In a deal with just $50 million up front but the potential to reach $2.5 billion, Tokyo’s Taiho Pharmaceutical Co. Ltd. and Astex Pharmaceuticals Ltd., of Cambridge, U.K., are joining Merck & Co. Inc. in an exclusive worldwide research collaboration and license agreement to develop small-molecule inhibitors against several cancer targets, including the KRAS oncogene.
The three companies will pool their preclinical candidates and research data. Merck receives the global license to the candidates while Taiho and Astex get an aggregate $50 million. Taiho and Astex could bring in about $2.5 billion if they hit preclinical, clinical, regulatory and sales milestones, plus tiered royalties on sales. Merck will pay for R&D and global commercialization while Taiho retains Japanese commercialization rights and the option to promote the products in Southeast Asia.
Merck, of Kenilworth, N.J., currently has Keytruda (pembrolizumab), its monoclonal antibody targeting PD-1, in a phase III trial studying first-line metastatic nonsquamous non-small-cell lung cancer with PD-L1 expression. Exploratory analysis of the Keynote-042 study showed Keytruda reduced the risk of death by 58% in patients with any KRAS mutation and by 72% in patients with the KRAS G12C mutation compared to chemotherapy.
In December, Taiho terminated its co-promotion contract in Japan for Keytruda with MSD, a trade name for Merck. MSD continues its manufacturing, distribution and promotion of Keytruda.
KRAS is overall the most frequently deregulated oncogene in solid tumors, playing a role in about one out of every seven solid tumors. The G12C mutation is present in somewhere between 10% and 15% of lung cancer patients, and smaller fractions of other tumors.
Taiho and Astex, a wholly owned subsidiary of Otsuka Pharmaceutical Co. Ltd., are already linked. In June, Astex and Otsuka announced top-line results from the phase III ASCERTAIN study evaluating ASTX-727 vs. decitabine I.V. in adults with intermediate and high-risk myelodysplastic syndromes or chronic myelomonocytic leukemia. The trial met its primary endpoint of decitabine area-under-the-curve equivalence of a total five-day dosing between orally administered ASTX-727 and I.V. decitabine. A day later a deal was announced in which Taiho assumed commercialization responsibility from Otsuka for the fixed-dose combination of cedazuridine and decitabine (ASTX-727) and guadecitabine (SGI-110) in the U.S. and Canada. Taiho Pharma Canada Inc. will commercialize the compounds in Canada.
Last February, the FDA approved Taiho’s cancer agent, Lonsurf (trifluridine/tipiracil), to treat patients previously treated with at least two prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy. Lonsurf is a nucleoside analogue of thymidine phosphorylase.
The China National Medical Products Administration approved Lonsurf in September for treating metastatic colorectal cancer for those previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, who in addition might be treated or not able to be treated by an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. The approval springs from the phase III TERRA study, which met its primary efficacy endpoint of statistically prolonging overall survival in patients with unresectable advanced or recurrent colorectal cancer.
In November, another KRAS/Asia collaboration began as Amgen Inc. undertook a massive $2.7 billion cash equity investment in Beigene Ltd., buying itself an oncology footprint in China. In all, 23 drug candidates are in play as Beigene, one of China's few elite biotechs, will commercialize three of Amgen's approved products in China, and the two firms will jointly develop 20 drug candidates globally. Eight are in phase I for hematologic tumors, six in phase I for solid tumors and six are in preclinical development. Amgen's first-in-class KRAS inhibitor, AMG-510, is included. Beigene will also step up with $1.25 billion for R&D.
Amgen announced new data last fall from an ongoing phase I study evaluating AMG-510 in patients with previously treated KRAS G12C-mutant solid tumors. The data include the first evidence of antitumor activity reported in patients with colorectal cancer and appendiceal cancer, as well as previously presented non-small-cell lung cancer findings. The study enrolled 76 patients with KRAS G12C-mutant solid tumors.
Other collaborations are in a similar hunt. Machavert Pharmaceuticals Inc. announced in November that it will develop University of Colorado's small-molecule RAL GTPase inhibitors for KRAS-mutant cancers. No financial terms were released.
After a deal with Abbvie Inc. in 2018, Mumbai, India-based Lupin Ltd. inked a deal last September with German pharma Boehringer Ingelheim GmbH, to deepen its drug research efforts in gastrointestinal and lung cancers. Under the new agreement, the companies will explore the potential of a combination therapy using Lupin's MEK inhibitor compound, LNP-3794, and Boehringer Ingelheim's KRAS inhibitor. Lupin will receive $20 million up front and, if defined clinical, regulatory and commercial milestones are achieved, it could receive more than $700 million.