Malignant melanoma is a tumor of pigment-producing cells called melanocytes in the epidermis and is considered extremely malignant with a high metastasis rate among skin cancers. According to a survey conducted by the Japanese Association of Clinical Cancer Centers (2010-2014), the 5-year survival rate is 54.7% for stage 3 (stage with metastasis in lymph nodes or surrounding skin or subcutaneous sites) and 8.3% for stage 4 (stage with metastasis in other organs), making the disease extremely difficult to treat.

Current Treatments and Challenges

Though malignant melanoma has been a highly malignant and difficult-to-treat disease, the approval of the immune checkpoint inhibitor anti-PD-1 antibody in 2014 and the subsequent development of new drugs have led to a breakthrough in pharmacotherapy.

The immune checkpoint inhibitors are novel therapeutics developed as cancer immunotherapy, including anti-PD-1 antibody (nivolumab, trade name: Opdivo) against “the brake” on the immune system (immune checkpoint molecule) PD-1 discovered by Dr Tasuku Honjo and his team at Kyoto University (Dr. Tasuku Honjo was awarded the Nobel Prize in physiology or medicine in 2018). Immune checkpoint inhibitors release “the brake” on the immune system (immune checkpoint molecule) so that the body’s natural immunity can attack tumors.

Since a major type of malignant melanoma in Japan (called “Acral Lentiginous Melanoma”) do not respond well to anti-PD-1 antibodies unlike in Europe and the United States, the effectiveness of anti-PD-1 antibodies is not sufficient, and the second-line treatment for the patients refractory to anti-PD-1 antibodies is eagerly anticipated. Currently, another immune checkpoint inhibitor, the anti-CTLA-4 antibody ipilimumab, is approved as a concomitant use with the anti-PD-1 antibody nivolumab, and the nivolumab plus ipilimumab combination therapy has shown a higher response rate (13.5%) compared to the nivolumab alone. However, this combination therapy has also become a social problem, as more than half of patients experience serious side effects, and as the frequency of severe immune-related side effects that result in discontinuation of treatment is four times higher than with single treatment with nivolumab, requiring several months of hospitalization and cessation of cancer treatment. In addition, the use of two antibodies results in higher medical costs.

Characteristics of Our Solution

We have discovered that PAI-1 suppresses immunity to cancer via immune checkpoint molecules. In addition, studies in animal models have shown that administration of RS5614 inhibits the growth of tumors such as malignant melanoma and colorectal cancer. Furthermore, while the immune checkpoint inhibitor anti-PD-1 antibody alone inhibited tumor growth, the combination of RS5614 with the anti-PD-1 antibody enhanced cancer immunity even more strongly. As a result, the combination of these drugs strongly inhibited the growth of various cancers, and some types of tumors regressed. The PAI-1 inhibitor improve the immune environment in tumors to facilitate the action of the anti-PD-1 antibody. The inhibition of immune checkpoint molecules by the PAI-1 inhibitor RS5614 is expected to be useful in the treatment of malignant melanoma.

While side effects have been a problem with the existing nivolumab + ipilimumab combination therapy, RS5614 will be a safe and convenient medication that can be taken at home. In addition, unlike antibodies, RS5614 is chemically synthesized, so its price is expected to be lower than that of antibodies.

Results to date

In collaboration with Tohoku University, Tsukuba University, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Kinki University, Nagoya City University, and Kumamoto University, which have established the Japan Skin Cancer Network (JSCaN), a non-profit organization, and are working together to improve treatment outcomes for malignant melanoma, we have conducted an investigator-initiated clinical trial (Phase II) to confirm the efficacy and safety of the combination of a PAI-1 inhibitor and nivolumab from July 2021, and the enrollment of subjects was completed as scheduled in May 2023. As a result of this study, 29 patients with malignant melanoma who failed nivolumab (second-line treatment) were treated with RS5614, our PAI-1 inhibitor, for 8 weeks, and the responses were observed in 7 patients on the primary endpoint (the response rate: 24.1%). This was higher than the currently approved response rate of 13.5% in Japan for the combination of nivolumab and ipilimumab (published data, referred to as “historical control”) (for your information, the response rate for the combination of nivolumab and ipilimumab overseas is 21%). While the combination of nivolumab and ipilimumab in second-line therapy is associated with a high incidence of serious adverse reactions in more than half of the patients, in the combination of nivolumab and RS5614, two adverse events (5.7%) occurred that may have been causally related to the study drug: liver dysfunction, both of which were resolved.

The results of the Phase II study was analyzed in detail and compiled into a clinical study report in Feb 2024. In addition, we discussed with the regulatory authorities regarding the next phase study necessary for the application for regulatory approval, and the protocol is finalized. Now since we have confirmed the immune checkpoint inhibitory activity of RS5614 in malignant melanoma, we have started Phase II investigator-initiated clinical trials for other solid tumors such as non-small cell lung cancer and cutaneous hemangiosarcoma.