Early Data Presented from Investigational Molecules that Target Apoptosis and Growth Regulation Pathways
Abstract Numbers: 3162, 1326, 3999, 2804, 4001, 3994
SAN DIEGO--(BUSINESS WIRE)--April 15, 2008--Amgen (NASDAQ:AMGN) today announced data generated by the company's robust oncology research and development programs in the areas of apoptosis (programmed cell death) and cell growth regulation. The data, presented at the American Association for Cancer Research (AACR) Annual Meeting in San Diego were from five preclinical studies evaluating anti-tumor activity, pharmacodynamics, and potential pre-clinical and clinical biomarkers for investigational molecules AMG 655, AMG 479 and AMG 102.
"We are excited to be pushing the boundaries of knowledge around known oncology pathways such as apoptosis and growth regulation by exploring new and innovative approaches to attack tumor cells," said David Chang, M.D., vice president, Global Oncology Development at Amgen. "While still early, we are pleased to be presenting a broad spectrum of data at this meeting reinforcing the biologic plausibility of targeting newly-discovered approaches to attack cancer via these pathways."
Targeting Apoptosis via Death Receptors
AMG 655 is an investigational fully human monoclonal antibody (mAb) agonist directed against death receptor 5 (DR5). AMG 655 is designed to activate caspases and induce apoptosis in sensitive tumor cells.
Apoptosis is a form of cell suicide in which a controlled sequence of biochemical events leads to cell death. In cancer, the dysregulation of apoptosis is critical in the development and survival of tumors. Apoptosis can be triggered by cell stress and DNA damage, but it also occurs normally during development of the body.
Data presented at AACR showed that, when combined with the chemotherapeutic agent gemcitabine, AMG 655 enhanced apoptosis in both in vitro, and in vivo, pancreatic cancer models. The combination of AMG 655 and gemcitabine was more effective in these models than either agent alone.
In another study, AMG 655 was combined with a chemotherapeutic agent (irinotecan or 5-fluorouracil (5-FU)) enhanced apoptosis relative to either agent alone in both in vitro and in vivo colon cancer cell models. AMG 655 is currently being tested against colorectal cancer in a Phase 1b/2 clinical trial.
In a third study, positron emission tomography (PET) was evaluated for its potential as a non-invasive method to measure receptor occupancy of DR5, the target of AMG 655. The preclinical results support the potential of using PET for imaging DR5 positive tumors and measuring receptor occupancy in patients. This imaging technology also is being applied to the study of other antibodies in the Amgen pipeline.
Targeting Growth Regulation in Cancer
AMG 479 is an investigational fully human monoclonal antibody that binds to insulin-like growth factor-1 receptor (IGF-1R) without cross-reacting with the closely related insulin receptor.
IGF-1 and IGF-2 activate the IGF-1R receptor, which is expressed in many human cancers. The expression of IGF-1 mediates tumor proliferation and reduces apoptosis and is associated with higher incidences and more aggressive progression of many common cancers.
Activation of these growth and survival pathways may allow tumor cells to resist the apoptosis-inducing activity of chemotherapy, radiation, and hormonal therapy and can increase cellular proliferation.
The preclinical data presented showed that AMG 479 inhibited more than 80 percent of IGF-1 induced growth activation in certain sarcoma cell line. Treatment of these cell lines with a combination of AMG 479 and cyclophosphamide resulted in significant (p=0.0020 vs. AMG 479, p=0.0002 vs. cyclophosphamide) tumor growth inhibition compared to either treatment alone. AMG 479 is currently in phase 2 Ewing's sarcoma trial.
AMG 102
AMG 102 is an investigational fully human monoclonal antibody that targets the action of anti-hepatocyte growth factor (HGF)/scatter factor (SF). HGF signaling through its receptor c-Met appears to play an important role in many types of human cancers.
The HGF/SF:c-Met pathway mediates a large number of normal activities in cells of epithelial origin - including proliferation, survival, migration, and invasion. The dysregulation of the HGF/SF:c-Met pathway appears to play an important role in many types of cancers, often leading to tumorigenesis and metastasis.
The data presented at AACR examined exploratory biomarkers that might be useful pharmacodynamic or patient enrichment markers for HGF/SF:c-Met therapies like AMG 102. Preclinical glioblastoma tumor xenograft models were treated with a single dose of AMG 102 ranging from 3- 300 ug IP. On days 3 and 7 after treatment initiation, plasma was harvested and levels of tumor-derived total human HGF, soluble human c-Met and CD44v6 (a c-Met associated protein) were quantified. Plasma samples from patients enrolled in the AMG 102 first-in-human trial were also examined. Total HGF and soluble c-Met levels were determined in plasma from patients in sequential dose cohorts (4-6 pts/cohort) that had been treated with AMG 102 at 0.5, 1, 3, 5, 10, or 20 mg/kg.
The study found that the treatment of tumor bearing preclinical models or cancer patients with AMG 102 gave rise to a dose-dependent increase in circulating HGF levels which suggests that monitoring HGF levels during treatment may serve as a biomarker for inhibition of the HGF/SF:c-Met pathway.
About Amgen
Amgen discovers, develops, manufactures and delivers innovative human therapeutics. A biotechnology pioneer since 1980, Amgen was one of the first companies to realize the new science's promise by bringing safe and effective medicines from lab, to manufacturing plant, to patient. Amgen therapeutics have changed the practice of medicine, helping millions of people around the world in the fight against cancer, kidney disease, rheumatoid arthritis and other serious illnesses. With a deep and broad pipeline of potential new medicines, Amgen remains committed to advancing science to dramatically improve people's lives. To learn more about our pioneering science and our vital medicines, visit www.amgen.com.
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