- Recommendation is Based on RECOURSE Study Results Demonstrating Survival Advantage for Patients with Refractory Disease -

Taiho Pharmaceutical Co., Ltd. (Tokyo) today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion, recommending LONSURF (R) (trifluridine/tipiracil), formerly known as TAS-102, for the treatment of adult patients with metastatic colorectal cancer (mCRC) who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents, and anti-EGFR agents. (*1) LONSURF is originally developed by Taiho Pharmaceutical, and Servier is the applicant for marketing authorization of LONSURF in EU countries under the license agreement with Taiho Pharmaceutical.   

The CHMP positive opinion is based on data from the international, double-blind, placebo-controlled Phase III RECOURSE study, which investigated the efficacy and safety of LONSURF with best supportive care (BSC) compared to placebo with BSC in 800 patients with previously treated mCRC. The trial met the primary endpoint of statistically significant improvement in overall survival (OS).  Results demonstrated a 32% reduction in risk of death compared to BSC, with 364 deaths (68%) in the LONSURF group compared to 210 deaths (79%) in the placebo group (HR=0.68; CI: 0.58 to 0.81; p less than 0.001) and an improvement of 1.8 months of median OS (median OS was 7.1 for LONSURF vs. 5.3 months for placebo); (*2, *3) The most common adverse events or laboratory abnormalities were neutropenia (67% for LONSURF vs. less than 1% for placebo), nausea (48% vs. 24%), fatigue (35% vs. 23%), anaemia (77% vs. 33%) and leucopenia (77% vs. 5%). (*2)

The CHMP positive opinion will now be reviewed by the European Commission and if marketing authorization is granted, LONSURF will be approved in the 28 member countries of the European Union (EU), as well as Iceland, Lichtenstein and Norway.

In June 2015, Taiho Pharmaceutical and Servier entered into an exclusive license agreement for the co-development and commercialization of LONSURF. Under the terms of the agreement, Servier will commercialize LONSURF in Europe and other countries outside of the United States, Canada, Mexico and Asia. Taiho Pharmaceutical retains the right to develop and commercialize LONSURF in the United States, Canada, Mexico, and Japan/Asia and to manufacture and supply the product.  

About Metastatic Colorectal Cancer in Europe

There remains a high unmet need in the treatment of colorectal cancer (CRC), which was the second leading cause of cancer-related deaths in Europe in 2012, responsible for 215,000 deaths. (*4) Approximately 25% of patients with CRC present with metastases at initial diagnosis and almost 50% of patients with CRC will develop metastases. (*5) This contributes to the high mortality rates reported for CRC; the five-year survival rate of patients diagnosed with stage IV mCRC is about 11%. (*6)

About LONSURF

LONSURF is currently available in the United States for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine -, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. LONSURF is marketed by Taiho Pharmaceutical in Japan and by Taiho Oncology, Inc. a subsidiary of Taiho Pharmaceutical, in the U.S. LONSURF is an oral combination anticancer drug of trifluridine (FTD) and tipiracil (TPI). FTD is a thymidine-based nucleoside analog, which is incorporated directly into DNA, thereby interfering with DNA synthesis and inhibits cell proliferation. The blood concentration of FTD is maintained via TPI, which is an inhibitor of the FTD-degrading enzyme, thymidine phosphorylase.  

Important Safety Information (U.S.) (*3)

WARNINGS AND PRECAUTIONS

Severe Myelosuppression: In Study 1, LONSURF caused severe and life-threatening myelosuppression (Grade 3-4) consisting of anemia (18%), neutropenia (38%), thrombocytopenia (5%), and febrile neutropenia (3.8%). One patient (0.2%) died due to neutropenic infection. In Study 1, 9.4% of LONSURF-treated patients received granulocyte-colony stimulating factors.

Obtain complete blood counts prior to and on Day 15 of each cycle of LONSURF and more frequently as clinically indicated. Withhold LONSURF for febrile neutropenia, Grade 4 neutropenia, or platelets less than 50,000/cubic millimeters. Upon recovery, resume LONSURF at a reduced dose.

Embryo-Fetal Toxicity: LONSURF can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with LONSURF.  

USE IN SPECIFIC POPULATIONS

Lactation: It is not known whether LONSURF or its metabolites are present in human milk. There are no data to assess the effects of LONSURF or its metabolites on the breastfed infant or the effects on milk production. Because of the potential for serious adverse reactions in breastfeeding infants, advise women not to breastfeed during treatment with LONSURF and for one day following the final dose.

Male Contraception: Advise males with female partners of reproductive potential to use condoms during treatment with LONSURF and for at least three months after the final dose.

Geriatric Use: Grade 3 or 4 neutropenia and thrombocytopenia and Grade 3 anemia occurred more commonly in patients 65 years old or older who received LONSURF.  

Renal Impairment: Patients with moderate renal impairment may require dose modifications for increased toxicity. No patients with severe renal impairment were enrolled in Study 1.

Hepatic Impairment: Patients with moderate or severe hepatic impairment were not enrolled in Study 1.

ADVERSE REACTIONS

Most Common Adverse Drug Reactions in Patients Treated with LONSURF

(More than 5 percent): The most common adverse drug reactions in LONSURF-treated patients vs. placebo-treated patients with refractory mCRC, respectively, were: asthenia/fatigue (52% vs. 35%), nausea (48% vs. 24%), decreased appetite (39% vs. 29%), diarrhea (32% vs. 12%), vomiting (28% vs. 14%), abdominal pain (21% vs. 18%), pyrexia (19% vs. 14%), stomatitis (8% vs. 6%), dysgeusia (7% vs. 2%), and alopecia (7% vs. 1%).

Additional Important Adverse Drug Reactions: The following occurred more frequently in LONSURF-treated patients compared to placebo: infections (27% vs. 15%), and pulmonary emboli (2% vs. 0%).

Interstitial lung disease (0.2%), including fatalities, has been reported in clinical studies and clinical practice settings in Asia.

Laboratory Test Abnormalities in Patients Treated with LONSURF: Laboratory test abnormalities in LONSURF-treated patients vs. placebo-treated patients with refractory mCRC, respectively, were: anemia (77% vs. 33%), neutropenia (67% vs. 1%), and thrombocytopenia (42% vs. 8%).

Please see Full U.S. Prescribing Information.

http://www.taihooncology.com/us/prescribing-information.pdf

About Taiho Pharmaceutical Co., Ltd. (Japan)

Taiho Pharmaceutical, a subsidiary of Otsuka Holdings Co., Ltd., is an R&D-driven specialty pharma focusing on the three fields of oncology, allergies and immunology, and urology. Its corporate philosophy takes the form of a pledge: "We strive to improve human health and contribute to a society enriched by smiles." In the field of oncology in particular, Taiho Pharmaceutical is known as a leading company in Japan for developing innovative medicines for the treatment of cancer. In areas other than oncology, as well, the company creates quality products that effectively treat medical conditions and can help improve people's quality of life. Always putting customers first, Taiho Pharmaceutical aims to also offer over-the-counter medicinal products that support people's efforts to lead fulfilling and rewarding lives.

For more information about Taiho Pharmaceutical, please visit: http://www.taiho.co.jp/english/

About Taiho Oncology, Inc. (U.S.)

Taiho Oncology, Inc., a subsidiary of Taiho Pharmaceutical Co., Ltd. and Otsuka Holdings Co., Ltd., has established a world class clinical development organization that works urgently to develop innovative cancer treatments and has built a commercial business in the U.S. Taiho has an oral oncology pipeline consisting of both novel antimetabolic agents and selectively targeted agents. Advanced technology, dedicated researchers, and state of the art facilities are helping us to define the way the world treats cancer. It's our work; it's our passion; it's our legacy.

For more information about Taiho Oncology, please visit: http://www.taihooncology.com

About Servier

Servier is an independent research-based pharmaceutical company headquartered in France.  With a strong international presence in 148 countries and 92% of its medicines being prescribed outside of France, Servier employs more than 21,200 people worldwide. In 2015, the company recorded a turnover of 3.9 billion euros of which 24% was reinvested in research and development. Currently, there are nine new molecular entities in clinical development for oncology respectively in breast, lung and other solid tumors as well as various leukemias and lymphomas.

This portfolio of innovative cancer treatments is being developed with various partners worldwide, and covers different hallmarks of cancer including cytotoxics, proapoptotic, targeted, immune and cellular therapies.

(*1) European Medicines Agency (EMA). Committee for Medicinal Products for Human Use (CHMP). LONSURF summary of opinion (initial authorisation). February 25, 2016. Available at:  http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/003897/smops/Positive/human_smop_000941.jsp&mid=WC0b01ac058001d127

(Accessed February 26, 2016)

(*2) Mayer RJ, et al. Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer. N Engl J Med 2015; 372:1909-19.

(*3) LONSURF (prescribing information); Princeton, NJ: Taiho Oncology, Inc.; 2015. Available at: http://www.taihooncology.com/us/prescribing-information.pdf

(Accessed February 26, 2016)

(*4) Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 2013;49: 1374-1403.

(*5) Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol (2014) 25 (suppl 3): iii1-iii9.

(*6) American Cancer Society. Colorectal Cancer. Available at: http://www.cancer.org/cancer/colonandrectumcancer/detailedguide/colorectal-cancer-survival-rates

(Accessed February 26, 2016)