Printer Friendly

Glyko Biomedical Ltd.'s 30.6%-owned affiliate, BioMarin Completes Important Milestone in the Manufacturing of Aldurazyme.

Business/Health Editors

NOVATO, Calif.--(BW HealthWire)--April 24, 2001

BioMarin Senior Management Provides Comprehensive

Manufacturing Update

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."
COPYRIGHT 2001 Business Wire
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2001, Gale Group. All rights reserved. Gale Group is a Thomson Corporation Company.

 Reader Opinion

Title:

Comment:



 

Article Details
Printer friendly Cite/link Email Feedback
Publication:Business Wire
Geographic Code:1USA
Date:Apr 24, 2001
Words:2704
Previous Article:Intel Extends Its Optical Networking Capabilities.
Next Article:Mackie Designs Sets Distribution Agreement With Soundscape.
Topics:


Related Articles
BIOMARIN'S RHASB GETS EUROPEAN ORPHAN DRUG DESIGNATION.
Glyko Biomedical Ltd.'s 31%-Owned Affiliate, BioMarin Announces Completion of Enrollment of Phase III Trial of Aldurazyme for MPS-I.
Glyko Biomedical Ltd.'s 30.6%-owned Affiliate, BioMarin Announces First Quarter 2001 Financial Results.
Glyko Biomedical Ltd.'s 30.6%-owned Affiliate, BioMarin Announces $45 Million Private Placement; UBS Warburg LLC Served as Placement Agent.
BIOMARIN FILES CTX TO CONDUCT CLINICAL TRIAL OF VIBRIOLYSIN.
Glyko Biomedical Ltd.'s 21%-owned Affiliate, BioMarin, Announces First Quarter 2002 Financial Results.
PHASE 3 TRIAL/STUDY OF ALDURAZYME FOR MPS I PROMISING.
Work on Yeshiva College medical building to be completed May 1.
Einstein College tops out its new medical pavillion.
AnGes MG to Market and Distribute BioMarin's Naglazyme in Japan.

Terms of use | Copyright © 2014 Farlex, Inc. | Feedback | For webmasters