Roche Pharmaceuticals has given privately held Plexxikon $46 million to help it develop what Plexxikon believes will be the first drug to target the mutant BRAF kinase, a pathway common in melanoma and colorectal cancer.
In a separate yet related effort Roche will collaborate with Plexxikon to develop a test to detect mutant BRAF in patient samples. Plexxikon hopes to begin phase 1 clinical trials by the end of the year, and to enroll patients whose tumors carry the BRAF mutation in phase 2 trials late next year.
The drug and diagnostic will be sold as separate products, and it’s not immediately clear whether the companies will promote their combined use.
“We’re presuming at this point that efficacy will be higher in patients with the mutation — that’s one of the things we will be learning in the clinic,” Gideon Bollag, Plexxikon’s vice president of discovery biology, told Pharmacogenomics Reporter last week. “If that is very clearly the case, then it would certainly be on the label that patients with the mutation would be the ones to which it would be prescribed.”
“If the hypothesis is correct — that patients who have the mutation will respond more favorably — that should enable us to accelerate clinical development,” added Cathy Glaub, president of Plexxikon.
It is not clear on which platform any BRAF mutation diagnostic would run on, and Roche was not able to respond to questions before deadline.
Plexxikon last month filed an Investigational New Drug application for the drug, known as PLX4032, and Roche will fund its development with a $40 million upfront payment and $6 million for research over the next two years. Plexxikon also stands to pocket as much as $660 million in milestone payments contingent upon progress.
Plexxikon hasn’t officially stated which indication it hopes to address with the drug, but melanoma and colorectal cancer are most likely, due to the prevalence of the BRAF mutation in these types of tumors.
A paucity of existing treatments also gives melanoma a boost. “We’re really looking at melanoma as a good opportunity where we can test our drug as a single agent because there really isn’t a standard of care,” said Glaub. “From a clinical development viewpoint, and trying to get something quickly to the market, this is a very good entry indication,” she added.
Roche will have a worldwide, exclusive license to PLX4032, or any other drugs resulting from the deal, while Plexxikon will have the right to co-promote “any product in the collaboration” in the United States, the companies said. “This will be an opportunity to build a sales force and to begin building a commercial infrastructure,” said Glaub. The privately owned company currently employs about 60 people.
The milestone payments Roche will make to Plexxikon are contingent upon the company’s success in developing and commercializing the drug for multiple indications, or for development and commercialization of multiple compounds, the firms said. Plexxikon will also get royalties on product sales.
PLX4032 inhibits both wild-type BRAF and a defective version of the kinase produced by a mutation called V600E, which is believed to help cause and promote some cancers, Bollag said.
According to the terms of an earlier agreement, Roche Molecular Diagnostics has been collaborating with Plexxikon in developing an in vitro assay for detecting cells carrying the V600E BRAF mutation, said Glaub.
As for competing devices, Biotage last year launched a Pyromark BRAF assay. According to a Biotage spokesperson, the company’s device is for research use only.
Assuming Plexxikon’s drug does not appear toxic during phase 1 trials, the company hopes it will prove effective at halting the cell-growth signals that mutated BRAF proteins constantly send.
“In the [tumor] cell, the mutated kinase is clearly important for either the proliferation or even the survival of the cell,” said Bollag.
The phase 1 study will include patients with many types of solid tumors, but Plexxikon hopes to bias the subject population toward patients who are likely to harbor the BRAF mutation, and it will genotype patients to learn more about it, Bollag said.
Plexxikon will select patients with a V600E BRAF mutation for its phase 2 trials, which may begin during the second half of 2007, he added.
Approximately 60 percent to 70 percent of malignant melanomas and 10 percent to 15 percent of colorectal cancers carry a BRAF V600E mutation, said Bollag. The mutation also plays a part in 30 percent to 50 percent of thyroid cancers, and in a small proportion of as many as 30 other tumor types, he said.
The V600E mutation is present in about 100,000 US cancer cases diagnosed annually, estimated Plexxikon’s Glaub.
About 62,190 people in the United States will be diagnosed with melanoma by the end of 2006, and a total of about 662,433 people in the country have the disease, according to the US National Cancer Institute.
In an overview of melanoma, the NCI calls early, contained melanoma “easily cured” by surgery, though if surgery fails, there is currently no widely effective treatment for the disease.
The NCI also said that “[m]elanoma that has spread to distant sites is rarely curable with standard therapy,” although interleukin-2 has shown promise in small studies. Approximately 7,910 patients will die from the disease by the end of the year, according to the institute.
In patients where the disease has spread to lymph nodes, surgery is sometimes followed by adjuvant interferon therapy, which can improve relapse-free survival. In patients whose cancer has spread, chemotherapy can follow failed interferon or vaccination therapy, but it shows no survival advantage, according to the NCI.
“From a clinical development viewpoint, and trying to get something quickly to the market, this is a very good entry indication.”
In addition to performing a role in the signaling pathways of a large number of growth factor receptors, BRAF passes along growth-promoting signals from two receptors that are well studied in the pharmacogenomics field: the epidermal growth factor receptor and the vascular endothelial growth factor receptor.
(Click here for an animated depiction of BRAF’s signaling pathway created by Expert Reviews in Molecular Medicine. Note that the cartoon represents three types of RAS and RAF proteins using only one symbol for each — RAS has three family members, and the RAF family also includes ARAF and RAF-1 protein kinases.)
The only BRAF-inhibiting drug currently on the market is Bayer’s Nexavar, which also inhibits VEGF. The drug is only approved for treating renal cancer, but there are five clinical trials underway to test its efficacy in treating melanoma, in combination with various chemotherapeutics, according to information available from the US National Library of Medicine. Two of these are in phase 3 trials, but none appears to genotype patients prospectively for BRAF mutations.
Novartis’ RAF265 also targets the BRAF protein kinase, and is undergoing phase 1 clinical trials in patients with locally advanced or metastatic melanoma. Novartis’ trial intends to “[e]valuate whether somatic mutations in BRAF and N-RAS genes are associated with modulation of pharmacodynamic markers and clinical response,” as a secondary goal.
Novartis did not respond to questions about its drug before deadline.