Chugai files innovative cancer medicine Avastin for fast approval in Japan

Faster approval process aims to make Avastin available to patients as soon as possible

Basel, 21 April 2006 Roche today announced that Chugai has submitted a New Drug Application (NDA) with the Japanese Ministry of Health, Labour and Welfare (MHLW) for the use of Avastin (bevacizumab) in patients with advanced or recurrent colorectal cancer.

Avastin has been filed under a new ‘fast regulatory’ scheme that has been established by the Investigational Committee for Usage of Unapproved Drugs (a body established by the MHLW). The system has been set up to enable faster regulatory approval of certain medicines with proven efficacy which are approved in the US and/or Europe but that are not yet available in Japan. Avastin is the first medicine to be filed under this scheme for an indication as significant as colorectal cancer.

“Today’s submission comes just after Tarceva’s initial filing in advanced or recurrent non-small cell lung cancer and represents a further significant milestone for oncologists and patients in Japan. The Japanese authorities have recognized that Avastin is a breakthrough drug which addresses an unmet medical need for patients suffering with advanced colorectal cancer” said Ed Holdener, Head of Roche’s Global Pharma Development. “We will continue to work closely with the Investigational Committee to ensure that this groundbreaking treatment becomes available to colorectal cancer patients as quickly as possible.”

The Avastin filing is based on local Phase I data, along with supporting US and European Phase II and pivotal Phase III data1,2,3. At the same time, Chugai is conducting a Safety Confirmation Study in order to provide data on Japanese patients during the review procedure.

In Japan, the incidence of colorectal cancer has increased significantly in the last 50 years and research interest in this cancer has grown rapidly among Japanese clinicians and pathologists4. In 2005, colorectal cancer was one of the most commonly reported cancer with an estimated incidence of 115,000 people in Japan5.

Avastin is the first and only anti-angiogenic agent to have demonstrated improved overall and/or progression-free survival in the three major types of cancer leading to death: colorectal cancer, non-small cell lung cancer and breast cancer. In Europe, Avastin was approved early 2005 for first-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with the chemotherapy regimens of intravenous 5-fluorouracil/folinic acid or intravenous 5-fluorouracil/folinic acid/irinotecan. Avastin received approval by the US Food and Drug Administration (FDA) in February 2004. In addition, filing occurred in the US on April 10, 2006, for use of Avastin in previously untreated advanced non-squamous, non-small cell lung cancer.

Data used for filing
The local Phase I study was conducted in 18 patients with metastatic carcinoma of the colon or rectum to investigate the pharmacokinetics and safety of Avastin in Japanese patients when used in combination with 5-fluorouracil/folinic acid.

A Phase II study (AVF2192) demonstrated that Avastin, when added to a combination of 5-fluorouracil/folinic acid, prolonged the time until disease progression or death by an extra four months compared to chemotherapy alone (a 67% increase in progression-free survival).

In the Phase III pivotal trial (AVF2107), patients with previously untreated metastatic carcinoma of the colon or rectum (mCRC) who received Avastin in combination with intravenous 5-fluorouracil/folinic acid/irinotecan lived significantly longer than patients receiving the same chemotherapy without Avastin- on average by nearly five months (20.3 months versus 15.6 months). Also, the addition of Avastin increased the amount of time that patients were without disease progression, on average four months, compared to patients receiving chemotherapy alone (10.6 months versus 6.2 months).

In a second Phase III study (E3200), conducted by the Eastern Cooperative Oncology Group (ECOG), Avastin was also shown to significantly improve survival when added to another widely prescribed chemotherapy regimen (oxaliplatin/5-fluorouracil/leucovorin). With Avastin, patients who had failed previous irinotecan or 5-FU containing chemotherapy for their disease, lived nearly two months longer, on average, compared to those who received chemotherapy alone (12.9 months vs. 10.8 months).

About Avastin
Avastin is the first treatment that inhibits angiogenesis, which is defined as the growth of a network of blood vessels that supply nutrients and oxygen to cancerous tissues. Avastin targets a naturally occurring protein called VEGF (Vascular Endothelial Growth Factor), a key mediator of angiogenesis, thus choking off the blood supply that is essential for the growth of the tumour and its spread throughout the body (metastasis). Roche and Genentech are pursuing a comprehensive clinical programme investigating the use of Avastin in various tumour types (including colorectal, breast, lung, pancreatic, ovarian cancer, renal cell carcinoma and others) and different settings (advanced, adjuvant and neoadjuvant) The total development program is expected to include over 25,000 patients worldwide.

About Roche
Headquartered in Basel, Switzerland, Roche is one of the world’s leading research-focused healthcare groups in the fields of pharmaceuticals and diagnostics. As a supplier of innovative products and services for the early detection, prevention, diagnosis and treatment of disease, the Group contributes on a broad range of fronts to improving people’s health and quality of life. Roche is a world leader in diagnostics, the leading supplier of medicines for cancer and transplantation and a market leader in virology. In 2005 sales by the Pharmaceuticals Division totalled 27.3 billion Swiss francs, and the Diagnostics Division posted sales of 8.2 billion Swiss francs. Roche employs roughly 70,000 people in 150 countries and has R&D agreements and strategic alliances with numerous partners, including majority ownership interests in Genentech and Chugai. Additional information about the Roche Group is available on the Internet (www.roche.com).

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Further information
- Chugai Pharmaceutical Co.
- Roche in oncology
- Cancer



References
1. Hurwitz, H, Fehrenbacher, L, Novotny, W, et al. Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer. New England Journal of Medicine 2004; 350(23): 2335–2342
2. Kabbinavar FF, Joseph Schulz J, McCleod M, et al. Addition of Bevacizumab to Bolus 5-FU/Leucovorin in First-Line Metastatic Colorectal Cancer: Results of a Randomized Phase II Trial.) J Clin Oncol 23:10.1200/JCO.2005.05.112, 2005
3. Mitchell EP, Alberts SR, Schwartz BJ, et al. High-dose bevacizumab in combination with FOLFOX4 improves survival in patients with previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study E3200. ASCO Gastrointestinal 2005 Cancer Symposium, January 2005 (abstract 169a)
4. Koyame Y, Kotake K. Overview of colorectal cancer in Japan: report from the Registry of the Japanese Society for Cancer of the Colon and Rectum.; Dis Colon Rectum 1997, Oct, 40 (10 Suppl): S2-9.
5. A.Oshima, T.Kuroishi, K.Tajima, Cancer White Paper -Incidence/Death/Progonosis - 2004

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