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Plexxikon Announces PLX4032 Phase 1 Data Showing Objective Responses in Metastatic Melanoma Patients

--Personalized Medicine for Deadliest Form of Skin Cancer --

ORLANDO, Fla. & BERKELEY, Calif.--(BUSINESS WIRE)--Jun 1, 2009 - Plexxikon Inc. today announced preliminary data from a Phase 1 clinical study investigating PLX4032 (R7204). PLX4032 is a novel, oral and highly selective drug that targets the BRAFV600E cancer-causing mutation that occurs in most melanomas and about eight percent of all solid tumors. In patients whose cancer harbors this mutation and who were treated with therapeutic doses of PLX4032, tumor shrinkage and extended progression-free survival have been observed. Currently, two extension studies are being conducted in mutation-positive melanoma and colorectal cancer patients. Following the initial positive findings announced today, larger clinical trials to support a registration program for product approval are targeted to start later in 2009. Plexxikon and Roche are co-developing PLX4032 under their 2006 license and collaboration agreement.

“PLX4032 has shown both tumor shrinkage and delay in tumor progression in patients whose tumors harbor a BRAF mutation as well as reports of clinical symptom improvement in some patients,” stated Keith T. Flaherty, M.D., assistant professor at the Abramson Cancer Center of the University of Pennsylvania and principal investigator for the PLX4032 Phase 1 clinical trial. “Seven years after BRAF mutations were first identified, we have validation that this mutation is a cancer driver and therapeutic target. This is a new and important chapter in the story of targeted therapy development in cancer, and we are especially excited for our melanoma patients, for whom there are currently few treatment options.” Link to video clip of Dr. Flaherty

In the dose escalation phase of the study, 55 cancer patients have been treated, including 24 mutation-positive melanoma patients and 3 mutation-positive thyroid patients, as well as 28 melanoma, rectal and ovarian cancer patients who did not have the mutation or whose mutation status was not known.

In 16 BRAF mutation-positive melanoma patients treated with PLX4032 doses at or above 240 mg twice daily (BID), representing targeted drug exposure levels, data show:


  • PLX4032 is well tolerated at very high doses, with 960 mg BID under evaluation as the maximum tolerated dose
     
  • Partial responses in 9 patients showing greater than 30% tumor regression by RECIST (Response Evaluation Criteria in Solid Tumors) criteria, with 7 confirmed
     
  • Regression of metastatic lesions in every site to which melanoma commonly spreads, including liver, lung and bone
     
  • Minor responses in 4 patients showing tumor regression greater than 10% but less than 30%
     
  • Disease control lasting up to 14 months with continuous therapy, with many patients still receiving treatment
     
  • Interim median progression-free survival of at least six months, with many responding patients still receiving treatment
     

By contrast, no treatment response was observed in a small group of patients without the mutation, and progression-free survival was less than 2 months, consistent with historical data.

Dose-limiting toxicities, primarily rash, fatigue and joint pains, were seen at 1120 mg BID. Drug-related adverse events have been predominantly mild in severity and transient, including rash and photosensitivity. Serious adverse events were observed in some patients after chronic treatment, including possibly drug-related cutaneous squamous cell carcinoma. A risk management plan has been implemented for baseline evaluation of the skin and monitoring of all patients while on study. Cutaneous squamous cell carcinoma is typically excised by a patient's dermatologist.

“This is a significant day for us at Plexxikon. The clinical data for PLX4032 so far support our hypothesis that a truly selective drug can target tumors harboring this cancer-causing mutation, while at the same time, deliver a treatment that is well tolerated by patients,” stated K. Peter Hirth, Ph.D., chief executive officer of Plexxikon. “In conjunction with bio-response markers and a companion diagnostic test, PLX4032 has all the hallmarks of an ideal personalized medicine. Plexxikon's pipeline includes several highly selective kinase inhibitors, including novel therapies for other cancers as well as other chronic diseases such as rheumatoid arthritis where such precision is anticipated to provide a safety advantage.”

Companion Diagnostic in Parallel Development

Along with the development of PLX4032 therapy, a diagnostic test to identify patients with the BRAF mutation is being co-developed by Plexxikon and Roche, under a separate 2005 agreement. This test is already being used to identify mutation-positive patients for ongoing clinical trials. Most importantly, this companion diagnostic enables the identification of mutation-positive cancer patients considered most likely to respond to PLX4032 treatment.

Exploring PLX4032 in Colorectal and Other Cancers

The prevalence of the BRAF mutation is about eight percent of all solid tumors. Preclinical studies in colorectal cancer models also suggest that PLX4032 causes tumor regression, either as a single agent or in combination. Hence, future clinical trials may evaluate PLX4032 in tumor types beyond melanoma.

Currently, one of two extension cohorts is recruiting mutation-positive colorectal cancer patients in order to evaluate PLX4032 in this target population. In a retrospective study of 600 patients with colorectal cancer, including all stages and both genders, tumor tissue was tested for the presence of the BRAF mutation and correlated with outcomes. The data confirmed that approximately 10 percent of colorectal cancer patients carry this mutation, which is independent of the KRAS mutation, and those BRAF mutation-positive patients have a much poorer prognosis than patients with wild-type BRAF (ASCO 2009 Abstract #1103).

Additionally, in the Phase 1 dose escalation study which enrolled patients with several different tumor types, one mutation-positive thyroid patient showed a confirmed partial response, while two others showed stable disease with prolonged therapy.

Biomarkers Enhance Development of Personalized Medicine

The development of PLX4032 has employed a variety of translational tools, including bio-response markers and an in vitro diagnostic test. These tools can potentially enable early detection of targeted pathway modulation and treatment response, as well as identification of the targeted patient population for this treatment.

Biomarker data from patient tumor biopsies before and after PLX4032 treatment showed early target modulation and when dosed at higher levels, have shown nearly complete inhibition of the desired target (ASCO 2009 Abstract #9021).

About PLX4032 (R7204)—A Personalized Medicine for Cancer Treatment

PLX4032 is a novel, oral small molecule for the treatment of melanoma and other cancers harboring the V600E mutation of the BRAF kinase gene. This defect is present in approximately 60 percent of melanoma skin cancers, and occurs in about eight percent of all solid tumors, including melanoma, colorectal, thyroid and other cancers. Preclinical data suggest that Plexxikon's novel anti-cancer compound selectively targets and inhibits tumor cells which contain this cancer-causing mutation. In contrast to many other kinase inhibitors available, PLX4032 is highly selective for its primary target, and does not have significant activity on other kinase targets.

About Melanoma

Melanoma is the most serious type of skin cancer. More than 50,000 people in the U.S. are diagnosed with melanoma each year, but the percentage of people in the U.S. who develop melanoma has more than doubled in the past 30 years. Worldwide, about 160,000 new cases of melanoma are diagnosed annually. Melanoma is treatable if caught early but is very deadly when it becomes metastatic. 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 less than 12 months. Patients who develop metastatic disease are rarely cured with available treatments.

About Roche

Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world's largest biotech company with truly differentiated medicines in oncology, virology, inflammation, metabolism and CNS. Roche is also the world leader in in-vitro diagnostics, tissue-based cancer diagnostics and a pioneer in diabetes management. Roche's personalized healthcare strategy aims at providing medicines and diagnostic tools that enable tangible improvements in the health, quality of life and survival of patients.

In 2008, Roche had over 80,000 employees worldwide and invested almost 9 billion Swiss francs in R&D. The Group posted sales of 45.6 billion Swiss francs. Genentech, United States, is a wholly owned member of the Roche Group. Roche has a majority stake in Chugai Pharmaceutical, Japan. For more information: www.roche.com.

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 clinical stage programs include PLX4032 for the treatment of melanoma and colorectal cancer, PLX5568 for the treatment of polycystic kidney disease and PLX204 for the treatment of diabetes. Among the company's preclinical development programs, candidates are being developed for the treatment of rheumatoid arthritis, multiple sclerosis and other autoimmune diseases as well as for the treatment of pancreatic and metastatic breast cancer.

Plexxikon's proprietary Scaffold-Based Drug Discovery™ platform integrates multiple 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 being developed to address significant unmet medical needs in cardio-renal disease, CNS disorders, inflammatory and neuro-inflammatory diseases and oncology. For more information: www.plexxikon.com.

Photos/Multimedia Gallery Available: http://www.businesswire.com/cgi-bin/mmg.cgi?eid=5976391&lang=en

Contact: Plexxikon Inc.
Kathleen Sereda Glaub, President, +1-510-647-4009
kglaub@plexxikon.com
or
For Plexxikon Inc.
Jennifer Cook Williams, +1-360-668-3701
jennifer@cwcomm.org

Posted: June 2009

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