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Plexxikon Files for Approval of Highly Touted Melanoma Drug

May 12, 2011 - BioWorld Today

By Jennifer Boggs
Assistant Managing Editor

A mere four and a half years after launching clinical development, Plexxikon Inc. fi led marketing applications in the U.S. and Europe for its targeted melanoma drug PLX4032, now known as vemurafenib.

The firm, which was bought recently by Daiichi Sankyo Co. Ltd., has asked for priority review in the U.S. If granted, vemurafenib could be available to patients about five years after Plexxikon recruited the first patients in its Phase I trial in December 2006.

“I don’t know whether it’s a record,” said CEO Peter Hirth, adding, “We just tried to move forward as quickly as possible.”

For Berkeley, Calif.-based Plexxikon, the decision to accelerate the program was an easy one. The firm reported stunning data from a Phase I extension trial, which showed an 81 percent response rate in metastatic melanoma patients with the BRAF V600E mutation treated with the selective kinase inhibitor – in some patients, those effects were seen in as early as two weeks. (See BioWorld Today, Aug. 27, 2010.)

Initial data from that trial prompted the company to launch a Phase II open-label study in previously treated patients aimed at measuring response rate based on tumor shrinkage and, rather than waiting for Phase II data, Plexxikon and partner Roche AG chose to advance vemurafenib immediately into a randomized Phase III study in first-line patients with a primary endpoint of overall survival. In fact, those studies “were almost started in parallel,” said Kathleen Sereda Glaub, Plexxikon’s president.

“The data all along have been highly, highly consistent,” she told BioWorld Today.

The first patient was enrolled into the pivotal BRIM3 study in January 2010. Almost exactly a year later, Plexxikon wowed with interim data showing both an overall survival benefit and a progression-free survival benefit in patients receiving vemurafenib as a single agent. Data were so strong that BRIM3 was terminated early and patients in the control arm were allowed to cross over into vemurafenib treatment. (See BioWorld Today, Jan. 20, 2011.)

Hirth attributed the speed of vemurafenib’s development largely to the “power of personalized medicine.” The company was able to test patients specifi cally for the V600E mutation for recruitment into its trials. And Plexxikon is seeking a pre-marketing application in the U.S. – as well as registration in Europe – for a companion diagnostic to help physicians determine whether patients have that specific BRAF mutation.

So far the use of companion diagnostics in clinical development and commercialization has been limited, despite the early success of Roche’s Herceptin (trastuzumab) and HER2 tests. But the FDA has made it clear that companion diagnostics will be critical for selective therapies. Last year, the FDA’s Oncology Drugs Advisory Committee asked regulators to delay a decision on ChemGenex Pharmaceuticals Ltd.’s Omapro (omacetaxine) until a diagnostic test became available to identify chronic myelogenous leukemia patients with the T3151 mutation. (See BioWorld Today, April 13, 2010.)

Plexxikon’s story underscores the benefits of a personalized medicine approach, not only in helping to accelerate drug development but also helping to keep costs down. Plus, it provides a “much, much higher probability of success,” Hirth added.

About 160,000 people are diagnosed with melanoma each year, and the BRAF V600E mutation occurs in about 50 percent of melanoma patients.

Hirth said he does not see vemurafenib competing directly with Yervoy (ipilimumab), the melanoma drug from New York-based Bristol-Myers Squibb Co. approved earlier this year and gaining attention as the fi rst approved melanoma drug shown to actually improve overall survival. Yervoy’s nod marks a “very important milestone” in the disease space, but its mechanism – the drug is a T-cell potentiator blocking CLTA-4, is for broader use in that patient population rather than targeted to specific patients, he said. (See BioWorld Today, March 28, 2011 .)

The potential for combining those therapies also isn’t out of the question. Vemurafenib’s safety profile should lend itself to combination treatment, possibly in melanoma but also in other cancers. The BRAF V600E mutation is estimated to occur in about 8 percent of solid tumors.

During last year’s American Society of Clinical Oncology meeting, Plexxikon reported positive early data in colorectal cancer. Other possibilities include thyroid cancer, another area of unmet need.

“The science is still new,” Hirth told BioWorld Today. “I don’t want to use the word ‘blockbuster,’ but it could be a very significant opportunity.”

Daiichi Sankyo clearly agreed. The Japanese pharma firm shelled out $805 million up front to buy Plexxikon, even though it will only have U.S. co-promotion rights to vemurafenib under Plexxikon’s existing collaboration with Basel, Switzerland-based Roche. Another $130 million in milestones from Daiichi are tied to the drug’s commercial success. (See BioWorld Today, March 2, 2011 .)

But Plexxikon’s pipeline includes more than just vemurafenib. The company has about 10 additional programs in various stages of preclinical and clinical development, including PLX3397, a selective inhibitor designed to downmodulate macrophages and mast cells, which started a Phase II study in Hodgkin lymphoma in March. And the firm has earlier-stage kinase inhibitors in metabolic, inflammatory and central nervous system diseases.

“We’re just following a paradigm of targeting very specific [patient populations] with very targeted, clean inhibitors,” Hirth said.

Terms of its acquisition by Daiichi call for Plexxikon to continue operations, basically running as a 42-member independent R&D unit. “So we have our own committed budget, and we continue to make the decisions,” Glaub said.

Plexxikon focuses on getting programs through proof of concept, at which point they will be handed off to its new parent company. “It’s a somewhat unique approach to an acquisition,” she added.