Plexxikon Novel Agents Aim to Address Cancer Treatment in New Ways

  • PLX3397 Cancer Program Targets Tumor Microenvironment
  • Next Generation BRAF Inhibitors Profiled
Berkeley, CA, November 13, 2011 – Plexxikon Inc., a member of Daiichi Sankyo Group, today announced scientific findings from two key programs in its oncology pipeline. First, findings from preclinical studies showed that treatment with a novel oral agent, PLX3397, re-programmed the tumor microenvironment, supporting further development of this single agent treatment for certain cancers and malignancies such as prostate cancer. In another presentation, Plexxikon researchers characterized the discovery of next generation BRAF inhibitors based on a preclinical model showing that these new inhibitors avoided the drug-induced skin lesions (cutaneous squamous cell carcinoma) observed with other BRAF inhibitors. These scientific findings were presented during the AACR-NCI- EORTC International Conference on Molecular Targets and Cancer Therapeutics, taking place November 12-16, 2011 in San Francisco.
“We have generated a significant set of preclinical data supporting the advancement of PLX3397 as a potential treatment for cancers in which the tumor microenvironment plays an essential role. These new data underscore our plan to explore the utility of PLX3397 as a single agent in another malignancy—prostate cancer,” said Gideon E. Bollag, Ph.D., senior vice president of Plexxikon. “Additionally, in the field of BRAF research, our goal is to build upon the significant success of first generation BRAF inhibitors in order to improve safety and efficacy of these treatments for BRAF mutation positive patients. Our preclinical research shows that our new ‘paradox breakers’ may be able to achieve those goals in the form of a single drug.”


New scientific findings were presented for Plexxikon’s novel agent, PLX3397, an oral drug candidate targeting macrophages and osteoclasts. These cells play an important role in the tumor microenvironment, particularly in enabling the metastases of cancer to bone which can result in significant pain and disability. PLX3397 was shown to alter the tumor microenvironment and even re-program certain immune cells involved in killing cancer cells. Specifically, the findings showed:
  • Significant tumor growth inhibition, reduction in cancer bone pain and prevention of pathologic bone remodeling in preclinical studies of prostate cancer, conducted by collaborators led by Dr. Pat Mantyh at the University of Arizona College of Medicine.
  • Increased tumor cell death and decreased tumor burden by decreasing macrophage and increasing cytotoxic T-cell infiltration in preclinical studies of malignant mesothelioma, conducted by collaborators led by Dr. Lisa Coussens at the University of California, San Francisco.

PLX3397 is currently in a Phase 2 study in Hodgkin lymphoma. Additional Phase 2 studies are planned in a number of other cancers, including glioblastoma, acute myelogenous leukemia, metastatic breast cancer and prostate cancer.

Next Generation BRAF Inhibitors

Plexxikon scientists have discovered novel agents, called ‘paradox breakers’, with potential to address the drug-induced skin lesion side effect, and improve treatment durability, compared to first generation BRAF inhibitors. Specifically, their preclinical findings identified novel mechanisms that showed:
  • Following the paradoxical re-activation of a key signaling pathway involved in tumor growth in RAS mutant tumors, first generation BRAF inhibitors induced up-regulation of ligands for the HER family of receptors, potentially explaining disease progression.
  • First generation BRAF inhibitors also induced growth of skin cells carrying pre-existing oncogenes, observed as cutaneous squamous cell carcinoma in sun exposed skin of melanoma patients. In contrast, data showed that treatment with Plexxikon’s ‘paradox breakers’ did not induce growth of these cells.
  • Separately, combination treatment—using an EGFR inhibitor with a first generation BRAF inhibitor—also prevented these drug-induced skin lesions
Plexxikon plans to advance its ‘paradox breaker’ by filing an Investigational New Drug (IND) application with the FDA for a Phase 1 clinical trial in 2012.

About Plexxikon

Plexxikon, a member of Daiichi Sankyo Group, is a leader in the structure-guided discovery and development of novel small molecule pharmaceuticals to treat human disease. The company’s lead drug ZelborafTM (vemurafenib/PLX4032) was approved by the FDA in August 2011, and is being co-promoted in the U.S. by Daiichi Sankyo Inc. and Genentech. The company is developing a portfolio of clinical and preclinical stage compounds to address significant unmet medical needs in oncology, as well as in several other therapeutic indications. Plexxikon’s Scaffold-Based Drug DiscoveryTM platform integrates multiple state-of-the-art technologies, including structural screening as a key component that provides a significant competitive advantage over other drug discovery approaches.


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