BioMarin Completes Important Milestone in the Manufacturing of Aldurazyme (TM)

Senior Management Provides Comprehensive Manufacturing Update



Apr 24, 2001, 01:00 ET

    NOVATO, Calif., April 24 /PRNewswire Interactive News Release/ --
 BioMarin Pharmaceutical Inc. (Nasdaq and Swiss SWX New Market: BMRN) announced
 today that it has completed the last major manufacturing milestone for
 Aldurazyme 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., 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."
     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."
 
      Contacts:
      Fredric D. Price
      Chairman and Chief Executive Officer
      BioMarin Pharmaceutical Inc.
      (415) 884-6700
 
      Investor Relations
      (415) 884-6777
 
      Sharon Karlsberg
      Director
      Feinstein Kean Healthcare
      (617) 577-8110
                     MAKE YOUR OPINION COUNT -  Click Here
                http://tbutton.prnewswire.com/prn/11690X23825728
 
 

SOURCE
    NOVATO, Calif., April 24 /PRNewswire Interactive News Release/ --
 BioMarin Pharmaceutical Inc. (Nasdaq and Swiss SWX New Market: BMRN) announced
 today that it has completed the last major manufacturing milestone for
 Aldurazyme 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., 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."
     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."
 
      Contacts:
      Fredric D. Price
      Chairman and Chief Executive Officer
      BioMarin Pharmaceutical Inc.
      (415) 884-6700
 
      Investor Relations
      (415) 884-6777
 
      Sharon Karlsberg
      Director
      Feinstein Kean Healthcare
      (617) 577-8110
                     MAKE YOUR OPINION COUNT -  Click Here
                http://tbutton.prnewswire.com/prn/11690X23825728
 
 SOURCE