The clinical trial information provided in this public disclosure synopsis is supplied for informational purposes only.

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1 The clinical trial information provided in this public disclosure synopsis is supplied for informational purposes only. Please note that the results reported in any single trial may not reflect the overall potential risks or benefits of a product which are based on an evaluation of an entire research program. Before prescribing any Takeda products, healthcare professionals should consult prescribing information for the product approved in their country.

2 Page 4 2 SYNOPSIS Title of Study: A Randomized, Open-Label Study to Evaluate the Pharmacokinetics of When Administered with Food and When Coadministered with Metformin or Cimetidine Investigator and Study Center: Thomas Hunt, MD, PhD, PPD Clinic Publication (reference): None Study Period: 07 April June 2005 Phase of Development: I Objectives: The primary objectives of this study were: To assess the effect of food administration on the pharmacokinetics of To determine the effect of metformin on the steady-state pharmacokinetics of in healthy To determine the effect of cimetidine on the steady-state pharmacokinetics of in healthy To determine the effect of on the steady-state pharmacokinetics of metformin in healthy To determine the effect of on the steady-state pharmacokinetics of cimetidine in healthy To assess the safety of when coadministered with metformin or cimetidine Methodology: This was a randomized, open-label, single-center, 2-phase, single-dose and multiple-dose study conducted in healthy male and female. Subjects were confined to the clinical facility for the duration of the study. Single-Dose Phase: The first phase of the study employed a 2-period crossover design and examined the effect of food administration on the single-dose pharmacokinetics of. In Period 1, all received a single dose of after an overnight fast of at least 10 hours (fasted condition) or immediately after consuming a standard high-fat meal (fed condition). In Period 2, all received a single dose of in the alternate condition (fasted/fed). A 96-hour washout separated dosing in the 2 periods. Pharmacokinetic blood and urine samples were collected over 96 hours after dosing in each period. After completion of the single-dose phase, continued into the multiple-dose phase of the study.

3 Page 5 Multiple-Dose Phase: The second phase of the study employed a 3-period crossover design and examined the potential for drug-drug interactions between and metformin and and cimetidine. Subjects were randomized into 1 or 2 treatment arms within the multiple-dose phase: a metformin arm or a cimetidine arm. Subjects randomized to the metformin arm received the following 3 treatments in a crossover fashion, with the order of treatment determined by random assignment: 100 mg once daily (QD) for 6 days Metformin 1000 mg twice a day (BID) for 6 days Metformin 1000 mg BID mg QD for 6 days On the sixth and final day of dosing, only the morning dose of metformin was administered (for those receiving the metformin regimens). A 96-hour washout separated dosing in each of the 3 periods. Subjects randomized to the cimetidine arm received the following 3 treatments in a crossover fashion, with the order of treatment determined by random assignment: 100 mg QD for 6 days Cimetidine 400 mg QD for 6 days Cimetidine 400 mg QD mg QD for 6 days A 96-hour washout separated dosing in each of the 3 periods. Pharmacokinetic blood and urine samples were collected over the 96 hours after dosing in each period. Subjects were discharged from the clinic after completion of all exit procedures on the morning of Day 10 of Period 3, provided no clinically significant abnormalities were noted. Number of Subjects (planned and analyzed): Thirty-six healthy were planned, 36 were enrolled, and 34 completed the study. All 36 were included in the safety analysis, 36 were included in the single-dose pharmacokinetic analysis, and 35 were included in the multiple-dose pharmacokinetic analysis. Diagnosis and Main Criteria for Inclusion: Subjects in this study were healthy adults (aged 18 to 55 years, inclusive) with no clinically significant diseases or laboratory abnormalities. Specifically, they had to have a creatinine clearance >80 ml/min, body mass index (BMI) 18 and 30 kg/m 2, normal vital sign measurements and electrocardiogram findings, and negative results on urine alcohol and drug screen. For female only: if of childbearing potential, the subject must have been practicing adequate contraception and agreed to continue using adequate contraception through completion of the study. All provided written informed consent for participation. Test Product, Dose and Mode of Administration, Batch Number:, 100 mg orally administered as two 50-mg tablets, Lot Number 13512/F14523 Duration of Treatment: The duration of the study was approximately 9 weeks: 3 weeks for the screening period, approximately 2 weeks for the single-dose phase, and approximately 4 weeks for the multiple-dose phase.

4 Page 6 Reference Therapy, Dose, and Mode of Administration, Batch Number: Metformin hydrochloride 1000-mg tablet administered BID, Lot Number C4F0659 Cimetidine 400-mg tablet, Lot Number PA Criteria for Evaluation: The following pharmacokinetic parameters were calculated from plasma and urine concentrations of : area under the plasma concentration-time curve from the time of dosing (0 hour) to the time of the last quantifiable concentration (AUC 0-t ), area under the plasma concentration-time curve extrapolated to infinity (AUC 0-inf ) for the single-dose phase, area under the plasma concentration-time curve over the dosing interval tau (AUC 0-tau ) for the multiple-dose phase only, maximum plasma concentration (C max ), time to achieve maximum plasma concentration (T max ), apparent terminal elimination half-life (t 1/2,z ), apparent oral clearance (CL/F), apparent volume of distribution (V z /F), total amount excreted in urine from 0 to 96 hours after dosing (XU 0-96 ), fraction of the dose excreted unchanged in the urine from 0 to 96 hours after dosing (Fe% 0-96 ), and renal clearance (CLr). Safety assessments included clinical laboratory evaluations (hematology, serum chemistry, and urinalysis), vital sign measurements, physical examination findings, 12-lead electrocardiogram tracings, and adverse event reporting. In addition, were closely monitored for signs and symptoms of hypoglycemia. Statistical Methods: Pharmacokinetic parameters were summarized by treatment using descriptive statistics: number of (n), mean, geometric mean, standard deviation (SD), standard error (SE), coefficient of variation (CV [%]), median, minimum, maximum, and the 25 th and 75 th percentiles. For the assessment of a food-effect on the single-dose pharmacokinetics of, an analysis of variance (ANOVA) was performed on log-transformed pharmacokinetic parameters. The ANOVA model included terms for sequence, subject within sequence, period, and treatment. The effects of food administration on the single-dose pharmacokinetics of were estimated by the ratios and 90% confidence intervals (CIs) of AUC 0-inf and C max. If the 2-sided 90% CIs for the ratios of least squares (LS) geometric means (based on log-transformed parameters) of fed and fasted treatments fell within 80% to 125% or AUC 0-inf and C max, then the presence of a food effect was excluded. If the 90% CIs for these ratios fell outside the above limits, then a food effect was assumed. In addition, point estimates and 90% CIs for differences in median T max values were calculated using nonparametric techniques. For the assessment of drug-drug interactions, an ANOVA was performed on log-transformed pharmacokinetic parameters. The ANOVA model included terms for sequence, subject within sequence, period, and treatment. The effects of on the steady-state pharmacokinetics of metformin and cimetidine and the effects of metformin and cimetidine on the steady-state pharmacokinetics of were estimated by the ratios and 90% CIs of AUC 0-tau and C max. The lack of significant drugdrug interactions was concluded if the 90% CIs for these ratios fell within the range of 80% to 125%.

5 Page 7 Statistical Methods (continued): All safety data were summarized using descriptive statistics, where appropriate. Changes from baseline and shifts from baseline were also summarized. Adverse events were coded by system organ class and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA, Version 7.1) and summarized by treatment, by number of events, and by the number of who experienced them. Adverse events were also summarized by system organ class, severity, and seriousness. Clinical laboratory and vital sign measurements were summarized by treatment and change from baseline. Summary and Conclusions: Pharmacokinetic Results: The administration of food had only a small effect on the rate of absorption of, with median times to peak exposure increasing from 2.00 hours in the fasted state to 2.51 hours in the fed state. While total (AUC) was slightly lower in the fed state, the 90% CI for AUC 0-inf fell within the range of 80% to 125% (0.938 to 0.968). However, the lower limit of the 90% CI for C max fell outside of the 80% to 125% range (0.798 to 0.917). Thus, administration of under fed conditions resulted in a statistically significantly lower rate (C max ) but similar total extent (AUC 0-inf ) of absorption of compared to fasted conditions. However, the magnitude of the change in C max suggests that the effect of food administration on exposure to is not clinically significant. Analysis of Food-Effect on Pharmacokinetics 100 mg fasted (N=36) 100 mg fed (N=36) Ratio (90% CI) AUC 0-inf (ng h/ml) (0.938, 0.968) C max (ng/ml) (0.798, 0.917) Source: Table Note: Values presented for AUC 0-inf and C max are LS means.

6 Page 8 Pharmacokinetic Results (continued): Coadministration of with cimetidine resulted in slightly higher total exposure to than when was administered alone, while coadministration of with metformin produced slightly lower peak exposure to than when was administered alone. However, the 90% CIs for both AUC 0-tau and C max for when coadministered with cimetidine and when coadministered with metformin fell within the range of 80% to 125%, indicating that coadministration of with either cimetidine or metformin has no effect on the steady-state plasma pharmacokinetics of. Analysis of the Effects of Cimetidine and Metformin on the Steady-State Pharmacokinetics of 100 mg mg (N=18) Cimetidine 400 mg (N=18) Ratio (90% CI) AUC 0-tau (ng h/ml) (1.032, 1.099) C max (ng/ml) (0.984, 1.116) 100 mg (N=17) 100 mg + Metformin 2000 mg (N=17) Ratio (90% CI) AUC 0-tau (ng h/ml) (0.972, 1.029) C max (ng/ml) (0.820, 0.977) Source: Table Note: Values presented for AUC 0-tau and C max are LS means. Total and peak exposure to cimetidine were similar when cimetidine was administered alone and when coadministered with. The 90% CIs for both AUC 0-tau and C max for cimetidine coadministered with with relative to cimetidine administered alone fell within the range of 80% to 125%, indicating that coadministration of has no effect on the steady-state plasma pharmacokinetics of cimetidine. Likewise, coadministration of had no effect on the steady-state urine pharmacokinetics of cimetidine based on similar values of XU 0-96, Fe%, and CLr. Total exposure to metformin was higher following coadministration of metformin with. The upper limit of the 90% CI for AUC 0-tau for metformin fell outside the range of 80% to 125% (1.095 to 1.291). However, peak exposure to metformin was similar between the 2 treatments, and the 90% CI for C max for metformin fell within the range of 80% to 125%. Thus, administration of does not influence the rate of absorption of metformin but does increase total exposure to metformin by approximately 10% to 30%. However, the magnitude of the change in AUC 0-tau suggests that coadministration of will not have a clinically significant effect on metformin exposure in patients with normal renal function.

7 Page 9 Safety Results: No deaths and no serious adverse events were reported, and no discontinued due to adverse events. During the single-dose phase of the study, the percentage of reporting adverse events was higher when was administered in the fasting state (11 [30.6%]) than when was administered in the fed state (6 [16.7%]). Likewise, the number of adverse events reported after administration of in the fasting state was higher (18) than when SYR11032 was administered in the fed state (9). All adverse events reported in the single-dose phase of the study were considered mild in severity by the investigator. In the metformin arm of the multiple-dose phase of the study, the percentage of reporting adverse events was highest following administration of the metformin containing regimens. Fourteen (82.4%) reported 51 events following coadministration of with metformin and 13 (76.5%) reported 46 events following administration of metformin alone. Both the number of reporting adverse events and the number of events reported were lowest when was administered alone (7 41.2% reported 19 events). The most commonly reported adverse events reported during the metformin regimens were gastrointestinal disorders, which were experienced by 13 (76.5%) following both coadministration of with metformin and following administration of metformin alone. In the cimetidine arm of the multiple-dose phase of the study, the percentage of reporting adverse events was highest following coadministration of with cimetidine (9 50.0% reported 17 events), followed by administration of alone (7 38.9% reported 16 events), and cimetidine alone (5 27.8% reported 13 events). Headache was the most frequently reported treatment-emergent adverse events following administration of all 3 treatments. Conclusion: The administration of food produced a statistically, but not clinically, significant slowing of the rate of absorption of ; however, food administration had no effect on the overall extent of absorption of. Coadministration of either cimetidine or metformin had no effect on the steady-state pharmacokinetics of. Coadministration of with cimetidine had no effect on the steady-state pharmacokinetics of cimetidine. Coadministration of with metformin produced a statistically, but not clinically, significant increase in total metformin exposure; however, the small changes observed do not necessitate dose adjustment of metformin. Coadministration of with cimetidine and metformin was well tolerated and did not produce any untoward effects that were not otherwise seen with cimetidine and metformin use. Date of the Report: 15 August 2005