Three Additional Cancer Trials With PLX3397 Planned for 2011
Plexxikon today announced that it has treated the first patient in a Phase 2 clinical trial in Hodgkin lymphoma with PLX3397. This novel agent is an oral, selective inhibitor that down-modulates two key cell types that are thought to mediate the progression of Hodgkin lymphoma tumors - macrophages and mast cells. The Phase 2 trial is one of several planned proof-of-concept trials to be initiated with PLX3397 in 2011.
The trial is a multi-center, single-arm trial expected to enroll approximately 30 patients with Hodgkin lymphoma who have relapsed or become refractory to standard therapies. Objectives of this trial include assessing the efficacy of orally administered PLX3397 as measured by overall response rate, as well as the duration of response, the disease control rate, progression-free survival, response biomarkers and overall safety. Additional information about the Phase 2 trial is available at www.clinicaltrials.gov.
Tumor-associated macrophages comprise a significant amount of the tumor bulk in Hodgkin lymphoma, and increased numbers are associated with a worse prognosis. Mast cells are also an important inflammatory cell type that can stimulate the tumor cells directly. In addition, over-expression of CSF-1, the primary ligand for the Fms receptor - one of the key targets of PLX3397 - has been demonstrated to stimulate growth of primary Hodgkin tumor cells; inhibition of Fms blocks the growth of these cells.
"PLX3397 is an important product candidate both for Plexxikon's growing oncology franchise and for our FMS portfolio. Since PLX3397 targets multiple facets of Hodgkin lymphoma pathology, we expect treatment benefits to include both tumor growth inhibition, and reduction of invasiveness and metastatic spread," said K. Peter Hirth, Ph.D., chief executive officer of Plexxikon. "In other cancers, we are hopeful about a variety of combination treatments since preclinical models have shown that PLX3397 can overcome chemotherapy- and radiation-resistance in tumors driven by increased levels of CSF-1, such as metastatic breast cancer. Additionally, we expect to see a reduction in metastases and tumor growth for cancers that metastasize to the bone; consequently we anticipate a reduction in cancer bone pain as well."
Additional Phase 2 Cancer Trials Planned
Beyond Hodgkin lymphoma, Plexxikon plans to explore potential efficacy in additional trials also to be initiated in 2011. Those trials are expected to focus on recurrent glioblastoma multiforme, mutated relapsed acute myelogenous leukemia (AML) and metastatic breast cancer. Data from the ongoing Phase 1 dose escalation clinical trial of PLX3397 in patients with metastatic disease are expected to be presented at a medical oncology conference in 2011. In this Phase 1 study, response biomarkers for macrophages and mast cells demonstrated that drug exposures are adequate to modulate the relevant targets without dose limiting toxicities, suggesting that PLX3397 is well tolerated.
About Hodgkin Lymphoma
Hodgkin lymphoma, previously known as Hodgkin's disease, is a type of cancer originating from specific B-lymphocytes (white blood cells) called Reed-Sternberg cells. This particular lymphocyte is not present in other types of lymphomas, the rest of which are categorized as non-Hodgkin lymphoma. Early-stage Hodgkin lymphoma generally responds well to a combination of modalities including chemotherapy, radiation and stem cell transplantation often resulting in long-term survival, but there remains an unmet need for refractory patients and those who relapse. According to the Leukemia and Lymphoma Society, approximately 150,000 people in the U.S. are living with Hodgkin lymphoma.
Plexxikon is a leader in the structure-guided discovery and development of novel small molecule pharmaceuticals to treat human disease. The company's lead compound, PLX4032, recently met overall survival and progression-free survival endpoints in a Phase 3 trial of melanoma patients. The company is developing a portfolio of clinical and preclinical stage compounds to address significant unmet medical needs in cardio-renal disease, CNS disorders, autoimmune and neuro-inflammatory diseases, and oncology. Plexxikon's proprietary 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.
PLX3397 is an orally available inhibitor that selectively co-inhibits three key targets - FMS, Kit and FIt3-ITD - allowing for down-modulation of a number of cell types, including macrophages, microglia, osteoclasts and mast cells, as well as selectively targeting the Flt3 mutation, a driver in AML. Growth factors for these cells are elevated in significant subsets of different human cancers, including glioblastoma, AML, breast, colorectal, lung and prostate cancer. These growth factors consequently activate the target cells, leading to a microenvironment that supports tumor growth and enables metastases to distant sites, particularly to bone. Additionally, PLX3397 has the ability to penetrate the blood-brain barrier, indicating potential efficacy in central nervous system primary or metastatic tumors, as well as a range of other diseases.
In February 2011, Plexxikon announced that it had agreed to be acquired by Daiichi Sankyo, a Japan-based global pharmaceutical company. Closure of the transaction is pending clearance under the Hart-Scott-Rodino (HSR) Antitrust Improvements Act.