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Supplementary Information on the Immune Checkpoint Inhibition by the PAI-1 inhibitor (RS5614)

Renascience disclosed “Announcement of Collaboration Agreement with Hiroshima University” on Monday, October 31, 2022.

In this news release, we would like to provide a supplemental explanation of “Immune Checkpoint Inhibition by the PAI-1 Inhibitor (RS5614)” related to the Collaboration Agreement with Hiroshima University in a question-and-answer format.

Question	Answer
What is cancer immunotherapy?	Currently, there are four major treatments for cancer: (1) surgery, (2) radiation therapy, (3) chemotherapy (anticancer drugs), and (4) immunotherapy. Immunotherapy is a treatment method that attacks cancer using the body’s own immune system. Various immunotherapies have been proposed, but the major immunotherapies that have proven to be effective are the immune checkpoint inhibitors, which release the brake on the immune system.
What are the immune checkpoint inhibitors?	The body has mechanism to suppress excessive immune response, since it is harmful to the body. The molecules that perform such a brake function are called “immune checkpoint molecules”. In fact, the cancer abuses the immune checkpoint molecules to prevent the immune system from attacking the cancer itself. The immune checkpoint inhibitors release this brake by inhibiting the immune checkpoint molecules, thereby activating the immune response against cancer.
What is the difference between the immune checkpoint inhibitors and anticancer agents?	Anticancer agents are cytotoxic drugs that directly kill cancer cells. In contrast, the immune checkpoint inhibitors attack cancer by inhibiting the immune checkpoint molecules in the body and activating the body’s own immune system.
What kind of medicine is RS5614	It is the compound that specifically inhibits the protein in the body, called plasminogen activator inhibitor 1 (PAI-1). We have discovered that PAI-1 inhibits anticancer immunity via the immune checkpoint molecules. On the other hand, the PAI-1 inhibitor activates anticancer immunity by inhibiting the immune checkpoint molecules. In the animal studies, tumors such as malignant melanoma and colorectal cancer, regressed in animals treated with RS5614, and when combined with an immune checkpoint inhibitor antibody, RS5614 synergistically enhanced anticancer immunity.
How is RS5614 administered?	The tablets are taken orally once a day.
Does RS5614 have any side effects?	More than 200 subjects have been treated with RS5614 in numerous clinical studies to date and no noticeable side effects have been observed. The safety of RS5614 has also been confirmed after long-term administration for one year.
How is RS5614 different from other immune checkpoint inhibitors?	The existing immune checkpoint inhibitors are all antibody therapeutics, so they need to be administered by injection after hospitalization. In addition, the antibody therapeutics may have various side effects. The costs of the antibodies are high. RS5614 will be an oral medication that cancer patients can take at home. Since RS5614 is chemically synthesized unlike antibodies, its price is expected to be much lower than that of antibodies.
What is malignant melanoma?	Malignant melanoma is a type of skin cancer. It is a tumor formed by malignant transformation of skin cells called melanocytes that produce melanin pigment, which is related to skin color. The immune checkpoint inhibitor antibodies can be used effectively in the treatment of malignant melanoma, but their therapeutic effect is not satisfactory in some cases. We have discovered in animal models that the combination of an immune checkpoint inhibitor antibody and RS5614 synergistically enhances anticancer immunity. We are currently conducting a phase II study of RS5614 in combination with nivolumab, an immune checkpoint inhibitor antibody, in patients with malignant melanoma. We are advised that it would be impossible to conduct domestic clinical trials for malignant melanoma since it is a rare cancer in Japan. However, we made the trial possible, because many physicians at the major university hospitals that belong to a non-profit organization for promoting research on skin cancer have participated in the study.
What is non-small cell lung cancer?	Non-small cell lung cancer accounts for 80-90% of all lung cancers and is classified into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. The immune checkpoint inhibitor antibodies are sometimes effective to treat non-small cell lung cancer, but the therapeutic effect is not satisfactory in some cases. We have discovered in animal models that the combination of an immune checkpoint inhibitor antibody and RS5614 synergistically enhances anticancer immunity. We are now preparing for a phase II study to evaluate the efficacy of RS5614 in combination with nivolumab, an immune checkpoint inhibitor antibody, in patients with non-small cell lung cancer.