Rakuten Medical's Poster Presentation at AACR 2024 Demonstrates Reduction in Photoimmunotherapy-induced Edema in Mice with COX-2 Inhibition

• Prophylactic administration of a selective COX-2 inhibitor reduces the volume of edema associated with photoimmunotherapy by 30-50%
• Reduced edema volume by 25%, even when administered post photoimmunotherapy
• Suggested the COX-2 inhibitor may manage edema without compromising anti-tumor efficacy

SAN DIEGO, April 11, 2024 /PRNewswire/ -- Rakuten Medical, Inc., a global biotechnology company developing and commercializing precision, cell targeting therapies based on its proprietary Alluminoxtm platform, today announced a poster presentation of its study to manage edema following photoimmunotherapy at the 115^th Annual Meeting of the American Association for Cancer Research (AACR 2024) in San Diego, California, on April 8^th, 2024.

In the study presented in this poster, Rakuten Medical developed a mouse tumor model to assess edema following photoimmunotherapy and evaluated various steroidal and non-steroidal anti-inflammatory drugs (NSAIDs) for edema reduction using the model. As a result, a reduction in edema was observed when the selective COX-2 inhibitor meloxicam, one of NSAIDs, was administered before or after illumination of photoimmunotherapy (30-50% reduction with prophylactic administration, 25% reduction with post-illumination administration). It was also confirmed that the reduction in edema with meloxicam was not associated with a loss of therapeutic benefit based on measurement of tumor growth.

Rakuten Medical's photoimmunotherapy consists of a drug and a laser light. In pre-clinical studies, local illumination results in highly selective and rapid necrosis of target cells such as tumors. Early clinical studies have shown a manageable safety profile for head and neck cancer.^* However, edema is a commonly reported adverse event with severe laryngeal edema noted in some patients, and prophylactic tracheostomy is required if laryngeal edema threatens to obstruct the airway. Thus, new tools to manage edema are needed to reduce the burden on the patient. Based on the results of this study, Rakuten Medical will conduct further research to address the challenges of edema associated with photoimmunotherapy in clinical trials and in clinical practice.

Key findings presented at AACR 2024
Title: Reduction in photoimmunotherapy-induced edema with COX-2 inhibition: Combatting clinically relevant adverse events without compromising efficacy
Abstract Number: 1415
Abstract Link: https://www.abstractsonline.com/pp8/#!/20272/presentation/5855

• Cohorts of mice bearing syngeneic LL/2 tumors engineered to express Ephrin A2 (EphA2) were administered an anti-EphA2 antibody conjugated to IR700 (conjugate) or saline control and illuminated with light. Control mice did not generate edema, but mice treated with conjugate plus light showed a light-dose dependent increase in edema volume which peaked at 6h post light delivery.
• Inflammatory cytokine and immune cell populations in the blood and tumor region were then evaluated at the onset (2h post-light), peak (6h), and resolution (24h) of the edema associated with photoimmunotherapy. The results showed a striking increase in neutrophils in the blood at the peak of edema formation (500-fold greater than control mice, n=10, p<0.0001) and a significant increase in IL-6 (n=5, p<0.001) and IL-10 (n=5, p<0.05), indicating the onset of a heightened inflammatory response.
• To address edema formation, the effect of steroids or NSAIDs including the selective COX-2 inhibitor meloxicam were evaluated. Results showed that steroids did not reduce edema volume. Meloxicam, one of the selective COX-2 inhibitors, on the other hand, resulted in a reduction in edema volume at all time points and light doses evaluated.
• Prophylactic administration (2h prior to light) of meloxicam resulted in a 30-50% reduction in edema at both 2h and 6h post-light illumination. Post-light administration (2h post light) of meloxicam resulted in a 25% reduction at 6h post-light illumination (all settings, n=10, p<0.0001).
• The reduction in edema with meloxicam did not have negative impact on tumor growth inhibition.

* Cognetti DM, Johnson JM, Curry JM, et al. Phase 1/2a, open-label, multicenter study of RM-1929 photoimmunotherapy in patients with locoregional, recurrent head and neck squamous cell carcinoma. Head Neck. 2021;43(12):3875-3887. doi:10.1002/hed.26885

About Rakuten Medical, Inc.
Rakuten Medical, Inc. is a global biotechnology company developing and commercializing precision, cell targeting therapies based on its proprietary Alluminoxtm platform, which, in pre-clinical studies, has been shown to induce rapid and selective cell killing and tumor necrosis. Alluminox therapies have not yet been approved outside of Japan. Rakuten Medical is committed to its mission to conquer cancer by delivering its innovative treatments as quickly as possible to as many patients as possible all over the world. The company has offices in 5 countries/regions, including the United States, where it is headquartered, Japan, Taiwan, Switzerland and India. For more information, visit www.rakuten-med.com.

About Alluminoxtm platform 
The Alluminoxtm platform is an investigational technology 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 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 the Alluminox platform 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 by any regulatory authority.

Forward Looking Statements 
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 Alluminoxtm 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.

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SOURCE Rakuten Medical, Inc.