Millennium Pharmaceuticals, Inc. announced that it has submitted a new drug application (NDA) with the U.S. Food and Drug Administration (FDA) for approval to market Velcade (bortezomib) as a treatment for relapsed and refractory multiple myeloma.
2003 FEB 19 - (NewsRx.com article prepared by Biotech Week editors from staff and other reports.)
In June 2002, Velcade was granted fast-track status by the FDA as having the potential to treat a serious, life-threatening condition and address an unmet medical need. The NDA was submitted under the provisions of Subpart H - Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses.
The NDA filing for Velcade is based primarily on the results of the company's phase II SUMMIT clinical trial, a multi-center study that included 202 patients with relapsed and refractory multiple myeloma. The results of this trial were presented in full at the December 2002 meeting of the American Society for Hematology.
"The submission of this NDA represents a significant milestone for Millennium and an important step toward fulfilling our mission of making novel treatment options available to patients with significant unmet medical needs," said Robert Tepper, MD, Millennium. "Since the initial Velcade patient dosing just over four years ago, we have been committed to the thorough and expeditious clinical development of Velcade and are proud that this strategy has resulted in an accelerated filing."
Velcade (bortezomib) for Injection has also received Orphan Product Designation from the FDA for multiple myeloma. Orphan Product Designation is granted for treatments that may provide significant benefit to patients with serious life-threatening diseases that have a prevalence of no more than 200,000 patients in the U.S. Upon FDA approval of the product, Orphan Product Designation provides seven-year marketing exclusivity in the U.S.
Millennium recently initiated two phase II trials with Velcade, one in patients with metastatic colorectal cancer and another in patients with advanced non-small cell lung cancer. The company also has an ongoing international, multi-center, phase III (APEX) trial of Velcade in patients with multiple myeloma as well as several phase I/II trials in patients with various hematologic and solid tumors. The company also plans to initiate additional phase I/II studies later in 2003.
Velcade is designed to specifically block the proteasome, which is an enzyme complex in cells responsible for breaking down a variety of proteins, including many that regulate cell division. In preclinical studies, inhibition of the proteasome has been shown to lead to the disruption of cell cycle progression, resulting in cancer cell death (apoptosis). Velcade is the first and only proteasome inhibitor currently being evaluated in clinical trials for the treatment of cancer.
Positive results reported from rHu-KGF study
2003 FEB 21 - (NewsRx.com article prepared by Drug Week editors from staff and other reports. Copyright 2003, Drug Week via NewsRx.com. )
Amgen (AMGN) announced that rHu-KGF decreased the duration and incidence of severe oral mucositis in a phase 3 study of patients undergoing bone marrow transplantation treatment for hematologic malignancies such as lymphoma, multiple myeloma, and leukemia.
Natural keratinocyte growth factor stimulates the growth and development of epithelial cells, including the cells that line the gastrointestinal tract. Amgen is studying a recombinant human keratinocyte growth factor (rHu-KGF) to protect epithelial cells from injury caused by anti-tumor treatments such as radiation and chemotherapy. Mucositis is a painful and debilitating condition in which patients experience severe mouth ulcerations that can make swallowing difficult or impossible.
Preliminary results from the phase III randomized, double-blind trial were positive on all end-points showing a highly significant decrease in both the duration and incidence of severe mucositis. The trial also showed that KGF was well tolerated.
Roger Perlmutter, Amgen's executive vice president of research and development, said: "There is no currently approved therapy to treat oral mucositis, a sometimes devastating complication of cancer treatments. We are looking forward to discussing our phase 3 results that address this critical unmet medical need with regulatory agencies in the near future."
Amgen will now investigate the efficacy and safety of KGF in other patient populations who suffer from high rates of mucositis associated with their anti-tumor treatments.
Drug Week, February 21, 2003, page 59.
Antiangiogenic therapy may be of use in hematological cancer
2003 FEB 21 - (NewsRx.com article prepared by Angiogenesis Weekly editors from staff and other reports. Copyright 2003, Angiogenesis Weekly via NewsRx.com)
According to recent research from Japan, "angiogenic factors are major causes of tumor progression in hematological malignancies, particularly multiple myeloma, as well as solid tumors. The introduction of thalidomide as an anti-angiogenic agent in myeloma treatment has demonstrated the importance of angiogenic factors in the progression of myeloma. However, the direct effects of angiogenic factors, particularly VEGFs, hypoxia, and thalidomide, on myeloma cells are not been documented."
"In this study, we demonstrate increased expression and production levels of VEGF in myeloma compared to non-myelomatous hematological lines, resistance to hypoxia and enhancement of VEGF-A production by hypoxia in myeloma, and direct growth inhibition of myeloma cells due to apoptosis and G(1) arrest caused by TNF-alpha upregulation induced by thalidomide," wrote K. Yata and colleagues, Kawasaki Medical University, Department of Hygiene.
"These findings may encourage the clinical use of antiangiogenic agents for their cytostatic effects and the prevention of progression," concluded the investigators (Expression of angiogenic factors including VEGFs and the effects of hypoxia and thalidomide on human myeloma cells. International Journal of Oncology, 2003;22(1):165-173).
For additional information, contact T. Otsuki, Kawasaki Medical University, Department of Hygiene, 577 Matsushima, Okayama 7010192, Japan.
Angiogenesis Weekly, February 21, 2003, page 17
Increased activation of N-ras and K-ras pools induced by increases in IL-6
2003 FEB 18 - (NewsRx.com article prepared by Cancer Weekly editors from staff and other reports. Copyright 2003, Cancer Weekly via NewsRx.com.)
According to a study from the United States, "ras is a major signaling molecule activated by interleukin-6. There have been no published reports, however, that specifically examine the kinetics and percentage of ras activation in response to IL-6. Model cell lines were used to study activation of N-ras and K-ras induced by IL-6.
"All of the myeloma cell lines we tested express both N-ras and K-ras, but not H-ras. GTP bound ras was measured and the percentage of the total Ras pool that was activated in response to IL-6 was calculated. IL-6 is able to transiently activate both N and K-ras in the ANBL6 cell tine.
"In addition, increasing concentrations of IL-6 are able to activate increasing levels of both N and K-ras. One ng/ml of IL-6 is able to activate approximately 10% of the N-ras pool and 18% of the K-ras pool. The amount of Ras-GTP in the cells correlates with the level of proliferation at low levels, but proliferation plateaus when higher levels of Ras-GTP are present. Protection from dexamethasone induced apoptosis correlates with IL-6 concentration and ras activation. However, IL-6 enhances apoptosis induced by doxorubicin. Interestingly, the ANBL6 cell line transfected with an N-ras12 or a K-ras12 gene is protected from doxorubicin induced apoptosis," stated M. Rowley and coauthors.
Rowley and colleagues published the results of their study in Oncogene (Activation of N-ras and K-ras induced by interleukin-6 in a myeloma cell line: Implications for disease progression and therapeutic response. Oncogene, 2002;21(57):8769-8775).
The corresponding author for this report is M. Rowley, Cancer Center Research Bldg, Mayo Mail Code 806, Minneapolis, MN 55455, USA. Cancer Weekly, February 18, 2003, page 72