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April 3, 2006

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Merck KGaA Receives EMEA Approval for Erbitux in Head and Neck Cancer

Erbitux approval in European Union heralds hope for head and neck cancer patients


Darmstadt, April 3, 2006 – Merck KGaA announced today that the European Commission has granted marketing authorization to extend the use of the targeted cancer therapy Erbitux® (cetuximab), in combination with radiotherapy, for the treatment of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Erbitux will be available for the treatment of head and neck cancer in all 25 member states of the European Union as well as Iceland and Norway in accordance with local legal regulations. Erbitux is already licensed in 53 countries for metastatic colorectal cancer after failure of irinotecan-based chemotherapy.

Erbitux is the first targeted cancer therapy to be approved for the treatment of SCCHN and provides a much-needed new treatment option for this challenging and increasingly prevalent cancer type. The new indication granted by the European Medicines Agency (EMEA) approves Erbitux for use in combination with radiotherapy for locally advanced SCCHN, i.e. cancer that has not yet spread to other parts of the body.

The marketing authorization is based on results of an international, randomized phase III study of 424 patients. For patients treated with Erbitux combined with radiotherapy, median survival significantly improved by nearly 20 months (49.0 months versus 29.3 months) and the duration of locoregional control (ie time from treatment start to spread of the tumor beyond the head and neck) improved by 9.5 months (24.4 versus 14.9 months) compared to radiotherapy alone.(1)

“Erbitux takes head and neck cancer treatment an enormous step forward, providing more patients with the potential for a long-term benefit or cure. We are conscious that these results open a new era in the management of locally advanced SCCHN,” said Dr. Wolfgang Wein, Merck Senior Vice President Global Oncology Commercialization. “The approval of Erbitux across the EU for a second indication is a continuation of our commitment to ongoing research in the oncology field, with the aim of improving the health and quality of life for cancer patients.”

“Head and neck cancer is an extremely challenging cancer type, with five-year survival rates typically low. The approval of Erbitux to treat head and neck cancer represents a major advancement to addressing an escalating unmet medical need,” said Dr. James Bonner, M.D., University of Alabama, principal investigator for the study. “Erbitux offers the potential for improved control and extended survival even in severe disease.”

The most commonly reported side effect with Erbitux is an acne-like skin rash (1) which is generally manageable (2,3) and has been associated with a good response to therapy in a number of tumor types.(4) Erbitux does not significantly increase typical radiotherapy related side effects, in particular mucositis, in the treatment of locally advanced squamous cell carcinoma of the head and neck.(1)

Erbitux was granted approval by SwissMedic in December 2005 for use in combination with radiotherapy in the treatment of patients with previously untreated advanced SCCHN. 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.(5) In Argentina, Erbitux is also approved as a single agent and in combination with radiotherapy. Erbitux continues to be studied as a first-line treatment in combination with platinum-based chemotherapy in recurrent or metastatic head and neck cancer (the EXTREME study).

Head and neck cancer
Every year in Europe, around 100,800 people are diagnosed with head and neck cancer and almost 40,000 die from the disease.(6) Head and neck cancer is the sixth-most frequently occurring cancer worldwide.(7) Head and neck cancer includes cancers of the tongue, mouth, salivary glands, pharynx, larynx, sinus, and other sites located in the head and neck area. About 90 percent of head and neck cancers are of the squamous cell variety (8) and more than 90 percent of these express EGFR, which is critical for tumor growth.(9) Although there have been significant improvements in chemotherapy and surgical techniques, the disease is often particularly challenging to treat since most patients present with advanced disease, have secondary tumors and suffer from other co-morbidities.(10)

About Erbitux
ERBITUX® is a first-in-class and highly active IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR). As a monoclonal antibody, the mode of action of Erbitux is distinct from standard non-selective chemotherapy treatments in that it specifically targets and binds to the EGFR. This binding inhibits the activation of the receptor and the subsequent signal-transduction pathway, which results in reducing both the invasion of normal tissues by tumor cells and the spread of tumors to new sites. It is also believed to inhibit the ability of tumor cells to repair the damage caused by chemotherapy and radiotherapy and to inhibit the formation of new blood vessels inside tumors, which appears to lead to an overall suppression of tumor growth. The most commonly reported side effect with Erbitux is an acne-like skin rash that seems to be correlated with a good response to therapy. In approximately five percent of patients, hypersensitivity reactions may occur during treatment with Erbitux; about half of these reactions are severe.

Erbitux has already obtained market authorization to treat colorectal cancer in 53 countries: Switzerland, the US, Mexico, Argentina, Chile, Iceland, Norway, the European Union, Peru, Australia, Croatia, Israel, Bulgaria, Panama, Guatemala, Colombia, Singapore, Hong Kong, South Korea, Canada, Ecuador, Malaysia, the Philippines, Taiwan, China, India, Lebanon, Venezuela and Nicaragua for the use in combination with irinotecan in patients with EGFR-expressing mCRC who have failed prior irinotecan therapy. In the US, Argentina, Chile, Mexico, Peru, Singapore, Australia, Panama, Colombia, Guatemala, Hong Kong, Canada, Ecuador, the Philippines, Lebanon, Venezuela and Nicaragua Erbitux is also approved for single-agent use.

In addition, Erbitux in combination with radiotherapy has been approved for the treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN) in Switzerland, Argentina and Colombia. In Argentina Erbitux is also approved as monotherapy in patients with recurrent and/or metastatic SCCHN who failed prior chemotherapy. In March 2006, FDA granted approval for both indications in the U.S.

Merck KGaA, Darmstadt, Germany, licensed the right to market Erbitux outside the US and Canada from ImClone Systems Incorporated of New York in 1998. In Japan, Merck KGaA has co-exclusive marketing rights with ImClone Systems.

Extensive background information, pictures and illustrations for Erbitux are available at:
http://www.media-highlights.merck.de



References:
1. Bonner J et al. Radiotherapy plus cetuximab for squamous cell carcinoma of the head and neck. N Engl J Med 2006; 354: 567–78
2. Segaert S et al., The management of skin reactions in cancer patients receiving epidermal growth factor receptor targeted therapies. J Dtsch Dermatol Ges. 2005 Aug;3(8):599-606.
3. Segaert S, Van Cutsem E., Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol. 2005 Sep;16(9):1425-33.
4. Saltz L, Kies M, Abbruzzese JL, Azarnia N, Needle M. The presence and intensity of the cetuximab-induced acne-like rash predicts increased survival in studies across multiple malignancies. Proc Am Soc Clin Oncol 2003; 22:Abstract 817.
5. Trigo JM et al. Cetuximab (Erbitux™) monotherapy is active in patients (pts) with platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN J Clin Oncol 2004;22(Suppl. 14s):488s Abstract No. 5502
6. www-dep.iarc.fr. GLOBOCAN. April 2002
7. Hunter KD et al. Profiling early head and neck cancer. Nat Rev Cancer. 2005 Feb; 5 (2): 127-35
8. Bourhis J and Pinto H. Redefining ‘State of the Art’ in Head and Neck Cancer. Oral presentation, 6th International Conference on Head and Neck Cancer 7-11 August 2004.
9. Forastiere A, Koch W, Trotti A, Sidransky D, et al. Head and neck cancer. N Engl J Med 2001:345(26), 1890-1900.
10. Lefebvre J-L. Redefining ‘State of the Art’ in Head and Neck Cancer. Oral presentation, 6th International Conference on Head and Neck Cancer 7-11 August 2004.

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Merck is a global pharmaceutical and chemical company with sales of EUR 5.9 billion in 2005, a history that began in 1668, and a future shaped by 29,133 employees in 54 countries. Its success is characterized by innovations from entrepreneurial employees. Merck's operating activities come under the umbrella of Merck KGaA, in which the Merck family holds a 73% interest and free shareholders own the remaining 27%. The former U.S. subsidiary, Merck & Co., has been completely independent of the Merck Group since 1917.