Status: approved, marketed

Organizations involved:

Bristol-Myers Squibb Co. – R&D; USA mark.; Japan mark.

ImClone Systems Inc. – Manuf.; R&D; Tech.

Eli Lilly & Co – Parent

Boehringer Ingelheim Pharma KG – Manuf.

Merck Serono S.A. – Intl. mark.

Merck KGaA – Parent

National Cancer Institute (NCI) – R&D; Former

National Institutes of Health (NIH) – Parent

Rorer Pharmaceuticals – R&D; Tech.; Former

Sanofi Aventis S.A. – Tech.

Lonza Biologics plc – Manuf.; Tech.

Celltech Group plc – Tech.; Former

UCB Bioproducts S.A. – Parent

Damon Biotech, Inc. – R&D; Tech.; Former

Repligen Corp. – Tech.; Patent dispute

Abbott Laboratories, Inc. – Tech.; Patent dispute

Weizmann Inst. – R&D; Tech.; Patent dispute

Yeda Res. and Dev. Co. Ltd. – Patent dispute

Sanofi Aventis Pharm., Inc. – Patent dispute

Stanford University – Tech.

Genentech, Inc. – Tech.

University of California – Tech.

Centocor, Inc. – Tech.

Johnson & Johnson Co. – Parent

Cross ref.: See Monoclonal Antibodies (entry #300).

Description: Erbitux is an aqueous formulation of cetuximab (C225), a recombinant chimeric human/mouse monoclonal antibody with specificity for extracellular N-terminal portion of the cellular epidermal growth factor receptor (EGFr; HER1, c-ErbB-1), expressed by a transformed murine (mouse) myeloma cell line. Cetuximab is composed of the Fv (variable; antigen-binding) regions of the 225 murine EGFr monoclonal antibody specific for the N-terminal portion of human EGFr with human IgG1 heavy and kappa light chain constant (framework) regions. Cetuximab binds to EGFr overexpressed on the surface of cells over 35% solid tumors, preventing epidermal growth factor (EGF) and transforming growth factor (TGF) from binding to EGFr, and inhibiting tumor growth. Cetuximab has a molecular weight of ~152 kDa.

Erbitux is packaged in cartons with one single-use, 50-mL vial containing 100 mg of cetuximab at a concentration of 2 mg/mL in a preservative-free solution with pH 7.0-7.4, along with 8.48 mg/mL sodium chloride, 1.88 mg/mL sodium phosphate dibasic heptahydrate, 0.42 mg/mL sodium phosphate monobasic monohydrate, and Water for Injection, USP. Erbitux is stored at 2-8˚C (refrigerated).

Nomenclature: EGF receptor Mab, chimeric, rDNA [BIO]; Erbitux [TR to ImClone]; cetuximab [FDA USAN]; immunoglobulin G1, anti-(human epidermal growth factor receptor) (human-mouse monoclonal C225 gamma1-chain), disulfide with human-mouse monoclonal C225 kappa-chain, dimer [CAS]; 205923-56-4 [CAS RN]; chimeric 225 [SY]; C225 [SY]; IMC-C225 [SY]; epidermal growth factor receptor monoclonal antibody, chimeric [SY]; NDC 66733-948-23 [NDC]

Biological.: The cellular EGF receptor (EGFr) is a transmembrane glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases including EGFr (HER1), HER2, HER3, and HER4. EGFr is constitutively expressed in many normal epithelial tissues, including the skin and hair follicles. Amplification or overexpression of EGFr is associated with the uncontrolled cell division of many tumors. Both EGF and transforming growth factor-alpha (TGF-alpha) have been shown to bind to EGFr, and to lead to cellular proliferation and tumor growth. The EGFr is involved in cell transformation and maintenance of the transformed cell phenotype. EGFr has been demonstrated to be overexpressed on many types of human solid tumors, including breast carcinomas, gliomas, squamous cell carcinomas, melanomas, invasive bladder carcinomas, and esophageal cancers. Studies with primary human mammary (breast) tumors have shown a correlation between high EGFr expression and the presence of metastases, higher rates of proliferation, and shorter patient survival.

The EGFr is a 170-180 kD membrane-spanning glycoprotein detectable on a wide variety of cell types. The extracellular N-terminal domain of the receptor is highly glycosylated and binds EGF. The cytoplasmic C-terminal domain of the receptor contains an EGF-dependent tyrosine-specific protein kinase that is capable of both autophosphorylation and phosphorylation of other protein substrates. The two domains are connected by a single 21 amino acid hydrophobic transmembrane region. The binding of EGF to its receptor activates the receptor tyrosine kinase, which phosphorylates a variety of cellular proteins (including EGFr itself). This initiates a signal transduction pathway that ultimately leads to DNA replication, RNA and protein synthesis, and cell division. EGF also induces the concentration of the receptor into clathrin-coated pits, internalization into intracellular vesicles, and finally degradation in the lysosomes.

EGFr monoclonal antibodies, e.g., murine 225 and chimeric 225 (C225; cetuximab), bind specifically to EGFr on both normal and tumor cells, and competitively inhibit the binding of epidermal growth factor (EGF) and other ligands, e.g., transforming growth factor–alpha. Binding of cetuximab to the EGFr blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis (programmed cell death), and decreased matrix metalloproteinase and vascular endothelial growth factor production. In vitro assays and in vivo animal studies have shown that cetuximab inhibits the growth and survival of tumor cells that overexpress the EGFr, and no anti-tumor effects of cetuximab were observed in human tumor xenografts lacking EGFr expression. Cetuximab inhibits EGF-mediated tumor cell growth in vitro and inhibits human tumor formation in vivo in nude mice models. Addition of Erbitux to irinotecan or to irinotecan plus 5-fluorouracil in animal studies resulted in an increase in anti-tumor effects compared to chemotherapy alone. Cetuximab has appeared to act in synergy with certain chemotherapeutic agents to eradicate human tumors in xenograft mouse models, suggesting it may have increased efficacy in combination with other chemotherepeutic drugs.

Companies.: Cetuximab was discovered at the University of California and originally developed by Rorer Pharmaceuticals, which became Rhone-Poulenc Rorer, later Aventis Pharma, now Sanofi Aventis S.A.. Cetuximab was subsequently exclusively licensed by ImClone Systems, Inc. which pursued its development, including clinical trials. [Note, Eli Lilly acquired ImClone in Nov. 2008].

In Sept. 2001, Bristol-Myers Squibb Co. (BMS) concluded a licensing agreement with ImClone, potentially worth $2 billion to ImClone, for joint development and marketing of Erbitux in the U.S. and Canada. BMS paid $200 million upon signing, and was to pay $300 million upon acceptance to the BLA and $500 million upon FDA approval. The deal also included $300 in development milestone payments; and BMS acquired ~$1 billion (20%) of ImClone stock, and could not sell this for three years.

Merck KGaA licensed exclusive international marketing rights outside of North America and Japan in 1998, with its primary market in Europe. Both Merck and ImClone have co-exclusive marketing rights in Japan. Merck reported pays royalties of 6.5-7.5% to ImClone. In Jan. 2007, Merck KGaA acquired Serono, and the new company was renamed Merck Serono S.A.

In March 2002 (after FDA refused to accept ImClone’s BLA; see the Status section), BMS and ImClone revised some terms of their original agreement, with ImClone receiving much less than its original deal. Instead of the $300 million in development milestone payments to ImClone, BMS paid $140 million upon signing of the new agreement and $60 million one year later. BMS pays the originally agreed upon $500 million milestone payment upon FDA approval in two parts: $250 million upon approval for the initial indication (refractory colon cancer; already received by ImClone), and $250 million upon approval for a second indication (presumably, head and neck cancer). ImClone receives a 39% flat rate royalty on N. American sales by BMS. This new agrement runs through 2018. BMS and ImClone will collaborate on clinical trials and obtaining approvals for Erbitux.

Cetuximab for the U.S. market is manufactured by ImClone Systems, now Eli Lilly, and also under contract by Lonza Biologics plc (CBER/FDA est. 1209) at facilities in Slough, U.K. Boehringer Ingelheim Pharma KG (BI; Biberach ad der Riss, Germany) manufactures the product for Merck KGaA (European market). Lonza’s product, which has been reported to be manufactured at the 2,000 liter scale, was used for U.S. and other product launches and initial marketing. Prior to deciding to rely on a contract manufacturer (BI), Merck had announced in March 3, 2003 that it was considering construction of a €300 million manufacturing facility in Jena, Germany.

Based on reported 2010 Erbitux manufacturing revenue (and presuming all supplies manufactured by ImClone/Lilly) Lilly receives 4% (or more) royalty on total worldwide sales/revenue.

Erbitux is ImClone's only marketed product. The company received 39% of Eribtux U.S. revenue from sales by BMS, and collects 9.5% royalties for sales outside the U.S. by Merck Serono.

On June 24, 2004, ImClone received FDA approval for its “BB36” 30,000 liter capacity, single-product (dedicated), Branchburg, NJ, manufacturing facility for manufacture of Erbitux, capable of producing ~250 kg (~500,000 doses) per year. From the start of 2002 through the end of 2003, ImClone produced ~200 kg of bulk product, which is about 400,000 doses of Erbitux (with FDA approval allowing release of this product). ImClone reports having invested about $260 million in this new facility.

Some analysts have noted that BMS might lose money on Erbitux over the first years of its marketing, given the expenses of product launch and marketing, and milestone payments and 39% royalty paid to ImClone.

On April 3, 2006, ImClone received a $250 million milestone payment from BMS linked to the FDA supplemental approval of Erbitux for head and neck cancer. With this, ImClone had received milestone payments totaling $900 million.

In July 2006, ImClone and Merck KGaA entered into agreements amending and supplementing their 1998 development and license agreement for Erbitux. Merck agreed to increase its fixed royalty paid to ImClone to 9.5% for all sales of Erbitux outside the U.S. and Canada, effective July 1, 2006. ImClone consented to Merck’s sublicense of certain intellectual property rights relating to the development and commercialization of an anti-EGFR antibody to Takeda Pharmaceutical Co. Merck and Takeda had signed an alliance in Sept. 2005 for the development and commercialization of matuzumab (EMD72000), a humanized EGFr monoclonal antibody. The agreement also grants Merck freedom to operate in the commercialization of matuzumab outside the U.S. and Canada, and for IMC-11F8 (a fully human EGFr IgG1 monoclonal antibody being developed by ImClone) within the U.S. and Canada through the granting of certain reciprocal rights, including the sharing of confidential technical information. The agreements do not extend to key intellectual property rights in the U.S. and Canada, where ImClone and BMS continue to hold exclusive licenses to key patents (one later lost; see Tech. transfer section below) covering certain uses of EGFr-targeted monoclonal antibodies.

In Aug. 2006, implementing its plans to bring manufacture of its supplies of Erbitux in-house, Merck KGaA reported its biggest investment in pharmaceuticals in its 338-year-old history, allocating €190 million for the construction of its first biopharmaceutical production plant at its headquarters in Darmstadt, Germany. Boehringer Ingelheim currently manufactures Erbitux for Merck, but this will change after the new plant comes on stream in 2010.

In Oct. 2006, after buying a significant portion of ImClone stock, noted billionaire investor Carl C. Icahn became Chairman of the Board of ImClone, and effectively took control of the company, including ousting the company’s current board and management.

In July 2007, ImClone and BMS agreed to expand ongoing clinical development plans for Erbitux by up to several hundred million dollars. Costs, up to a threshold value, will be the sole responsibility of BMS; and costs in excess of this threshold will be shared by both companies according to a pre-determined ratio.     

In Aug. 2007, ImClone received FDA approval for its new “BB50” manufacturing suite in Branchburg, NJ. Mechanical completion was reported in Aug. 2005, This second facility (in addition to BB36) more than doubles production capacity for Erbitux. This 250,000 sq. ft. facility has 110,000 L of bioreactor capacity with three different suites -- two suites with a total of 66,000 L capacity., and a 44,000 L suite in the planning stages. Erbitux manufacture in one of the suites began in June 2006. The other two suites may be used for manufacture of Erbitux, if needed, or other products.

In Oct. 2007, ImClone and BMS concluded an agreement with Merck Serono for the co-development and co-commercialization of Erbitux in Japan. The theee companies will collaborate on a joint effort to develop and, following regulatory approval, market Erbitux in Japan for the treatment of epidermal growth factor receptor (EGFr)-expressing metastatic colorectal cancer (mCRC), as well as for the treatment of any other cancers the parties agree to pursue. BMS and Merck will utilize their respective sales forces in Japan. Merck Serono Japan will distribute the product and record the sales for the collaboration. Merck KGaA will receive 50% of the profit/loss from sales in Japan, and ImClone and BMS will each receive 25%. The sharing of profit/loss reflect the co- exclusive rights in Japan previously granted by ImClone to Merck and BMS. In addition to its percentage of profits, ImClone will receive from Merck KGaA a royalty equal to 4.75% of total net sales in Japan. The companies submitted an application in Japan earlier in 2007 for the use of Erbitux in treating patients with EGFR-expressing mCRC.

In Nov. 2008, ImClone received FDA approval for its BB50 manufacturing facility.

On Nov. 21, 2008, Eli Lilly & Co. completed its acquisition of ImClone (for ~$6.4 billion). ImClone Systems is now a wholly-owned subsidiary of Lilly.

In Aug. 2010, ImClone (Lilly) closed its relatively new BB50 Branchburg, NJ, manufacturing facility.

FDA class: Biologic BLA

Approvals: Date = 20040212; BLA, first approval; Indications: = colorectal cancer

Date = 20050618; BLA supplement; Indication = approval of ImClone’s BB36 manufacturing facility

Date = 20060301; BLA supplement; Indication = approval for use in combination with radiation to treat patients with squamous cell cancer of the head and neck that cannot be removed by surgery.

Date = 20070821; BLA supplement; Indication = approval of BB50 manufacturing facility

Date = 20071002; BLA supplement; Indication = update to product labeling to include overall survival data as a single agent in EGFr-expressing metastatic colorectal cancer (mCRC) patients after failure of both irinotecan- and oxaliplatin-based regimens.

Date = 20081020; BLA supplement; Indications: = approval of the BB50 manufacturing facility

Date = 20090720; BLA supplement; Indications: = Labeling revisions include a modification to the indication, which now includes a statement that retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had K-ras mutations in codon 12 or 13 and that the use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations. Revisions concerning the use of Erbitux in colorectal cancer tumors with K-ras mutations were also made to the clinical studies and clinical pharmacology sections of the product’s prescribing information.

Date = 20111107; BLA supplement; Indication = use with chemotherapy to treat patients with late-stage (metastatic) head and neck cancer.

Date = 20120709; BLA supplement; Indication = Erbitux in combination with the FOLFIRI (infusional 5FU and irinotecan) chemotherapy regimen for the first-line treatment of patients with KRAS mutation-negative (KRAS wild-type), epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer [Note, approval is linked to approval of Qiagen's companion diagnostic kit for KRAS gene mutation].

Indications: [Full text of the "INDICATIONS AND USAGE” section of product insert/labeling, 6/2012]:

Head and Neck Cancer
• Locally or regionally advanced squamous cell carcinoma of the head and neck in combination with radiation therapy.
• Recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck in combination with platinum-based therapy with 5-FU.
• Recurrent or metastatic squamous cell carcinoma of the head and neck progressing after platinum-based therapy.
Colorectal Cancer
• As a single agent, EGFR-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens or in patients who are intolerant to irinotecan-based regimens.
• In combination with irinotecan, EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. Approval is based on objective response rate; no data are available demonstrating an improvement in increased survival.
• Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux (cetuximab) in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations.

Status: ImClone submitted its original fast-track BLA in several sections between June 28 and Oct. 31, 2001 seeking accelerated approval of Erbitux for use in combination with irinotecan in the treatment of patients with EGFr-expressing metastatic colorectal cancer who are refractory to irinotecan-based chemotherapy, and for use as a single agent in the treatment of patients with EGFr-expressing, metastatic colorectal cancer who are intolerant to irinotecan-based chemotherapy.

On Dec. 28, 2001, FDA issued a refusal to file letter. In Jan. 2002, Dr. S.D. Waksal, President/CEO, ImClone publicly admitted receipt of the FDA letter (and that the BLA was defective). A major deficiency was that the refractory condition of the 120 patients in the pivotal trial had not been sufficiently documented. Only the responsivity of patients to Erbitux had been documented, and this was not considered by FDA as evidence patients in the trial were refractory to irinotecan. ImClone later (upon approval) explained the rejection, “because approximately half of the patients (94) studied had not failed the approved treatments for colon cancer; and important information about the safety and effectiveness of Erbitux in a portion of the remaining patients (102) was missing.” Starting soon after public announcement of the FDA refusal to file, ImClone stockholders began filing lawsuits alleging the company had made false and misleading statements about its BLA. Also, Dr. Waksal, family and friends, including celebrity and corporate magnate Martha Stewart, sold ImClone shares upon learning of and before ImClone’s public announcement of the FDA refusal (i.e., committed insider trading). Dr. Waksal and others sold about $100 million in stock before it lost significant value (after public disclosure of FDA’s refusal to file).

In Jan. 2002, a Congressional committee held hearings concerning ImClone and Erbitux.

In Feb. 2004, the FDA approved Lonza’s facilities in Slough, U.K., for commercial manufacture of cetuximab. As discussed below, ImClone has also been developing its own manufacturing facilities.

Dr. Waksal resigned in May 2002, was arrested in June 2002; and in Oct. 2002, he pleaded guilty in federal court on six counts, including securities fraud for insider trading, obstruction of justice, perjury, and bank fraud. Dr. Waksal was sentenced to 87 months in federal prison without parole and was fined over $4 million for insider trading and tax evasion. This scandal did not significantly delay the development of Erbitux. Dr. Waksal is now serving an 87-month sentence in federal prison for insider trading.

ImClone had followed a very high risk route to seeking FDA approval—basing its BLA on a single open-label Phase II trial of Erbitux plus irinotecan. This trial was not originally designed as a pivotal trial to support approval. The company had not conducted trials with Erbitux monotherapy, nor trials comparing Erbitux plus irinotecan vs. irinotecan alone In this context, ImClone essentially asserted that Erbitux lacked efficacy by itself, but was effective in combination with irinotecan, which has known serious adverse effects. Generally, FDA would at least require a trial of Erbitux plus irinotecan vs. irinotecan monotherapy, to potentially spare patients from irinotecan toxicity.

Prior to a meeting with ImClone in Aug. 2000, some FDA staff had internally warned against encouraging ImClone to file its BLA based on the Phase II combination trial alone, but they were overruled after ImClone claimed at the meeting to have sufficient efficacy data to show lack of efficacy with Erbitux monotherapy (apparently untrue), with ImClone contending it would be unethical to test Erbitux monotherapy. ImClone subsequently also claimed that Erbitux acts synergistically with irinotecan. Only after reviewing the completed BLA, did FDA realize that ImClone’s data supporting lack of efficacy with Erbitux monotherapy were from testing in renal/kidney, not colorectal, cancer patients.

Despite the regulatory and legal problems, ImClone, BMS and the medical community presumed that Erbitux was still a safe and effective product, and during these difficulties BMS continued its development for irinotecan-refractory colorectal cancer.

On Aug. 14, 2003, ImClone (re)submitted another BLA seeking priority review and accelerated approval for Erbitux plus irinotecan for the treatment of patients with EGFr-expressing irinotecan-refractory metastatic colorectal cancer. This included results of a large, well-run trial that included 329 patients, as well as the results of two earlier studies. For the studies submitted in their original 2001 filing, ImClone provided substantial amounts of missing information from hospital records and other sources.

Accelerated approval was granted on Feb. 12, 2004; approval time = ~7 months; ~.58 years). Approval was granted on the basis of surrogate markers of efficacy, primarily on the ability of combination treatment to shrink tumors in some patients and delay tumor growth, rather than proven clinical efficacy (e.g., improved survival). Accelerated approval based on surrogate markers has also been granted to an EGRr inhibitor drug, Iressa (gefitinib).

On Dec. 1, 2003, Erbitux received its first approval, in Switzerland.

On Feb. 12, 2004, the same day as Erbitux approval, FDA granted DakoCytomation A/S (Copenhagen, Denmark) a PMA (medical device approval) for its EGFR pharmaDx kit as a companion diagnostic to identify colorectal cancer patients eligible for treatment with Erbitux. EGFR pharmaDx kit is used to identify EGFr in tumor tissue sections. ImClone, BMS, and Merck had used this kit in their clinical trials to identify candidates for Erbitux therapy.

In April 2004, FDA accepted for review a CMC supplemental BLA for ImClone’s “BB36” manufacturing facility (see Companies section above), with a PDUFA (target decision date) of June 18, 2004. Approval was granted on June 18, allowing release of already-Manufactured bulk cetuximab equivalent to ~400,000 doses. This facility is expected to meet “full commercial demand.” The BB36 facility had earlier been approved for manufacture of Erbitux used in clinical trials, and has been approved by Swiss authorities as part of their approval of Erbitux. To avoid further delays related to this new facility, the BB36 facility had been removed from the CMC section of the later-approved BLA. This withdrawal (and resubmission) of the CMC section for BB36 followed an FDA request for information on a larger number of patients treated with Erbitux manufactured at BB36. FDA approved the BB36 facility for manufacture of Erbitux in June 2004.

In June 2004, Merck KGaA received European Union (EU) approval for Erbitux in combination with irinotecan to treat patients with epidermal growth factor (EGF) receptor-expressing colorectal tumors after failure with a regimen including irinotecan.

In March 2005, two additional persons, including a leading cancer researcher, were charged with criminal conspiracy and securities fraud in relation to their sale of ImClone stock, allegedly having dumped their stock after receiving a tip from Samuel Waksal.

In Aug. 2005, Merck KGaA submitted a Variation Application to the EMEA/European Union and Swissmedic seeking approval for treatment of squamous cell carcinoma of the head and neck (SCCHN). This was based on the same trial results submitted in support of the similar U.S. filing (see next paragraph and discussion of supporting trials in the Trials section).

On Sept. 13, 2005, FDA issued a warning, a 2-page “Dear Doctor” letter, and modified the labeling for Erbitux. This concerned potential hypomagesia, a drop in magnesium levels, associated with Erbitux, which can be easily treated with magnesium supplements. The product’s label had mentioned these side effects since May. New warnings were added to the product lableing recommending a one-hour observation period to watch for reactions, citing only a few percent of patients receiving an Erbitux injection have a severe reaction and that fatalities are rare, < 0.1%. These actions were expected to have negligible effect on the use and market for Erbitux, since the adverse effects were already well-known to oncologists, and monitoring of patients’ electrolyte levels was common practice.

On Oct 31, 2005, ImClone filed a supplemental BLA for approval of Erbitux for treatment of squamous cell carcinoma of the head and neck (SCCHN) in combination with radiation for locally or regionally advanced head and neck cancer, and as monotherapy in patients with recurrent and/or metastatic disease where prior platinum-based chemotherapy has failed or where platinum-based therapy would not be appropriate. The FDA granted the application a priority review. The sBLA filing had been delayed from April to allow for an additional independent analysis of the primary endpoint the pivotal Phase III trial (IMC-9815). (See the discussion of supporting trials in the Trials section). Unlike prior problems/delays, the companies had all needed clinical data in hand.

On Dec. 22, 2005, Swissmedic, the Swiss agency for therapeutics, granted Merck KGaA approval of Erbitux for treatment of patients with previously untreated, advanced squamous cell carcinoma of the head and neck.

On March 1, 2006, the FDA approved Erbitux for use in combination with radiotherapy for the treatment of locally or regionally advanced SCCHN and as a single agent in recurrent or metastatic SCCHN where prior platinum-based chemotherapy has failed.

On April 3, 2006, the European Union granted supplemental approval of Erbitux for treatment of squamous cell carcinoma of the head and neck (SCCHN).

In mid-2006, after failing to reach agreement with the Patented Medicine Prices Review Board, Bristol-Myers Squibb Canada refused to market Erbitux in Canada, citing government price controls and the inability to charge the price is wants/needs.

In Feb. 2007, ImClone and Bristol-Myers Squibb jointly submitted an sBLA application for approval of Erbitux in Japan for treatment of advanced colorectal cancer. In June 2007, FDA granted the filing priority review status, with a PDUFA (target approval) date in October/

In Oct. 2007, the FDA approved an update to the product labeling to include overall survival data as a single agent in EGFr-expressing metastatic colorectal cancer (mCRC) patients after failure of both irinotecan- and oxaliplatin-based regimens. With this approval, Erbitux is the only approved biologic therapy proven to improve overall survival as a single agent in patients with mCRC. The approval was based on prolonged overall survival from a large, randomized, multicenter, Phase III trial comparing ERBITUX plus best supportive care (BSC) to BSC alone in 572 EGFR-expressing mCRC patients after failure of irinotecan- and oxaliplatin-based regimens. BSC was considered to be all approved palliative therapies designed to alleviate pain and treat other effects caused by mCRC in this patient population.

In June 2008, Merck KGaA submitted an supplmental MAA to EMEA/EU to broaden the use of Erbitux to include first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN).

On Aug. 29, 2008, ImClone submitted a BLA supplement to broaden the use of Erbitux to include first-line treatment of patients with recurrent and/or metastatic SCCHN. ImClone requested Priority Review, which, if granted, would make involve a decision on the application within six months.

In early Sept. 2008, Merck Serono submitted a supplemental MAA to the European Medicines Agency (EMEA), European Union, for license for the firstline treatment of epidermal growth factor receptor (EGFR) expressing, advanced or metastatic non-small cell lung cancer (NSCLC). Erbitux has already been licensed in the European Union for all lines of treatment for patients with EGFR-expressing, KRAS wild-type metastatic colorectal cancer (mCRC) in combination with chemotherapy, and as a single agent for patients who have failed oxaliplatin- and irinotecan-based therapy and who are intolerant to irinotecan. Erbitux is also licensed in combination with radiotherapy for locally advanced squamous cell carcinoma of the head and neck (SCCHN).

On Nov. 20, 2008, ImClone received FDA approval for its state-of-the-art "BB50" manufacturing facility to manufacture multiple products, including Erbitux. This approval significantly expanded ImClone's (Lilly's) total available recombinant antibody production volume capacity.

On Dec. 1. 2008, the European Union granted supplemental approval to Erbitux for 1st-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). Erbitux was previously approved for use in combination with radiotherapy for locally advanced disease. This approval was primarily based upon the results of the EXTREMEa study, published in the New England Journal of Medicine in September 2008.

In Jan. 2009, ImClone Systems and Bristol-Myers Squibb withdrew their advanced non-small cell lung cancer sBLA for Erbitux because the FDA had requested an additional pharmacokinetic study to confirm the comparability of Erbitux used in the first-line head and neck submission as compared to Erbitux currently marketed in the United States. Clinical supplies used in this sBLA were provided by Merck KGaA (ImClone's partner for ERBITUX outside of North America).

On March 2, 2009, ImClone (now part of Eli Lilly & Co.) and Bristol-Myers Squibb received a complete response letter from FDA regarding their first-line squamous cell carcinoma of the head and neck (SCCHN) supplemental Biologics License Application (sBLA) for Erbitux. The sBLA was accepted for filing and granted a priority review status in Oct. 2008. The FDA requested an additional pharmacokinetic study to confirm the comparability of Erbitux used in the first-line head and neck submission as compared to Erbitux currently marketed in the U.S. Clinical supplies used in this sBLA were provided by Merck KGaA (ImClone's partner for Erbitux outside of North America). ImClone/Lilly and BMS Erbitux planned to continue with both of the sBLAs for which they had recently received complete response letters [i.e., planned to perform the requested comparability trial(s)].

On Nov. 20, 2009, the Committee for Medicinal Products for Human Use (CHMP), European Medicines Agency (EMEA), adopted a negative opinion for the use of Erbitux in combination with platinum-based chemotherapy for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing, advanced or metastatic non-small cell lung cancer (NSCLC). Merck reported it would continue with Erbitux clinical trials for NSCLC.

In July 2012, FDA approved Erbitux use in combination with the FOLFIRI (infusional 5FU and irinotecan) chemotherapy regimen for the first-line treatment of patients with KRAS mutation-negative (KRAS wild-type), epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer. This approval was linked to approval of Qiagen's companion diagnostic kit for KRAS gene mutation. Approval was based on data from the CRYSTAL Phase III study conducted by Merck in Europe which showed a significant overall survival advantage for patients who were treated with Erbitux in combination with FOLFIRI compared to those who received chemotherapy alone; 8.9 versus 8.1 months. The presence or absence of KRAS mutations in tumours affects patient outcomes. Approximately 60% of patients with wild-type KRAS genes may benefit from anti-EGFR therapy, while 40% whose tumors have KRAS mutations may not. Quigen estimates the U.S. could save $600 million annually "by avoiding unnecessary use of medicines in colorectal cancer patients through determinations of their KRAS status." Some 110,000 colorectal cancer patients each year in the USA could benefit from this testing, Qiagen's kit is the first to get FDA approval for a KRAS test in colon cancer alone. Sales are expected to be to be about $20 million annually.

In Sept. 2012, Merck voluntarily withdrew a pendng MAA with EMA/EU for a label extension for Erbitux in combination with standard first-line platinum-based chemotherapy in patients with advanced or metastatic non-small cell lung cancer (NSCLC) with high epidermal growth factor receptor (EGFR) expression. The decision to withdraw the application was based on feedback from European regulatory authorities indicating that further data would be required. The decision does not alter the proven utility of Erbitux in its already approved indications in metastatic colorectal cancer (mCRC) and squamous cell carcinoma of the head and neck (SCCHN). Merch announced plants to initiate a randomized Phase III trial of TH-302 in patients with advanced first-line pancreatic cancer together with its partner Threshold Pharmaceuticals, Inc.

Tech. transfer: The product insert cites only one patent, U.S. 6,217,866, “Monoclonal antibodies specific to human epidermal growth factor receptor and therapeutic methods employing same,” assigned to Rhone-Poulenc Rorer Inc., later Aventis S.A., now Sanof Aventis S.A. [See also information below about ImClone losing assignment/ownership of the patent]. This describes various EGF receptor monoclonal antibodies, including C225 (cetuximab). U.S. 4,943,533, Mendelsohn , et al., assigned to the University of California, July 24, 1990 (also European Patent No. 359,282), describes hybridoma cell lines expressing monoclonal antibodies against epidermal growth factor receptor, including the hybridoma secreting the IgG1 murine 225 monoclonal antibody (deposited as ATCC HB8508) with specificity for the N-terminal region of the human EGF receptor. Rorer (Rhone-Poulenc Rorer, later Aventis Pharma, now Sanofi Aventis S.A.) collaborated with the Univ. of California in the development of the 225 Mab.

Sanofi Aventis has been estimated by analysts to likely receive from ImClone about 3.5% of Erbitux U.S. sales.

In July 2004, ImClone disclosed (in a 10-K filing) for the first time that it has license agreements with the University of California, San Diego, and Aventis S.A. (now Sanofi Aventis S.A.), with ImClone solely paying royalties (not shared with BMS, since the licensing was concluded prior to BMS’ involvement).

See the ‘Tech. transfer (rDNA)” section of the Monoclonal Antibodies entry (#300) for further information about the complex patent, licensing, cross-licensing and patent disputes concerning recombinant chimeric and humanized monoclonal antibodies. ImClone has licensed recombinant chimeric/humanized monoclonal antibody design/construction and expression patents from Celltech Group plc. Celltech’s U.S. “Boss” patent covering basic recombinant chimeric/humanized monoclonal antibody technology was subsequently revoked, the claims of the Boss patent incorporated into the recent “New Cabilly” patent assigned to Genentech, and Celltech and Genentech cross-licensed their chimeric/humanized monoclonal antibody patents. As a result, those having licensed the Boss patent from Celltech, which would have expired in 2006, now apparently need to license Genentech’s patents (covering essentially the same technology), particularly the “New Cabilly” patent expiring in 2018.

In Jan. 2005, ImClone announced licensing agreements with Genentech and Centocor, a subsidiary of Johnson & Johnson (J&J), for the rights to patents covering various antibody technologies. These include U.S. 4,816,567 and 6,331,415, the Boss/Cabilly patents of Genentech; U.S. 5,807,715, the Morrison patent of Centocor; and U.S. Patent 5,770,195, the Hudziak patent of Genentech concerning use of epidermal growth factor receptor antibodies. These licenses related to Erbitux (and IMC-11F8, an fully-human EGFR-targeted antibody then in Phase I testing). Gross royalty expenses as a percentage of North American Erbitux sales for 2005 are now reported to be 12.75%, with a net royalty of 8.25% after reimbursements that ImClone receives for a portion of the royalties.

U.S. 5,807,715 (Morrison patent), “Methods and transformed mammalian lymphocyte cells for producing functional antigen-binding protein including chimeric immunoglobulin,” assigned to Stanford University and exclusively licensed to Centocor/J&J, concerns recombinant methods for expression of chimeric monoclonal antibodies.

U.S. 5,770,567 (Hudziak patent; a continuation of 5,677,877), “Monoclonal antibodies directed to the her2 receptor,” assigned to Genentech claims methods for use of HER2 (EGF) receptor antibodies, including treatment of various types of cancer.

In Jan. 2005, ImClone reported, “For Erbitux use in combination with anti-neoplastic agents, ImClone Systems’ gross royalty expense for all licenses, including Genentech, Centocor, Aventis and the University of California, is approximately 12.75 percent of North American sales and is effective from February 24, 2004. ImClone Systems receives reimbursements for a portion of these royalty expenses, resulting in a net royalty expense to ImClone Systems of 8.25 percent. After the first quarter of 2006, gross royalty expense will decrease to 9.75 percent and net royalty expense will decrease to 7.25 percent. For Erbitux monotherapy use, gross and net royalty expenses will be reduced because certain licenses are not applicable.”

In Sept. 2006, in Yeda Research And Development Co. vs. ImClone Systems and Aventis Pharmaceuticals (03 Civ. 8484), Yeda (Rehovot, Israel), acting as licensing/legal representative for the Weizmann Institute of Science (Rehovot, Israel), won an infringement suit in U.S. District Court, New York, and became the assignee/owner of U.S. 6,217,866, the main U.S. patent covering cetuximab. The suit was originally filed in 2003. The judge ruled that three scientists (Sela, Pirak and Hurwitz) from the Weizmann Institute were the true inventors of this patent, rather than the seven Aventis-associated staff listed on the patent, after finding no documentary evidence suggesting that any of the other named inventors even contemplated the claimed invention. Originally, the claimed Aventis-assocated inventors developed two monoclonal antibodies for use as research tools and gave samples to the Weizmann scientists, who found that one monoclonal antibody, mAb 108, administered in vivo in a mixture with chemotherapy drugs had synergistic effects on human tumor cells. A draft manuscript was sent to Meloy Labs (which later became Rorer then part of Aventis, now Sanofi Aventis), which began pursuing patent protection for both the antibodies and for the method of administering them with chemotherapy drugs (discovered by the Weizmann scientists). However, only the scientists employed by Meloy/Rorer were included as inventors on the patent applications. Meloy/Rorer and later, ImClone, even directly copied the text and figures from Weizmann manuscripts into their patent applications. The defendants claimed they had entirely conceived of the research conducted by the Weizmann scientists, who had simply followed their directions. The issued patent only includes claims concerning administering an antibody in a mixture with chemotherapy drugs (Weizmann contribution), and does not cover the antibodies themselves (Meloy/Aventis contribution). The Court denied a defense based on the the legal doctrine of laches which would have negated the suit due to unreasonable delays in bringing suit, finding that “in light of the defendants’ unclean hands, i.e., their copying from the Weizmann scientists’ draft material and their efforts to prevent Yeda from discovering defendants’ patent applications, Yeda did not unreasonably delay asserting its rights relative to the ‘866 patent.”

ImClone, after losing its patent to Yeda, concluded a license agreement with Yeda, and now is reported to pay royalties approaching 2%. Amgen, concerned about its EGFr monoclonal antibody, Vectibix (see related entry), also took a license from Yeda.

On May 4, 2004, Repligen Corp. filed a suit against ImClone alleging that use of a cell line for Erbitux manufacture infringes U.S. 4,663,281, “Enhanced production of proteinaceous materials in eucaryotic cells,” assigned to the Massachusetts Institute of Technology (MIT), and licensed to Repligen. The patent claims enhancer sequences used in plasmids and other recombinant constructs to increase transcription, e.g., by increasing the copy number of mRNA, and related expression of recombinant proteins. Repligen sought damages and a share or royalty income from Erbitux. The patent was originally exclusively licensed to Damon Biotech, from which Repligen acquired certain assets in 1991. The suit was filed a day before the patent expired, but Repligen had filed for an extension in April 2004 (based on the time spent in trials and consideration by FDA), which could add up to five years to the life of the patent. Repligen will share half of any award with MIT and its lawyers (working on contingency basis). The patent is commonly reported to expire in 2009.

According to Repligen, Dr. J. Mendelson, University of California, the inventor of recombinant cetuximab (see discussion at beginning of this section), collaborated with the National Cancer Inst. (NCI) and entered into a contract with Damon Biotech in 1989 to provide a transformed murine cell line (M225) for devleopment and manufacture of murine EGFr monoclonal antibody. Damon developed a recombinant chimeric EGFr Mab in 1990-1991, allegedly using MIT’s enhancer element. The cell line was allegedly eventually obtained by ImClone from NCI. Repligen originally approached ImClone about licensing its patent in 1996, seeking $200,000 plus 1% royalties, was denied, and waited for commercialization to pursue its dispute.

In July 2006, the U.S. District Court for Massachusetts refused to dismiss claims of patent infringement against ImClone and issued a Summary Judgment ruling in favor of Repligen and MIT, rejecting ImClone’s defense of patent exhaustion (in upcoming/future trials). The Court found that neither the transfer of patented technology by Damon Biotech (now Repligen) to the National Cancer Institute (NCI) nor the subsequent transfer to ImClone by NCI exhausted the proprietary rights of Repligen and MIT. The Court’s ruling eliminated patent exhaustion arguments as a potential defense for ImClone in future trials.

In June 2007, the Court found that ImClone lawyers had attempted to block the cooperation of a key witness; that ImClone’s actions prejudiced Repligen and MIT from prosecuting their case; barred one of ImClone’s in-house counsel from the case; and prohibited ImClone from any contact with the witness. The court allowed Repligen and MIT to introduce evidence of the improper conduct to the jury. Repligen and MIT continued with their case, including seeking a multiplier of any damage award based on ImClone’s willful infringement.

In Sept. 2007, prior to the start of a jury trial, ImClone and Repligen settled their patent dispute, with ImClone paying Repligen $65 million (of which it expects to keep about $40 million after giving MIT and its lawyers' their shares) for a nonexclusive license. ImClone also received a nonexclusive license from Repligen for enhancer sequences it had licensed (with the ability to sublicense) from Abbott Labs. (see next paragraph).

In Feb. 2007, Abbott Laboratories, Inc. filed a suit against ImClone in U.S. District Court alleging patent infringement. Abbott noted that the infringed patent covers “enhancer sequences” used to stimulate expression of the gene for the C225 antibody. This apparently refers to U.S. 6,783,756, “ Methods for regulating gene expression,” assigned to Abbott GmbH & Co., KG. This concerns the tetracycline-controllable transactivator (tTA), comprising a Tet repressor linked to a polypeptide activator of transcription, e.g., tet operator, and modulation of expression in eukaryotic cells by control of the concentration of tetracycline or analogs.

In Dec. 2007, ImClone, Sanofi Aventis and Yeda settled their dispute concerning Erbitux patent. Yeda, a commercial arm of the Weizmann Institute, was recognized as the sole owner of a U.S. 6,217,866 in the U.S. (previously assigned to Sanofi Aventis), while Yeda and Sanofi were recognized as co-owners of the patent's foreign counterparts. ImClone and Sanofi each paid Yeda $60 million in cash, and receive a worldwide licence under the 866 patent. with this settling all disputes. ImClone will pay a contingent payment to Yeda of a low single-digit royalty on sales in and outside the U.S., and will also pay Sanofi Aventis a low single-digit royalty on sales abroad. ImClone’s royalty rates for Erbitux sales, e.g., to BMS, remains unchanged.

In March 2013, in the case of Eli Lilly and Company et al. v. Genentech, Inc. et al. (4:13-cv-00919; filed February 28, 2013) in the Northern District of California - Plaintiffs: Eli Lilly and Company; Imclone Systems LLC and Defendants: Genentech, Inc.; City of Hope - Lilly/ImClone filed for a Declaratory judgment of invalidity, unenforceability, and noninfringement of of U.S. Patent No. 6,331,415 ("Methods of Immunoglobulins, Vectors, and Transformed Host Cells for Use Therein," Genentech/Roche's "Cabilly" patent) regardng Lilly's manufacture and sale of Erbitux.

Lonza (and ImClone and Boehringer Ingelheim) may use its glutamine synthetase (GS) system technology for expression of cetuximab (or may use the Abbott/Repligen tTA technology). This is covered by U.S. 5,846,534, originally assigned to Celltech Biologics plc, now assigned to Lonza Biologics plc, a subsidiary of Alusuise-Lonza Group, concerning use of GS gene as a selectable marker for identification and amplification of transformed CHO cells. Related patents include U.S. 5,770,359 and 5,747,308. The technology is coassigned to the University of Glasgow (which presumably receives a share of royalties). The GS system involves use of glutamine synthetase 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 spliced into recombinant vectors as a marker along with the gene(s) for the desired protein, with only successfully transformed cells capable of producing their own GS enzyme and surviving in glutamine-deficient culture media. Over 40 companies have licensed GS System technology for various uses.

Trials: Erbitux has not been proven to extend the lives of colorectal cancer patients. However, studies have shown the drug to shrink some tumors and delay the growth of others, especially when used with another cancer drug. The original early planned (2001, 2002) studies of Erbitux with chemotherapy compared to chemo alone for first-line use with endpoints including survival were never completed after ImClone experienced its stock trading scandal. This is in contrast with Avastin, for which Genentech has demonstrated extended survival. With Avastin now, largely based on this data, the standard-of-care for various types of tumors, any new trials with Erbitux would have to include comparison with Avastin. With the high cost of Avastin (tens of $1,000/patient) and Genentech unlikely to provide it free to a competitor, irrespective of other costs of conducting a large Phase III study, such a trial would be very expensive.

The efficacy and safety of Erbitux alone and in combination with irinotecan were studied in a randomized, controlled trial (329 patients), and Erbitux in combination with irinotecan was studies in an open-label, single-arm trial (138 patients). Erbitux was evaluated as a single agent trial in 57 patients. Safety data from 111 patients treated with Erbitux monotherapy were also submitted to support approval. All trials studied patients with EGFr-expressing metastatic colorectal cancer, whose disease had progressed after receiving an irinotecan-containing regimen.

In April 2003, Merck KGaA reported that positive preliminary analyses of results from its European pivotal controlled randomized Phase II clinical trial (BOND) of Erbitux in 330 patients with irinotecan-refractory colorectal cancer had been confirmed by an independent expert panel, and the company expressed confidence that the trial would support European Union approval. This trial compared Eribitux monotherapy vs. Eribitux plus irinotecan chemotherapy (i.e., it was not a placebo-controlled trial) in patients whose disease progressed on irinotecan chemotherapy or had relapsed within three months after treatment (while ImClone trials enrolled patients who had progressed within six months of irinotecan treatment). Patients failing on Erbitux monotherapy were allowed to cross-over to the combination regimen.

Results from Merck’s trial were reported at a meeting on June 1, 2003. Although results were in close agreement with earlier ImClone trials, BOND failed to support ImClone’s original strategy and trial designs, with the trial disproving ImClone’s belief that Erbitux would be effective as monotherapy. The combination of Erbitux plus irinotecan was significantly more effective than Erbitux monotherapy, although unexpectedly high efficacy was observed with monotherapy. A response rate based on tumor shrinkage of 22.9% was observed in the combination group vs. 10.8% response rate in the monotherapy group, with patients receiving the combination showing significantly improved rates of disease control and a significantly longer time to disease progression. For comparison, the only other two drugs approved for colorectal cancer in the past decade (since 1994), irinotecan (Camptosar; approved in 1998) and oxaliplatin (Eloxatin from Sanofi Aventis; approved in 2002), had response rates of about 13% and 9%, respectively, in their monotherapy clinical trials. Unlike prior ImClone trials, BOND used a stricter definition of patients being refractory to chemotherapy (irinotecan), with over 75% of patients having progressed or relapsed within 30 days after treatment. There was no signifcant difference in survival (a parameter for which the trial was not designed, and not needed for acellerated approval) between the two arms of the BOND trial. Based on the results of BOND, BMS resubmitted its BLA seeking FDA approval of Erbitux.

In mid-2003, BMS initiated several new Phase III trials with Erbitux for second-line treatment of colorectal cancer, both comparing Erbitux plus chemotherapy vs. chemotherapy alone, with survival being the primary endpoint. One trial studying patients having failed first-line treatment with the FOLFOX (5-FU/LV/oxaliplatin) regimen is comparing irinotecan monotherapy vs. Erbitux plus irinotecan. Another trial in patients having failed on first-line 5-FU/LV/irinotecan therapy is comparing FOLFOX vs. FOLFOX plus Erbitux.

In Oct. 2004, Merck KGaA began a European, Latin American and Asian Phase III trial (EMR-046 ) in 1,100 patients for first-line treatment of advanced non-small cell lung cancer (NSCLC). Overall survival is being compared in patients receiving Erbitux plus platinum-based chemotherapy and vinorelbine vs. chemotherapy and vinorelbine alone ( a standard treatment in Europe). This is essentially a repeat of the LUCAS Phase II trial, which showed that 84% of patients in the Erbitux plus chemotherapy. In the same month, ImClone and BMS started a Phase III trial (IMCL-0452)in 800 patients for second-line NSCLC treatment. The trial has an a Special Protocol Assessment (SPA) from FDA, and is comparing chemotherapy alone (either docetaxel or pemetrexed) vs. Erbitux plus chemotherapy. Promising results in second-line treatment could support supplemental approval in late 2006/early 2007, with this potentially increasing sales by $1 billion or more (with 134,000 cases of NSCLC in the U.S. alone, of which about 30% or 41,000 are second- and third-line patients).

In Jan. 2005, the National Cancer Institute (NCI, NIH) halted patient enrollment in an open-label U.S. Phase III trial of Erbitux for colorectal cancer. The study was expected to enroll 2,200 patients, but experienced difficulty enrolling patients after the approval of Avastin from Genentech (see related entry). NCI started another trial later in the year (see below).

The Aug. 2005 sBLA, approved in March 2006, for squamous cell carcinoma of the head and neck (SCCHN) was primarily based on re-analysis of results of the randomized, international IMC-9815 Phase III trial conducted by ImClone Systems and Merck KGaA. The trial examined the impact of combining radiation with or without ERBITUX on locoregional control and overall survival in 424 patients with locally or regionally advanced SCCHN. Erbitux plus radiation showed a statistically significant improvement in locoregional control compared to radiation alone, including a near doubling in median survival. Adding Erbitux to radiation can boost patient survival rates by about 20 months without significantly increasing side effects. Average overall survival was more than four years (49 months) for patients treated with both radiation plus Erbitux, a major improvement of about 20 months over the average 29.3 months for patients treated with radiation alone. The average time of “locoregional control” — the time elapsed before cancer spread further — was 14.9 months for those in the radiation-only group and 24.4 months for those receiving the combination. Final results from this study were reported in the Feb. 9, 2006, issue of the New England Journal of Medicine. The sBLA also included results from an open-label, multicenter Phase II trial (EMR-016), conducted by MerckKGaA, which evaluated the response rate of ERBITUX monotherapy in 103 patients with recurrent and/or metastatic SCCHN who have failed platinum-based chemotherapy.

In Sept. 2005, the National Cancer Institute (NCI) initiated a 2,289 patient Phase III trial (CALGB 80405) to evaluate the clinical efficacy of Erbitux and/or Avastin plus chemotherapy for first-line treatment of advanced or metastatic colorectal cancer. The primary endpoints include survival. Patients receive Erbitux plus FOLFOX (5-fluorouracil, oxaliplatin and leucovorin) or FOLFIRI (5-fluorouracil, leucovorin and irinotecan), Erbitux and Avastin plus FOLFOX or FOLFIRI, or Avastin plus FOLFOX or FOLFIRI as control. This trial will likely take several years to enroll patients and several more years before results become available. If the combination of Erbitux and Avastin works best, it will present a major problem -- treating a patient with both Erbitux and Avastin, plus chemo, for 15 months could cost nearly $250,000.

In Nov. 2006, mixed results were reported from two randomized Phase III trials of Erbitux in patients with metastatic colorectal cancer. These were the first large, randomized studies to examine the impact of Erbitux treatment on overall survival in colon cancer. One randomized, multicenter, Phase III trial (NCIC-CO.17) compared Erbitux monotherapy plus best supportive care with best supportive care alone in patients with metastatic colorectal cancer whose disease was refractory to all available chemotherapy, including irinotecan, oxaliplatin and fluoropyrimidines. The study was conducted by the National Cancer Institute of Canada Clinical Trials Group in collaboration with the Australasian Gastro-Intestinal Trials Group. This was a 572-patient randomized study without a crossover. Erbitux met its primary efficacy endpoint of a statistically significant improvement in overall survival. These are the first data of an anticancer therapy improving overall survival in this refractory colorectal cancer treatment setting.

The second trial reported in Nov. 2006 was Merck’s Phase III, randomized study, Erbitux Plus Irinotecan in Colorectal Cancer (EPIC) study comparing irinotecan vs. irinotecan plus Erbitux in ~1,300 patients not responding to first-line oxaliplatin-based chemotherapy (i.e, the trial tested second-line therapy; FOLFOX failures). Patients were treated until their disease progressed. A number of patients in the irinotecan arm of EPIC had progressed on their therapy and subsequently received Erbitux plus irinotecan, a highly active treatment, which may have made it harder for an effect on overall survival to be seen. Secondary efficacy endpoints (progression-free survival, response rate) strongly favored the combination of Erbitux plus irinotecan, but the primary endpoint (overall survival) was not met. Merck claimed, “These are the first data of an EGFr targeted antibody to demonstrate overall survival in the third-line treatment setting.” EPIC was important, because it would have opened up the second-line colorectal market, where Erbitux then had a 10% market share, and payors can continue to resist Erbitux second line use. Further EPIC results were reported in 2007 (see below).

In Jan. 2007, ImClone reported that the Phase III CRYSTAL trial of Erbitux plus FOLFIRI (5-fluorouracil, leucovorin and irinotecan) chemotherapy, conducted by Merck KGaA, now Merck Serono, in Europe, met its primary endpoint in patients with previously untreated metastatic colorectal cancer. Erbitux plus irinotecan-based therapy met the primary endpoint of increasing median duration of progression-free survival in patients with previously untreated metastatic colorectal cancer compared with chemotherapy alone. In this 1,000-plus patient trial randomized trial, patients received an initial dose of Erbitux (400mg/m2) followed by a weekly dose (250mg/m2), and chemotherapy, while the second arm received chemotherapy alone. This trial will likely be used to eventually seek approvals for first-line treatment of colorectal cancer, which would open Erbitux to a much larger market. The efficacy observed was particularly welcomed by ImClone, since Erbitux did not improve overall survival when used as a second-line treatment for metastatic colorectal cancer, as shown in the Phase III EPIC trial, while a second study of third-line therapy did meet that endpoint.

In April 2007, results were reported from the EXTREME (Erbitux+chemo in head-and-neck cancer) study – a Phase III study of first-line treatment with Erbitux combined with cisplatin plus 5-fluorouracil (5-FU) or carboplatin plus 5-FU in patients with previously untreated recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). An estimated one-third of recent head and neck cancer patients have been treated with the platinum-based agent chemotherapy regimens. The study met its primary endpoint of increased overall survival. This was the first large, randomized clinical trial to examine the impact of Erbitux in combination with platinum-based chemotherapy on overall survival in SCCHN. Patients were treated with either primary plus platinum-based chemotherapy (cisplatin or carboplatin plus infusional 5-fluorouracil [5-FU]) or platinum-based chemotherapy alone. The study met the primary endpoint of significantly increasing overall survival. The median overall survival for patients in the primary plus platinum-based chemotherapy arm was 10.1 months, and 7.4 months for patients treated with platinum-based chemotherapy alone (Hazard Ratio [HR], 0.797 [p = 0.036]). Erbitux plus platinum-based chemotherapy also conferred increased progression-free survival (PFS) and a higher response rate compared with chemotherapy alone. The median PFS values were 5.6 months and 3.3 months (HR = 0.538 [p < 0.0001]) and the response rates were 35.6% and 19.5% (p = 0.0002) for patients treated with Erbitux plus chemotherapy and chemotherapy alone, respectively. This was the primary trial supporting the Oct. 2008 BLA supplement filing for first-line head and neck cancer treatment.

In April 2007, a Phase III trial with Erbitux plus gemcitabine (a chemotherapy drug) failed to show first-line efficacy in patients with locally advanced unresectable or metastatic pancreatic cancer. The trial did not meet its primary endpoint of improving overall survival. This open-label, randomized study sponsored by the National Cancer Institute (NCI) compared Erbitux plus gemcitabine to gemcitabine alone in more than 700 patients with pancreatic cancer in the first-line treatment setting. Encouraged by prior positive Phase II trial results, ImClone stated, “We still consider pancreatic cancer to be of the utmost priority and we intend to pursue additional evaluations with Erbitux including a pilot study of ERBITUX and bevacizumab (Avastin from Genentech) with or without gemcitabine, as well as our pipeline agents, to improve the outcome for patients with pancreatic cancer.”

In April 2007, further results from the EPIC randomized, open-label, multi-center Phase III trial were reported comparing Erbitux plus irinotecan to irinotecan alone in patients with metastatic colorectal cancer (mCRC) who failed first-line therapy. The secondary endpoints of progression-free survival and response rate were significantly higher in the Erbitux-irinotecan arm, with the median time of survival without disease progression improved by 54% and a significant 31% reduction in the risk of disease progression (Hazard ratio, 0.692; 95% CI = 0.617– 0.776; p<0.0001). Patients in the Erbitux-irinotecan arm were four times more likely to experience a 50% reduction in tumor size over patients treated with irinotecan alone (p<0.0001). As previously reported, the study’s primary endpoint of overall survival was not different between the two groups (Hazard ratio, 0.975; 95.03% CI = 0.854 – 1.114; p=0.7115). Patients who received Erbitux-irinotecan had a median overall survival of 10.71 months and median progression-free survival of 4 months, had an overall response rate in 16.4% of patients, and 61.4% of patients experienced disease control. Patients who received irinotecan alone experienced median overall survival of 9.99 months and median progression-free survival of 2.6 months, an overall response rate of 4.2% of patients and 45.8% of patients experienced disease control.

A study in the May 2007 issue of The Lancet Oncology found that 97% of patients with cancer treated with EGFr monoclonal antibodies (cetuximab or panitumumab) have some degree of magnesium loss (hypomagnesaemia) and “magnesium wasting will occur in all patients.”

In July 2007, results were reported from an open-label Phase III FLEX (First-Line Treatment for Patients with Epidermal growth factor inhibitor (EGFR)-EXpressing Advanced NSCLC) trial of Erbitux plus a taxane and carboplatin in the first-line treatment for metastatic non-small cell lung cancer (NSCLC). Patients with newly diagnosed non-small cell lung cancer were randomized to receive chemotherapy plus Erbitux or chemotherapy alone. The study failed to meet its primary endpoint of progression-free survival (PFS) as assessed by an independent radiology review committee. Overall survival in the Erbitux-chemo patients was 11.3 months compared to 10.1 months for the chemotherapy-only patients, a difference of five weeks. Restated. the FLEX study's hazard ratio was 0.87, which means that patients treated with Erbitux had a 13% reduction in the relative risk of death compared to patients treated with chemotherapy alone. The result was statistically significant with a p=0.044. The generally accepted threshold for statistical significance in a clinical trial is a p value of 0.05, or 5%, so the overall survival benefit for Erbitux was not very robust. The response rate, or the percentage of patients whose tumors shrank significantly, was higher in the Erbitux-chemo patients (36.3%) compared to the chemo-only patients (29.2%). This was a statistically significant result. This was the first study in which an EGFr inhibitor has produced a survival benefit that is both statistically significant and clinically relevant. FLEX also showed variations in efficacy in Causasian vs. Asian patients. Asian patients treated with Erbitux plus chemo showed a median overall survival of 17.6 months compared to 20.4 months for those reated with chemotherapy alone (i.e., shortened survival), compareded to a median overall survival of 10.5 months vs. 9.1 months (slight survival advantage) for Caucasian patients. Dissimilarly, Tarceva, another EFGr inhibiting drug marketed by OSI Pharmaceuticals, is recognized as more effective in some Asians than Caucasians.

;In early 2008, studies noted that severe allergic reactions to Erbitux were unusually high in many southern U.S. states. The nationwide rate of severe allergic reactions to Erbitux is only about 2%. However, 22% of patients who lived on a line across North Carolina, Tennessee, northern Arkansas and southern Missouri showed severe allergic reactions. ImClone and BMS planned to test some U.S. cancer patients for a tick-bite antibody that can cause severe allergic reactions with Erbitux.

The sBLA approval for 1st-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) was primarily based upon the results of the EXTREME study, published in the New England Journal of Medicine in Sept. 2008. EXTREME showed that adding Erbitux to platinum-based chemotherapy significantly prolonged median overall and progression-free survival, and also significantly increased response rate. Patients treated with Erbitux plus chemotherapy experienced the following improvements compared to chemotherapy alone: median overall survival increase of nearly three months (10.1 vs. 7.4 months; p=0.04), equating to a 20% reduction in the risk of death (HR: 0.80) during the study period; 70% increase in median progression-free survival (5.6 vs. 3.3 months; p<0.001);and 80% relative increase in response rate (36% vs. 20%; p<0.001).

In late spring-early summer 2012, disappointing results were reported from two Phase III trials with Erbitux. First, efficacy fell short in a trial of adjuvant treatment after colon-cancer surgery; and then in a stomach cancer trial, Erbitux failed (didn't delay tumor growth for longer than standard chemotherapy). This was expected to result in slowing of growth in Erbitux sales. At about the same time, Erbitux was facing refusal by the EU to extend approval to lung cancer.

In July 2012, it was reported that the EXPAND Trial of Erbitux in advanced gastric cancer did not meet the primary endpoint of extending progression-free survival (PFS), and also failed to increase overall survival, the secondary endpoint of the study. The Phase III clinical trial EXPAND had assessed Erbitux in combination with cisplatin and capecitabine as a first-line treatment for patients with advanced gastric adenocarcinoma including adenocarcinoma of the gastro-esophageal junction (GEJ).

Medical: The recommended dose for colorectal cancer is 300 mg by intravenous infusion every four weeks. The contents of the vial (300 mg/15 mL) are diluted in 100 mL 0.9% Sodium Chloride Injection, USP, and infused over about one hour. Tysabri’s labeling allows use in first-line patients and those failing other MS therapies, either as monotherapy or in combination with other MS therapeutics. Currently, these include two forms of beta interferon, Avonex from Biogen Idec and Betaseron from Berlex/Schering; and copaxome glatiramin from Teva Pharmaceuticals.

The recommended dose of Erbitux in combination with radiation therapy for squamous cell carcinoma of the head and neck is 400 mg/m2 as an initial loading dose (first infusion) administered as a 120-minute intavenous infusion (maximum infusion rate 5 mL/min) one week prior to initiation of a course of radiation therapy. The recommended weekly maintenance dose (all other infusions) is 250 mg/m2 infused over 60 minutes (maximum infusion rate 5 mL/min) weekly for the duration of radiation therapy (6-7 weeks). In clinical studies, Erbitux was administered 1 hour prior to radiation therapy. The recommended regimen for single-agent Erbitux in the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck is a 400-mg/m2 initial dose followed by 250 mg/m2 weekly until disease progression or unacceptable toxicity.

The recommended dose of Erbitux, in combination with irinotecan or as monotherapy, is 400 mg/m2 as an initial loading dose (first infusion) administered as a 120-minute intravenous infusion (maximum rate 5 mL/min). The recommended weekly maintenance dose (all other infusions) is 250 mg/m2 infused over 60 minutes (maximum rate 5 mL/min). Erbitux may be administered using an infusion or syringe pump. Premedication with an H1 antagonist (e.g., 50 mg of diphenhydramine i.v.) is recommended. The package insert includes a prominent black box warning of severe, but rarely fatal (<1/1000), infusion reactions upon administration in about 3% of patients, with about 90% of severe infusion reactions associated with the first infusion of Erbitux.

Besides its approved indications:, Erbitux has increasingly used off-label (until approved) for treatment of other cancers, particularly head and neck cancer.

Disease: Colorectal cancer is one of the most common cancers in the U.S., with about 147,500 new cases diagnosed in 2003. More than 200,000 Western Europeans develop colorectal cancer each year , with more than half of these already at an advanced stage of the disease at first diagnosis. About 29,000 Americans are diagnosed with head and neck cancer a year, according to the FDA. This includes cancers of the tongue, mouth, pharynx and larynx.

About 77% of patients with colon cancer express EGFr (have detectable EGFr), and are potential candidates for Erbitux treatment. Erbitux can dramatically shrink colon tumors in many of these patients, but has little effect in others lacking EGFr+ tumors.

There are an estimated ~45,000 new cases of squamous cell carcinoma of the head and neck (SCCHN) cancer each year in the U.S. About 30,000 of those patients are treated with radiation and the remaining 15,000 are treated with chemotherapy. About three-fourths of SCCHN patients are diagnosed with stage III or IV disease.

Market: Despite the problems it encountered in development and associated scandals, e.g., involving Dr. Waksal and M. Stewart, Erbitux is a much needed product and, sales are now over $1 billion/year, even with competition from Vectibix (see entry below).      

The Average Wholesale Price (AWP) reported in the 2007 edition of the Red Book is $576.00/syringe with no Direct Price (DP; bulk discount price) reported. The 2005 AWP was $576/vial.

The cost for colon cancer treatment with Erbitux in the U.S. is commonly reported to about $2,400 weekly dose or about $10,000/month ($120,000/year). Other sources report $8,800/month, but this could be based on wholesale acquisition costs. The average duration of treatment (course) for colorectal cancer is three months, with this costing $26,400-$28,700. The total treatment duration, but not dosage, in head and neck cancer of six to seven weeks is significantly shorter than the durations in colorectal cancer, so the average cost per treatment course is closer to ~$14,000. Note, Vectibix (see entry below), an EGRr monoclonal antibody also approved for colon cancer, is priced at a ~20% discount relative to Erbitux.

Erbitux from Merck typically costs €4,000/month in Western Europe.

In 2012, Merck had 887 million euros ($1.15 billion) in Erbitux sales, while Bristol-Myers Squibb generated $702 million in sales.

2013 international sales reported by Merck Serono were $1.225 billion.

Total worldwide 2012 sales were $1.591 billion; $1.82 billion in 2011; $1.79 billion in 2010; 1.63 billion in 2009' $1.47 billion in 2008; $1.153 billion in 2007 (IMS); ~$1.089 billion in 2006, and $778.1 million in 2005. Erbitux achieved blockbuster (>$1 billion/year) sales in 2006.

Total BMS/U.S. sales of Erbitux were $662 million in 2010; $692 million in 2007; about $652.6 million in 2006, and $413.1 million in 2005. Total 2006 international (European) sales of Erbitux by Merck KGaA were about $436 million, and were 218 million euros (~$265 million) in 2005. For 2004, ImClone reported, “Full-year in-market sales of Erbitux were $260.8 million in the U.S.” From its U.S. launch to the end of 2005, ImClone received $650 million in milestone and royalty payments from BMS and $60 million from Merck KGaA.

Lilly reported Erbitux manufacturing revenue of $71.9 million in 2010, or about 4% of total revenue.

Presuming Erbitux is approved for non-small cell lung cancer, its market will further expand to, particularly, include patients ineligible to receive treatment with Avastin (see related entry), which has shown much better survival results in clinical trials. Avastin cannot be used in about 50% of patients, including those with squamous cell carcinoma type of lung cancer, due to safety concerns. However, the five week survival advantage provided by adding Erbitux to chemotherapy may not be perceived as cost-effective by many.

In March 2008, analysts with Friedman, Billings and Ramsey (FBR) projected U.S. sales of Erbitux to be $805 million in 2008; $1.012 billion in 2009; $1.253 billion in 2010; $1.339 billion in 2011. European sales were estimated to be $770 million in 2008; $795 million in 2009; $845 million in 2010; and $915 billion in 2011.

In spring 2007, negative results from a Phase III trial with competing Vectibix from Amgen for first-line colorectal cancer (see Trials section of the Vectibix entry below), combined with building medical community consensus that Erbitux apparently has fewer safety problems resulted in many analysts increasing their sales projections for Erbitux (at the expense of Vectibix). However, Erbitux experienced its own negative trial results – failing to show efficacy (improve survival) in first line pancreatic cancer patients (see the Trials section above).

In Nov. 2006, a Decision Resources/Pharmacor report projected that Erbitux will become the market leader among treatments for squamous cell carcinoma of the head and neck, with sales of $250 million in 2015, a five-fold increase over the total head and neck cancer market in 2005. Erbitux is expected to set the clinical and sales benchmarks for these products.

With the spring 2007 positive results on squamous cell carcinoma of the head and neck (SCCHN) cancer survival reported by the EXTREME study (see trials section below), up to 60% of SCCHN patients in coming years are projected to be treated by an Erbitux/chemotherapy combination (up from about 1/3 treated with chemotherapy), further expanding the market for Erbitux.

Erbitux is expected to continue to be used widely in refractory colorectal cancer. However, it has not yet been shown to prolong survival, and the market for Erbitux will likely be influenced by reports from clinical trials, including trials with Erbitux, itself, and competitors, e.g., Vectibix.

In Jan. 2007, after completion of an appeal process, the National Institute for Health and Clinical Excellence (NICE), U.K., published final guidance on the use of Erbitux for the treatment of metastatic colorectal cancer. NICE performs cost-benefit analyses used to determine use of pharmaceuticals by the U.S. National Health Service (NHS). NICE rule that Erbitux was not cost-effective, not a good use of NHS funds. Treatment activists and others were considerably upset with this ruling, effectively making Erbitux unavailable to patients in England and Wales on the basis of cost, rather than its proven efficacy. At the same time, NICE ruled in against use of Avastin (see related entry) for treatment of metastatic colorectal cancer. The U.K. is the only country in Europe where Erbitux has been licensed but is not routinely available to patients.

In May 2007, NICE published final guidance on the use of Erbitux for the treatment of head and neck cancer. As with Erbitux for colorectal cancer, NICE refused to recommend its use. NICE’s chief executive noted that the evidence presented did not persuade NICE that cetuximab “works any better or offers better therapeutic value than existing treatments for head and neck cancer.”

In April 2008, after delaying introduction of Erbitux in Canada for two years due to disputes with the federal Patented Medicine Prices Review Board (PMPRB) over reimbursement prices, BMS accepted the PMPRB price. Once formal approval, including acceptance of the price, is completed, coverage will be up to each of Canada's provinces.

In July 2009, Merck KGaA requested re-examination of a prior negative opinion from the Committee for Medicinal Products for Human Use (CHMP), European Medicines Agency (EMEA), concerning the use of Erbitux in combination with platinum-based chemotherapy for the first-line treatment of patients with non-small cell lung cancer (NSCLC).

In Aug. 2009, the National Institute for Health and Clinical Excellence (NICE), U.K., confirmed its recommendation of Erbitux (cetuximab) as a first-line treatment for metastatic colorectal cancer..

In Nov. 2011, the National Institute for Health and Clinical Excellence (NICE), U.K., rejected Erbitux as second-line treatment for advanced colon cancer.

R&D: Erbitux is showing promise in trial for treatment of prostate and pancreatic cancers used as a sensitizer for radiation therapy.

Competition: The current major competition for Erbitux is panintumomab (Vectibix; from Amgen/Abgenix; see entry below). Other than differences in efficacy and safety to be resolved by clinical trials, Vectibix is cited by some as having some advantages, including reduced incidence of allergic reactions, higher potency (less agent required), lower price, and every-other-week dosing convenience, while others disagree. Any differences in incidence rates of allergic reactions are expected to be negligible or small, with Erbitux having only a 2%-3% allergic reaction rate. Erbitux does not appear to induce human anti-chimeric antibodies (HACA) or antibody reactions to the non-human portions of the molecule, while Vectibix is a fully human monoclonal antibody similarly expected not to induce antibodies. Erbitux’s weekly dosing schedule is not a significant problem in third-line patients, the initial market for Vectibix, because these patients are typically monitored weekly anyway. Patient chair time is an hour per infusion for both Erbitux and Vectibix, but the more frequent dosing with Erbitux provides physicians greater office-time reimbursement (i.e., chair time and $130 per-infusion payment).

The main marketing-related difference between Erbitux and Vectibix is expected to be costs, with Amgen initially pricing its product about 20% below that of Erbitux. ImClone has noted that lower price is only an advantage if it can be sustained, and the company has the option of reducing the price in response to Vectibix, and that inertia/momentum from Erbitux treatment of earlier-stage patients will make any competitior’s capturing of market share more difficult than many expect. Also, differences between the two molecules may result in different efficacy profiles. Vectibix is an IgG2 antibody and lacks the “effector” function that IgG1 antibodies have, including Erbitux and all other currently marketed recombinant monoclonal antibodies. Effector function enables IgG1 antibodies to mark cancer cells for destruction, e.g., by antibody-dependent cell-mediated cytotoxicity (ADCC) immune responses in which antibodies, by coating target cells, make them vulnerable to attack by T-cells. Erbitux is also slightly ahead in terms of trials and related approvals.

Other companies are developing and bringing EGFr-targeted therapeutics to market. For example, Genentech, Hoffmann-La Roche, and OSI Pharmaceuticals developed and received approval for Erlotinib (Tarceva), an oral small molecule drug (not biopharmaceutical) EGFr inhibitor.