Plexxikon Announces Publication of Key Data Demonstrating Possible Personalized Medicine for a Variety of Cancers
Using its proprietary Scaffold-Based Drug Discovery(TM) platform, Plexxikon has identified a portfolio of unique anti-cancer compounds that selectively kill cells with the B-Raf(V600E) mutation, leaving healthy cells unharmed since the mutation only occurs in tumor cells. The co-crystallography platform enabled scientists at Plexxikon to determine the exact location where such inhibitors selectively bind to the cancer-causing enzyme.
Plexxikon is conducting a Phase 1 clinical trial utilizing PLX4032, one of Plexxikon's selective B-Raf(V600E) inhibitors, in collaboration with Roche. Separately, Plexxikon and Roche Molecular Diagnostics collaborated with Plexxikon to develop a test to identify patients who carry the tumor mutations and for whom a selective B-Raf(V600E) inhibitor may have the greatest therapeutic benefit.
"Through a series of in vivo and in vitro studies, we demonstrated that our B-Raf(V600E) inhibitor selectively destroys BRAF-oncogene driven tumors, supporting the development of a B-Raf inhibitor as a personalized medicine for patients with this mutation," said Gideon Bollag, Ph.D., vice president of discovery biology for Plexxikon.
Plexxikon's family of B-Raf(V600E) kinase inhibitors selectively target a unique binding site of the protein, minimizing the common side effects seen from other less selective kinase inhibitors. In several different cancer cell lines, Plexxikon's B-Raf(V600E) inhibitor induces cell cycle arrest and cell death (apoptosis) exclusively in B-Raf(V600E)-positive cells, with no damage to the healthy cells. These results were confirmed in tumor-bearing mice, which show tumor regression and delayed tumor growth in animals treated with the B-Raf(V600E) inhibitor. The comprehensive findings from Plexxikon and the Wistar Institute, a National Cancer Institute-Designated Cancer Center, are contained in an article entitled "Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity" in the February 19, 2008 Early Edition and the February 26, 2008 Print Edition of The Proceedings of the National Academy of Sciences. www.pnas.org/cgi/content/full/0711741105.
"Our kinase inhibitor can bind and act in an extremely selective way, providing a wide safety window not seen so far with other compounds in this category. With the Plexxikon approach, we have opened the door to the possibility of using kinase drugs not only for more effective cancer therapies, but also for the treatment of other chronic diseases like rheumatoid arthritis, pain and polycystic kidney disease," said K. Peter Hirth, Ph.D., chief executive officer of Plexxikon. "Designing highly selective drug candidates is a hallmark of Plexxikon's discovery platform for a number of different classes of targets, including kinases, nuclear receptors, phosphodiesterases and more recently, proteases."
PLX4032/R7204 Clinical Trials
Plexxikon is conducting a Phase 1 clinical trial in collaboration with Roche to evaluate PLX4032/R7204, an orally available anti-cancer agent designed to specifically inhibit the B-Raf(V600E) protein. Enrollment is complete for the dose escalation phase of the trial, which is being conducted in cancer patients. The next phase of this trial will test efficacy of the drug only in melanoma patients who have the B-Raf(V600E) mutation, and will include radiologic imaging studies such as positron emission tomography (PET) scans and CT scans to assess anti-tumor activity. Patients will be selected for this study using an investigational diagnostic test developed by Roche Molecular Diagnostics in collaboration with Plexxikon for this purpose. Enrollment for this trial is expected to be completed by the end of 2008. To date, PLX4032 has been safe and well tolerated even at the highest doses administered.
Plexxikon is a leader in structure-guided discovery and development of novel small molecule pharmaceuticals to treat human disease. The company's clinical stage programs include PLX204 for the treatment of diabetes, and PLX4032 for the treatment of melanoma and colorectal cancer. Preclinical development programs include a kinase inhibitor for the treatment of pain, and a portfolio of kinase inhibitors for the treatment of kidney disease, rheumatoid arthritis and metastatic breast cancer.
Plexxikon's proprietary Scaffold-Based Drug Discovery(TM) platform is being applied to build a pipeline of diverse product opportunities for the treatment of metabolic and cardiovascular disease, inflammation, oncology and CNS disorders. This discovery process integrates a number of state-of-the-art technologies, including structural screening as one key component that provides a significant competitive advantage over other drug discovery approaches. To date, the company has discovered a portfolio of clinical and preclinical stage compounds in multiple disease areas addressing significant unmet needs in each therapeutic category.
Plexxikon is seeking pharmaceutical and biotechnology partners for select collaboration opportunities. For more information, please visit www.plexxikon.com.
Posted: February 2008