ImClone Systems and Bristol-Myers Squibb Update Status of First-Line Squamous Cell Carcinoma of the Head and Neck Supplemental Biologics Application for Erbitux in U.S.

NEW YORK--(BUSINESS WIRE)--Mar 2, 2009 - ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company (NYSE: LLY), and Bristol-Myers Squibb Company (NYSE: BMY) today announced that the companies received a complete response letter from the U.S. Food and Drug Administration (FDA) for the first-line squamous cell carcinoma of the head and neck (SCCHN) supplemental Biologics License Application (sBLA) for Erbitux (cetuximab). The sBLA was accepted for filing and granted a priority review status in October 2008.

In its complete response letter, 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 United States. Clinical supplies used in this sBLA were provided by Merck KGaA (ImClone's partner for Erbitux outside of North America).

As previously announced, ImClone Systems and Bristol-Myers Squibb recently withdrew the advanced non-small cell lung cancer sBLA for Erbitux because of the same matter. In both cases, the companies continue to work with the FDA to confirm pharmacokinetic comparability.

The companies' discussions with the FDA do not have any impact on currently-marketed Erbitux, including the safety and efficacy of the product for approved indications. Commercial supply for currently-marketed Erbitux is provided by ImClone.

In head and neck cancer, Erbitux is approved by the FDA to treat locally or regionally advanced SCCHN in combination with radiation therapy, and as a single agent for the treatment of patients with recurrent or metastatic SCCHN for whom prior platinum-based therapy has failed. In colorectal cancer (CRC), Erbitux is approved by the FDA as: a single agent for the treatment of EGFR-expressing metastatic CRC after failure of both irinotecan- and oxaliplatin-based regimens; a single agent for the treatment of EGFR-expressing metastatic CRC in patients who are intolerant to irinotecan-based regimens; and in combination with irinotecan for the treatment of EGFR-expressing metastatic CRC in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing metastatic colorectal carcinoma.

For full prescribing information, including boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest, visit http://www.Erbitux.com.

About Head and Neck Cancer

According to the American Cancer Society, 87,290 Americans were diagnosed with head and neck cancer in 2008, including cancers of the tongue, the rest of the mouth, the salivary glands and inside the throat, the voice box, eye and orbit, thyroid and the lymph nodes in the upper neck. In addition, it is estimated that more than 13,090 Americans died from this disease in 2008. Head and neck cancer most often affects people over the age of 50, and men are twice as likely to be diagnosed as women. The most common risk factors are tobacco and excessive alcohol use.

About Erbitux (Cetuximab)

Erbitux (cetuximab) is a monoclonal antibody (IgG1 Mab) designed to inhibit the function of a molecular structure expressed on the surface of normal and tumor cells called the epidermal growth factor receptor (EGFR, HER1, c-ErbB-1). In vitro assays and in vivo animal studies have shown that binding of Erbitux to the EGFR blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased matrix metalloproteinase and vascular endothelial growth factor production. In vitro, Erbitux can mediate antibody-dependent cellular cytotoxicity (ADCC) against certain human tumor types. In vitro assays and in vivo animal studies have shown that Erbitux inhibits the growth and survival of tumor cells that express the EGFR. No anti-tumor effects of Erbitux were observed in human tumor xenografts lacking EGFR expression.

Important Safety Information

Infusion Reactions

Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving Erbitux® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000
Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest

Most (90%) of the severe infusion reactions were associated with the first infusion of Erbitux despite premedication with antihistamines
Caution must be exercised with every Erbitux infusion, as there were patients who experienced their first severe infusion reaction during later infusions
Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions
Cardiopulmonary Arrest

Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux, as compared to none of 212 patients treated with radiation therapy alone. Fatal events occurred within 1 to 43 days after the last Erbitux treatment

Carefully consider the use of Erbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks

Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after Erbitux therapy

Pulmonary Toxicity

Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in clinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux where ILD is confirmed


Dermatologic Toxicities

In clinical studies of Erbitux, dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving Erbitux therapy. Acneform rash occurred in 76-88% of 1373 patients receiving Erbitux in clinical trials. Severe acneform rash occurred in 1-17% of patients


Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days
Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae
Sun exposure may exacerbate these effects


Erbitux Plus Radiation Therapy and Cisplatin

The safety of Erbitux in combination with radiation therapy and cisplatin has not been established
Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck


Two of 21 patients died, one as a result of pneumonia and one of an unknown cause
Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events
Electrolyte Depletion

Hypomagnesemia occurred in 55% (199/365) of patients receiving Erbitux and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux therapy
Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, Erbitux therapy
Replete electrolytes as necessary
Late Radiation Toxicities

The overall incidence of late radiation toxicities (any grade) was higher with Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the Erbitux and radiation versus radiation alone arms, respectively

The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the Erbitux plus radiation therapy arms
Pregnancy

In women of childbearing potential, appropriate contraceptive measures must be used during treatment with Erbitux and for 6 months following the last dose of Erbitux. Erbitux should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus
Adverse Events

The most serious adverse reactions associated with Erbitux across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus
The most common adverse reactions associated with Erbitux (incidence (>=)25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection
The most frequent adverse events seen in patients with carcinomas of the head and neck receiving Erbitux in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ‰¥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for Erbitux in combination with radiation therapy ((>=)10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%)
The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the Erbitux + best supportive care arm (incidence ‰¥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events ((>=)10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/desquamation (12%), and other-gastrointestinal (10%)
The most frequent adverse events seen in patients with metastatic colorectal cancer (n=354) treated with Erbitux plus irinotecan in clinical trials (incidence ‰¥50%) were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common grade 3/4 adverse events ((>=) 10%) included: diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneform rash (14%)

About ImClone Systems
ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company, is committed to advancing oncology care by developing and commercializing a portfolio of targeted biologic treatments designed to address the medical needs of patients with a variety of cancers. ImClone's research and development programs include growth factor blockers and angiogenesis inhibitors. ImClone's research operations are located in New York City, with additional administration and manufacturing facilities in Branchburg, New Jersey. Additional information about ImClone is available at www.imclone.com.

About Eli Lilly and Company
Lilly, a leading innovation-driven corporation, is developing a growing portfolio of first-in-class and best-in-class pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers – through medicines and information – for some of the world's most urgent medical needs. Additional information about Lilly is available at www.lilly.com.

About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to extend and enhance human life. For more information, visit www.bms.com.
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding product development. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. Among other risks, there can be no guarantee that the supplemental application will be approved. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's and Lilly's businesses, particularly those identified in the cautionary statement and risk factors discussion in Bristol-Myers Squibb's and Lilly's Annual Reports on Form 10-K, in their Quarterly Reports on Form 10-Q and their Current Reports on Form 8-K. Neither Bristol-Myers Squibb nor Lilly undertakes any obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

Contact: Bristol-Myers Squibb
Media:
Sarah Koenig, 609-252-4145
sarah.koenig@bms.com
Investors:
John Elicker, 609-252-4611
John.Elicker@bms.com
or
ImClone Systems
Tracy Henrikson, 908-243-9945
Tracy.Henrikson@imclone.com
or
Eli Lilly and Company
Judy Kay Moore, 317-277-6265
moore_judy_k@lilly.com

Posted: March 2009

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