Report on the Deliberation Results

1 This English version of the Japanese review Report is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. The PMDA will not be responsible for any consequence resulting from the use of this English version. Report on the Deliberation Results February 7, 2014 Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau Ministry of Health, Labour and Welfare [Brand name] (1) Lonsurf combination tablets T15 (2) Lonsurf combination tablets T20 [Non-proprietary name] Trifluridine and Tipiracil Hydrochloride (JAN*) [Name of applicant] Taiho Pharmaceutical Co., Ltd. [Date of application] February 26, 2013 [ Results of Deliberation ] In the meeting held on February 3, 2014, the Second Committee on New Drugs concluded that the product may be approved and that this result should be presented to the Pharmaceutical Affairs Department of the Pharmaceutical Affairs and Food Sanitation Council.

2 The re-examination period for the product is 8 years. Trifluridine, one of the drug substances, and the drug product are classified as powerful drugs. The product is not classified as a biological product or a specified biological product. [Conditions for approval] The applicant is required to submit the Results of the ongoing phase III study that is conducted to confirm the efficacy and safety of the product in patients with unresectable advanced or recurrent colorectal cancer without delay after the completion of the study for review. *Japanese Accepted Name (modified INN) This English version of the Japanese review Report is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. The PMDA will not be responsible for any consequence resulting from the use of this English version. Review Report January 15, 2014 The Pharmaceuticals and Medical Devices Agency The Results of a regulatory review conducted by the Pharmaceuticals and Medical Devices Agency on the following pharmaceutical product submitted for registration are as follows.

3 [Brand name] (1) Lonsurf combination tablets T15, (2) Lonsurf combination tablets T20 [Non-proprietary name] Trifluridine and Tipiracil Hydrochloride [Name of applicant] Taiho Pharmaceutical Co., Ltd. [Date of application] February 26, 2013 [Dosage form/Strength] (1) Each tablet contains 15 mg of trifluridine and mg of tipiracil hydrochloride. (2) Each tablet contains 20 mg of trifluridine and mg of tipiracil hydrochloride. [Application classification] Prescription drug (1) Drug with a new active ingredient, (2) New prescription combination product [Chemical structure] Molecular formula: C10H11F3N2O5 Molecular weight: Chemical name: 2'-Deoxy-5-(trifluoromethyl)uridine Molecular formula: C9H11 ClN4O2 HCl Molecular weight: Chemical name: 5-Chloro-6-[(2-iminopyrrolidin-1-yl)meth yl]pyrimidine-2,4(1H,3H)-dione monohydrochloride [Items warranting special mention] None [Reviewing office] Office of New Drug V 3 Review Results January 15, 2014 [Brand name] Lonsurf combination tablets T15 and Lonsurf combination tablets T20 [Non-proprietary name] Trifluridine and Tipiracil Hydrochloride [Name of applicant] Taiho Pharmaceutical Co.

4 , Ltd. [Date of application] February 26, 2013 [ Results of review] Based on the data submitted by the applicant, the Pharmaceuticals and Medical Devices Agency (PMDA) has concluded that the efficacy of the product is expected for the treatment of unresectable advanced or recurrent colorectal cancer (only if refractory to standard therapies), and the safety of the product is acceptable in view of the observed benefits. The occurrence of bone marrow suppression and infections needs to be further investigated via post-marketing surveillance. As a result of its regulatory review, PMDA concluded that the product may be approved for the indication and dosage and administration as shown below with the following conditions. [Indication] Unresectable advanced or recurrent colorectal cancer (only if refractory to standard therapies) [Dosage and administration] The usual initial adult dose of the combination product of trifluridine and tipiracil tydrochloride (FTD-TPI) is determined based on body surface area (BSA) and shown in the dosing table below, which presents predefined ranges of BSA and the corresponding initial doses (on the basis of trifluridine at approximately 35 mg/m2/dose).

5 FTD-TPI is orally administered twice daily, after breakfast and after supper, in 28-day cycles, each consisting of two 5 days on/2 days off treatment sub-cycles, followed by a 14-day rest period. The dose may be reduced according to the patient's condition. Body surface area (m2) Initial dose (as trifluridine) < 35 mg/dose (70 mg/day) - < 40 mg/dose (80 mg/day) - < 45 mg/dose (90 mg/day) - < 50 mg/dose (100 mg/day) - < 55 mg/dose (110 mg/day) - < 60 mg/dose (120 mg/day) - < 65 mg/dose (130 mg/day) - < 70 mg/dose (140 mg/day) 75 mg/dose (150 mg/day) 4 [Conditions for approval] The applicant is required to submit the Results of ongoing phase III study that is conducted to confirm the efficacy and safety of the product in patients with unresectable advanced or recurrent colorectal cancer without delay after the completion of the study for review. 5 Review Report (1) November 13, 2013 I.

6 Product Submitted for Registration [Brand name] (1) Lonsurf combination tablets T15, (2) Lonsurf combination tablets T20 [Non-proprietary name] Trifluridine and Tipiracil Hydrochloride [Name of applicant] Taiho Pharmaceutical Co., Ltd. [Date of application] February 26, 2013 [Dosage form/Strength] (1) Each tablet contains 15 mg of trifluridine and mg of tipiracil hydrochloride. (2) Each tablet contains 20 mg of trifluridine and mg of tipiracil hydrochloride. [Proposed indication] Unresectable advanced or recurrent colorectal cancer [Proposed dosage and administration] The usual initial adult dose of the combination product of trifluridine and tipiracil tydrochloride (FTD-TPI) is determined based on body surface area (BSA) and shown in the dosing table below, which presents predefined ranges of BSA and the corresponding initial doses (on the basis of trifluridine at approximately 35 mg/m2/dose).

7 FTD-TPI is orally administered twice daily, after breakfast and after supper, in 28-day cycles, each consisting of two 5 days on/2 days off treatment sub-cycles, followed by a 14-day rest period. The dose may be reduced according to the patient's condition. Body surface area (m2) Initial dose (as trifluridine) < 35 mg/dose (70 mg/day) - < 40 mg/dose (80 mg/day) - < 45 mg/dose (90 mg/day) - < 50 mg/dose (100 mg/day) - < 55 mg/dose (110 mg/day) - < 60 mg/dose (120 mg/day) - < 65 mg/dose (130 mg/day) - < 70 mg/dose (140 mg/day) 75 mg/dose (150 mg/day) II. Summary of the Submitted Data and Outline of Review by the Pharmaceuticals and Medical Devices Agency A summary of the data submitted by the applicant and an outline of the review by the Pharmaceuticals and Medical Devices Agency (PMDA) are as shown below. 6 1. Origin or history of discovery and usage conditions in foreign countries etc. (1) Drug overview Trifluridine (FTD) is an antineoplastic nucleoside analog discovered by Heidelberger and others at the University of Wisconsin as a drug that inhibits thymidylate synthetase (TS) similarly to existing fluoropyrimidines but exerts a growth inhibitory effect mainly by being incorporated into DNA of tumor cells.

8 FTD has not been developed as a single-component antitumor drug because of its rapid metabolism in the body and other reasons. Tipiracil hydrochloride (TPI), discovered by the applicant, is considered to inhibit thymidine phosphorylase (TPase), an enzyme that degrades FTD. Lonsurf combination tablets T15 and T20 are a combination of FTD and TPI at a molar ratio of 2:1 (hereinafter referred to as FTD-TPI). The applicant developed the combination product in and outside Japan on the basis of the expectation that the combination with TPI helps maintain plasma FTD concentration over time and thereby enhance the tumor growth inhibitory effect of FTD. (2) Pharmaceutical development ** Outside Japan, a phase I study in patients with solid tumors (TAS102-9801) was initiated in ** **, and additional 4 phase I studies in patients with solid tumors (TAS102-9802, TAS102-9803, TAS102-9804, and TAS102-9805) have been conducted through **.

9 In Japan, a phase I study in patients with solid tumors (TAS102-J001) was initiated in ** **, and a phase II study in patients with unresectable advanced or recurrent colorectal cancer (TAS102-J003) was initiated in ** **. A global phase III study in patients with unresectable advanced or recurrent colorectal cancer (TPU-TAS-102-301), initiated in ** **, is ongoing in 13 countries including Japan. In February 2013, the applicant submitted a new drug application for the combination product in Japan mainly on the basis of the Results of Study TAS102-J003. 2. Data relating to quality Summary of the submitted data (1) Drug substance (1).1) Trifluridine ** i) Characterization FTD is white crystals or crystalline powder, and its properties including description, solubility, hygroscopicity, melting point, decomposition point, ultraviolet-visible absorption spectrum, optical 7 rotation, pH, acid dissociation constant, partition coefficient, and polymorphism have been determined.

10 ** **. The chemical structure of FTD has been confirmed by elemental analysis, mass spectrometry, ultraviolet visible spectrophotometry (UV/VIS), infrared spectrophotometry (IR), nuclear magnetic resonance spectroscopy (1H-NMR, 13C-NMR), and X-ray crystallography. ii) Manufacturing process See Appendix. iii) Control of FTD The proposed specifications for FTD include content, appearance, identification (UV/VIS, IR), optical rotation, purity (heavy metals, related substances [high-performance liquid chromatography (HPLC)], and residual solvents [gas chromatography (GC)]), water content, residue on ignition, and assay (HPLC). iv) Stability of FTD The following stability studies were conducted for FTD. The photostability testing showed FTD is photostable. Stability studies of FTD Primary batches TemperatureHumidityStorage form Duration of storage Long-term testing 3 production batches 25 C 60%RH Double low-density polyethylene pouches and a polyethylene bottle 18 months Accelerated testing 3 production batches 40 C 75%RH 6 months On the basis of the Results of the above studies, a re-test period of ** months has been proposed for FTD if the drug substance is packaged with double low-density polyethylene pouches and a polyethylene bottle or an equivalent polyethylene drum and is stored at room temperature, according to the "Guideline on Evaluation of Stability Data" (PFSB/ELD Notification No.