Status: approved; marketed; manufacture halted in 2009 and coming slowly back online

Organizations involved:

Genzyme Corp. – Manuf.; R&D; Tech.; World mark.

Sanofi – Parent

Mount Sinai School of Medicine – Tech.

Research Corporation Technologies Inc. (RCT) – Tech.

Royalty Pharma, AG – Tech.

Transkaryotic Therapies, Inc. – Patent Dispute

Shire Pharmaceuticals Group plc – Parent

Columbia University – Tech.; Patent dispute

Hospira – Manuf. other

Cross ref.: See the entries above for Galactosidase Products and agalsidase alpha (Replagal).

Description: Fabrazyme or agalsidase beta is a lyophilized (freeze-dried) formulation of recombinant alpha-galactosidase enzyme glycoprotein produced by a transformed Chinese hamster ovary (CHO) cell line. Agalsidase beta is a recombinant form of human alpha-galactosidase A enzyme with the same amino acid sequence as the native human enzyme. Purified agalsidase beta is a homodimeric glycoprotein with a molecular weight of ~100 kDa. The mature protein is comprised of two identical subunits of 398 amino acids each containing three N-linked glycosylation sites and having a molecular weight of ~50 kDa.

Fabrazyme is packaged as a lyophilized powder in glass vials for reconstitution with Sterile Water for Injection, USP. Vial contain 37 mg of agalsidase beta, 222 mg mannitol, 20.4 mg sodium phosphate monobasic monohydrate, and 59.2 mg sodium phosphate dibasic heptahydrate. After reconstitution, 35 mg of agalsidase beta (7 mL) may be extracted from each vial. The dating period for Fabrazyme is 24 months when stored at 2-8°C (refrigerated). The date of manufacture is the date of final sterile filtration of the final formulated product.

Biological.: This enzyme catalyzes the hydrolysis of globotriaosylceramide (GL-3) and other alpha-galactyl-terminated neutral glycosphingolipids, such as galabiosylceramide, and blood group B substances to ceramide dihexoside and galactose. See the Galactosidase Products entry above for further biological activity information. The specific activity of agalsidase beta is ~70 U/mg. One unit is defined as the amount of activity that results in the hydrolysis of 1 µmole of a synthetic substrate, p-nitrophenyl-a-D-galactopyranoside, per minute under the assay conditions.

Nomenclature: Galactosidase, beta, rDNA [BIO]; Fabrazyme [TR]; Agalsidase beta [FDA USAN INN]; galactosidase, alpha-(CHO cell line CTH-158 plasmid PGB86) [CAS]; alpha-galactosidase b [SY]; 104138-64-9 [RN]; alpha-Gal A [SY]; EC 3.2.1.22[EC]; NDC 58468-0040-1 [NDC]

The FDA’ s use of “beta” in the proper name for this product is reportedly based on it being the second alpha-galactosidase product it received for review.

Companies.: Fabrazyme was developed and is manufactured by Genzyme General, a subsidiary of Genzyme Corp., CBER/FDA est. no. 1596. It is marketed in the U.S., Europe and other countries by Genzyme and affiliates. Filling and finishing at least for the European market, probably for worldwide use, are performed at Genzyme facilities in Waterford, Ireland.

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. Besides having to pay the federal government $175 million disgorgement (giving up of profits) payment nas part of a consent agreement allowing the company to continue operations, Genzyme had to ceded control/oversight of manufacturing operations to a third party and close down its Allston manufacturing facilities until they are reapproved. Genzyme also had to move fill/finish operations out of the plant for Cerezyme.

In July 2010, a part of its consent decree with FDA, Genzyme concluded a new contract with Hospira for fill and finish operations for Fabrazyme. Hospira had already been providing fill and finish services for Genzyme's recombinant proteins.

In Aug. 2010, Genzyme reported it would continue to have minimal levels of inventories of Fabrazyme until its new plant in Framingham, MA, manufacturing facility is approved.

In Jan. 2012, FDA and EMA approved the new manufacturing plant in Framingham, MA., for the production of Fabrazyme.

In Feb. 2012, Sanofi acquired Genzyme.

In March 2012, Genzyme (now part of Sanofi), began shipping Fabrazyme from its new Framingham manufacturing facility, with full supplies expected to be restored by the end of the year. During the shortage, European patients had been shifted to receive partial dosage (portion of usual/prescribed supply), and the process of moving the most severely affected patients to full dose of Fabrazyme began in March 2012.

In Nov. 2013, Genzyme/Sanofi reported it was investing $80 million to expand Fabrazyme manufacturing capacity at its Framingham, MA, facilities, building an new downstream processing facility. A new fillng line was also being added at Waterford, Ireland, where all Fabrazyme undergoes fill and finish.

Manufacture: Agalsidase beta is produced by growth of a recombinant Chinese Hamster Ovary (CHO) cell line transfected with an expression vector containing the cDNA coding region for human alpha-galactosidase, and purified from the cell culture media by chromatographic methods. Development of the Master and Working Cell Banks (MCB and WCB), scale-up and manufacture included/includes use of serum and/or other unspecified bovine-derived media components obtained from BSE-free USDA-inspected herds in the U.S. and Ministry of Agriculture-inspected herds in New Zealand.

Bioprocessing has been reported to involve multiple bioreactors (2 each) at Allston and Framingham operating in perfusion mode using a gravity settler. [Farid, S., Operational & Economic Evaluation of Integrated Continuous Biomanufacturing Strategies for Clinical & Commercial mAb Production, presented at ECI Integrated Continuous Biomanufacturing, Barcelona, Spain, 20-24 October 2013]

FDA class: Biologic BLA

CBER to CDER: Among the products transferred within FDA on June 30, 2003

Approvals: Date = 20030424; first approval, BLA Date = 20120124; BLA supplement; Indication = approval of manufacture at new Framingham facilities

Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling]:

Fabrazyme (agalsidase beta) is indicated for use in patients with Fabry disease. Fabrazyme reduces globotriaosylceramide (GL-3) deposition in capillary endothelium of the kidney and certain other cell types (see CLINICAL STUDIES).

Status: Genzyme’s BLA for accelerated approval was filed on June 23, 2000; was accepted for review on September 19, 2000; and was approved in April 24, 2003 (review time = ~2.83 years) with orphan designation. The application received fast track and priority review.

This was the first case of two substantially identical biopharmaceutical products essentially simultaneously seeking orphan drug approval. Genzyme’s filing followed that of Transkaryotic Technologies for its galactosidase product (Replagal; see entry above) by only one week. Since Fabrazyme received approval first (with orphan designation), it receives seven years of U.S. marketing exclusivity (i.e., no other substantially equivalent product will be approved by FDA for these indications: for seven years). Fabrazyme is the first and only treatment option available to patients with Fabry disease.

On Dec. 22, 2000, FDA sent its first complete response letter, confirming its had completed its review of the BLA, but requesting additional information and clarifications. FDA also sent a complete response letter to TKT concerning Replagal on this same day (to be fair to both companies). Genzyme formally responded in April 2001. Genzyme initiated further trials in early 2001. Genzyme received a second complete response letter in Oct. 2001, responded to this in May 2002, and received a third complete response letter in June 2002. Genzyme responded to this third letter with resubmission of its BLA) in Oct. 2002, and FDA set a PDUFA deadline or six month target approval date of April 24, 2003.

In Jan. 2003, the Endocrinologic and Metabolic Drugs Advisory Committee, FDA, voted 14-1 that Fabrazyme showed a statistically relevant impact on disease markers, is an “appropriate” treatment for Fabry disease, but did not explicitly recommend approval. Fabrazyme (unlike Replagal) achieved its primary endpoint, reduction of pain and improved heart and kidney function, but (like Replagal) did not significantly slow damage to the kidneys and heart. Genzyme (and TKT) was criticized for rushing clinical trials (to try to be the first to gain approval and seven years exclusivity).

The PDUFA deadline (target approval date) for Fabrazyme was missed by FDA, reportedly due to concerns that approval would make it difficult to keep patients in ongoing placebo-controlled Phase IV studies (with trials for Gaucher disease, a long-term disease, requiring years to complete). Besides patients likely to drop out of trials to receive the product once approved (and covered by insurance), there were concerns it would be unethical. Placebo-controlled trials are ethically very difficult to conduct find it difficult to retain patients, when involving serious diseases for which effective treatments are available, particularly for diseases such as Fabry’s disease where failure to halt disease advancement can cause permanent physical impairments. Fabrazyme’s FDA approval established new precedents related to the acceptance of historical control data in determine placebo controls in patients who cross-over to active treatment, particularly in post-approval (Phase IV) trials. Fabrazyme’s accelerated approval, based on surrogate rather than clinical endpoints, included requirements to conduct post-approval, placebo-controlled trials to confirm efficacy. Genzyme committed to conducting trial AGAL0008, with one-third of patients receiving placebo, and started this trial prior to approval. However, once Fabrazyme was approved, the product became readily available to Fabry patients, and few would be expected to remain in this trial (with 1/3 chance of receiving placebo). In preparation for this likelihood, during the approximate two years review of its BLA, Genzyme developed statistical strategies involving Bayesian analysis, with blinded statistical controls used to extend trends in serum creatinine levels for placebo-controlled patients. Upon approval, FDA accepted Genzyme’s proposed methodologies,and also mandated development of a Fabry disease patient registry to track patients over the years (decades) that will be required to confirm efficacy. FDA has stated that failure of the AGAL0008 trial would not cause revocation of approval of Fabrazyme. No product approved under an accelerated approval has yet to have its approval revoked, although some have accused companies of purposeful inattention to completion of mandated post-approval studies. Genzyme will conduct its required Phase IV studies as an open-label trial using historical data rather than placebo controls.

With its FDA approval including orphan drug designation, Fabrazyme received seven years of market exclusivity (i.e., FDA will not approve any product with substantially identical composition for substantially the same indications: for this period). Thus, Replagal from Transkaryotic Technologies will not receive approval for quite some time, and its U.S. development efforts have been halted.

Fabrazyme received European Union (EMEA) approval on August 3, 2001 for long-term enzyme replacement therapy in patients with a confirmed diagnosis of Fabry disease. Approval in Japan was granted in late Jan. 2004. Fabrazyme is also approved in Iceland, Norway, Czech Republic, New Zealand, Australia, and Israel

On Feb. 27, 2009, FDA reported finding significant deviations from cGMP) in the manufacture of Fabrazyme (and also Cerezyme and Myozyme) at its Allston, MA, plant, and issued a form FDA 483. The problems noted involved CMC aspects of manufacture, including animal virus contamination with Vesivirus 2117. manufacture of Fabrazyme and Cerezyme at the Allston facility was halted due to viral contaimation in June 2009. In Nov. 2009, the company announced that stainless steel fragments, rubber and fiber-like materials had been found in some of its products due to aging machinery in the fill/finish area. The FDA estimated the contamination only affected about 1% of Genzyme's products, and no adverse events had been reported to the government. This prompted the company to move some of those processes to its facility in Ireland and to outsource some to Hospira Inc.

On April 2010, Genzyme came under an FDA consent decreee allowing it to continue to operate. This included payment of an approximate $175 million fine. The consent decree essentially placed the plant under third-party control. Proposed terms of the decree would also require Genzyme to pay further fines and royalties if it failed to meet deadlines for bringing the plant into compliance with good manufacturing standards. The consent decree also required Genzyme to move fill and finish operations to a different facility. Genzyme would have to pay 18.5% of sales of the products if it failed to move the vial-filling and finishing process out of the plant by a set deadline. The FDA proposed to set deadlines by which time the company must complete that task, and also bring other aspects of the plant into manufacturing compliance. If the company did not meet broader remediation goals by 2011 and 2012, it would be required to pay $15,000 per violation for each day it remained out of compliance.

In Spring 2010, Genzyme had been trying to rebuild inventory of Cerezyme and Fabrazyme, and said it achieved its goal of building a small inventory buffer of Cerezyme in the first quarter. However, a citywide power outage affecting the water system at the plant further disrupted production. As a result, the company was able to supply 50% of the required amount of Cerezyme to meet demand for another two to three months. Previously the company had said it expected to be meeting 100 percent of demand by this time.

In Aug. 2010, Genzyme reported it would be ending rationing of Cerezyme for U.S. patients in Sept. 2010, with patients expected to resume their normal dosing schedules. However, Genzyme's problems continued.

In Jan. 2011, a Citizen's Petition was filed with FDA seeking Genzyme to distribute available Fabrazyme supplies under the Consent Decree in the U.S., rather than exporting most of it (with a severe shortage in the U.S., while availability of Replagal eased shortages in other countries). At the time, 62% of Fabrazyme supplies were being exported. [Note, in some respects, Genzyme may need to export much of its short supplies to prevent those in other countries, where Replagal is available, from switching, while Fabrazyme remains the only approved enzyme in the U.S.].

In Jan. 2011, Genzyme reported that manufacture of Fabrazyme had been moved to Framingham, but production levels remain low and supplies would continue to be short. Genzyme expected to fully meet demand after the site gains regulatory approval in the second half of 2011. At the time, Genzyme had nearly completed engineering runs; and process validation, which will produce material to be used in regulatory approval, were due to start that month. In addition to starting-up the Framingham plant, Genzyme is also working on fill/finish at Waterford, Ireland and transferring operations from Allston, MA, to a third-party manufacturer.

In Jan 2012, the EMA/EU approved Genzyme unit's new manufacturing plant in Framingham, MA, clearing a the way for EU marketing of Fabrazyme.

On Jan. 24, 2012, FDA approved Genzyme unit's new manufacturing plant in Framingham, MA, clearing a the way for U.S. marketing of Fabrazyme.

On March 1, 2012, Genzyme began shipping Fabrazyme® produced at its newly approved plant in Framingham. Globally, the complete return to normal supply levels of Fabrazyme was expected to begin in the second quarter and continue throughout the year as planned, as Genzyme works to obtain all global regulatory approvals throughout the year and to build inventory.

Tech. transfer: U.S. patents assigned to the Mount Sinai School of Medicine exclusively licensed by Genzyme include U.S. 5,356,804, “Cloning and expression of biologically active human alpha-galactosidase A,” Oct. 18, 1994, and 5,580,757, “Cloning and expression of biologically active alpha-galactosidase A as a fusion protein,” same inventors, Dec. 3, 1996. These describe Chinese hamster ovary (CHO) expression of recombinant alpha-galactosidase A as a fusion protein, which simplifies purification, with subsequent proper processing, e.g., glycosylation, phosphorylation, etc. and sorting of the expression product. Recombinant overexpression at high yield into the culture medium provided sufficient enzyme to enable the first testing and demonstration of the utility of alpha-galactosidase A for treatment of Fabry disease. This was also the first successful manufacture of a human lysosomal hydrolase enzyme retaining activity in humans. Section 6.2.6 of 5,356,804, “Production in Bioreactors,” describes production of alpha-Gal A using transformed DG5.3 cells in a hollow fiber bioreactor (charged with 108 cells), with the level of alpha-Gal A produced reaching about 10,000 U/ml per day and remaining constant for three months, along with reductions in serum concentration to below 1% without decreasing production. A single 90-day run of this bioreactor resulted in >350 mg of active recombinant alpha-Gal A secreted into the culture media

Patents related to use of recombinant alpha-galactosidase A for treatment of Fabry disease licensed from Research Corporation Technologies (RCT) include, "Recombinant alpha-galactosidase a therapy for Fabry disease," U.S. 5,658,567; 6,461,609; and 7,011,831. RCT licenses these and other glucosidase technologies on behalf of the Mount Sinai School of Medicine.

Genzyme was a licensee of Columbia University’s patents concerning cotransformation, a broadly-useful genetic engineering method allowing selection and isolation of transformed cells. The original patents and license expired in 2000, but Columbia received another patent in 2002 and ws again seeking royalties, which Genzyme and other companies challenged in court. Recently, the University decided not to continue to press infringement suits and seek royalties, but the patent office is reexaming the relevant patent, and the university could against pursue infringement and royalties at a later date. See the “Tech. transfer” section of the Recombinant DNA Products entry (#100) for further information.

In Aug. 2010, patent lawyer Allen Black Jr. filed a petition with the DHHS on behalf of three patients with Fabry disease, arguing that Genzyme has "harmed" patients by "severely rationing" Fabrazyme due to the manufacturing problems that had then plagued the firm's Allston plant over the past year. The petion seeks the National Institutes of Health (NIH) to exercise its "march-in" rights under the Bayh-Dole Act and forceably grant open nonexclusive license for the use of NIH patents related to Genzyme for Fabrazyme. The petition requested that NIH authorize responsible entities and individuals to use U.S. 5,356,804 and U.S. Patent No. 5,580,757 in order to manufacture, import, export or sell agalsidase beta. The development of Fabrazyme was partially funded by an NIH grant to Mt. Sinai Medical Center. March-in can be granted where the licensee cannot reasonably meet the public health needs. There a no precedents for such federal government revoking of patent licenses, and the petition will likely not be granted, particularly since Fabrazyme alread has or will likley have several competing products on the market well before any new licensee could bring a new product to the market.

In Dec. 2010, NIH/DHHS denied the "march-in" petition, explaining such a move would not address the supply problem in the short run, due to the length of time required to conduct the necessary clinical trials and receive FDA approval. NIH also cited the fact that, since no manufacturer has previously requested a license, an open license would not be granted based on the patient request (Shire Pharmaceuticals recently withdrew its application with the FDA for its Replagal while more clinical data is obtained).

Trials: The results of the pivotal Phase III trial of Fabrazyme, the largest ever conducted for Fabry disease -- were published in the July 5, 2001 New England Journal of Medicine. This randomized, double-blind, placebo-controlled , multinational, multicenter study enrolled 58 Fabry patients (56 males and two females) ages 16-61 years, none of whom had previously received enzyme replacement therapy. Patients received either 1.0 mg/kg of Fabrazyme or placebo every two weeks for five months (20 weeks) for a total of 11 infusions. The primary efficacy endpoint of GL-3 inclusions in renal interstitial capillary endothelial cells was assessed by light microscopy and was graded on an inclusion severity score ranging from 0 (normal or near normal) to 3 (severe inclusions).

In Sept. 2004, Genzyme completed its main Phase IV study of Fabrazyme and submitted an analysis of the results to FDA a month later. This was one of several requirements specified by the FDA for accelerated approval.

Medical: Fabrazyme is intended as a lifelong enzyme replacement therapy for Fabry disease. The recommended dosage is 1.0 mg/kg body weight infused every two weeks as an intravenous infusion. Even though a large percentage (~88%) of patients develop detectable alpha galactosidase antibodies, this does not cause any significant side effects (and may actually facilitate enzyme efficacy).

Tech. transfer: See the Disease section in the Galactosidase Products entry. Genzyme estimates a total of 5,000 Fabry patients worldwide.

Market: Total worldwide sales were $184 million in 2011 and $188 million in 2010. Total 2009 worldwide sales of Fabrazyme were $431 million (down from a projected $510 million due to manufacturing-related problems); $494 million in 2008; $424 million in 2007; $359 million in 2006; and $305 million in 2005, then with “More than 1,700 patients in over 40 countries are currently treated with Fabrazyme.” Total sales were $209.6 million in 2004, $81 million in 2003; $26.1 million in 2002, and $6 million in 2001. Total U.S. 2003 sales (launched in June) were $19.5 million.

Note, Fabrazyme recently experienced over 2 years of short supplies and supply disruptions, allowing competing products to gain market share. For example, in Jan. 2012, Replagal had 80% market share in Europe, up from 45% in 2008.

Fabrazyme is marketed by BioMarin Pharmaceutical Inc. with Genzyme, and product sales are not reflected in Genzyme’s revenue.

The 2007 Average Wholesale Price (AWP) is $5,040.00/35 mg vial, with a Direct Price (Manufacturer’s discount price) of $4,200.00; and $720/5 mg vial, with a Direct Price of $600/vial (Red Book, 2007). For comparison, the 2005 Average Wholesale Price (AWP) was $4,800.00/35 mg vial ($4,560.00 in 2004), and the Direct Cost was $4,000.00 ($3,800 in 2004).

Fabrazyme is commonly reported to cost U.S. patients ~$180,000/year. Fabrazyme has been marketed in Europe for several years where it has been reported to cost ~$165,000/year. The high cost of Fabrazyme is primarily due to the small patient population, Genzyme’s considerable investment in Fabrazyme development over a period of 16 years, and its high cost of manufacture.

     In April 2010, with Genzyme coming under an FDA consent decreee allowing it to continue to operate, Genzyme continued to provide Fabrazyme patients in the U.S. with 30% of their usual dosage through the 3rd quarter of 2010..