Plexxikon Advances Novel Targeted Treatment PLX3397 in Blood Cancer

Berkeley, CA, December 12, 2011

Plexxikon Inc., a member of Daiichi Sankyo Group, today announced scientific findings from preclinical studies showing that treatment with a novel oral agent, PLX3397, selectively inhibited key cancer-driving Flt3 mutations that occur in 20-30 percent of acute myeloid leukemia (AML) patients. In a preclinical model of AML, PLX3397 showed significant tumor regression. This preclinical work also showed that PLX3397 retained activity against certain drug-resistant forms of mutated Flt3 that can occur with other treatments. These scientific findings were presented during the American Society of Hematology (ASH) Conference, taking place December 10-13, 2011 in San Diego (Abstracts #764 and #3632). Plexxikon recently initiated a Phase 1/2 study in AML patients, further described at www.clinicaltrials.gov.

“Given PLX3397’s selectivity for relevant mutations, we are exploring this potential personalized medicine for AML patients with Flt3 mutations,” said K. Peter Hirth, Ph.D., chief executive officer of Plexxikon. “Plexxikon’s hallmark capability to design selective kinase inhibitors enables clinical researchers to test the hypotheses of such targeted therapies directly and rapidly.”

Phase 1 dose escalation testing in patients with solid tumors has been completed, and showed that PLX3397 reached therapeutic drug levels that were well tolerated at the doses tested. Two Phase 2 studies are now under way to further evaluate PLX3397, including one study in Hodgkin lymphoma and another study recently initiated in patients with Flt3-mutated AML. Plasma from Phase 1 patients contained sufficient levels of PLX3397 to block signaling in Flt3-mutant AML cells ex vivo. Additionally, PLX3397 has been tested in primary AML patient blood samples, which showed a clear dose response to drug at clinically achievable drug levels.

About PLX3397
PLX3397 is an oral agent that is being evaluated in several clinical trials for the treatment of different cancers, including AML. PLX3397 selectively co-inhibits three key targets, allowing down-modulation of a number of cell types, including macrophages, microglia, osteoclasts and mast cells, as well as the inhibition of Flt3 mutations that are key oncogenic drivers in AML.

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 Zelboraf™ (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 several other therapeutic indications. Plexxikon’s 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.

They came from all parts of North Carolina’s Research Triangle, and several of them from far beyond, to hear the story of how a small biotechnology company developed a breakthrough cancer treatment, blazed a path for future development of personalized medicine treatments and was purchased in a deal valued at $935 million — the biggest venture-backed acquisition this year.

The company is California biotech Plexxikon. And one of its investors was Durham, North Carolina-based Pappas Ventures, which saw a return greater than 10 times its original investment. Plexxikon President Kathy Glaub was the guest speaker at a packed house for Pappas Ventures’ annual life sciences symposium. Pappas was one of Plexxikon’s early investors, pumping money into the company shortly after its 2001 launch. Art Pappas, founder and managing partner of the firm, said the investment was as much in founder and CEO Peter Hirth as it was in the science. Pappas said he thought Hirth could do with Plexxikon what he had done with previous company Sugen, whose cancer drug Sutent is now a blockbuster drug for Pfizer (NYSE:PFE).

Plexxikon’s breakthrough melanoma drug Zelboraf received U.S. Food and Drug Administration approval in August. But buzz about the drug started building years before while the drug was still in clinical trials.

Zelboraf was discovered through Plexxikon’s proprietary drug-discovery platform that develops families of protein targets. The technology allows researchers to see the way a compound binds to a particular target. That information guides Plexxikon on where to go. Cancer was not Plexxikon’s overall goal. If you’re looking for cancer drugs, you’re not going to see the diabetes drug staring you in the face, Glaub said.

Diabetes was in fact Plexxikon’s first target. PLX204 showed promise as a diabetes treatment and in 2004 the company partnered with Wyeth to develop the compound. But emerging safety concerns around GlaxoSmithKline‘s (NYSE:GSK) diabetes drug Avandia made development of all diabetes drugs a riskier endeavor. Glaub said that while PLX204 showed safety and efficacy, the partnership was terminated because of economic risks.

PLX4032, the compound that would become Zelboraf, was next in the drug pipeline. Here the company sought to continue its strategy of “ongoing partnering.” In 2006, the company entered into what would be its first partnership with Roche (OTC:RHHBY). In clinical trials, results were dramatic with some patients even being able to return to work after just two weeks of treatment.

“You hear patients saying, ‘I can see the lesions melting before my eyes,’” Glaub said of patients in phase 1 studies.

PLX4032 works only for patients whose tumors express a particular gene mutation. Plexxikon also sought to develop a test to identify patients that would respond to the treatment. When the FDA approved Zelboraf in August, the agency also approved a Roche companion diagnostic for the drug.

Plexxikon raised just $67 million in venture funding, the last round coming in 2006 before the company’s first deal with Roche. Partnerships have yielded more money: $243 million to date. Ten years is a long time for venture capitalists to hold on to an investment and Glaub said that last year, as the company weighed financing options, it considered going public. The company also sought bids from pharma companies, an effort complicated by the fact that its lead melanoma drug candidate was already committed to Roche’s oncology unit Genentech in a co-promotion agreement.

Daiichi Sankyo‘s acquisition of Plexxikon was announced in February. The Japanese pharma paid Plexxikon shareholders $805 million up front with up to an additional $130 million to be paid upon achieving milestones. As for Zelboraf, Daiichi Sankyo gets Plexxikon’s rights to co-promote the drug with Genentech.

The deal also allows Plexxicon to continue as an independent operation for two years. Plexxikon’s pipeline has so far turned out eight new chemical entities, all of which Glaub says are blockbuster drug opportunities. Glaub said that Plexxikon believes the personalized medicine approach taken with Zelboraf can also be applied to its other compounds.

“We love personalizing medicine,” Glaub said. “We think this is the way to go for patients.”

 
August 17, 2011

Genentech, the South San Francisco-based unit of Roche, and its Berkeley, CA-based Plexxikon, a unit of Daiichi Sankyo, said today that the FDA has approved their new drug for certain patients with melanoma that has spread through the body. The FDA said the companies can now start selling vemurafenib (Zelboraf) for patients who have mutations of a protein called BRAF that is implicated in their melanoma. The drug, which showed startlingly positive results in clinical trials, was approved ahead of the FDA’s legal deadline of Oct. 28, an action the agency rarely takes.

Genentech, the South San Francisco-based unit of Roche, and its Berkeley, CA-based Plexxikon, a unit of Daiichi Sankyo, said today that the FDA has approved their new drug for certain patients with melanoma that has spread through the body. The FDA said the companies can now start selling vemurafenib (Zelboraf) for patients who have mutations of a protein called BRAF that is implicated in their melanoma. The drug, which showed startlingly positive results in clinical trials, was approved ahead of the FDA’s legal deadline of Oct. 28, an action the agency rarely takes.

 

NEW YORK, August 10, 2011 – The genotyping era of melanoma management is poised to launch.

The era will start with genetic assessment of every patient with advanced-stage melanoma becoming the standard of care, as soon as the Food and Drug Administration approves marketing of vemurafenib, the small-molecule inhibitor of a mutated form of the BRAF gene. Reuters reports that approval is imminent, based on strikingly good results from a phase III study presented in June at the annual meeting of the American Society of Clinical Oncology, and published in the New England Journal of Medicine (2011;364:2507-16).

"If and when [vemurafenib] is approved by the FDA, we will need some sort of commercially available test to assess patients [with unresectable stage IIIC or stage IV melanoma] for BRAF [mutations]," Dr. Richard D. Carvajal said in an interview after speaking at the American Academy of Dermatology’s Summer Academy meeting. "In a large, phase III trial, vemurafenib impacted survival in patients with tumors with a BRAF mutation. You’ll need to know the BRAF status to use [vemurafenib]."

NEW YORK – The genotyping era of melanoma management is poised to launch.

The era will start with genetic assessment of every patient with advanced-stage melanoma becoming the standard of care, as soon as the Food and Drug Administration approves marketing of vemurafenib, the small-molecule inhibitor of a mutated form of the BRAF gene. Reuters reports that approval is imminent, based on strikingly good results from a phase III study presented in June at the annual meeting of the American Society of Clinical Oncology, and published in the New England Journal of Medicine (2011;364:2507-16).

"If and when [vemurafenib] is approved by the FDA, we will need some sort of commercially available test to assess patients [with unresectable stage IIIC or stage IV melanoma] for BRAF [mutations]," Dr. Richard D. Carvajal said in an interview after speaking at the American Academy of Dermatology’s Summer Academy meeting. "In a large, phase III trial, vemurafenib impacted survival in patients with tumors with a BRAF mutation. You’ll need to know the BRAF status to use [vemurafenib]."

In May, Genentech, a Roche subsidiary developing vemurafenib with Daiichi Sankyo subsidiary Plexxikon, announced that it had submitted a new drug approval application to the FDA.

"At my institution and at others, it’s becoming standard of care to do genotyping on these patients. We need to know how to prioritize them to experimental or standard treatments," said Dr. Carvajal, a medical oncologist specializing in melanoma and sarcomas at Memorial Sloan-Kettering Cancer Center in New York. "In the not too distant future, it will be standard to get a panel" of genotyping results, probably also including NRAS, KIT, and several other oncogenes now emerging as important players in the genetic progression of metastatic melanoma.

"As these markers become relevant for choosing treatment, they will be available in CLIA-certified tests," Dr. Carvajal said. Genotyping "should be done on all [advanced melanoma] patients; it’s just a matter of how you pay for it. The panel of genes we’ll need to look at will grow with time."

Results from genotyping studies of metastatic melanoma tumors have shown a BRAF mutation prevalence of about 43% and a NRAS mutation prevalence of about 14%, with the remaining 43% of tumors having wild type forms of both genes, Dr. Nancy E. Thomas said in a separate talk at the meeting.

The BRAF and NRAS mutations, as well as several others found with less frequency, appear mutually exclusive, so that, for example, essentially all studied tumors with BRAF mutations are wild type for NRAS, and essentially all tumors with a NRAS mutation have wild type BRAF, said Dr. Thomas, professor of dermatology at the University of North Carolina at Chapel Hill.

When vemurafenib gets U.S. marketing approval, it will also muddy the treatment algorithm for metastatic melanoma. For the time being, ipilimumab (Yervoy), an immunotherapy approved for treating advanced-stage melanoma in March 2011, is unrivaled for survival benefits as first-line therapy.

"Ipilimumab is the only FDA-approved drug [for advanced melanoma] that has demonstrated an improvement in overall survival. Right now, it’s the standard of care," Dr. Carvajal said.

But ipilimumab also has some drawbacks. The evidence base to date gives no guidance on whether ipilimumab can be targeted to certain genotypic subgroups of melanoma, and it works relatively slowly, which makes it problematic for patients with rapidly progressing disease or a large disease burden. The ipilimumab studies done so far enrolled patients regardless of their genotype status, so no information exists on whether tumors with specific gene mutations respond especially well or poorly.

"When vemurafenib is approved, the question will be how to sequence these two drugs in patients with BRAF mutations. That’s something we’re struggling with," Dr. Carvajal said.

Despite that, the success scored so far by both ipilimumab and vemurafenib represents major advances at least for certain, responsive patients, Dr. Carvajal said. "For both drugs we can see tumor shrinkage, but what we really look for is prolongation of life. A significant proportion of patients will have benefit from treatment that lasts years and years."

Dr. Carvajal said that he has been a consultant to Novartis.