Trastuzumab - Herceptin; HER2 receptor monoclonal antibody, recombinant
Status - approved; marketed
Organizations involved:
Genentech, Inc. – Manuf.; R&D; USA Mark.
Pfizer – Manuf.
Hoffmann-La Roche Ltd. – Intl. Mark.; Parent
Emcure Pharmaceuticals Ltd. – Manuf.
Chugai Pharmaceutical Co. Ltd.. – Japan mark.
Protein Design Labs, Inc. – Tech.; Patent dispute
Celltech Biologics plc – Tech.
UCB Group S.A. – Parent
Chiron Corp. – Patent dispute
Novartis AG – Parent
Pfizer – Parent
University of Glasgow – Tech.
University of Pennsylvania – Tech.
Genentech/Roche - Patent dispute
GlaxoSmithKline Inc. – Patent dispute
Massachusetts Inst. of Technology (MIT) – R&D
University of California – R&D
City of Hope National Med. Center – Patent dispute
Columbia University – Tech.; Patent dispute
Amgen Inc. – Tech.
Cross ref.: See the entry for Monoclonal Antibodies, Recombinant. See the HER2 Receptor Mab-DM1, rDNA (trastuzumab-DM1) concerning this HER2 monoclonal antibody linked to a cytotoxin.
Description: Trastuzumab or Herceptin is a lyophilized (freeze-dried) formulation of a recombinant humanized (chimeric human-mouse) IgG1k (IgG1-kappa )monoclonal antibody glycoprotein produced by a transformed Chinese hamster ovary (CHO) cell line. This humanized antibody (huMAb 4D5-8) contains primarily human constant frame-work regions, with the complementarity-determining regions (CDR; functional immunogen-binding domains) from a murine antibody (4D5) with specificity for human HER-2. Trastuzumab has a molecular mass (weight) of 145,531.5 (~145.5 kDa)
Trastuzumab selectively binds with high affinity, e.g., in a cell-based assay (Kd = 5 nM), to the extracellular domain of human epidermal growth factor receptor-2 (HER-2) protein expressed by the HER2 or neu (c-erbB2) proto-oncogene. Overexpression of the HER2/neu oncogene results in increased expression of HER2 cell surface receptors, leading to increased cell multiplication and tumors. Herceptin binds to and blocks these cell surface receptor sites.
Herceptin is packaged as powder in vials for intravenous administration after reconstitution with of Bacteriostatic Water for Injection, USP. Each vial of Herceptin contains 440 mg trastuzumab, 9.9 mg L-histidine HCl, 6.4 mg L-histidine, 400 mg alpha-trehalose dihydrate, and 1.8 mg polysorbate 20 USP (Tween 20) under vacuum. Herceptin (powder vials) contains no preservatives. Each carton contains one vial of Herceptin and one 30 mL vial of Bacteriostatic Water for Injection, USP preserved with 1.1% benzyl alcohol for reconstitution. [Note, diluent manufactured by Roche for its European and international markets does not contain benzyl alcohol]. This yields 21 mL of a multi-dose solution containing 21 mg/mL trastuzumab, at a pH of about 6. The dating period is 30 months from the date of manufacture when stored at 2-8˚C (refrigerated). The date of manufacture is the date of final sterile filtration of the final formulated product. The dating period for the diluent is 24 months. The expiration date for the packaged product, Herceptin plus diluent, is based on the earliest expiration date of either component. Trastuzumab is usable for 28 days after reconstitution when refrigerated. Bulk antibody may be stored frozen for up to 24 months at -20˚C (in freezer).
Finished product, Herceptin, manufactured by Roche for its European and international markets has a somewhat different formulation. Vials contain trastuzumab sufficient to provide 150 mg, and also contain 3.36 mg l-histidine HCl; 2.15 mg L-histidine; 135.2 mg trehalose, dihydrate; and 0.6 mg polysorbate 20, with Sterile Water for Injection without preservative as the diluent. The vial is reconstituted with 7.6 mL diluent to yield a single dose of 21 mg/mL trastuzumab at ph ~6.0. This single-dose vial 150 mg product was used in clinical trials outside the U.S.
Nomenclature: HER2 Receptor Mab, rDNA [BIO]; Trastuzumab [FDA USAN]; HER2 receptor monoclonal antibody, recombinant [SY]; c-erbB2 monoclonal antibody [SY]; MDX-210 [SY]; 520C9x22 [SY]; Metavert [SY]; epidermal growth factor receptor-2 protein (HER2) monoclonal antibody [SY]; NDC 50242-0134-60. [NDC]
Biological.: The HER2 (or c-erbB2 or HER-2) proto-oncogene encodes a cellular transmembrane receptor protein of 185 kDa molecular weight, which is structurally related to the human eºpidermal growth factor (EGF) receptor. The presence of multiple copies of the HER2 gene in a cell results in over-expression of HER2 protein. This is observed in 25%-30% of primary breast cancer patients. HER2 protein overexpression can be determined using immunohistochemistry-based assessment of fixed tumor blocks (from biopsy), and other tests under development. HER2-positive breast cancer patients generally experience rapid tumor growth, are resistance to conventional therapy, and have decreased survival.
Trastuzumab binding to HER2 mediates antibody-dependent cellular cytotoxicity (ADCC), a type of cellular immunity, preferentially affecting cancer cells overexpressing HER-2. Trastuzumab inhibits HER2 cleavage to the active, truncated HER-2 protein, which may also contribute to antitumor activity. Trastuzumab has been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumor cells that overexpress HER2. In vitro, Herceptin-mediated ADCC is preferentially directed to HER2 overexpressing tumor cells, compared with tumor cells not overexpressing HER2.
Companies.: The HER2/neu gene was first identified in 1979 by Weinberg, et al., Massachusetts Institute of Technology (MIT). It was first isolated from neurological tumors in rats (the source for ‘neu’). A second epidermal growth receptor was (re)discovered and the protein/receptor expressed by the HER2 gene was identified in 1983 by Ulrich, et al., Genentech, Inc. The gene was cloned by Genentech starting with the protein sequence. After recognizing that neu and HER2 were identical, the names were combined, e.g., ‘HER2/neu’ proto-oncogene.
HER2/neu was identified in and associated with breast tumors in 1985. Dr. Slamon, et al., University of California (Los Angeles, CA), performed studies showing the prognostic utility of HER2/neu diagnostics for predicting breast cancer aggressiveness and recurrence. Genentech subsequently developed a hybridoma cell line to produce HER2/neu monoclonal antibodies. These were found to have potent activity against mammary tumors in vitro and in vivo. Commercial development of Herceptin by Genentech began around 1990. [Note, a book (HER-2: The Making of Herceptin, a Revolutionary Treatment for Breast Cancer, Random House, New York, 1998) has been written about the development of Herceptin, but was not examined].
Herceptin was developed and is manufactured by (i.e., approval granted to) Genentech, Inc., CBER/FDA est. no. 1048. Herceptin is marketed in the U.S. by Genentech, now a part of Roche.
Hoffmann-La Roche Ltd. (majority owner of Genentech) holds exclusive marketing rights outside of the U.S. for Herceptin, except for Japan where the product is exclusively marketed by Chugai Pharmaceutical Co. Ltd.. Roche’s licensing agreement provided for Roche to pay a $40 million up-front fee (3rd quarter 1998), cash milestones tied to product development activities, sharing of global development costs, and payment of royalties on product sales. As part of Roche’s broad licensing agreement with Genentech (amended in 1999 and extended to 2015), Genentech sells finished product to Roche for international marketing at cost plus 20%. Roche pays Genentech a royalty of 12.5% on the first $100 million total sales/year and 15% after that, until either the expiration of Genentech’s patents in that country or 25 years from the first launch of the product.
Herceptin was originally manufactured at Genentech’s S. San Francisco facilities, with culture performed in building 3A/3B. Genentech finished construction of a new $250 million manufacturing facility in Vacaville, CA, in Oct. 1998. At 310,000 square foot, this was then “the world’s largest biotech manufacturing facility for the large-scale production of pharmaceutical proteins.” Herceptin was the first product manufactured in this facility. Genentech received FDA approval for Herceptin manufacture at these facilities in April 2000.
During late-stage development for Roche’s European markets, Genentech changed the manufacturing process to remove benzyl alcohol from the diluent for final reconstituted product to assure compliance with the European Pharmacopeia, changed the manufacturing procedure, changed the fill size of the finished product, and transferred finished product manufacturing for international markets to Hoffmann-La Roche facilities. Starting in 2003, Hoffmann-La Roche’s facility in Penzberg, Germany became Roche’s primary site for manufacture of Herceptin for sales outside the U.S., using bulk product from Genentech’s Vacaville facilities. Genentech continues to receive royalties on Roche’s international sales of Herceptin.
In June 2004, Hoffmann-La Roche Ltd. announced its would spend ~$640 million for construction of two new facilities in Basel, Switzerland, and Penzberg, Germany, for the manufacture of Herceptin and Avastin.
In Sept. 2004, Genentech entered into an agreement for manufacture Herceptin with Wyeth Pharmaceuticals, a division of Wyeth (now Pfizer), for manufacture of Herceptin bulk drug substance for Genentech at its production facility in Andover, MA. Genentech anticipated that Wyeth will start production of Herceptin in 2006, with FDA approval expected in late 2006. Once the plant is online, the majority of Genentech’s supply of Herceptin will come from this facility.
In May 2007, Roche inaugurated its new manufacturing facility in Basel, Switzerland; and in July 2007, inaugurated a new manufacturing facility in Penzberg, Germany. Both will eventually contribute to manufacture of Herceptin.
In March 2012, Roche concluded an agreement with Emcure Pharmaceuticals (India) for manufacture of Herceptin in India for the Indian market. This is likely an effort by Roche to deflect Indian concerns about it having a monopoly and Herceptin prices being high (relatively) in India.
Manufacture: The source murine monoclonal antibody from which trastuzumab was derived was originally obtained from BALB/c mice immunized with cells expressing cell surface Her-2 receptors and partially purified membranes containing p185 Her-2, according to standard hybridoma techniques. Hybridoma cell lines were generated and screened by an ELISA utilizing immobilized p185-Her-2 protein, an assay detecting Her-2 mediated growth inhibition of SK-BR-3 cells, and/or a nude mice breast cancer xenograft model. This resulted in the selection of murine monoclonal antibody 4D5 (muMAB 4D5) and its hybridoma cell line. muMAB 4D5 was humanized after determination of the primary sequence of its VH+L chain regions. The resulting constructs were modified to express the human Fc gamma-1 isotype to maximize cell-dependent cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) ADCC responses. Human monoclonal antibody 4D5-8 (huMAb 4D5-8), resulting from recombinant humanization and optimization, binds to the extracellular domain of Her-2 about 3-fold more tightly than muMAB 4D5.
Traztuzumab (huMAb 4D5-8) is expressed in recombinant Chinese hamster ovary (CHO) cells using a serum-free culture medium. Manufacturing starts with thawing and expansion of cells from the Master Cell Bank (MCB) or the Working Cell Bank (WCB), derived from the MCB. Cells are expanded using a seed train and sequential transfer through fermentors ranging from 80 up to 12,000 L. The antibiotic gentamicin is used in the culture media, but it is not detectable in the final product. After harvesting, undesired protein and endotoxin contaminants are removed using Protein A affinity chromatography. Cation ion exchange chromatography is used to remove antibody aggregates and fragments and CHO cell impurities. Anion ion exchange chromatography is used to remove DNA, endotoxin, and retroviruses (if present). Hydrophobic interaction chromatography is used to further remove antibody aggregates, fragments and CHO proteins. Virus removal relies primarily on the chromatography steps, and to a lesser extent on incubation at low/acidic pH (<3.7).
Manufacture involves progressive culture and transfer of contents to larger culture vessels. Defrosted cells from the MCB or WCB are cultured in a 3 L flask. When the cells fill that, they are transferred to a 20-liter steel tank. When that is filled, they are moved into vessels of 80 liters, 400 liters, 2,000 liters and finally 12,000 liters (about 3,200 gallons).
Trastuzumab bulk drug substance (Bulk for Storage) is aseptically filled into 120 L stainless steel tanks prior to filtration and stored frozen at ≤-20˚C. manufacture of the final product begins with thawing of bulk material, pooling of multiple bulk lots (up to 3, as approved in the EU for manufacture by Roche), followed by aseptic filtration, filling, lyophilization, sealing of vials, labeling and packaging. Testing for purity and molecular consistency is performed on the Bulk for Storage. Multiple complementary assays are used to determine the degradation pattern of trastuzumab, which is complex and not addressed by a single assay.
Trastuzumab used in Phase I and II trials was manufactured using a different process than that scaled-up and used to manufactured product for Phase III trials and commercialization. Drug substances manufactured by both processes were equivalent, except for the absence of a polymorphism at heavy chain residue 376. [This manufacturing information is primarily from the European Product Assessment Report (EPAR)].
Originally manufactured for clinical trials by Genentech's South San Francisco, CA, facilities, commercial manufacture takes place at Genentech's Vacaville, CA, plant, which has (7/2007) capacity of 144,000 liters (about 38,000 gallons), using large steel tanks, and is also used for manufacture of Avastin, Rituxan, Herceptin and Xolair. However, when initially transferring manufacture of Herceptin to Vacaville, the transformed CHO cells would not grow. It was found that tungsten leaching from bearing seals was toxic to the cells. This has surely been resolved.
FDA class: Biologic BLA
CBER to CDER: Among the products transferred within FDA on June 30, 2003
Approvals: Date = 19980925; first approval, BLA (no. 98-0369); orphan designation (granted 10/5/1993; expires 9/2005); Indication = second-line monotherapy breast cancer treatment
Date = 20000426; BLA supplement; Indication = for manufacture at Genentech’s new Vacaville, CA, facility
Date = 20000209; BLA supplement; Indication = changes in product insert/labeling, container, and package to clarify the instructions for reconstitution
Date = 20011200; BLA supplement; Indication = inclusion in the product label of data that showed an improved median overall survival for women with HER2-positive metastatic breast cancer treated initially with Herceptin and chemotherapy, compared to chemotherapy alone (median 25.1 months compared to 20.3 months).
Date = 20020829; BLA supplement; Indication = include information the labeling of the product insert about a breast cancer gene-detection test method, FISH (fluorescence in situ hybridization), trade name PathVysion
Date = 20061116; BLA supplement; Indication = use in combination with other cancer drugs for the treatment of early-stage HER2-positive breast cancer after surgery (lumpectomy or mastectomy) as part of a treatment combination regimen containing doxorubicin, cyclophosphamide, and paclitaxel (commonly referred to as adjuvant therapy)
Date = 20080118; BLA supplement; Indication = approval for use as a single agent for the adjuvant treatment of HER2-overexpressing node-negative (ER/PR negative or with one highrisk feature) or node-positive breast cancer, following multi-modality anthracycline based therapy
Date = 20102020; BLA supplement; Indication = combination with chemotherapy (cisplatin plus either capecitabine or 5-fluorouracil [5-FU]) for HER2-positive metastatic (cancer that has spread) cancer of the stomach or gastroesophageal junction, in men and women who have not received prior medicines for their metastatic disease.
Date = 20110614; BLA supplement; Indication = approval of Inform Dual ISH, a new genetic test from Ventana Medical Systems, that will help health care professionals determine if women with breast cancer are HER2-positive and, therefore, candidates for Herceptin. The test test involves counting the number of copies of HER2 genes on chromosome 17 in a small sample of the breast tumor. The sample is stained with chemicals that cause copies of HER2 genes and chromosome 17 to change color. Copies of the HER2 gene appear black and copies of chromosome 17 appear red. These color changes can be seen under a standard microscope (similar to HER2 amplification measurements that have traditionally only been available using fluorescence microscopes).
Indications: [full text of the "INDICATIONS AND USAGE” section from recent product insert/labeling, 10/27/2010]:
1.1 Adjuvant Breast Cancer
Herceptin is indicated for adjuvant treatment of HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature [see Clinical Studies (14.1)]) breast cancer
• as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
• with docetaxel and carboplatin
• as a single agent following multi-modality anthracycline based therapy.
1.2 Metastatic Breast Cancer
Herceptin is indicated:
• In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer
• As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease.
1.3 Metastatic Gastric Cancer
Herceptin is indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, who have not received prior treatment for metastatic disease.
Status: The BLA was filed on May 4, 1998, was granted fast track and priority review designations, and was approved on September 25, 1998; a review time of 4.7 months (0.39 year). Herceptin was launched on October 5, 1998, 10 days after approval. Herceptin received its first approval and was first marketed in the U.S.
Herceptin is exempt from FDA CBER lot release requirements.
With its Aug. 2002 sBLA, Herceptin was approved for use with FISH (fluorescence in situ hybridization), marketed as PathVysion by Vysis, a subsidiary of Abbott Labs. This assays is used to detect HER2 gene amplification in a patient’s breast cancer cells to determine whether the patient is a candidate for Herceptin treatment. In early 2005, FDA granted a PMA to InSite Her-2/neu Kit from BioGenex Laboratories Inc. as an in vitro diagnostic kit to identify breast cancer patients eligible for Herceptin treatment for use with the BioGenex i6000 Automated Staining System and the Optimax Plus Consolidated Staining System.
Roche received European Union (EU) approval for Herceptin monotherapy for advanced/metastatic cancer on Aug. 28, 2000. Herceptin is available in most other countries worldwide. The Roche/European 150 mg single-dose vial formulation of Herceptin was used by Roche in its trials outside the U.S. Roche’s original MAA filing for EU approval was for the 440 mg multi-dose vial Genentech formulation, with its diluent containing benzyl alcohol as an antimicrobial preservative. Since this use of benzyl alcohol was not in compliance with the European Pharmacopeia, Roche switched to filing for approval of the single-dose formulation lacking benzyl alcohol. In June 2004, Roche received approval for Herceptin in combination with Taxotere (docetaxel) as a first-line therapy in HER2-positive metastatic chemotherapy-naive breast cancer patients.
In late Aug. 2005, Genentech issued a “Dear Healthcare Professional” reporting data on cardiotoxicity reported in recent trials. The Phase III NSABP B-31 study in 2,043 patients and the NCCTG trial had shown increases in the three-year cumulative incidence of NYHA class III-IV congestive heart failure (CHF) and cardiac death among recipients of Herceptin plus chemotherapy (4.1%, compared with 0.8% for chemotherapy alone). Herceptin’s label already had a cardiotoxicity warning that included class III-IV CHF.
On Oct. 4, 2005, FDA approved a Pre-Market Approval (PMA) application from BioGenex Laboratories Inc. (San Ramon, CA) for the InSite HER-2/neu (CB11) Monoclonal Antibody test to identify breast cancer patients eligible for treatment with Herceptin. The immunoassay is used to identify women with breat tumors overexpressing HER-2/neu protein.
On Feb. 15, 2006, Genentech filed a BLA supplement seeking approval of Herceptin for treatment of early-stage, HER2-positive breast cancer (adjuvant therapy) with Priority Review (6 month review target). On Aug. 11, 2006, after Genentech submitted additional analyses, considered a ‘major amendment,’ FDA extended the review period up to an additional 90 days beyond the August 17, 2006 action date.
On Feb. 17, 2006, Hoffmann-La Roche filed a supplemental application in the European Union with Priority Review, and on May 24, 2006, received approval of Herceptin for treatment of early-stage, HER2-positive breast cancer (adjuvant therapy) following surgery and standard chemotherapy (adjuvant therapy).
In Oct. 2006, Roche filed for supplemental European Union (EU) approval of Herceptin for certain advanced breast cancer indications:, based on a study that showed that “the addition of Herceptin to hormonal therapy doubles the median progression-free survival.”
On Nov. 16, 2006, Herceptin received FDA supplemental approval as part of a treatment regimen containing doxorubicin, cyclophosphamide, and paclitaxel for the adjuvant treatment of HER2-positive node-positive breast cancer. Adjuvant therapy is given to women with early-stage (localized) breast cancer who have had initial treatment surgery with or without radiation therapy with the goal of reducing the risk of cancer recurrence and/or the occurrence of metastatic disease. This was a major milestone for Herceptin.
On Jan. 2007, Ventana Medical Systems, Inc. received FDA approval for the use of its PATHWAY HER-2/neu (4B5) Rabbit Monoclonal Antibody as an aid in the assessment of breast cancer patients for whom Herceptin treatment is considered. This antibody has also been approved for use on the Ventana Image Analysis System (VIAS).
On May 3, 2007, Herceptin received supplemental approval in the European Union (EU) for use in combination with an aromatase inhibitor for the treatment of postmenopausal patients with HER2 and hormone receptor co-positive metastatic breast cancer. . Comprehensive reviews have suggested that about two thirds of breast tumurs are hormone receptor positive. Of these, a significant percentage (up to 25%) are also HER2-positive.
On Jan. 16, 2008, Aperio Technologies, Inc. received a PMA from FDA to market the manual reading of digital HER2 slides from a computer monitor using its patented ScanScope digital slide scanning system. This system is intended for use as an accessory to the Dako HercepTest to aid pathologists in the detection and semi-quantitative measurement of HER2 protein expression to assess breast cancer patients for whom Herceptin treatment is being considered.
On Jan 29, 2010, the European Union (EU) approved Herceptin in combination with chemotherapy for use in patients with HER2-positive metastatic stomach (gastric) cancer.
On April 22, 2010, Genentech/Roche filed a sBLA fro approval of Herceptin plus chemotherapy for treatment of advanced, HER2-positive adenocarcinoma of the stomach, including gastroesophageal junction cancer. The application was based on positive results from a Phase III study, known as ToGA, which showed that advanced adenocarcinoma patients who received Herceptin plus chemotherapy lived longer compared to people who received chemotherapy alone.
Tech. transfer: Genentech has received patents covering aspects of recombinant her2 receptor monoclonal antibodies and their uses including U.S. 6,399,063, "6,399,063, "Monoclonal antibodies directed to the HER2 receptor," expired Jan 12, 2008.
. Immunoglobulin versions similar to Herceptin were claimed in 4,816,567. U.S. 6,267,958 and related patents cover stable lyophilized formulations, U.S. 6,627,196, "Dosages for treatment with anti-ErbB2 antibodies," claims dosages for treatment. U.S.7,038,017 claims antibody purification methods.
Genentech has reported relevant patents include 6,339,142, "Protein purification," expriing May 3, 2019; 7,074,404, "Protein purification," expiring; and 6,407,213, "Method for making humanized antibodies," expiring June 18, 2019. No EU or PCT equivalent filings were identified.
Antibody humanization design technology for Herceptin was nonexclusively licensed by Genentech from Protein Design Labs. (PDL), now PDL Biopharma, on Nov. 8, 1998. For a short period, this seemed to settle a long-running patent dispute over each other’s antibody humanization patents. Genentech paid PDL a $6 million fee for the right to license the technology for use with up to six antibodies. Upon licensing the technology specifically for Herceptin, Genentech paid the $1 million fee and pays unspecified royalties to PDL on product sales. Based on a Jan. 2003 CIBC World Markets Report on PDL, PDL receives royalties of 2.85% of total sales. See the Tech. transfer (rDNA) section of the Monoclonal Antibodies entry (#300) for further information about PDL, recombinant monoclonal antibody technologies, and the complex patent, licensing, cross-licensing and patent disputes concerning recombinant chimeric/humanized monoclonal antibodies. Currently, Genentech, with its New Cabilly patent (6,113,415) appears to hold a dominant position with U.S. patents covering recombinant expression of monoclonal antibodies (co-expression of heavy and light chains), with this patent including claims from a rejected Celltech Group patent, and Genentech and Celltech having cross-licensed their antibody humanization patents.
Celltech Biologics plc, now Celltech Group plc, which merged into UCB Group S.A. in May 2004 , receives unspecified royalties from Genentech on sales of Herceptin from licensing of its patents for use of the GS mammalian gene expression system. Related patents include U.S. 5,770,359 and 5,747,308. This technology involves use of glutamine synthetase (GS) as a dominant selectable marker for use in co-amplification of non-selected genes and in transforming host cell lines to glutamine independence. The GS gene is used in recombinant vectors as a marker along with another exogenous gene(s), with only successfully transformed cells capable of producing their own GS and surviving in glutamine-deficient culture media. The technology is coassigned to the University of Glasgow (which presumably receives a share of royalties).
In June 2000, Chiron Corp. filed a patent infringement suit against Genentech in federal court alleging that the manufacture and sale of Herceptin infringes Chiron’s U.S. patent 6,054,561, granted April 25, 2000. This patent concerns monoclonal antibodies that bind selectively to human breast cancer cells, specifically, the c-erbB-2 (HER-2) antigen, including antigen-binding sites of immunoglobulins having affinity for tumor antigens including c-erbB-2. The first/exemplary claim concerns a monoclonal antibody (hybridoma, ATCC acc. no. No. HB 8484) that binds to a human breast cancer antigen (c-erbB-2). The patent is the latest in a series of patents first issued in 1988 (priority filing in 1984) to Cetus Corp., which was later acquired by Chiron. Some critics labeled the recent U.S. patent a “submarine patent,” suggesting that it was purposely not disclosed and its issuance delayed until after the launch of Herceptin.
The U.S. Patent & Trademark Office (PTO) declared an interference between Chiron’s 6,054,561 patent and a patent application exclusively licensed by Genentech from the University of Pennsylvania relating to anti-HER2 antibodies. The PTO determined Chiron may not have been the first to invent this technology. In Sept. 2002, a U.S. District Court jury ruled that all claims of 6,054,561 are invalid. Chiron filed other motions seeking to declare the Univ. of Pennsylvania patent invalid, an issue deferred until after the jury trial, and appealed the jury trial decision. In April 2004, the U.S. Court of Appeals for the Federal Circuit (CAFC) upheld the 2002 ruling by the District Court that all claims of Chiron’s 6,054,561 were invalid. In late 2005, Chiron Corp. merged into Novartis AG.
Chiron has separately filed a suit in U.S. District Court against Genentech alleging infringement of its U.S. patent 4,753,894.
In May 1999, GlaxoSmithKline Inc. (GSK) filed a suit alleging that Herceptin (and also Rituxan from Genentech) infringes its U.S. patents 5,545,403 and 5,545,405 concerning CHO expression of recombinant monoclonal antibody glycoproteins. Genentech prevailed in this dispute in May 2001.
In May 2002, a German District Court ruled that Herceptin did not infringe European patent 0513114 (similar to U.S. 6,054,561) assigned to Chiron Corp.
In Sept. 2000, GlaxoSmithKline Inc. (GSK) filed suit alleging that Herceptin (and also Rituxan) infringes its U.S. 5,633,162 concerning methods for culturing Chinese hamster ovary (CHO) cells. With nothing disclosed by either company about the resolution of this dispute (which would not be the case, if Genentech lost), this dispute apparently was resolved in favor of Genentech, settled out-of-court or the dispute is continuing.
Genentech and the City of Hope National Medical Center are involved in an arbitration proceeding regarding a contract dispute related to recombinant monoclonal antibody patents used in the production of Herceptin.
Genentech was a licensee of Columbia University’s patents concerning cotransformation, a broadly-useful genetic engineering method allowing selection and isolation of transformed cells. These patents and license expired in 2000, but Columbia received another patent in 2002 and was seeking further royalties, which Genentech and other companies are challenging 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 Jan. 2006, Genentech and Amgen cross-licensed recombinant monoclonal antibody technologies. The technology Genentech received from Amgen has not been disclosed, while Amgen received rights to Genentech’s New Cabilly portfolio (see the Monoclonal Antibodies entry for further information).
In Aug. 2010, Genentech, now fully part of Hoffmnn-La Roche, informed PDL BioPharma Inc. it believes that four of its marketed products, including Herceptin, are not covered by patents that had been licensed by Genentech from PDL. Genentech plans to continue to pay patent royalties (while presumably trying to renegotiate of get out of its prior licensing agreement). PDL will surely appeal any actions by Genentech/Roche, since is receives 30% of its revenue from these licenses.
In Sept. 2010, GlaxoSmithKline filed a patent infringment suit alleging that manufacture of Herceptin infinges antibody purification patents; and Genentech/Roche countersued. The patents at issue are "Antibody purification," U.S. RE41,595 and RE41,555. These appear to rather broadly cover aspects of hydrophobic interaction chromatography (HIC) purification of monoclonal antibodies the integration of HIC into a combination chromatographic protocol for the purification of IgG antibody molecules.
Trials: Prior to Herceptin, metastatic breast cancer patients with HER2-expressing tumors typically had a life expectancy of 10-12 months from diagnosis, compared to a life expectancy of about 6-7 years for women not overexpressing HER2. In a Phase III trial in 469 women with HER2-expressing metastatic breast cancer, Herceptin-receiving patients had an average of 7.6 months without disease progression compared to 4.6 months in those receiving chemotherapy alone, a 65% improvement. Although this is a significant increase in survival, based on this data (which does not account for incremental improvements, e.g., in combination therapies, since approval), the typical Herceptin-receiving patient would still likely die within a year of starting treatment.
In a retrospective analysis of patients enrolled in Genentech’s pivotal trials, those selected using FISH testing and treated with Herceptin in addition to standard chemotherapy had a 30% decrease in the risk of death and a 56% decrease in the risk of disease progression, compared to patients treated with chemotherapy alone (demonstrating the importance of identifying appropriate candidates for Herceptin therapy).
In Jan 2004, disappointing results were reported from a trial of Herceptin in combination with two chemotherapy drugs for treatment of lung cancer, with addition of Herceptin providing no significant additional improvement in survival, despite Herceptin showing better efficacy in vitro against lung vs. breast tumors. A few (5 out of ~100 in the trial) with extremely high HER2 levels responded, but this was too small a percentage to pursue further development for lung cancer.
In the Aug. 10, 2006, issue of the Journal of Clinical Oncology, university investigators reported that Herceptin used in combination with certain cancer chemotherapies effectively treated breast cancer tumors that produce low or undetectable amounts of HER-2, but overexpress the growth factor heregulin (HRG), an activator of the HER-2 cancer oncoprotein. Until this study, it was presumed that Herceptin combined was effective only in HER-2--positive or HER-2--overexpressing breast cancer. Laboratory studies by the same researchers found continuous production of HRG in breast cancer cells that do not overexpress HER-2 causes the HER-2 receptor to be continuously activated and, therefore, constantly signals breast cancer cells to grow and proliferate.
In Sept. 2005, positive results were reported from the BCIRG study of adjuvant treatment with Herceptin. The study evaluated 3,222 early stage breast cancer patients randomized to anthracycline-based chemotherapy (control arm), anthracycline-based chemotherapy followed by Taxotere and Herceptin (AC-H arm), or Taxotere/carboplatin plus Herceptin (TCH). The risk of disease recurrence was lowered by 51% and 39%, respectively, for patients in the AC-H arm and TCH arm (both statistically significant). The 51% reduction was similar to results in adjuvant HER2+ breast cancer. The anthracycline-sparing Herceptin regimen had minimal cardiotoxicity, but efficacy may not be enough to justify using this regimen instead of AC-based chemotherapy plus Herceptin. These results were not expected to significantly change current use of Herceptin.
The BLA and MAA filings for early-stage, HER2-positive breast cancer were based on the combined analysis of two Phase III trials. Interim results from this joint interim analysis were published in the Oct. 19, 2005 issue of the New England Journal of Medicine. Final results were reported in the Jan. 2007 issue of the Lancet. This involved joint analysis of more than 3,500 patients enrolled in two Phase III clinical trials. These randomized, controlled trials studied four cycles of doxorubicin (adriamycin) and cyclophosphamide followed by paclitaxel, either every three weeks or weekly for 12 weeks, compared with the same regimen plus 52 weeks of Herceptin beginning with the first dose of paclitaxel. A total of 1,703 women received Herceptin and 1,698 received placebo for one year after surgery and chemotherapy. The addition of Herceptin to standard adjuvant therapy significantly reduced the risk of breast cancer recurrence, the primary endpoint of the studies, by 52% (or a hazard ratio of 0.48) in women with HER2-positive breast cancer, compared to those patients who received standard adjuvant therapy alone. After three-and-a-half years in the study, 87% of women treated with Herceptin plus chemotherapy were disease free, compared to 71% treated with chemotherapy alone. A survival analysis conducted after patients had been followed for a median of 24 months showed a 33% reduction in the risk of death (based on a hazard ratio of 0.67), equivalent to a 49% improvement in overall survival. There were some serious side effects reported, e.g., cardiac damage, but results were generally positive. An associated Lancet editorial noted that the price of treating patients with Herceptin falls within usually acceptable levels of cost effectiveness. This trial showed the largest improvement in outcome for any group of women with breast cancer in 25 years.
In Jan. 2007, the Pharmaceutical Management Agency (PHARMAC), New Zealand, announced its financial support for an international trial to examine whether nine weeks or 12 months is the better treatment duration for Herceptin. Unlike most other governments and payers, PHARMAC does not want to commit to the long-term, 12-month treatment regimen, as promoted by Roche and approved in most countries. PHARMAC originally decided not to fund 12 months of Herceptin use for early stage breast cancer in July 2006.
In Sept. 2007, Roche reported results from the GeparQuattro study in 1,510 patients, 453 of whom had HER2-positive disease. Herceptin in combination with standard chemotherapy prior to breast cancer surgery completely eradicated HER2-positive tumours in 45.5% of women in the early stages of the disease. The results are consistent with other Herceptin neoadjuvant studies, such as NOAH (NeOAdjuvant Herceptin, which included 228 evaluable HER2-positive patients) and TECHNO (Taxol-Epirubicin-Cyclophosphamid-Herceptin Neoadjuvant). Roche stated that “this is an impressive finding since the proportion of women achieving total tumour eradication with standard chemotherapy alone is less than 30%” and “and raise[s] the prospect of a cure.”
In Sept. 2007, results were reported from the NeOAdjuvant Herceptin (NOAH), a Phase III trial assessing neoadjuvant Herceptin in combination with chemotherapy in patients with inflammatory HER2-positive breast cancer. Addition of Herceptin to chemotherapy prior to breast cancer surgery (neoadjuvant therapy) completely eradicated tumors in nearly three times as many women with inflammatory HER2-positive breast cancer compared to chemotherapy alone (55% vs. 19%, p=0.004). The combination led to complete disappearance of the tumors from both the breast and the lymph nodes (a total pathological complete response to treatment) in 48% of patients, compared to only 13% of those who received chemotherapy alone (p=0.002). Inflammatory breast cancer is a rare, but highly aggressive form of the disease - the tumors spread quickly, often leading to the need for total mastectomies, and it has a worse outlook than other breast cancers. These results are particularly significant as treatment with Herceptin in this setting may lead to more breast conserving surgery and improved survival.
In March 2009, Roche reported results from a major international study showed that adding Herceptin (trastuzumab) to standard chemotherapy significantly prolongs the lives of patients with HER2-positive stomach (gastric) cancer. The results were from ToGA, a large international Phase III trial investigating the benefit of Herceptin as the first therapy for patients with advanced and inoperable stomach cancer (first line). i Approximately 22% of stomach tumours overexpress HER2.
Medical: The recommended dose of Herceptin is 4 mg/kg as an initial loading dose, followed by weekly administration of 2 mg/kg, by intravenous infusion. Women with breast tumors overexpressing HER2 and treated with Herceptin still have a relatively poor prognosis, e.g., their survival may be significantly extended, but likely <1 year.
Combining Herceptin with conventional chemotherapy has been shown to result in breast tumor shrinkage of 50% or more in 49% of patients, compared to 32% of patients who received chemotherapy alone. Results are often particularly striking when used in combination with paclitaxel, a form of taxol.
Cardiomyopathy (heart failure or weak heart muscle) is a recognized adverse effect of Herceptin. Patients must be screened for heart function before beginning and during Herceptin treatment. sLess common but serious side effects include infusion reactions (chills, fever, shortness of breath) that rarely are accompanied by lung problems, low white blood counts, and low red blood cell counts.
Disease: According to the American Cancer Society, about 1.6 million women in the U.S. have breast cancer, with 180,000 new cases are diagnosed each year. Metastatic breast cancer affects only about 10% of women diagnosed with breast cancer. Genentech reports that 25-30% of the estimated 164,000 women in the U.S. with metastatic breast cancer are candidates for Herceptin, i.e, their tumors overexpress HER2.
Market: Total 2012 sales reported by Roche were about CHF 5.9 billion ($6.4 billion). Total 2008 worldwide Herceptin sales ( by Roche and Genentech) were 5.09 billion Swiss francs ($4.59 billion); and $3.255 billion in 2007. Total 2006 worldwide Herceptin sales ( by Roche and Genentech) were CHF 3.927 billion (~$3.225 billion, at 7/6/2007 exchange rate), up 81% from 2005 (~$1.782 billion, based on 2007 sales at 7/07 exchange rates). Total worldwide sales have been reported to be $1.279 billion in 2004, and $972 million in 2003.
Total Herceptin sales (U.S.) by Genentech were $1.287 billion in 2007, $1.234 billion in 2006, $747.2 million in 2005, $483.2 million in 2004, $424.8 million in 2003, $385.2 million in 2002, $346.7 million in 2001; $276.0 million in 2000; $188.4 million in 1999; and $30.5 million in 1998. Without actual reported sales, it can be presumed that Roche’s sales, primarily in Europe, are roughly comparable to Genentech’s U.S. sales.
The very significant increase in sales in 2006 can be largely attributed to increased use for adjuvant breast cancer treatment (including off-label use prior to approvals). The value of the adjuvant market is higher than that of the prior metastatic market, because the patient pool is larger and the duration of therapy is longer.
In June 2006, with positive trials’ results for adjuvant early treatment, a Decision Resources, Inc. study projected that sales of Herceptin by Genentech, Roche and Chugai will nearly triple to more than $3.3 billion in 2015.
The 2007 Average Wholesale Price (AWP) is $2,928.89/440 mg vial (Red Book, 2007), down from $3,047.21/440 mg vial in 2005.
An average course for treatment of metastatic breast cancer involves 24 weekly infusions. For a 100 kg patient, a course of treatment would involve injection of ~3,400 mg [400 mg loading dose + (200 mg/week x 15 weeks)] trastuzumab, requiring 9 vials costing >$26,000 at the AWP.
In Nov. 2006, Genentech reported that average cost per course of one-year adjuvant therapy is $38,007. In the metastatic setting, the cost is ~$23,000 for 7.2 months of treatment (average course duration). For patients that are uninsured and qualified, Genentech provides Herceptin free. For patients who need assistance with co-pays, the company can put them in touch with several independent public charities that provide co-pay assistance.
As with many other biopharmaceuticals and Genentech products, costs have been a recurring issue. With Herceptin, Genentech has noted that Herceptin use should not just be looked at in terms of the months of survival improvement it may provide. Rather, Herceptin prevents further metastases, which lead to death, “so the cost effectiveness becomes very attractive because you are paying the same cost for a huge benefit now.”
Although Herceptin is a significant advance for treatment of metastatic breast cancer, until proven effective and approved for expanded indications:, the market for Herceptin remains relatively limited (i.e, it is not a blockbuster product), due to its second-line status, the small percentage of qualified patients and their relatively short survival.
In the U.K. in March 2002, the National Institute of Clinical Excellence (NICE), which sets prescribing/reimbursement policy for the National Health Service (NHS), recommended that Herceptin be made available by the NHS to all qualified advanced (not early) patients, then at an average cost of £13,000 per patient. However, a survey by Roche in Oct. 2003 found that only one-third of British women eligible for Herceptin were receiving it. Cancer activists noted that lack of follow-up and enforcement of NICE recommendations by NHS caused this. Adding to the controversy in the U.K. regarding access to (cost-benefits of) Herceptin for early-stage breast cancer, an editorial in the Nov. 10, 2005 issue of Lancet, a British publication, stated “The available evidence is insufficient to make reliable judgments.” This was in stark contrast with a U.S. periodical, New England Journal of Medicine, which on Oct. 20th, 2005, had proclaimed Herceptin a revolutionary and possible cure for some hard-to-treat breast cancers. Similar controversies have flared in France, where pressure for access to Herceptin was so intense that regulators bypassed normal channels to make it more widely available to breast cancer patients.
In Feb. 2006, a lawsuit concerning U.K. National Health Service (NHS) restrictions on access to Herceptin was denied by the High Court, leaving a lower court ruling in place allowing NHS components to refuse to provide Herceptin treatment for early-stage Her2+ breast cancer. The suit was seeking broader guidelines (and improved access) for eligibility for early-stage breast cancer treatment, an as yet unapproved indiction. Despite the Health Department stating in fall 2005 that local/regional NHS health care delivery organizations should not withhold treatment “solely on the grounds of cost,” with treatment costing $36,000 to $47,000 a year for each patient, many local authorities had been denying treatment primarily due to costs. Individual local/regional primary care trusts were making their own decisions about whether patients should be treated with Herceptin and when. NICE fast-tracked its appraisal of Herceptin.
On June 6, 2006 (several weeks after European Union approval for adjuvant breast cancer treatment), NICE formally recommended that Herceptin be made available to women with early-stage breast cancer, with regional health authorities having three months to comply, after which they would be subject to lawsuits from patients. This ended the controversy over lack of access to Herceptin in the U.K. At about the same time, Australian authorities approved Herceptin use for early adjuvant breast cancer treatment.
In March 2007, Tykerb, a small molecule drug targeting the Her-2 receptor, from GlaxoSmith Kline received FDA approval.
Approvals for stomach cancer are further expanding the market for Herceptin, the first targeted biological therapy to show a survival benefit in advanced stomach cancer. This represents a significant advance in the treatment of this disease. Stomach cancer is the second most common cause of cancer-related death in the world and is the fourth most commonly diagnosed cancer, with over 1,000,000 cases of stomach cancer diagnosed each year.
In July 2010, the National Institute of Clinical Excellence (NICE), which sets prescribing/reimbursement policy for the National Health Service (NHS), recommended against use of Herceptin for treatment of stomach cancer largely "due to the uncertainty surrounding the extent to which it can extend life." Otherwise, about 500 patients would typically be receiving Herceptin for this indication in the U.K., with each course of treatment costing about $15,750.
In Sept. 2010, the National Institute of Clinical Excellence (NICE) recommended the National Health Service should pay for Herceptin in some cases for patients where stomach cancer has spread, i.e., in combination with common chemotherapy drugs for people with HER2-positive, metastatic adenocarcinoma of the stomach or gastro-esophageal junction who have not received prior treatment for their spreading disease. Patients should also have tumors that express high levels of HER2 as defined by a positive immunohistochemistry score of 3 (IHC3 positive).
In Sept. 2010, the National Institute of Clinical Excellence (NICE) issued final guidance endorsing Herceptin in combination with cisplatin and either capecitabine or 5-fluorouracil as an option for certain patients with metastatic adenocarcinoma of the stomach and gastro-oesophageal junction. However, the Institute has stipulated that treatment should be restricted to patients who have high levels of human epidermal growth factor receptor 2, as defined by a positive immunohistochemistry score of 3 (IHC3), and have not received prior treatment for metastatic disease. NICE’s cost-modelling - based on the new data from Roche, calculated that the most plausible estimates of cost effectiveness for the IHC3 positive subgroup were between £45,000 and £50,000, while those for an unrestricted population fell between £63,100 and £71,500 per QALY gained - and so well above what would normally be considered a cost-effective use of NHS resources.
Ongoing: In May 2006, Genentech entered into a agreement with ImmunoGen to have the company develop a commercial manufacturing process for trastuzumab-DM1, a trastuzumab (Herceptin)-based immunotoxin, using its tumor-activated prodrug (TAP) technology. DM1 is a potent cytotoxic agent ImmunoGen specifically developed for antibody-guided delivery to cancer cells. Promising results from a Phase I trial were reported in sping 2007.
R&D: In April 2007, Genentech reported positive results from a Phase II trial of pertuzumab (Omnitarg; 2C4), another recombinant Her-2 monoclonal antibody, plus gemcitabine in advanced ovarian cancer. Pertuzumab binds to different regions of the extracellular portion of HER-2 than Herceptin and has different biological activity. Genentech and Roche are evaluating pertuzumab in solid tumors (ovarian and breast cancers), and in combination with other therapies.
In Jan. 2010, it was reported that Roche had invested roughly CHF190m (~$183 million) at two production sites, Kaiseraugst, Switzerland, and Mannheim, Germany, to manufacture devices that will allow patients to self-administer a subcutaneous formulation of Herceptin, i.e., the company is developing a s.c. formulation. This involves use of Enhanze (Hylenex; recombinant hyaluronidase) from Halozyme Therapeutics (see related entry). This Herceptin formulation together with the ready-to-use administration device allows for injection of larger volumes of medicines into the tissue under the skin. The production line in Kaiseraugst will provide the supply for clinical studies and market launch, and a full scale automated production line in Mannheim will deliver commercial supply to markets. In a Phase III study, 552 patients with stage I-IIIc breast cancer will receive chemotherapy in combination with either subcutaneous or intravenous Herceptin before surgery, followed by 10 three-weekly infusions of subcutaneous or intravenous Herceptin. Currently, breast cancer patients treated with Herceptin generally receive it as an infusion in a hospital; the infusion time is around 60 minutes. In contrast, subcutaneous Herceptin administration takes only about five minutes and means that patients with early HER2-positive breast cancer completing their one year of Herceptin therapy would have greater convenience of being able to receive treatment at their family doctor’s office or a do it themselves at home.
However, Roche could find it difficult to encourage uptake of subcutaneous Herceptin, because it will make it more difficult for physicians to ensure patient compliance. In the U.S., financial incentives, e.g., Medicare payments, for oncologists to prescribe intravenous drugs could further restrict uptake of the subcutaneous formulation. Phase III studies may have to show that the more convenient subcutaneous formulation also has superior efficacy in order to drive appreciable uptake.
Companies involvement:
Full monograph
179 HER2 Receptor Mab, rDNA
Nomenclature:
HER2 Receptor Mab, rDNA [BIO]
Herceptin [TR]
Trastuzumab [FDA USAN]
520C9x22 [SY]
c-erbB2 monoclonal antibody [SY]
epidermal growth factor receptor-2 protein (HER2) monoclonal antibody [SY]
HER2 receptor monoclonal antibody, recombinant [SY]
MDX-210 [SY]
Metavert [SY]
NDC 50242-0134-60. [NUM NDC]
molecular weight (kDa) = 145.5
FDA Class: Biologic BLA
Year of approval (FDA) = 1998
Date of 1st FDA approval = 19980925
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2019, based on 6,339,142; 7,074,404; and 6,407,213 (reported by Genentech)
2014 is commonly reported. Thomson Reuters had reported late 2014 (or 2015) Tech. Catalysts Intl., affiliated with Harvest Moon Pharm., has reported 2013-2018.
A Nature Review of Drug Discovery article has reported 2015. |
U.S. Patent Expiration Year: | 2019 |
U.S. Biosimilars Data Exclusivity Expiration: | 2010 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2005 |
U.S. Biosimilars Launchability Year: | 2019 |
U.S. Biobetters Launchability Year: | 2019 |
Biosimilars/biobetters-related EU Patents: | 2019, based on EP 1075488 and EP 1308455 |
EU Patent Expiration Year: | 2019 |
EU Biosimilars Data Exclusivity Expiration: | 2010 |
EU Biosimilars Orphan Exclusivity Expiration: | 2010 |
EU Biosimilars Launchability Year: | 2019 |
EU Biobetters Launchability Year: | 2019 |
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
biopharmaceutical products
blepharospasm
exempt from CBER lot release requirements
hamster source materials
monoclonal antibodies, recombinant
murine (mouse) materials used
periplastic E. coli proteins (PECP)
recombinant DNA
rodent source materials
4D5 murine hybridoma cells
4D5 murine hybridoma cells
Chinese hamster ovary (CHO) cells
gentamicin (gentamycin)
glutamine synthetase (GS) expression system
mammalian cell culture
media, serum-based
rodent cells <!-- rodentcells -->
suspension cell culture
Bacteriostatic Water for Injection
benzyl alcohol
gentamicin (gentamycin)
HER-2/neu (c-erbB2) proto-oncogene
histidine
hydrocortisone
lyophilized (freeze-dried)
monoclonal antibody 4D5
polysorbate 20 (Tween 20)
receptors, epidermal growth factor
Sterile Water for Injection
trehalose dihydrate
viral inactivation, acid (low pH)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
catheter clearance
exempt from CBER lot release requirements
orphan status
priority review status
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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