LILLY, BRISTOL-MYERS SQUIBB RESTRUCTURE ERBITUX® (CETUXIMAB) COLLABORATION IN NORTH AMERICA

Eli Lilly and Company(NYSE: LLY) and Bristol-Myers Squibb Company(NYSE: BMY) today announced that the companies have agreed to transfer Erbitux® (cetuximab) in North America, including the U.S., Canada and Puerto Rico from Bristol-Myers Squibb to Lilly. Rights include, but are not limited to,full commercialization and manufacturing operational responsibilities. The companies’ decision comes after a 14-year  successful collaboration, which includes Lilly’s wholly-owned subsidiary ImClone LLC.. Bristol-Myers Squibb and Lilly will work closely to ensure a smooth transition on this important product for patients with certain advanced colorectal and head and neck cancers.

“Fully bringing Erbitux into the Lilly Oncology portfolio accelerates Lilly’s commitment and leadership in gastrointestinal cancers to include an effective treatment for advanced colorectal cancer as well as head and neck cancer,” said Sue Mahony, Ph.D., senior vice president and president of Lilly Oncology. “Our good work on Erbitux began with its development at ImClone and has continued with Bristol-Myers Squibb. We look forward to carrying on these efforts for people battling select advanced colorectal and head and neck cancers.”

“Bristol-Myers Squibb is incredibly proud to have built Erbitux into a major brand and an important therapy for so many patients with certain colorectal and head and neck cancers,” said Murdo Gordon, head of worldwide markets, Bristol-Myers Squibb. “This agreement further aligns our Oncology organization with our prioritized opportunities in immuno-oncology, across both solid tumors and hematologic malignancies.”

The transition is expected to be completed in the fourth quarter of 2015.Bristol-Myers Squibb will receive tiered royalties based on net product sales in North America after the completion of the transition through September 2018.  

About ERBITUX

Erbitux is an epidermal growth factor receptor (EGFR) antagonist indicated for treatment of:

Colorectal Cancer

Erbitux(cetuximab) is indicated for the treatment of EGFR-expressing K-ras wild-type metastatic colorectal carcinoma (mCRC)

·         in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment. The benefits and risks of ERBITUX in combination with FOLFIRI, for first-line treatment in mCRC patients, have been observed only in a subgroup analysis of patients with ECOG performance status of 0 or 1.

·         in combination with irinotecan in patients who are refractory to other irinotecan-based chemotherapy regimens.

·         as a single agent in patients who are intolerant to irinotecan-based chemotherapy.

·         as a single agent for the treatment of patients who have failed both irinotecan- and oxaliplatin-based regimens and who have received a fluoropyrimidine.

Use of Erbitux is not indicated for the treatment of colorectal cancer in patients with K-ras mutations or unknown K-ras status.

Squamous Cell Carcinoma of the Head and Neck (SCCHN)

ERBITUX (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck.

CONTRAINDICATIONS

ERBITUX (cetuximab) is contraindicated in patients with known severe hypersensitivity to cetuximab or any component of this product (see WARNINGS AND PRECAUTIONS).

WARNINGS AND PRECAUTIONS

Infusion Reactions

Severe, potentially fatal infusion reactions characterized by rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction and/or cardiac arrest have occurred with the administration of ERBITUX (cetuximab).

In clinical studies, severe infusion reactions were observed in 2 – 5% of patients with fatal outcome in 1 patient (see DOSAGE AND ADMINISTRATION – Dose Modifications).

Approximately 90% of severe infusion reactions were associated with the first infusion of ERBITUX despite the use of prophylactic antihistamines. However, caution must be exercised with every ERBITUX infusion, as there are patients who experienced their first severe infusion reaction during later infusions.

Severe infusion reactions require immediate interruption of the ERBITUX infusion and permanent discontinuation from further treatment. Appropriate physician supervision and supportive medical resources for the treatment of severe infusion reactions, anaphylaxis and cardiac arrest/myocardial infarction must be available. Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (e.g., epinephrine, parenteral corticosteroids, intravenous antihistamines, bronchodilators, vasopressors and oxygen). Longer observation periods may be required in patients who experience infusion reactions to confirm resolution of the event. Patients should be observed until all signs and symptoms have completely resolved (see DOSAGE AND ADMINISTRATION – Dose Modifications).

Grade 1 and 2 infusion reactions including chills, fever, and dyspnea usually occurring on the first day of initial dosing, were observed in 11-19% of patients receiving ERBITUX in clinical trials.

Special attention is recommended for patients with poor performance status and pre-existing cardiopulmonary disease.

In clinical trials, mild to moderate infusion reactions have been managed by slowing the infusion rate of ERBITUX and by employing prophylactic use of antihistamine medications for subsequent doses (see DOSAGE AND ADMINISTRATION).

Cardiopulmonary Arrest

Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and ERBITUX as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlled ERBITUX trial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of ERBITUX. One patient with no prior history of coronary artery disease died one day after the last dose of ERBITUX. In some studies association with age ≥65 years or performance status has been observed. Carefully consider use of ERBITUX in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, arrhythmias and performance status. Concomitant administration of cardiotoxic compounds such as fluoropyrimidines should be taken into account in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after treatment with ERBITUX (see WARNINGS AND PRECAUTIONS – Monitoring and Laboratory Tests).

Pulmonary Toxicity

Interstitial lung disease (ILD), including 1 fatality, occurred in 6 (< 0.3%) patients receiving ERBITUX in clinical trials. In the events of acute onset or worsening pulmonary symptoms, ERBITUX therapy should be interrupted and a prompt investigation of these symptoms should occur. If ILD is confirmed, ERBITUX should be discontinued and the patient should be treated appropriately.

Dermatologic Toxicity

Dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychialinflammation, and infectious sequelae (eg, S. aureus sepsis, abscess formation, cheillitis and cellulitis) and hypertrichosis, have occurred in patients receiving ERBITUX. Acneiform rash occurred in 76-88% of patients receiving ERBITUX in clinical trials. Severe acneiform rash occurred in 1-18% of patients.

Acneiform 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.

Patients developing dermatologic toxicities while receiving ERBITUX should be monitored for the development of inflammatory or infectious sequelae, and appropriate treatment of these symptoms initiated.

Dose modifications of any future ERBITUX infusions should be instituted in case of severe acneiform rash (see DOSAGE AND ADMINISTRATION – Dose Modifications). Instruct patients to limit sun exposure during treatment with ERBITUX and for 2 months following the last dose of ERBITUX.

ERBITUX Plus Radiation Therapy and Cisplatin

Use of ERBITUX in Combination with Radiation 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 SCCHN. 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.

Monitoring and Laboratory Tests

In patients evaluated during clinical trials, hypomagnesemia occurred in 43% of patients receiving ERBITUX and was severe (NCI-CTC Grade 3 and 4) in 4-17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX.

Patients should be monitored for hypomagnesemia, and accompanying hypocalcemia and hypokalemia, before and periodically during and following the completion of ERBITUX therapy. Monitoring should continue for a period of time commensurate with the half-life and persistence of the product; i.e. at least 8 weeks following the completion of ERBITUX therapy. Replenish electrolytes as necessary (see ADVERSE REACTIONS – Abnormal Hematologic and Clinical Chemistry Findings).

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% vs 56%), larynx (52% vs 36%), subcutaneous tissue (49% vs 45%), mucous membranes (48% vs 39%), esophagus (44% vs 35%), and skin (42% vs 33%) in the ERBITUX and radiation versus radiation-alone arms, respectively
  • The incidence of grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

Pregnancy and Nursing

Special Populations

Pregnant Women: Animal data do not suggest a teratogenic effect. However an increased incidence of abortions was observed in monkeys administered doses 1.6 to 4 times greater than human exposure.

There are no adequate and well controlled studies of ERBITUX in pregnant women. It is also not known whether ERBITUX can cause foetal harm when administered to a pregnant woman or whether ERBITUX can affect reproduction capacity. IgG molecules are known to cross the placental barrier; therefore

ERBITUX may be transmitted from the mother to the developing foetus. Based on animal models, EGFR has been implicated in the control of prenatal development, may be essential for normal organogenesis, and may play a role in proliferation and differentiation in the developing embryo. Therefore, ERBITUX should not be given to a pregnant woman or any woman not employing adequate contraception unless the potential benefit justifies the potential risk to the foetus. If the patient becomes pregnant while receiving this drug, she should be apprised of the potential hazard to the foetus and/or the potential risk for loss of the pregnancy.

Nursing Women: It is not known whether ERBITUX is excreted in human milk. Because human IgG is excreted in human milk, and the potential for absorption and harm to the infant is unknown, women should be advised to discontinue nursing during treatment with ERBITUX and based on the mean halflife, for a minimum of 60 days after the last dose of ERBITUX.

Adverse Reactions

Adverse Drug Reactions Overview

Across all studies, the most common adverse reactions with ERBITUX (incidence ≥ 25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, stomatitis, pyrexia and infection.

The most serious adverse reactions with ERBITUX are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus.

Across all studies, ERBITUX was discontinued in 3–10% of patients because of adverse reactions.

Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 13–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient.

The incidence of infection was variable across studies, ranging from 13–48%. Sepsis occurred in 1–4% of patients.

Renal failure occurred in 1% of patients with colorectal cancer.

Please read the Canadian  Full Prescribing Informationincluding Serious Warnings and Precautions.

About Eli Lilly and Company

             Lilly is a global healthcare leader that unites caring with discovery to make life better for people around the world. We were founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today we remain true to that mission in all our work. Across the globe, Lilly employees work to discover and bring life-changing medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism. To learn more about Lilly, please visit us at www.lilly.comand http://newsroom.lilly.com/social-channels. 

About Lilly Canada

           Lilly Canada was established in 1938, the result of a research collaboration with scientists at the University of Toronto which eventually produced the world’s first commercially-available insulin. Lilly Canada now employs more than 550 people across the country, working in the areas of oncology, cardiovascular and endocrine disorders, men’s and women’s health, autoimmunity, neuroscience and diabetes. To learn more about Lilly Canada, please visit us at www.lilly.ca.

About Bristol-Myers Squibb

            Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.

About Bristol-Myers Squibb Canada

            Bristol-Myers Squibb Canada has been delivering innovative medicines for serious diseases to Canadian patients in the areas of cardiovascular health, oncology, neuroscience, immunoscience and virology for over 80 years. Bristol-Myers Squibb Canada employs over 300 employees across the country. For more information, please visit www.bmscanada.ca.

ERBITUX is a trademark owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates.

Bristol-Myers Squibb and Eli Lilly and Company Forward-Looking Statement

This press release contains "forward-looking statements" (as that term is defined in the Private Securities Litigation Reform Act of 1995) regarding the parties’ North American collaboration for ERBITUX. 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 transition will be completed in the timeframe described in this release. In addition, the amount of royalties paid to Bristol-Myers Squibb through September 2018 may differ from current expectations. 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 for the year ended December 31, 2014, 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.