Genentech BioOncology Fact Sheet: Translating Science into Life

Innovation in Oncology Genentech BioOncology is dedicated to understanding the science behind cancer and translating this knowledge into the development of novel biologic therapies that target the underlying biologic pathways that cause cancer cells to grow and spread. Our mission is to create medicines that will transform cancer into either a curable illness or a chronic condition.

The company is the leading provider of anti-tumor targeted therapeutics in the United States. Genentech is conducting clinical development programs for Avastin® (bevacizumab), Herceptin® (Trastuzumab), Rituxan® (Rituximab) 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).

Evolution: New Approaches to Cancer Therapy A turning point in the understanding and treatment of cancer came in the late 1980s and early 1990s as new biologic tools allowed scientists to study cancer at the molecular and genetic levels. The work of many within the life sciences industry, academia and government laboratories identified the connection between specific biologic pathways and the growth and spread of cancer cells in the body.

This research suggested that targeting specific proteins within these pathways might inhibit the growth of cancer. Genentech and its collaborators provided the first validation of this theory through the development of a new class of cancer medicines called therapeutic antibodies.

Rigorous, Groundbreaking Science The Genentech BioOncology philosophy of focusing on both the basic biology of cancer and its application to therapeutics in oncology continues to drive our program of groundbreaking scientific discovery and the identification of novel targets and molecules for therapeutic development. Many approved biotechnology products originated from or are based on Genentech science. Some of our important achievements in cancer biology and treatment include:

• Independent discovery and cloning of the human epidermal growth factor receptor-2 gene (her2/neu) in 1985 simultaneously with two other research groups^1-3
• More than two decades of research into the biology of the HER family of receptors, including the discovery of the correlation of high HER2 levels with an aggressive form of breast cancer and the development of the first humanized monoclonal antibody directed at HER2^4,5
• Cloning of vascular endothelial growth factor (VEGF) in 1989, a key mediator of both tumor angiogenesis and the maintenance of existing tumor blood vessels^6,7
• Development of a humanized monoclonal antibody directed at VEGF⁸
• Investigating new ways to activate apoptosis, a natural process that eliminates damaged or abnormal cells, such as cancer cells

A History of "Firsts" for Patients The scientific advances made by Genentech and its collaborators have led to a number of firsts in the treatment of cancer:

First FDA-approved therapeutic antibody for cancer in the LMSM	First treatment to improve survival for patients with first-line, diffuse large B-cell, CD20-positive, non-Hodgkin's lymphoma since the introduction of the CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapeutic regimen more than 25 years ago9,10
First FDA-approved therapeutic antibody targeted to a cancer-related molecular marker	First targeted treatment to improve survival for patients with HER2-positive metastatic breast cancer11
First FDA-approved anti-angiogenic cancer therapy	First targeted treatment to improve survival for patients with metastatic colorectal cancer12 First treatment to extend survival beyond one year for patients with advanced non-small cell lung cancer12
First EGFR therapy FDA-approved for pancreatic and non-small cell lung cancer	First EGFR targeted treatment to improve survival for patients with advanced pancreatic and advanced non-small cell lung cancers13

Genentech's FDA-approved products and late-stage clinical candidates have significant potential individually to extend lives and improve cancer care. Importantly, there is great excitement about the prospect of combining some of these therapies to create entirely new treatment paradigms that are highly targeted and have the potential to inhibit multiple mechanisms that support tumor growth without the use of chemotherapy. Combining agents that target different cancer pathways is an active area of investigation for Genentech.

Multiple Approaches to Targeted Cancer Therapy Cancer is a complex disease and is treated in a variety of ways. Genentech BioOncology is focusing on multiple approaches to targeted cancer therapy:

• Inhibiting tumor angiogenesis^14-16
• Targeting cell signaling^17-19
• Arming therapeutic antibodies^20-24

We believe that this comprehensive approach can shut down the growth and spread of cancer cells. Our expertise in product and process development has allowed the company to employ multiple technology platforms in each of these approaches.

Inhibiting Tumor Angiogenesis Angiogenesis is the process by which new blood vessels are formed. In the context of cancer, tumor angiogenesis is the creation of a network of blood vessels that supplies tumors with essential nutrients and oxygen and removes waste products.¹⁴

Agents that block vascular endothelial growth factor (VEGF) may have multiple effects on tumor angiogenesis, including:

• Causing existing blood vessels in the tumor to die^15,16
• Preventing new blood vessels from forming^15,16
• Making mature tumor vessels less leaky, thus facilitating the delivery of chemotherapy to tumor cells^15,16

Targeting Cell Signaling Numerous cell-signaling pathways promote tumor cell growth and keep tumors alive.¹⁷ Agents that target cell signaling combat cancer by:

• Blocking pathways that promote tumor cell growth and survival¹⁷
• Activating pathways that tell the cell to self-destruct (undergo apoptosis)^18,19

Arming Therapeutic Antibodies Therapeutic antibodies can be used to target specific proteins on the surface of cancer cells.¹¹ Genentech is creating "armed" antibodies to selectively kill cancer cells, using "stable" linkers to attach potent chemotherapy drugs to therapeutic antibodies.^20-22 The linker molecules potentially limit the release of the chemotherapy agent outside of the target cells, which may lessen the impact of chemotherapy on normal tissue. ^22-24

Safety Information Rituxan Indications
Rituxan is indicated for the treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell non-Hodgkin's lymphoma (NHL) as a single agent; for previously untreated diffuse large B-cell, CD20-positive, NHL in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or other anthracycline-based chemotherapy regimens; for previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP (cyclophosphamide, vincristine and prednisolone) chemotherapy; and for the treatment of non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent, after first-line CVP chemotherapy.

Boxed WARNINGS and Additional Important Safety Information
The most important serious adverse reactions of Rituxan are fatal infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation with fulminant hepatitis, other viral infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation. The most common adverse reactions of Rituxan (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia.

Herceptin Indications
Herceptin in combination with paclitaxel is indicated for treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have not received chemotherapy for their metastatic disease.

Herceptin as a single agent is indicated for the treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have received one or more chemotherapy regimens for their metastatic disease.

Herceptin, as part of a treatment regimen containing doxorubicin, cyclophosphamide, and paclitaxel, is indicated for the adjuvant treatment of patients with HER2-overexpressing, node-positive breast cancer.

Herceptin, as a single agent, is indicated for the adjuvant treatment of HER2-overexpressing node-negative (ER/PR-negative or with one high risk feature) or node-positive breast cancer, following multi-modality anthracycline-based therapy.

Boxed WARNINGS and Additional Important Safety Information
Herceptin administration can result in sub-clinical and clinical cardiac failure manifesting as congestive heart failure and decreased left ventricular ejection fraction. Serious infusion reactions and pulmonary toxicity have occurred; fatal infusion reactions have been reported. Exacerbation of chemotherapy-induced neutropenia has also occurred. Herceptin can cause oligohydramnios and fetal harm when administered to a pregnant woman. The most common adverse reactions associated with Herceptin use were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia.

Tarceva Indications
Tarceva monotherapy is indicated for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen.

Results from two multicenter, placebo-controlled, randomized, Phase III trials conducted in first-line patients with locally advanced or metastatic NSCLC showed no clinical benefit with the concurrent administration of Tarceva with platinum-based chemotherapy, and its use is not recommended in that setting.

Tarceva in combination with gemcitabine is indicated for the first-line treatment of patients with locally advanced, unresectable, or metastatic pancreatic cancer.

Important Safety Information
Severe and potential fatal adverse events included Interstitial Lung Disease-like events, myocardial infarction or ischemia, cerebrovascular accident, and micro-angiopathic hemolytic anemia with thrombocytopenia. While receiving Tarceva therapy, women should be advised against becoming pregnant or breastfeeding. The most common side effects in patients with NSCLC receiving Tarceva monotherapy 150 mg were mild to moderate rash and diarrhea. The most common adverse reactions in patients with pancreatic cancer receiving Tarceva 100 mg plus gemcitabine were fatigue, rash, nausea, anorexia, and diarrhea.

Avastin Indications
Avastin, in combination with intravenous 5-fluorouracil-based chemotherapy, is indicated for first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum. Avastin, in combination with carboplatin and paclitaxel, is indicated for first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer.

Boxed WARNINGS and Additional Important Safety Information
The most serious adverse events associate with Avastin across all trials were GI perforation, wound healing complication, hemorrhage, arterial thromboembolic events, hypertensive crisis, reversible posterior leukoencephalopathy syndrome, neutropenia and infection, nephrotic syndrome, and congestive heart failure. The most common adverse events seen in patients receiving Avastin across all studies were asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliative dermatitis, and proteinuria.

References

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2. King CR, Kraus MH, Aaronson SA. Amplification of a novel v-erB-related gene in a human mammary carcinoma. Science. 1985;229:974-976.
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