Amgen Presents New Data at ASCO on Four Investigational Molecules from Oncology Pipeline
Early Data from Apoptosis, Angiogenesis and Growth Regulation Programs Suggest Biologic Activity in a Range of Tumor Types
Abstract Numbers 3570, 2051, 3583 and 3539
CHICAGO--(BUSINESS WIRE)--May 31, 2008--Amgen (NASDAQ:AMGN) today announced interim results from four of the company's investigational cancer agents. Data presented from trials with recombinant human (rh) Apo2L/TRAIL, AMG 479, AMG 102 and motesanib alone, and in combination with chemotherapy or other targeted agents, are a part of the robust oncology therapeutic development program organized in the pathway areas of apoptosis, growth regulation and angiogenesis. These studies were presented at the 2008 American Society of Clinical Oncology's (ASCO) Annual Meeting in Chicago.
"Cancer is a complex disease which requires innovative therapeutic approaches to attack out-of-control cells," said David Chang, M.D., vice president, Global Oncology Development at Amgen. "While still early, we believe that developing and executing well-designed clinical trials will allow us to explore a range of therapeutic potentials to combat this devastating illness. Our aim is to generate clinical evidence to push the boundaries of conventional cancer treatment by employing novel strategies such as targeting multiple pathways or combining targeted therapies."
Apoptosis: Enhancing Cancer Cell Suicide
Apoptosis, also known as programmed cell death, is a process by which a controlled sequence of biochemical events triggers target cells to commit suicide. This is a normal cellular process by which unwanted or damaged cells are removed from the body. Cancer cells acquire the ability to evade apoptosis, which leads to uncontrolled growth. Amgen is using a pro-apoptotic approach to target the extrinsic cell death pathway, which is mediated through two key death receptors (DR4 and DR5), that may help provide a platform with which traditional cytotoxic and targeted therapies can be combined to treat a variety of cancers.
In a Phase 1b trial, patients with advanced non-small cell lung cancer (NSCLC), received rhApo2L/TRAIL, a pro-apoptotic receptor agonist (PARA) acting through death receptors DR4 and DR5, in combination with the regimen of paclitaxel, carboplatin and bevacizumab (PCB). Interim data from 24 patients found no dose-limiting toxicities in the four dosing cohorts. Four patients experienced a treatment-related serious adverse event. Best overall objective tumor response per the RECIST criteria was 58 percent. This molecule is being developed in collaboration with Genentech. A Phase 2 trial in bevacizumab-eligible and ineligible patients with advanced NSCLC is ongoing.
"The dysregulation of apoptosis is a hallmark of cancer, and targeting pathways with potential pro-apoptotic effects has great potential in the pursuit of new anti-cancer therapies," said David Chang, M.D., vice president, Global Oncology Development at Amgen. "The results of this study are encouraging as we continue to explore this pathway in a broad range of tumor types."
Growth Regulation: Blocking Pathways that Regulate Proliferation of Cancer Cells
There are multiple mechanisms by which cancer cells escape the regulatory processes that control the behavior and fate of normal cells. Restoring the cellular functions that regulate cell growth is of significant interest for the development of anti-cancer therapies. Amgen is developing inhibitors of the insulin-like growth factor-1 receptor (IGF-1R) and hepatocyte growth factor/scatter factor (HGF/SF):c-Met pathways that are potential first-in-class anti-cancer molecules.
At this meeting, Amgen presented data on AMG 479, a fully human monoclonal antibody that binds with a high affinity to IGF-1R. In a Phase 1b study, AMG 479 was combined with either Vectibix(R) (panitumumab) or gemcitabine for the treatment of patients with advanced solid tumors. This study of 21 patients evaluated the safety, pharmacokinetics, and maximum tolerated dose of AMG 479 for each regimen. The study found that AMG 479 could be safely combined with a standard dose of Vectibix or gemcitabine. There was one, grade 3, AMG 479-related, adverse event (high blood sugar) in the AMG 479 and Vectibix arm (n=10). There were no AMG 479 related adverse events greater than grade 3 in the AMG 479 and gemcitabine arm (n=11). A partial response (by WHO criteria) was observed in a patient with metastatic colorectal cancer treated with AMG 479 and Vectibix. Another partial response (also by WHO criteria) was seen in a patient with hormone-resistant prostate cancer treated with AMG 479 and gemcitabine. Stable disease as a best response was noted in an additional six patients in the AMG 479 and Vectibix arm and in an additional seven patients in the AMG 479 and gemcitabine arm.
Data were also presented from a separate trial combining targeted therapies, in which AMG 102, a fully human monoclonal antibody that selectively targets HGF/SF (the only ligand for the c-Met receptor), was combined with bevacizumab or motesanib. In the study, three cohorts of three to six patients with advanced solid tumors received AMG 102 and bevacizumab (n=12) or motesanib (n=2). Results showed that AMG 102 in combination with bevacizumab appeared to be well-tolerated in most patients. One grade 3, adverse event of arthralgia and one, grade 4 event of pulmonary embolism was seen. The most common related adverse events were nausea and fatigue. Among the evaluable patients receiving bevacizumab and AMG 102, most (7) had some tumor shrinkage as the best tumor response.
Additionally, an interim analysis of a Phase 2 study was presented in which AMG 102 was administered as a single agent to 40 patients with recurrent glioblastoma multiforme to assess its safety and efficacy. Recurrent glioblastoma is an aggressive disease for which no standard therapy is available and afflicted patients typically have a poor prognosis. One patient experienced a partial response by Macdonald criteria, and six patients experienced stable disease on therapy with AMG 102. At a data cut-off of January 2008, two patients with recurrent glioblastoma multiforme were still receiving AMG 102. Serious adverse events were reported in eight of 40 patients; only one was reported as a treatment-related serious adverse event. Five patients reported grade 3 or 4 treatment-related adverse events: peripheral edema (n=2), hypophosphatemia (n=3), and deep vein thrombosis (n=1). Grade 1 or 2, treatment-related, adverse events reported in more than two patients included nausea (n=3), diarrhea (n=2), fatigue (n=5), dyspnea (n=2), and dry skin (n=2). There were no treatment-related deaths reported.
Angiogenesis: Preventing Abnormal Formation of New Blood Vessels
Angiogenesis, the process of new blood vessel formation, plays a critical role in many diseases, including cancer. In cancer, tumors grow and metastasize in part by secreting angiogenic substances, such as vascular endothelial growth factor (VEGF) that can induce capillary growth into the tumor.
Amgen presented data from a Phase 1b study evaluating motesanib, a highly selective oral agent that targets VEGF receptors one, two and three (VEGFR 1-3), in combination with gemcitabine and erlotinib in patients with solid tumors (n=57; 48 of which have received one dose of motesanib). The data showed that combination of motesanib with gemcitabine and erlotinib appeared tolerable with little effect on pharmacokinetics. Serious adverse events (grade 3 or higher) included deep vein thrombosis, congestive cardiac failure, cholecystitis, febrile neutropenia, neutropenia and pulmonary embolism. One partial response was seen when motesanib was given 75mg BID in combination with gemcitabine and erlotinib.
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