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Tocilizumab (Actemra, RoActemra)

First Antibody Drug Developed in Japan

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Drug Discovery in Japan

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Abstract

Tocilizumab (Actemra) is a drug used to treat autoimmune diseases, including rheumatoid arthritis, through a novel mechanism of action discovered in Japan. It is also the first antibody drug developed in Japan. Chugai Pharmaceuticals started the basic research on autoimmune disease early, when neither a target molecule nor a disease mechanism was known. The research and development program was long and uncertain, taking 24 years to acquire the approval as a rheumatoid arthritis drug. Industry and university collaborations played critical roles in this innovation. Collaborations with the Kishimoto laboratory of Osaka University, which discovered IL-6 as well as its applicability to the autoimmune disease, were essential. Osaka University also contributed to the early implementation of a clinical trial. The discovery by Kawano at Hiroshima University of IL-6’s role in multiple myeloma was also important for keeping the project alive. Collaboration with the Medical Research Council of the UK was instrumental for applying humanization technology to the antibody development as a drug. Tocilizumab in turn significantly contributed to the scientific understanding of the role of IL-6 for autoimmune diseases. It was launched significantly later than infliximab (Remicade), even though they were created at roughly the same time. This delay was largely caused by concern that drug price regulation in Japan might not allow a sufficiently high price for a new drug for rheumatoid arthritis for which low price conventional drugs were available.

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Notes

  1. 1.

    From interview with Kiyoshi Hogawa in 2013.

  2. 2.

    Phase I clinical trials investigate the safety, distribution in the body, and excretion of drugs. Phase II clinical trials confirm safety and determine efficacy and dosage. A Phase I/II trial combines these tests.

  3. 3.

    In lymphoproliferative disorders, IL-6 secreted by enlarged lymph nodes induces a variety of clinical manifestations. In many cases, the patient dies. It is a rare disease, and in Japan, there are approximately 200 patients. Actemra was approved as the world’s first treatment for Castleman’s disease.

  4. 4.

    Reporting of Drug Pricing Organization. http://www.mhlw.go.jp/shingi/2005/05/dl/s0525-7a2.pdf (accessed 21 October 2014).

  5. 5.

    Drug price formation of new drug: http://www.mhlw.go.jp/shingi/2005/05/dl/s0525-7a1.pdf http://www.mhlw.go.jp/shingi/2005/05/dl/s0525-7a2.pdf (accessed 21 October 2014).

  6. 6.

    Rituxan 10 mg/mL, which was marketed as a drug for malignant lymphoma in 2001, and applied to rheumatoid arthritis treatment in foreign countries, was used for deriving the interspecification ratio, which was decided to be 98%. Drug price formation of new drug: http://www.mhlw.go.jp/shingi/2008/06/dl/s0604-5b.pdf (accessed 21 October 2014).

  7. 7.

    Drug price formation of new drug: http://www.mhlw.go.jp/shingi/2008/06/dl/s0604-5b.pdf (accessed 21 October 2014).

  8. 8.

    Results of promotion for new drug creation in FY 2010 Medical Price Revision. http://www.mhlw.go.jp/shingi/2010/06/dl/s0623-2c.pdf (accessed 23 October 2014).

  9. 9.

    Market expansion recalculated item in H24.1.25. http://www.mhlw.go.jp/stf/shingi/2r98520000020zbe-att/2r98520000020zfi.pdf (accessed 22 October 2014).

  10. 10.

    Subsequently, Neutrogin was launched as Granocyte in Korea and Ireland in 1993. It was then launched in Germany, the UK, Australia, Thailand, and France in 1994; in Belgium and Luxembourg in 1995; and in Taiwan in 1997. From Drug Interview Form: Recombinant human G CSF Preparation Neutrogin Inj. 50 µg, Neutrogin Inj. 100 µg, Neutrogin Inj. 250 µg.

  11. 11.

    Market expansion recalculated item, http://www.mhlw.go.jp/bunya/iryouhoken/iryouhoken15/dl/gaiyou_yakka_5.pdf (accessed 24 August 2014).

  12. 12.

    Score based on the European League Against Rheumatism calculation and is used as a measure of disease activity. The sum of the number of swollen and painful joints, the erythrocyte sedimentation rate, and the general symptoms of a given 28 joints is given by multiplying each of them by a factor. If the DAS28 score value is less than 2.6, it is evaluated as remission.

  13. 13.

    Antibodies in which the constant region has been replaced with a human gene, leaving the variable region from the mouse.

  14. 14.

    A type of inflammatory bowel disease in which the mucosa of the large and small intestines is chronically inflamed or ulcerated for no known reason. (http://www.nanbyou.or.jp/entry/81 accessed 9 October 2013).

  15. 15.

    An inflammatory disease of the large intestine in which erosions or ulcers form in the lining of the large intestine. (Centers for Intractable Diseases: http://www.nanbyou.or.jp/entry/62 accessed 9 October 2013).

  16. 16.

    Inflammation of the hip or shoulder joints. Inflammation called enthesitis occurs at the heel and on other parts of the tendon that attach to the bone. (http://www.rheuma-net.or.jp/rheuma/rm120/kouza/kyochoku.html accessed 9 October 2013).

  17. 17.

    Psoriasis, a skin disorder, is a complication of swollen, painful arthritis. (http://www.rheuma.net.or.jp/ rheuma/rm120/kouza/kansen.html accessed 9 October 2013).

  18. 18.

    Chronic recurrent systemic inflammatory disease with four main symptoms: aphthous ulcers of the oral mucosa, vulvar ulcers, cutaneous symptoms, and ocular symptoms. (http://www.nanbyou.or.jp/entry/187 accessed 9 October 2013).

  19. 19.

    An inflammatory condition that results from a systemic bacterial infection, with a significant reduction in tissue streaming. (Merck Manual: http://merckmanual.jp/mmpej/sec06/ch068/ch068a.html accessed 9 October 2013).

  20. 20.

    FDA Remicade Product Review. p. 14.

  21. 21.

    Chugai Pharmaceutical. IL-6 Discovery. http://ra-online.jp/pr/bone/act/il6/il6/002.html (accessed 5 October 2013).

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Authors and Affiliations

  1. CEAFJP/EHESS, Paris, France

    Yasushi Hara

  2. Faculty of Economics, Hitotsubashi University, Tokyo, Japan

    Yasushi Hara

  3. Ohsugi BioPharma Consulting Co., Ltd, Tokyo, Japan

    Yoshiyuki Ohsugi

  4. Tokyo Keizai University, Tokyo, Japan

    Sadao Nagaoka

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  1. Yasushi Hara
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  2. Yoshiyuki Ohsugi
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  3. Sadao Nagaoka
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Correspondence to Yasushi Hara .

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Editors and Affiliations

  1. Department of Economics, Tokyo Keizai University, Kokubunji, Tokyo, Japan

    Sadao Nagaoka

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Hara, Y., Ohsugi, Y., Nagaoka, S. (2019). Tocilizumab (Actemra, RoActemra). In: Nagaoka, S. (eds) Drug Discovery in Japan. Springer, Singapore. https://doi.org/10.1007/978-981-13-8906-1_13

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  • DOI: https://doi.org/10.1007/978-981-13-8906-1_13

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