Press Releases

Plexxikon Data Shows PLX4032 Selectivity Enables Substantial Pathway Inhibition and Significant Clinical Response

-Key Data Published in Nature-

BERKELEY, Calif. – September 7, 2010

Plexxikon today announced publication of key data in this week’s edition of Nature demonstrating that the high degree of selectivity of PLX4032 (RG7204) enables substantial RAF/MEK/ERK pathway inhibition, which may be necessary to achieve significant tumor shrinkage and clinical response in patients with BRAF mutant melanoma. The paper details the structure-guided discovery of PLX4032, a novel, investigational, targeted agent, selective for the oncogenic BRAF mutation prevalent in melanoma and other cancers. The findings support recently published data from the New England Journal of Medicine showing that nearly all mutation-positive patients in a Phase 1 clinical trial of PLX4032 experienced some tumor shrinkage.

Following the initial identification of mutant BRAF in melanomas and other cancers in 2002, Plexxikon leveraged its structure-guided discovery approach to identify and optimize a number of inhibitors selective for mutant BRAF, including PLX4032.

Preclinical studies showed that PLX4032 selectively blocks the RAF/MEK/ERK pathway in BRAF mutant cells and causes regression of tumors in BRAF mutant xenograft models. Toxicology studies confirmed a high therapeutic index consistent with a high degree of selectivity.

Tumor regression in cancer patients requires significant pathway inhibition
In the Phase 1 trial, paired biopsy specimens from a subset of patients, were analyzed for pathway inhibition before and after two weeks of treatment. Data showed that with increasing doses of PLX4032, more than 80% inhibition of ERK phosphorylation (a measure of RAF/MEK/ERK pathway activation) in the tumors of patients correlated with significant tumor shrinkage and clinical response. In contrast, in patients exposed to plasma levels of PLX4032 at sub-therapeutic doses (less than 240 mg BID), partial inhibition of RAF activity in the tumor tissue of a subset of patients did not result in meaningful tumor shrinkage or clinical response.

“These data provide important support for our clinical development of PLX4032, and are a direct translation of our preclinical data demonstrating that comprehensive inhibition of the ERK pathway may be necessary for significant tumor regression,” said K. Peter Hirth, Ph.D., chief executive officer of Plexxikon. “Plexxikon’s hallmark capability of making highly selective kinase inhibitors has enabled us to administer high doses of PLX4032 in the clinic to substantially inhibit this important pathway. The selectivity of this unique BRAF inhibitor is key to minimizing significant off-target toxicities, and is an important distinguishing feature of this first-in-class BRAF inhibitor.”

About PLX4032 (RG7204)—A Personalized Medicine for Cancer Treatment
PLX4032 is a novel, investigational, oral small molecule for melanoma and other cancers harboring the BRAF mutation. Plexxikon utilized its structure-guided chemistry platform to discover PLX4032, and initiated clinical development in 2006. PLX4032 is now being co-developed under a 2006 license and collaboration agreement between Plexxikon and Roche. A DNA-based companion diagnostic to identify patients whose tumors carry the BRAF mutation is being co-developed by Plexxikon and Roche Molecular Systems, Inc. in parallel with the development of PLX4032.

Patients with metastatic melanoma who test positive for the BRAF mutation are currently being enrolled in a Phase 3 trial for PLX4032 (BRIM3). Patients interested in enrolling in the trial may find additional information at the Roche Clinical Trials Registry (, at, by visiting, or by contacting the Roche/Genentech Call Center at 888-662-6728. Additionally, a Phase 2 trial in patients who received prior therapy is ongoing.

About Melanoma
Melanoma is the most serious type of skin cancer and is growing at a rate of about 5 to 6 percent annually. More than 50,000 people in the U.S. and 160,000 people worldwide are diagnosed with melanoma each year, which contribute to approximately 48,000 deaths. It is one of the deadliest cancers, with a five-year survival rate of 15 percent. The median progression-free survival for a patient with metastatic melanoma is less than 60 days, and the median overall survival for these patients is approximately eight months.

Risk factors for melanoma include a family history of melanoma, prior melanoma, multiple clinically atypical moles or dysplastic nevi, fair skin and sun exposure. However, melanoma can occur in any ethnic group and also in areas of the body without substantial exposure to the sun.

About Plexxikon
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, is in late-stage clinical trials for the treatment of melanoma. Other clinical-stage programs include PLX5568 for the treatment of polycystic kidney disease, PLX204 for the treatment of diabetes, and PLX3397 for the treatment of metastatic cancer. Among the company’s preclinical development programs, candidates are being developed for the treatment of rheumatoid arthritis, neuro-inflammatory disorders, multiple sclerosis and other autoimmune diseases as well as for the treatment of other cancers.

Plexxikon’s proprietary Scaffold-Based Drug Discovery™ 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. The company has discovered a portfolio of clinical and preclinical stage compounds to address significant unmet medical needs in cardio-renal disease, CNS disorders, inflammatory and neuro-inflammatory diseases, and oncology.