Rakuten Medical Presented at the 41st Annual J.P. Morgan Healthcare Conference on the Progress of its Pipeline including its Newly Added Antibody-Dye Conjugate RM-0256, Commercial Growth in Japan, and Important Milestones for the Next Few Years

RM-0256 – currently being evaluated in pre-clinical studies – is a conjugate of an anti-PD-L1 antibody and IRDye®700DX (IR700), a light-activatable dye, that accumulates specifically on PD-L1-expressing cells. PD-L1 is a protein that inhibits the anti-cancer immune response by deactivating killer T cells, by binding to PD-1 which is abundantly expressed on the T cell surface.¹ PD-L1 is expressed in many solid tumors such as melanoma, lung, urothelial, gastrointestinal, gynecological, breast, and head and neck, among others, helping these tumors evade the immune system.² In addition to being present on tumor cells, PD-L1 is also expressed on suppressive immune cells within the tumor microenvironment such as tumor associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs).³ In pre-clinical studies, Alluminox therapy using RM-0256 has been observed to enable the accumulation of RM-0256 on PD-L1-expressing target cells followed by activation of the IR700 by illumination with 690nm non-thermal light, resulting in destruction of the target cells by its photochemical reaction. This reaction may lead to immunogenic cell death (ICD) and activation of an anti-cancer immune response. Furthermore, the anti-PD-L1 antibody itself comprising RM-0256 has been observed to inhibit the PD-L1:PD-1 interaction and may act systemically as an immune checkpoint inhibitor, further enhancing the anticancer immune response after light irradiation.

In Japan, commercial launch of ASP-1929 (brand name in Japan: Akalux®) continues to accelerate. 230+ doctors at 100+ institutions have been certified to provide the novel treatment, leading to 200+ treatments being administered in the 2 years since launch.  (*ASP-1929 is investigational outside of Japan.) Publications based on real world data in Japan, "Quality-of-Life Evaluation of Patients with Unresectable Locally Advanced or Locally Recurrent Head and Neck Carcinoma Treated with Head and Neck Photoimmunotherapy"⁴ and "Near-Infrared Photoimmunotherapy for Oropharyngeal Cancer,"⁵ indicated that the treatment using ASP-1929 achieved good disease control without decreasing the Quality of Life (QOL).  (**ASP-1929 is investigational outside of Japan and these quality-of-life assessments are specific to the Japanese population studied.)

Leveraging on the data and knowledge that is being accumulated in Japan, Rakuten Medical is further pursuing global expansion. For India, where it has established a subsidiary in 2022, global phase III trial of ASP-1929 in locoregional recurrent head and neck squamous cell carcinoma (ASP-1929-301 / ClinicalTrials.gov Identifier: NCT03769506) is being prepared for initiation in the country. Subject to positive clinical trial results, ASP-1929 could be approved as early as 2025 in the U.S., Taiwan, India, and other countries. A number of pipeline milestones are expected in the next few years, including the initiation of RM-1995 and RM-0256 clinical trials and the progression of several clinical trials with ASP-1929.

Mickey started his J.P. Morgan presentation with the question "What kind of future would open up if we could kill only targeted cells?" and showcased the potential of Rakuten Medical's investigational technology by saying "In the decade since I first encountered this therapy, which is completely different from existing treatments, we have been developing the technology at a tremendous pace. Our goal goes beyond establishing a position as a local treatment. Existing therapies have taken over a century to evolve and establish themselves as standards of care – we aim to achieve this same position for our technology on a much shorter timeline."

The slides and audio of Mickey's presentation at JPM2023 are available for download at the following links.

• Slides: https://rakuten-med.com/jp/wp-content/uploads/sites/8/2023/01/Slides_JPM2023_Rakuten-Medical.pdf
• Audio: https://rakuten-med.com/jp/wp-content/uploads/sites/8/2023/01/Audio-Recording_JPM2023_Rakuten-Medical-1.mp3

Rakuten Medical, Inc. is a global biotechnology company developing and commercializing precision, cell targeting investigational therapies on its Alluminox™ platform, which, in pre-clinical studies, have been shown to induce rapid and selective cell killing and tumor necrosis. Outside of Japan, Alluminox therapies have not yet been approved as safe or effective by any regulatory authority. The company's first drug developed on the Alluminox platform, ASP-1929, has received approval from the Japanese Ministry of Health, Labour, and Welfare, and is currently the subject of a global phase 3 clinical trial for recurrent head and neck cancer. Rakuten Medical is committed to its mission to conquer cancer by delivering our innovative treatments as quickly and safely as possible to as many patients all over the world as possible. The company has offices in 6 countries, including the United States, where it is headquartered, Japan, the Netherlands, Taiwan, India, and Switzerland. For more information, visit www.rakuten-med.com.

The Alluminox™ platform is an investigational platform based on a cancer therapy called photoimmunotherapy, which was developed by Dr. Hisataka Kobayashi and team from the National Cancer Institute in the United States. Rakuten Medical is developing the Alluminox platform as a technology consisting of a drug, device, and other related components. The drug component of the platform consists of a targeting moiety conjugated with one or more dyes leading to selective cell surface binding. The device component consists of a light source that locally illuminates the targeted cells with non-thermal light to transiently activate the drug. Pre-clinical data have shown that this activation elicits rapid and selective necrosis of targeted cells through a biophysical process that compromises the membrane integrity of the targeted cells. Therapies developed on Alluminox may also result in local and systemic innate and adaptive immune activation due to immunogenic cell death of the targeted cancer cells and/or the removal of targeted immunosuppressive cells within the tumor microenvironment. Outside of Japan, Alluminox therapies have not yet been approved as safe or effective by any regulatory authority.

This press release contains forward looking statements that correspond to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements include various risks, uncertainties, and assumptions that may cause Rakuten Medical's business plans and results to differ from the anticipated results and expectations expressed in these statements. These "forward looking statements" contain information about the status and development of our products, including the Alluminox™ platform, as well as other regulatory and marketing authorization efforts, the potential benefits, efficacy, and safety of therapies created using the Alluminox platform, and the status of regulatory filings. The approval and commercial success of the product may not be achieved. Forward looking statements relate to the potential benefits, efficacy, and safety of our therapies, and the status of regulatory filings. Such statements may include words such as "expect," "believe," "hope," "estimate," "looks as though," "anticipate," "intend," "may," "suggest," "plan," "strategy," "will," and "do", and are based on our current beliefs. In addition, this press release uses terms such as "important," "notable," and "abnormal" to express opinions about clinical trial data. Ongoing clinical trial studies include various risks and uncertainties, in particular, problems that arise during the manufacturing stage of our therapies, the occurrence of adverse safety events, situations in failure to demonstrate therapeutic benefits, and other various risks and uncertainties, both reasonable and unreasonable. For this reason, actual results, including regulatory approvals and uncertainties in the commercialization process of our therapies, may differ from published information. Except to the extent required by applicable law, we undertake no obligation to publicly update this or any other forward-looking statement, whether because of new information, future developments or events, changes in assumptions, changes in the factors affecting forward-looking statements. If one or more forward-looking statement(s) is updated, no inference should be drawn that additional updates will be made to those or other forward-looking statements.

SOURCE Rakuten Medical, Inc.