Supplemental Biologics License Application For Avastin(R)

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With Chemotherapy In First-Line, Non-Squamous, Non-Small Cell Lung Cancer

http://www.medicalnewstoday.com/medical ... wsid=41539

Main Category: Lung Cancer News

Article Date: 16 Apr 2006 - 0:00am (PDT)

Genentech, Inc. (NYSE: DNA) announced today that the company submitted a supplemental Biologics License Application (sBLA) with the U.S. Food and Drug Administration (FDA) for Avastin® (bevacizumab) in combination with platinum-based chemotherapy for first-line treatment of advanced, non- squamous, non-small cell lung cancer (NSCLC). Genentech has requested Priority Review on the submission, which means that if accepted, the FDA would take action on the application within six months or in October 2006. The company also plans to submit an sBLA for Avastin for the treatment of metastatic breast cancer in the second quarter 2006. Avastin is currently approved as a first-line treatment of metastatic colorectal cancer in combination with intravenous 5-FU-based chemotherapy.

The sBLA submission is based on Genentech's analysis of results from a randomized, controlled, multicenter Phase III trial (E4599) that enrolled 878 patients with locally advanced, metastatic or recurrent non-small cell lung cancer with histology other than predominant squamous cell. The results showed that patients receiving Avastin plus paclitaxel and carboplatin chemotherapies had a 25 percent improvement in overall survival, the trial's primary endpoint, compared to patients who received chemotherapy alone (based on a hazard ratio of 0.80, which is equivalent to a 20 percent reduction in the risk of death). In addition, this study showed that median survival of patients treated with Avastin plus chemotherapy was 12.3 months, compared to 10.3 months for patients treated with chemotherapy alone.

"This is the first time that patient survival was extended beyond one year in a clinical study of advanced non-small cell lung cancer, a disease that typically has a one-year survival rate of 30 to 35 percent," said Alan Sandler, M.D., Director of Thoracic Oncology at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. "If approved for this indication, Avastin may have the potential to be part of an entirely new approach to treating patients with this type of lung cancer."

"These data are an important advance in lung cancer research and we look forward to the potential of bringing new hope to the patients who are diagnosed with this specific type of lung cancer," said Hal Barron, M.D., Genentech's senior vice president of Development and chief medical officer. "We are committed to working with the FDA throughout the review process of this application."

The study also showed a 54 percent improvement in progression-free survival (based on a hazard ratio of 0.65, which can also be referred to as a 35 percent reduction in the risk of progression). The response rate in patients with measurable disease was 29 percent in the group receiving Avastin plus chemotherapy, compared to 13 percent in the group receiving chemotherapy alone.

About E4599

The E4599 trial was sponsored by the National Cancer Institute (NCI), part of the NIH, under a Cooperative Research and Development Agreement between NCI and Genentech, Inc., and conducted by a network of researchers led by the Eastern Cooperative Oncology Group (ECOG).

This is the first Phase III study to evaluate the therapeutic antibody Avastin in combination with chemotherapy in NSCLC. This was a randomized, controlled, multicenter trial that enrolled 878 patients with previously- untreated advanced NSCLC. Patients enrolled in this trial were randomized to receive treatment with paclitaxel and carboplatin chemotherapies with or without Avastin. In the trial, Avastin was administered every three weeks. The Phase III trial also excluded patients who had squamous cell NSCLC based on safety concerns of Avastin in these patients observed in a Phase II trial.

Safety Analysis

In previous clinical experience with Avastin in combination with paclitaxel and carboplatin in NSCLC, patients with a specific type of NSCLC called squamous cell carcinoma had a higher risk of experiencing life-threatening or fatal pulmonary bleeding. Because of this risk, patients with NSCLC classified as predominantly squamous cell were not included in this Phase III study. An assessment of adverse events in E4599 showed that Grade 3/4/5 (severe) bleeding occurred in 4.7 percent of patients in the Avastin plus chemotherapy arm (pulmonary bleeding occurred in 2.3 percent of patients), compared to 1.1 percent of patients in the chemotherapy-alone arm (pulmonary bleeding in 0.5 percent). Bleeding events were fatal in 1.9 percent of patients in the Avastin plus chemotherapy arm (fatal pulmonary bleeding in 1.6 percent) compared to 0.7 percent of fatal bleeding in the chemotherapy-alone arm (0.2 percent were pulmonary).

Patients in the Avastin plus chemotherapy arm received a median of eight cycles of therapy (the first six cycles were in combination with chemotherapy followed by Avastin alone until disease progression), versus a median of five chemotherapy cycles in the chemotherapy-alone patients.

The most common adverse event in E4599 was neutropenia, which occurred in 27 percent of patients treated with Avastin plus chemotherapy and 17 percent of patients who received chemotherapy alone. Three cases of fatal infection with Grade 3/4 neutropenia occurred in the Avastin plus chemotherapy arm, compared to none in the chemotherapy alone arm. Hypertension occurred at a rate of 8 percent in the Avastin plus chemotherapy arm and less than one percent in the chemotherapy-alone arm. Venous thrombosis occurred in six percent of patients treated with Avastin plus chemotherapy, compared with three percent of patients treated with chemotherapy alone. Arterial thrombosis occurred in three percent of patients treated with Avastin plus chemotherapy, compared with one percent in patients treated with chemotherapy alone.

About Avastin

Avastin is a therapeutic antibody designed to inhibit Vascular Endothelial Growth Factor (VEGF), a protein that plays an important role in tumor angiogenesis and maintenance of existing tumor vessels. By inhibiting VEGF, Avastin is designed to interfere with the blood supply to a tumor, a process that is thought to be critical to a tumor's growth and metastasis. For full prescribing information and boxed warnings on Avastin and information about angiogenesis, visit http://www.gene.com . For more information on Avastin, visit http://www.avastin.com.

The FDA approved Avastin on February 26, 2004 as a first-line treatment for metastatic colorectal cancer in combination with intravenous 5-FU-based chemotherapy. Approval was based on data from two trials. The pivotal trial was a large, placebo-controlled, randomized study that demonstrated a prolongation in the median survival of patients treated with Avastin plus the IFL (5-FU/leucovorin/CPT-11) chemotherapy regimen by approximately five months, compared to patients treated with the IFL chemotherapy regimen alone (20.3 months versus 15.6 months). The addition of Avastin to IFL improved overall survival by 52 percent (based on a hazard ratio of 0.66). In addition, this study demonstrated an improvement in progression-free survival (PFS) of more than four months (10.6 months in the Avastin/IFL arm compared to 6.2 months in the IFL-alone arm).

Avastin Safety Profile

Avastin has a well-established safety profile. In Genentech-sponsored studies, the most serious adverse events associated with Avastin were gastrointestinal perforation, wound healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome and congestive heart failure. The most common Grade 3-4 adverse events (occurring in greater than two percent of patients in the Avastin arm, compared to the control group) were asthenia, pain, hypertension, diarrhea and leukopenia. The most common adverse events (occurring in greater than two percent of patients in the Avastin arm, compared to the control group) of any severity were asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliative dermatitis and proteinuria.

About the Avastin Development Program

Based on data showing that VEGF may play a broad role in a range of cancers, Genentech is pursuing a broad development program for Avastin that currently includes 130 clinical trials across 25 different types of cancer. Avastin is being evaluated in Phase III clinical trials for its potential use in adjuvant and metastatic colorectal, renal cell (kidney), breast, pancreatic, non-small cell lung, prostate and ovarian cancers. Avastin is also being evaluated in earlier stage trials as a potential therapy in a variety of solid tumor cancers and hematologic malignancies. For further information about Avastin clinical trials, please call 888-662-6728.

About VEGF and Tumor Angiogenesis

The link between angiogenesis and cancer growth has been discussed by many researchers for decades. It wasn't until 1989 that a key growth factor influencing the process, VEGF, was discovered by Napoleone Ferrara, M.D., a staff scientist at Genentech. Dr. Ferrara and his team cloned VEGF, providing some of the first evidence that a specific angiogenic growth factor existed. This research was published in the journal Science in 1989. Dr. Ferrara then created a mouse antibody to this protein. In 1993, Dr. Ferrara and his team at Genentech, in a study published in Nature, demonstrated that the antibody directed against VEGF could suppress angiogenesis and tumor growth in preclinical models, providing compelling evidence that VEGF can play a critical role in tumor growth. Clinical studies with a humanized version of the antibody, Avastin, began in 1997.

About Non-Small Cell Lung Cancer

According to the World Health Organization (WHO), there are more than 1.2 million cases worldwide of lung and bronchial cancers each year, causing approximately 1.1 million deaths annually. The American Cancer Society (ACS) estimates that approximately 172,470 people will be diagnosed with lung cancer in the United States in 2006, with a resulting 162,460 deaths that same year. According to the NCI, lung cancer is the single largest cause of cancer deaths in the United States and is responsible for nearly 30 percent of cancer deaths in this country. NSCLC is the most common form of the disease and accounts for approximately 87 percent of all lung cancers.

About Genentech BioOncology

Genentech is committed to changing the way cancer is treated by establishing a broad oncology portfolio of innovative, targeted therapies with the goal of improving patients' lives. The company is the leading provider of anti-tumor therapeutics in the United States. Genentech is conducting clinical development programs for Rituxan® (Rituximab), Herceptin® (Trastuzumab), Avastin® (bevacizumab), and Tarceva® (erlotinib), and markets all four products in the United States, either alone (Avastin and Herceptin) or with Biogen Idec Inc. (Rituxan) or OSI Pharmaceuticals, Inc. (Tarceva). Genentech has licensed Rituxan, Herceptin, and Avastin and OSI Pharmaceuticals has licensed Tarceva to Roche for sale by the Roche Group outside of the United States.

The company has a robust pipeline of potential oncology therapies with a focus on four key areas: angiogenesis, apoptosis (i.e., programmed cell death), the HER pathway, and B-cell biology. A therapeutic antibody directed at the HER pathway is currently in Phase II trials, and in early development, are a small molecule directed at the hedgehog pathway and a potential therapy targeting apoptosis.

Founded 30 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes biotherapeutics for significant unmet medical needs. A considerable number of the currently approved biotechnology products originated from or are based on Genentech science. Genentech manufactures and commercializes multiple biotechnology products directly in the United States and licenses several additional products to other companies. The company has headquarters in South San Francisco, Calif., and is listed on the New York Stock Exchange under the symbol DNA. For additional information about the company, please visit http://www.gene.com

For the full prescribing information for Tarceva and the full prescribing information and Boxed Warnings for Rituxan, Herceptin, and Avastin please visit http://www.gene.com

This press release contains forward-looking statements regarding the expected timing of the Avastin sBLA filing for metastatic breast cancer and the potential of Avastin. Such statements are predictions and involve risks and uncertainties such that actual results may differ materially. Among other things, the expected timing of the sBLA filing could be affected by a number of factors, including unexpected safety, efficacy or manufacturing issues, additional time requirements for data analysis, BLA preparation and decision making, and FDA actions or delays; and the potential of Avastin could be affected by all of the foregoing and by a number of other factors, including failure to obtain FDA approval, competition, pricing, reimbursement, the ability to supply product, product withdrawals and new product approvals and launches. Please also refer to Genentech's periodic reports filed with the Securities and Exchange Commission. Genentech disclaims, and does not undertake any obligation to, update or revise any forward-looking statements in this press release.

SOURCE Genentech, Inc.

http://www.gene.com