Notice of Publication of Article on Our Pipeline in Global Bio Investment Magazine

Professor Toshio Miyata, Tohoku University Graduate School of Medicine, who also serves as Director, Chairman of Renascience, gave a lecture on the plasminogen activator inhibitor 1 (PAI-1) inhibitor at the Bio Asia-Taiwan Asian Biotechnology Conference 2023 held in Taipei, Taiwan, from July 26 to 30, 2023, The above lecture and an interview with Dr. Miyata were published in the August 25, 2023 issue of Global Bio Investment’s monthly magazine as one of the innovative research leading to the medical innovation from Japan presented at Bio Asia.

(Outline of the lecture)

• Discovering a New Role for PAI-1 Beyond the Coagulation-Fibrinolysis System
  • The PAI-1 inhibitors are useful for the treatment of aging-related diseases (cancer, respiratory diseases, cardiovascular diseases, and diabetes).
• PAI-1 inhibitor RS5614
  • RS5614 was discovered by the virtual screening of over 2 million compounds by the computer engineering followed by synthesis and screening of numerous PAI-1 inhibitors.
  • RS5614 is an oral PAI-1 inhibitor with excellent efficacy and safety profile; its safety has been confirmed in over 200 subjects (no safety issues after 1 year of treatment); and it is currently the most advanced PAI-1 inhibitor under development worldwide
  • Inhibitory mechanism of RS5614: it binds to the vitronectin binding site of PAI-1 and destabilizes PAI-1.
• Role of PAI-1 in blood cancer (chronic myeloid leukemia)
  • In hematopoietic stem cells and chronic myeloid leukemia stem cells, intracellular PAI-1 inhibits the intracellular protein-processing enzyme, thus keeping these cells in the specialized space in the bone marrow, called “niche”.
  • RS5614 mobilizes chronic myeloid leukemia stem cells from the bone marrow niche by inhibiting PAI-1, making them susceptible to anticancer drugs. In other words, the combination of RS5614 and anticancer drugs eliminates not only chronic myelogenous leukemia cells but also the stem cells, which may lead to a complete cure that is difficult to achieve with anticancer drugs alone.
  • The above concept was proved in a late phase II study (obtained POC), and a phase III study, a validation study, is underway.
• Role of PAI-1 in Solid Tumors
  • PAI-1 induces immune checkpoint molecules in cancer cells and inhibits the immune attack on cancer.
  • RS5614 suppresses immune checkpoint molecules and activates cancer immunity (immune checkpoint inhibitor).
  • In malignant melanoma, colorectal cancer, and lung cancer models, RS5614 activated cancer immunity and inhibited tumor growth. In addition, RS5614 enhanced the effect of anti-PD-1 antibody, an existing immune checkpoint inhibitor, and synergistically activated cancer immunity (in some tumor, the combination eradicated the cancer).
  • In a phase II study of patients with malignant melanoma refractory to the anti-PD-1 antibody nivolumab, nivolumab plus RS5614 showed efficacy and safety superior to the existing drug nivolumab plus the anti-CTLA4 antibody ipilimumab (nivolumab + RS5614 response rate was 24.1% compared with nivolumab + Ipilimumab response rate was 13.5%; POC obtained).
  • Further non-small cell lung cancer and cutaneous angiosarcoma Phase II trials are being conducted based on this concept.
• Role of PAI-1 in aging
  • Senescent cells express high levels of PAI-1 in addition to p53. Senescent cells lose their ability to proliferate but can again proliferate by inhibiting PAI-1.
  • PAI-1 is highly expressed not only in cells but also in patients with progeria and in mice models of premature aging (klotho mice), and inhibition of PAI-1 in klotho mice improves various symptoms associated with aging.
  • Epidemiological studies of U.S. Amish immigrants have shown that people who lack the PAI-1 gene live about 10 years longer than those who have the PAI-1 genes, and have fewer diseases associated with aging, such as diabetes.
  • Recently, it has been shown that senescent cells express immune checkpoint molecules and that administration of immune checkpoint inhibitors to a senescence model eliminates senescent cells and improves various symptoms associated with aging. PAI-1 may play a role in aging by inducing immune checkpoint molecules, suggesting that PAI-1 inhibitors may ameliorate this process.

In the Global Bio Investment interview, Dr Miyata introduced the background of the establishment of Renascience, as well as Renascience’ s emphasis on development through open innovation and active collaboration with research and medical institutions in Japan and abroad. He introduced “it is important to Identify medical issues, formulate hypotheses, obtain scientific evidence (basic research), demonstrate the hypotheses in human (exploratory investigator-initiated clinical trials), and create new medical value.” He also emphasized the importance of building a network and framework in which academia, industry, and experts from different scientific fields can collaborate from the beginning.