ºÚÁÏÍø

In 1987, ºÚÁÏÍø first began research in the field of oncology. To date, we have accumulated proprietary knowledge through numerous trials and errors, leading to the creation of anticancer agents such as eribulin (Halaven®) and lenvatinib (Lenvima®). Leveraging partnerships in addition to this proprietary knowledge, we are working to improve the efficiency of innovative creations and continue to work toward relieving the anxiety of cancer patients over health.
ºÚÁÏÍø acknowledges oncology as one of its key strategic areas, and will continue to focus on the discovery and development of anti-cancer drugs based on Human Biology within drug discovery domains including “cancer microenvironment”, “proteostasis disruption”, “cell lineage and cell differentiation”, and “inflammation, hypoxia, oxidative stress and cell senescence” under the Deep Human Biology Learning (DHBL) drug discovery and development organization. ºÚÁÏÍø aspires to discover innovative new drugs with new target molecules and mechanisms of action from these domains, with the aim of contributing to the cure of cancers, as well as cancer prevention.

The research group was very small at the beginning. The research targets were chemotherapeutic agents, which were the mainstay of anticancer drugs at the time, and exploratory research was conducted on novel tubulin polymerization inhibitors, topoisomerase II inhibitors, folate antagonists, and other agents.

E7010 is an orally available tubulin polymerization inhibitor with a sulfonamide structure. The compound was the first anticancer drug discovered and developed in-house to be introduced into clinical trials. The same library was used to create indisulam (development code: E7070, introduced into clinical trial in 1998), which targets the G1 phase of the cell cycle, and E7820 (introduced into clinical trial in 2004), an anti-cancer agent with angiogenesis-inhibiting activity, both of which also have a sulfonamide structure.

Unfortunately, these compounds did not make it to commercialization, but research on their target molecules has progressed, and in 2017, indisulam and E7820 were shown to have protein degradation (proteolysis) inducing properties (). We are continuing our research on selective targeted proteolysis-inducers using our newly acquired knowledge. In order to conduct innovative drug discovery research in the same area, collaborative research agreements were signed with the University of Dundee in the UK in 2019 and the University of Tokyo in 2020.

In 2000, a 50-person organization specializing in oncology research was established and oncology was clearly designated as a key disease area, along with the neurology disease area. Organic chemical synthesis and pharmacology scientists were assigned to the laboratory. This led to the discovery of a novel multi-kinase inhibitor, which later became lenvatinib, and the creation of E7107, a synthetic derivative of the novel anti-tumor natural product pladienolide. Subsequently, research on target molecules of pladienolides progressed, and in 2007 it was found at the molecular level to target the splicing factor SF3b ().
Splicing research has continued at H3 Biomedicine Inc. since its inception in 2011, leading to the initiation of a collaboration with Bristol-Myers Squibb in 2018 on novel therapies to enhance cancer immunity using the splicing platform.

In 2006, ºÚÁÏÍø entered into an agreement with U.S.-based Ligand Pharmaceuticals, Inc. for the acquisition of four oncology-related products. With this agreement, we acquired our first oncology products and began to strengthen our anti-cancer sales structure.

In 2007, ºÚÁÏÍø acquired Morphotek Inc., a biopharmaceutical company specializing in the R&D of antibody drugs. At the time, Morphotek was developing a number of antibody therapeutics for cancer. One such product is farletuzumab (development code: MORAb-003), an anti-folate receptor α antibody.
Although MORAb-003 itself was never commercialized, farletuzumab is used in the antibody portion of the antibody-drug conjugate farletuzumab ecteribulin (FZEC, development code: MORAb-202) currently under development. The accumulated biologics knowledge has been passed on to EPAT (Epochal Precision Anti-Cancer Therapeutics), one of the ºÚÁÏÍø's research laboratories in the United States.

In 2007, ºÚÁÏÍø also entered into an agreement to acquire MGI PHARMA, Inc. for a total of approximately US$3.9 billion. Through this acquisition, we acquired marketed and pipeline products including a drug for the prevention of chemotherapy-induced nausea and vomiting, a myelodysplastic syndrome treatment, and a chemotherapeutic implant for malignant gliomas.

Eribulin is a non-taxane microtubule dynamics inhibitor discovered and developed at our Boston Research Institute, and is a synthetically produced version of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai.
Based on the results of the Phase III clinical study EMBRACE in previously treated locally recurrent or metastatic breast cancer, ºÚÁÏÍø’s first anticancer agent discovered and developed in-house eribulin was approved in November 2010. Currently, it is approved for the treatment of breast cancer in Japan, the United States, Europe, China, Asia, and other countries., and also for the treatment of liposarcoma (soft tissue sarcoma in Japan) in Japan, the U.S., Europe, Asia, and other regions.
Eribulin is still being used to create new innovations as the payload of the antibody-drug conjugates farletuzumab ecteribulin (MORAb-202) and BB-1701, which is currently under development.

In 2011, H3 Biomedicine Inc., an R&D subsidiary oriented toward drug discovery based on cancer genomics was established in Cambridge, Massachusetts, USA, where the world's leading R&D institutions in the life science field are located. Several oncology pipelines have been created from H3 Biomedicine. The establishment of H3 Biomedicine allowed ºÚÁÏÍø to join the world's most advanced, Cambridge biotech community and build relationships with many partners. (With the transition to DHBL drug discovery and development organization in 2022, H3 Biomedicine was integrated with the U.S. subsidiary ºÚÁÏÍø Inc. and the laboratory was closed.)

Lenvatinib is an orally available multiple receptor tyrosine kinase that was discovered at our Tsukuba Research Laboratories. It was introduced into clinical trials in 2005, and based on the results of the Phase III clinical study SELECT in radioiodine-refractory differentiated thyroid cancer, was granted approval by the U.S. FDA in February 2015 for the treatment of radioiodine-refractory differentiated thyroid cancer. It is currently approved as a monotherapy for the treatment of thyroid cancer in Japan, the United States, Europe, China, Asia, and other countries. It is also approved for the treatment of hepatocellular carcinoma in Japan, the U.S., Europe, China, Asia, and other countries , and for thymic carcinoma in Japan. In combination with everolimus, it is approved for the treatment of renal cell carcinoma in the U.S., Europe, and Asia.

In 2018, ºÚÁÏÍø and Merck & Co., Inc., Rahway, NJ, USA (MSD outside the U.S. and Canada,) entered into a strategic collaboration to jointly develop and commercialize lenvatinib globally. Under the terms of the agreement, the companies are jointly developing, manufacturing and commercializing lenvatinib as a monotherapy and in combination with Merck & Co., Inc., Rahway, NJ, USA’s anti-PD-1 antibody pembrolizumab.

Tazemetostat (Tazverik®) is a first-in-class oral EZH2 inhibitor created using the drug discovery platform of Epizyme, Inc. (acquired by Ipsen in June 2022). In 2021, the drug was approved in Japan for the treatment of EZH2 gene mutation-positive follicular lymphoma. ºÚÁÏÍø is responsible for the development and commercialization of this drug in Japan.
It has been reported that 7-27% of follicular lymphomas have gain-of-function mutations in the EZH2 gene, and the Cobas® EZH2 Mutation Detection Kit from Roche Diagnostics K.K. is used as a companion diagnostic agent to detect EZH2 mutations, making ºÚÁÏÍø the first company to offer a drug in combination with a diagnostic agent.

In July 2021, lenvatinib in combination with pembrolizumab was approved by the U.S. FDA for the treatment of advanced endometrial carcinoma based on the results of a Phase III clinical study (309/KEYNOTE-775) in advanced endometrial carcinoma patients who had received prior systemic therapy. Lenvatinib is approved for the treatment of endometrial carcinoma in combination with pembrolizumab in Japan, the United States, Europe, Asia, and other countries (including some countries with conditional approval). The combination therapy has been approved for renal cell carcinoma in Japan, the U.S., Europe, Asia, and other countries.
Multiple clinical trials are underway for the combination therapy of lenvatinib and Merck & Co., Inc., Rahway, NJ, USA's pembrolizumab in various types of cancer, and steady expansion in contribution to patients is expected in the future.
ºÚÁÏÍø is also developing E7386 (co-created with PRISM BioLab, Inc.), a CBP/β-catenin inhibitor that is expected to inhibit Wnt signaling involved in carcinogenesis, as a drug to overcome resistance to this combination therapy. We are pursuing the creation of new innovations by utilizing the knowledge accumulated through the development of this combination therapy.

BB-1701 is an antibody-drug conjugate (ADC) that is composed of ºÚÁÏÍø’s in-house developed anticancer agent eribulin, and anti-HER2 antibody trastuzumab using a linker. We have entered into a joint development agreement regarding BB-1701 with Bliss Biopharmaceutical (Hangzhou) Co., Ltd. (BlissBio) with option rights for a strategic collaboration.
Under a license agreement between the two companies entered into prior to this agreement, ºÚÁÏÍø granted BlissBio exclusive global development rights for several ADCs with eribulin as the payload. Based on the status of Phase I/II clinical trials currently being conducted by BlissBio, we will conduct joint development of BB-1701. This is our second ADC to be introduced into clinical trials, following MORAb-202, and we intend to expand our pipeline of ADCs with eribulin payloads.