Close-Up - Development of Anticancer Drugs

Our Heritage: Taking on the Challenge of Developing Anticancer Drugs to Improve Cancer Treatment Worldwide

  • Taiho's development of anticancer drugs began with the synthesis of Futraful at the Institute of Organic Synthesis in Riga, the capital of Latvia.

Taiho Pharmaceutical’s history of anticancer drugs began with an encounter with Futraful in Latvia.

In 1969, Taiho Pharmaceuticalʼs first president, Yukio Kobayashi, visited the former Soviet Union for business discussions on Pantocrin injection, a drug to ameliorate general malaise for which demand had suddenly started to increase at the time. Kobayashi, who devoted every spare moment during his time there to visit pharmaceutical-related sites, happened to see an injection ampule at a cancer research center in Moscow. It was Futraful, a derivative*1 of a novel anticancer drug, 5-fluorouracil (5-FU). Guided by intuition, Kobayashi sensed its great potential and instantly decided to conduct clinical trials in Japan.
After returning to Japan, he immediately established an anticancer team in the research center to initiate a research program. After confirming the drugʼs efficacy in basic research, the drug was taken into clinical trials. However, satisfying clinical results were not obtained, with investigators presenting negative reports on efficacy at the first investigatorsʼ meeting.
There was, however, one report that the compound showed efficacy in a patient with metastatic breast cancer, and this case became a ray of hope encouraging further research. Research showed that Futraful is converted into 5-FU as it is metabolized in the liver and then shows activity, and also that long-term exposure to cancer cells exerts a sufficient anticancer effect even at low blood concentration. This shifted the direction to the development of an oral anticancer agent, a very uncommon formulation in the world at that time. It was then, April 1972, when the possibility created by intuition started moving steadily toward becoming a reality.

Taiho Pharmaceutical’s researchers redefined cancer treatment by bringing small buds of potential to fruition.

  • Futraful injection 400mg Pamphlet
    Futraful injection 400mg Pamphlet

Futraful is an antimetabolite which prevents the cell division of cancer cells by encouraging uptake of “fake pieces” into cancer cells. It exerts its pharmacological effect by being gradually metabolized into 5-FU, which is one of these “fake pieces,” in the body. Taiho Pharmaceutical focused on this characteristic of Futraful to demonstrate its efficacy when in long-term contact with cancer cells. In 1974, the product was launched in Japan as an anticancer drug that could be administered orally.
Unlike conventional anticancer drugs, Futraful enabled outpatient therapy due to its long-term oral administration, later leading to the establishment of the concept of adjuvant chemotherapy.

1974

Futraful capsule 200mg and Futraful injection 400mg launched in Japan

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    The photo shows products at the time of initial launch.

Taiho Pharmaceutical overcame various challenges in pursuit of stronger efficacy.

Ten years later, Taiho Pharmaceutical succeeded in further extending the sustainability of 5-FU blood concentration by compounding uracil with Futraful, resulting in the launch of UFT in 1984. Clinical trials for UFT have been conducted for various cancers, generating a large body of evidence, especially for adjuvant chemotherapy. UFT was widely adopted as one of the primary choices for an anticancer drug based on the evidence obtained in these clinical studies.
Building on this success with UFT, research was advanced to pursue a new drug with even stronger efficacy. The result was the discovery of gimeracil, which prolongs the blood concentration of 5-FU further than uracil, and oteracil potassium, which reduces side-effect damage to the gastrointestinal tract. These two new compounds were compounded with Futraful as the principal component to create TS-1. TS-1 demonstrated a high response rate in a clinical trial in patients with metastatic gastric cancer and was accordingly given a priority review by Japanʼs Ministry of Health, Labour and Welfare (Ministry of Health and Welfare at the time). The product was approved and launched in 1999.
Furthermore, it was confirmed in a comparison study that the combination therapy using UFT and UZEL, an oral reduced folic acid formulation, was as effective against colorectal cancer as 5-fluorouracil/leucovorin (5-FU/LV) injection, the global standard therapy at that time. Then, a Japan-US bridging study was conducted, and UZEL tablet was launched in Japan in 2003.

1984

UFT combination capsule T100 launched in Japan

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    The photo shows products at the time of initial launch.

1999

TS-1 combination capsule T20/T25 launched in Japan

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    The photo shows products at the time of initial launch.

The company carefully developed the drugs to create new possibilities.

In 2004, the results of a clinical trial of UFT in the adjuvant setting in patients with lung cancer who had undergone a curative operation were published in the New England Journal of Medicine (NEJM), one of the worldʼs most prestigious medical journals. Thereafter, articles were published one after another on UFT as adjuvant chemotherapy in cancers such as gastric cancer, colorectal cancer, and breast cancer.

Similar to UFT, TS-1 has also shown its efficacy against various cancers and has been introduced in global medical journals including the NEJM. A body of evidence has been built up for TS-1, mainly for gastric cancer, followed by cancers such as colorectal cancer, lung cancer, pancreatic cancer, breast cancer, and head and neck cancer. TS-1 is described in various guidelines and is contributing to cancer treatment. Even now many medical and research institutions are reporting excellent clinical results in numerous medical journals, broadening TS-1ʼs possibilities as cancer treatment continues to evolve.

2003

UZEL tablet 25mg launched in Japan

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    The photo shows the half-weight type.

2009

TS-1 combination granule T20/T25 launched in Japan

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Taiho Pharmaceutical continues to support the present and pioneer the future of cancer treatment.

In recent years, Taiho Pharmaceutical has been conducting R&D aimed at comprehensive care in oncology, with an even greater awareness of patientsʼ quality of life. In addition to developing formulations that are easier for cancer patients to use, the company is going beyond cancer treatment, striving to contribute to better quality of life for patients, for instance by launching products such as Aloxi, an antiemetic agent which relieves nausea and vomiting associated with chemotherapy, and E-fen, a fentanyl buccal tablet which relieves cancer pain (breakthrough pain).
In 2009, the company acquired a research center in Tsukuba that was a part of the former Banyu Pharmaceutical Co., Ltd. and consolidated all of its in-house drug discovery functions into this Tsukuba Area. There, researchers are using cutting-edge technology to aggressively develop new types of anticancer drugs.
Then, Taiho Pharmaceutical in-licensed the anticancer drug Abraxane, which has been approved in over 70 countries worldwide. The company pursued the development of the drug in Japan*2 where it was launched in 2010 as a breast cancer treatment. Later, additional indications were approved for gastric cancer, non-small cell lung cancer, and unresectable pancreatic cancer.

2010

*1: As of January 2017. Taiho Pharmaceutical holds the development and marketing rights in Japan

Aloxi I.V. injection 0.75mg and Abraxane I.V. infusion 100mg launched in Japan

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Launched Abraxane I.V. infusion 100mg in Japan, an anticancer drug that has been approved in more than 65 countries*1

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2013

TS-1 combination OD tablet T20/T25 and E-fen buccal tablet launched in Japan

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    The photo shows products at the time of initial launch.

Launched E-fen buccal tablet, a cancer pain reliever for breakthrough pain, in Japan

2014

LONSURF combination tablet T15/T20 launched in Japan

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2015

Yondelis I.V. infusion 0.25mg/1mg launched in Japan

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Taiho Pharmaceutical aims to deliver innovative drugs from Japan to patients around the world.

TS-1, which has become the standard treatment for gastric cancer in Japan, is marketed in Asia, as well as in Europe, having received approval there in 2011.
In 2014, the anticancer agent LONSURF was first launched in Japan for the treatment of unresectable advanced or recurrent colorectal cancer. The following year, LONSURF was launched in the U.S., becoming the first U.S. FDA approved product for the company. In 2016, approval for the drug was obtained from the European Commission, and sales are being expanded in countries there.
In its half-century of anticancer drug research and development, Taiho Pharmaceutical has established a great body of evidence in cancer chemotherapy, making it one of Japanʼs leading companies in this field. Transforming that abundant experience into a dynamic asset, Taiho Pharma-ceutical will keep developing new drugs to help cancer patients in Japan and around the world.

* 1: Derivative: A compound created by a change in part of a molecule of a given compound.
* 2: Taiho Pharmaceutical holds the development and marketing rights in Japan.