Merck KGaA Seeks Approval for Erbitux for Colorectal Cancer in Japan

Announced today that an application has been submitted by Merck Ltd. Japan and ImClone Systems Inc. to the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) for the use of Erbitux (cetuximab) in treating patients with advanced colorectal cancer.

DARMSTADT, Germany and TOKYO, Japan | Feb 05, 2007 |
Merck Serono, a division of Merck KGaA, announced today that an application has been submitted by Merck Ltd. Japan and ImClone Systems Inc. to the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) for the use of Erbitux (cetuximab) in treating patients with advanced colorectal cancer. In Japan, ImClone Systems Inc. is represented by its agent Bristol-Myers K.K. Erbitux is the first IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR) for which marketing authorization in Japan has been filed.

“We are excited by the positive results we have seen for Erbitux in treating colorectal cancer in the Japanese population. This is a disease that takes the lives of more than 38,000 Japanese people every year,” said Dr Wolfgang Wein, Senior Executive Vice President, Oncology, Merck Serono. “If approved, Erbitux will provide patients and physicians with an additional treatment option for managing this challenging cancer type, which is often associated with poor outcome.”

In Japan, the incidence of colorectal cancer has increased markedly during the last 50 years.(1) Among men and women in Japan, the incidence is higher than for lung cancer (95,651 per year vs 66,453) and second to stomach cancer (95,651 per year vs 109,779).2 In terms of mortality, the ranking is slightly different: Colorectal cancer is now the third biggest cancer threat in Japan after lung and stomach cancer (38,206, 56,367 and 54,423 people per year, respectively).(2) Approximately 25% of patients present with metastatic disease.(3)

The Japanese submission was based on data from two European studies – BOND (Bowel Oncology with Cetuximab Antibody)(4) and MABEL (Monoclonal Antibody Erbitux in a European Pre-License)(5), and two studies in Japanese patients.

The BOND study demonstrated that Erbitux when used in combination with irinotecan-based chemotherapy in the treatment of patients with metastatic colorectal cancer (mCRC) whose cancer had progressed on irinotecan-based chemotherapy, slowed progression of the disease by more than four months and shrank tumors by 50% or more in 22.9% of the 218 patients involved in the combination arm of the trial. Half of these patients saw their disease stabilize or improve.

The MABEL study was conducted in 1,147 patients whose mCRC had failed prior irinotecan-based chemotherapy. A median survival of 9.2 months was demonstrated when patients were administered Erbitux in combination with irinotecan-based chemotherapy – a finding consistent with that of the BOND study.

A Phase I study in Japanese patients with solid tumors assessed the safety and pharmacokinetic profile of Erbitux as a single agent.(6) Results show that Erbitux is well tolerated as a single agent in Japanese patients.

A Phase II study in Japanese patients with colorectal cancer who had failed prior irinotecan based therapy(7) demonstrated similar efficacy and safety results of Erbitux in combination with irinotecan in Japanese patients as was seen with BOND and MABEL in non-Japanese patients.

Erbitux was first approved for the treatment of metastatic colorectal cancer in Switzerland in December 2003. It was approved for use in the United States by the FDA in February 2004 and was followed by EMEA approval in June 2004. The development in Japan was based on a collaborative effort between Merck KGaA, ImClone Systems Inc., Bristol-Myers Squibb Company, Merck Ltd. Japan and Bristol-Myers K.K.

Notes for editors
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 in 62 countries. It has been approved for the treatment of colorectal cancer in 61 countries so far: Argentina, Australia, Belarus, Bulgaria, Canada, Costa Rica, Chile, China, Colombia, Croatia, Ecuador, El Salvador, the European Union, Guatemala, Hong Kong, Iceland, India, Israel, Lebanon, Malaysia, Mexico, Montenegro, New Zealand, Nicaragua, Norway, Panama, Peru, the Philippines, Romania, Serbia, Singapore, South Korea, Switzerland, Taiwan, Ukraine, the US and Venezuela for use in combination with irinotecan in patients with EGFR-expressing mCRC who have failed prior irinotecan therapy. Erbitux is also approved for single-agent use in: Argentina, Australia, Canada, Chile, Colombia, Ecuador, El Salvador, Guatemala, Hong Kong, Lebanon, Mexico, New Zealand, Nicaragua, Panama, Peru, the Philippines, Singapore, the US and Venezuela.

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 48 countries: Argentina, Australia, Belarus, Brazil, Bulgaria, Chile, Colombia, Costa Rica, the European Union, Hong Kong, Iceland, India, Israel, Malaysia, Mexico, Montenegro, Norway, the Philippines, Romania, Serbia, Switzerland, Taiwan, Ukraine and the US. In Argentina, Chile, Costa Rica, Israel, Mexico, the Philippines and the US, Erbitux is also approved as monotherapy in patients with recurrent and/or metastatic SCCHN who failed prior chemotherapy.

About Merck KGaA
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. Merck KGaA has an ongoing commitment to the advancement of oncology treatment and is currently investigating novel therapies in highly targeted areas, such as the use of Erbitux in colorectal cancer, squamous cell carcinoma of the head and neck and non-small cell lung cancer. Merck KGaA has also acquired the rights for the cancer treatment UFT® (tegafur-uracil) – an oral chemotherapy administered with folinic acid (FA) for the first-line treatment of metastatic colorectal cancer.

Merck KGaA is also investigating among other cancer treatments the use of Stimuvax® (formerly referred to as BLP25 Liposome Vaccine) in the treatment of non-small cell lung cancer. The vaccine was granted fast-track status in September 2004 by the FDA. Merck obtained the exclusive worldwide licensing rights from Biomira Inc. of Edmonton, Alberta, Canada, with the exception of Canada where the companies share rights.

References:
1. Koyama Y and Kotake K. Dis Colon Rectum. 1997; 40: S2-9.
2. http://www-dep.iarc.fr/ (Globocan 2002)
3. Cunningham D et al. Eur J Cancer 1993; 29A: 2007–2079.
4. Cunningham D et al. New Eng J Med 2004;351:337-345.
5. Wilke H et al. Poster presentation at ASCO, 2006.
6. Shirao et al. ASCO 2005 proceedings
7. Data on File: Merck KGaA.

SOURCE: Merck Serono

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