Clinical Trials of Anti-cancer Agent FF-10832 to start in the US for Advanced Solid Tumors

Clinical Development of Liposome Drug for Improvement of Pharmacological Efficacy through Selective Delivery of Anti-Cancer Agent to Tumors

August 30, 2017

FUJIFILM Corporation (President: Kenji Sukeno) has decided to start clinical trials in the United States in 2018 for its anti-cancer agent FF-10832 to assess it as a potential treatment for advanced solid tumors. FF-10832 is a liposome-based agent which harnesses the advanced nano-dispersion technology, analysis technology and process technology nurtured through the photographic film business in order to incorporate the existing water-soluble anti-cancer agent gemcitabine*1 into liposomes.

Liposomes are artificially constructed vesicles made from the same organic phospholipids that make up cell membranes and bio membranes. As one of a variety of drug delivery system (DDS) technologies, liposomes are used to deliver the required amount of a drug to the specified part of the body on the necessary schedule. Certain anti-cancer agents act on healthy tissue in addition to the tumor that can result in severe adverse effects. Liposomes are currently attracting significant attention as an effective means of avoiding these adverse effects on healthy tissue. Preparing pharmaceuticals in the form of liposomes allows the pharmaceutical to be delivered selectively to the tumor, which can be expected to improve pharmacological efficacy and suppress adverse effects. In order to achieve this, the following conditions must all be met: (1) improve the stability of the pharmaceutical agent in the blood (2) the achievement of the Enhanced Permeability and Retention (EPR) effect*2 (namely the long-term, sustainable concentration of the agent within the tumor as a result of ensuring that the agent does not leak from healthy blood vessels) and (3) the release of the agent within the tumor. Generally, it is difficult to simultaneously achieve both (1) the improved stability of the pharmaceutical agent in the blood and (3) the release of the agent within the tumor. This is particularly the case with water-soluble drugs, where the technical barriers are very high, and these considerations have been an issue affecting the production of effective liposomes.

FF-10832 harnesses Fujifilm's expertise including nano-dispersion technology, analysis technology and process technology in order to incorporate gemcitabine, a drug with a short half-life*3 in blood, into liposomes, which is expected to lead to a significant increase in the stability of the agent within the blood. Furthermore, to achieve EPR benefits, the liposomes are designed to have a uniform size of approximately 80 nm, raising the concentration of the agent within the tumor. In experiments on mice transplanting human-derived pancreatic cancer cells, concentrations of FF-10832 within the pancreatic cancer cells reach higher levels than with the original preparation of gemcitabine – confirming the long-term sustainable presence of the agent within the tumor (in mice experiments).

Furthermore, the same experiments on mice also demonstrate that when FF-10832 is administered, it is possible to obtain a pharmacological benefit in excess of that produced by the original preparation of gemcitabine with only 1/60th of the dose. In addition, the release of the agent within the tumor was confirmed by demonstrating the efficacy including in the case of human-derived pancreatic cancer cells, which included a subtype that does not usually respond well to the original gemcitabine treatment, as well as in other mice experiments involving the transplantation of cancer cells other than pancreatic cancer cells. From these results, it can be expected that FF-10832 fulfills the conditions required of liposome preparations for human, and provides effective treatment not only for pancreatic cancer, a condition for which the number of promising treatments is currently limited, but also potentially in further applications for the treatment of other solid tumors.

Fujifilm plans to submit an investigational new drug (IND) application for FF-10832 in the US before the end of 2017 and plans to start clinical trials in 2018.

[Schematic diagram showing how FF-10832 is released into tumor]

Fujifilm is defining oncology as its focal area and the company is actively engaged in the research and development of pharmaceuticals by combining the technologies and knowledge accumulated in the photographic film business in fields including the synthesis and design of compounds in addition to nano-dispersion technology and analysis technology. Going forward, the company is committed not only to the development of new drugs, but also to the development of new Drug Delivery Systems, as the company works to address social issues through the provision of innovative pharmaceutical products.

*1 Gemcitabine (Gemzar) is an anti-cancer agent developed by the US company Eli Lilly and Company. It is used as a drug of first choice for the treatment of pancreatic cancer, and is also indicated for the treatment of a wide range of other cancers including lung cancer and ovarian cancer.

*2 Tumors produce new blood vessels for the purpose of nourishing the tumor, but these new blood vessels are immature, with the walls of the vessels containing gaps that do not exist in normal healthy vessels. When a high concentration of liposomes and high-molecular weight drugs is observed in these vessels, there is no leakage from the healthy vessels that do not contain these gaps, with the liposomes and high-molecular-weight drugs leaking only from the blood vessel walls of the tumor. In addition, since the lymphatic tissue within tumor is also immature, it is difficult to remove the liposomes and high-molecular-weight drugs that have permeated the surrounding tissue, causing the drug to accumulate within the tumor. This effect is called Enhanced Permeability and Retention effect. The effect was originally reported in 1986 by Hiroshi Maeda, Professor at the Sojo University DDS research center and Honorary Professor at Kumamoto University, and Yasuhiro Matsumura, Director at Division of Development Therapeutics at the National Cancer Center's Exploratory Oncology Research & Clinical Trials Center (NCC-EPOC) in the paper " A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs." In 2016, Maeda and Matsumura were recognized as Thomson Reuters Citation Laureates, distinction conferred by Thomson Reuters on researchers considered to be likely candidates for future Nobel prizes on the basis of an analysis of research literature and citations.

*3 The half-life is the time taken for the concentration of pharmaceutical in the blood to decrease by half.


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