical enzyme sufficient for the Phase III clinical trial of Aldurazyme in September 2000. In the production `campaign' that began in October 2000 and that is scheduled to end in May 2001, we have completed five Process Qualification (PQ) runs and will complete three additional runs for validation studies. Three PQ runs are required for the U.S. BLA submission and five PQ runs are required for the European MAA submission. We anticipate that the U.S. FDA will inspect the facility in a Pre-Approval Inspection (PAI) about two months after the filing of the BLA, and the European regulatory authorities will conduct their separate inspection approximately six months after the filing of the MAA. The preparation for both inspections is a major activity for the facility staff in the second half of 2001 and early 2002. The current staff, which is sized for cGMP production operations at schedules anticipated to be required for the near term, includes 73 professionals. "We are now conducting real time and accelerated stability studies in compliance with the International Conference on Harmonization (ICH) guidelines. Based on results to date, we are planning on dating of 18 to 24 months for final product." 5) Q - What level of success has BioMarin had with the Aldurazyme process to date? A - Dr. Jost - "The current process for the production of Aldurazyme yields enzyme with purity levels that meet or exceed industry standards for injectable proteins. The process to date has proven to be both robust and repeatable. For planning purposes, the Company's long-term capacity projections assume a manufacturing run success rate of 70%. However, the recent manufacturing run success rate is greater than 90%. With the complexity and variability inherent in biological processes, this is a highly positive result. "Most important, the production output in terms of vial equivalents per run in the current campaign has increased by a factor of at least four from earlier start-up runs and from our earlier projections. Like all active processes in early stages, we have a number of promising process development initiatives which we will be investigating to further improve production yields." 6) Q - What is the current status of quality systems for Aldurazyme? A - Dr. Baffi - "Over the last year, we have greatly strengthened the systems that are required to certify the product quality of Aldurazyme. We have developed and are validating a series of 19 assays to support product quality. The quality system is consistent with the leading industry standards and practices in the quality area in that it is considered to be `orthogonal' (that is, it measures different independent product characteristics in multiple, different product `dimensions'.) Upon completion of the last validation runs in May, the required validation studies and the quality systems will be in place for the Pre-Approval Inspections." 7) Q - What is the significance of the fact that Aldurazyme is properly glycosylated and phosphorylated? A - Dr. Jost - "Aldurazyme is administered at a dose of 0.7 mg per kg of patient weight per week and, as a result, a standard patient requires a total dose of about one and a quarter grams per year. Our weekly dose is approximately equal to the total body content (the calculated amount of enzyme present) in a healthy person of the same size. The reason for this low dose is that the enzyme produced by our CHO (Chinese Hamster Ovary) cell line has the proper structure and is properly glycosylated and phosphorylated. Specifically, the enzyme has sufficient quantities of mannose-6-phosphate (M-6-P) ligand to ensure efficient uptake by the patient's cells. Our CHO cell lines directly produce recombinant human alpha-L-iduronidase without the complexities inherent in additional manufacturing steps to remodel the enzyme. "Our manufacturing process has been validated to deliver Aldurazyme that is consistently and properly glycosylated and phosphorylated. This simple and direct process promises lower costs than the much more complex processes that may add extra M-6-P ligands. The well-known relationship between the cell surface receptor and the M-6-P ligand suggests that additional M-6-P ligands will not improve cellular uptake. In addition, extra M-6-P ligands may result in immunogenicity concerns and unanticipated side effects. Based on pharmacokinetic studies in MPS-I canines and in MPS-I human patients, Aldurazyme levels achieved in the bloodstream are saturating the M-6-P receptors on cells. Further increases in phosphorylation above the current level will not improve tissue uptake of the enzyme. "Our primary activity test for Aldurazyme is an assay that measures the uptake of Aldurazyme by human fibroblast cells isolated from an MPS-I patient. This `biomimetic' assay (direct measure of a key biological function) is consistent with the proposed mechanism of action of Aldurazyme and is considered to be a very predictive test of both enzymatic activity and proper glycosylation and phosphorylation. Multiple analytical methods are employed to assess product quality and consistency. Five of the eight assays that evaluate the structural integrity of Aldurazyme are sensitive to the quantity of glycosylation and phosphorylation." 8) Q - Have you had problems developing Aldurazyme and bringing it into production? A - Dr. Jost - "We have had no extraordinary difficulties in developing and producing Aldurazyme, but the multitude and breadth of the tasks required to be completed in parallel was challenging. In approximately nine months of 2000, we brought into operation a cGMP compliant new facility, closed and transferred the staff from a pilot facility, implemented an improved production process, developed a more stable formulation, began cGMP operations, made sufficient clinical product to enable and complete the Phase III trial, and improved per run output significantly. "By May, we will have completed eight successful, Process Qualification/validation runs that will supply all of our clinical product needs up to the time of the projected commercial launch with additional product available for the launch." 9) Q - What were the circumstances and decisions surrounding the closing of the Carson Street clinical facility in Torrance, California, from which the original Aldurazyme clinical materials were produced? A - Dr. Jost - "The location of the Carson Street facility was selected to be close to the Harbor-UCLA REI laboratory where Aldurazyme was originally produced for both preclinical requirements and the Phase I clinical trial. The Carson Street plant was prepared to meet the initial production needs for Aldurazyme while a second cGMP plant at Galli Drive was developed, but, being a smaller plant, the production capacity of the Carson Street facility could not reach the levels that were desired for an efficient commercial launch. When the Galli Drive facility came on line, the Carson Street facility was closed to improve operational efficiency. "We completed the last runs required from the Carson Street facility at the end of April 2000 and closed the facility. We were pleased that 16 of the 25 technical staff working at Carson Street transferred to our Galli Drive facility, thus contributing their experience in the production of the enzyme to the new facility." 10) Q - What is BioMarin's current manufacturing facility for the production of rhASB for MPS-VI? A - Dr. Jost - "We currently produce bulk rhASB for clinical trials in a clinical manufacturing facility in our Bel Marin Keys Boulevard (`BMK') facility in Novato, California. Specialized fill/finish operations are done by an experienced contract fill/finish manufacturer. The production technology is recombinant CHO cell culture. For cell culture using a perfusion process, the facility will operate at the 110-liter scale. The facility has protein purification capacity that is balanced with the cell culture capacity. The primary method of protein purification is column chromatography. In June 2000, the BMK facility was licensed by the California Food and Drug Branch for the production of clinical product." 11) Q - What is the size of and the investment in the BMK facility? A - Mr. Anderson - "The BMK manufacturing operations occupy approximately 2,700 square feet, of which, 1,500 square feet is for cGMP manufacturing process areas, 700 square feet is for materials, and 500 square feet is for utilities support and manufacturing-related administration. When current modifications are completed in July 2001, BioMarin will have invested approximately $1.9 million in the clinical manufacturing areas of the BMK facility." 12) Q - What is the capacity of the BMK facility as it relates to producing rhASB clinical materials? A - Dr. Jost - "We have already made sufficient amounts of rhASB to complete the Phase I clinical trial including enough to maintain the patients on the drug after the evaluation part of the trial is completed this summer. In addition, after facility modifications, the capacity will be sufficient for Phase II and potentially even Phase III clinical trials of rhASB for MPS-VI." 13) Q - What is the current status of the production process for rhASB? A - Dr. Jost - "The productivity of the process using recombinant DNA techniques in a CHO host cell line is sufficient to support clinical trials. Our assays indicate that rhASB is properly glycosylated and phosphorylated (has the proper structure of M-6-P ligands) for efficient uptake. With experience gained from the Aldurazyme purification process, we now have an improved purification process for rhASB with higher net yields and lower volumes of material to be handled. In the BMK operation, we have also recorded a very favorable production run success rate of greater than 90%. From early results of stability studies in progress, we anticipate product dating for rhASB that is similar to that projected for Aldurazyme."
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|Date:||Apr 24, 2001|
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