The KRAS gene has become a hot target for cancer research for a growing number of drug developers. Merck, which is already testing a KRAS vaccine candidate, is now spreading its bets with a licensing deal for small molecule KRAS drugs being developed by two Otsuka Pharmaceutical subsidiaries.
Merck (NYSE: [[ticker:MRK]]) is paying $25 million up front for global rights to the preclinical compounds from the Otsuka companies, Taiho Pharmaceutical and Astex Pharmaceuticals. According to the deal terms, the pharmaceutical giant will finance research and development of drugs addressing several cancer targets, including KRAS. Depending on their progress, Merck could be on the hook for up to $2.5 billion in milestone payments, plus royalties from sales if they reach the market. Merck would handle global commercialization, but Taiho is keeping co-commercialization rights to the cancer drugs in Japan and it has an option to promote them in parts of Southeast Asia.
The KRAS gene provides the instructions for making the KRAS protein, which plays a role in the signaling pathways governing the growth, maturation, and death of cancer cells. Mutated forms of the KRAS gene produce proteins that have been linked to lung cancers, colorectal cancer, and pancreatic cancer. Most of the companies chasing this drug target are developing compounds to block the problem proteins.
Merck already had a hand in the KRAS chase. Since 2016, the company has been working with messenger RNA therapeutics developer Moderna (NASDAQ: [[ticker:MRNA]]) in a partnership focused on cancer vaccines. Merck paid its partner $200 million up front to kick off the alliance. In 2018, the companies amended the deal to include mRNA-5671, a KRAS vaccine candidate that Moderna had developed prior to the Merck collaboration. Moderna designed the vaccine to prompt an immune response to cancers that have four KRAS mutations. In connection with the change to the partnership, Merck made a $125 million equity investment in its partner.
Moderna’s mRNA-5671, in development as a potential treatment for colorectal cancer, non-small cell lung cancer, and pancreatic cancer, is in a Phase 1 study testing the drug on its own and in combination with Merck’s immunotherapy pembrolizumab (Keytruda). The partnership calls for Merck to finance clinical testing with vaccine supplied by Moderna. With the Taiho and Astex deal, Merck can potentially add new approaches to KRAS, though the companies have not yet released details about their potential KRAS-targeting drugs. A Merck spokeswoman said that because the research is preclinical, it is too early to discuss when it might reach tests in humans. She added that the alliance is exploring a number of KRAS mutations prevalent in cancer.
So far, Amgen (NASDAQ: [[ticker:AMGN]]) leads the field of companies pursuing KRAS. The company’s small molecule drug, AMG 510, specifically targets KRAS-G12C, a mutation found in a fraction of tough-to-treat cancers. It was first KRAS inhibitor to enter clinical trials, according to the National Cancer Institute. In the past year, Amgen has released encouraging Phase 1 data for its drug in lung cancer and colorectal cancer. Preclinical and early clinical data for the Amgen drug were published in Nature in October.
Other companies enrolling clinical trials to test KRAS-G12C drugs include Mirati Therapeutics (NASDAQ: [[ticker:MRTX]]) and Eli Lilly (NYSE: [[ticker:LLY]]). San Diego-based Mirati released preliminary data in October from a Phase 1/2 study that showed partial responses to the drug in colorectal cancer and non-small cell lung cancer patients. The company said that the maximum tolerated dose has not yet been established and the study is currently enrolling more patients to test at 600 mg dose given twice daily.
Revolution Medicines is targeting the RAS family of proteins with drugs from its own research and from Warp Drive Bio, which it acquired in 2018. Redwood City, CA-based Revolution is developing its lead drug, RMC-4630, in partnership with Sanofi (NYSE: [[ticker:SNY]]). In November, Revolution also announced an agreement with Amgen to test RMC-4630 and AMG 510 together in patients who have solid tumors.
Image by the National Cancer Institute
