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TAK 475 EC302 CSR 23rd October 2007

SYNOPSIS Title of Study: A Placebo-Controlled, Double-Blind, Randomized Study to Evaluate the Efficacy and Safety of TAK-475 50 mg and 100 mg Versus Placebo, When Coadministered With 20 mg or 40 mg in Subjects With Primary Dyslipidemia Name of Sponsor: Takeda Global Research & Development Centre (Europe) Ltd. Name of Active Ingredient: Lapaquistat acetate Name of Finished Product: Not applicable Investigators/Study Centers: 81 sites in 7 countries (Europe and South Africa) Publication: None Study Period: Phase of Development: 22 October 2005 to 01 March 2007 Phase 3 OBJECTIVES Primary: The primary objective of this study was to evaluate the reduction in low-density lipoprotein (LDL-C) in subjects with primary dyslipidemia when treated with lapaquistat acetate 50 mg once daily (QD), lapaquistat acetate 100 mg QD, or placebo when coadministered with simvastatin 20 or 40 mg QD for 24 weeks. Secondary: The secondary objectives of this study were to evaluate the effects of lapaquistat acetate 50 mg QD, lapaquistat acetate 100 mg QD, or placebo when coadministered with simvastatin 20 or 40 mg QD for 24 weeks on • other lipid variables; • high-sensitivity C-reactive protein (hs-CRP); • the overall safety and tolerability during and after 24 weeks of treatment; • the percentage of subjects who achieved LDL-C concentrations of <1.813, 2.590, and 3.367 mmol/L (<70, 100, 130 mg/dL) at the Final Visit; and • plasma concentration-time profile of lapaquistat acetate, M-I, and M-II. An additional secondary objective was to identify subject factors (covariates) that affected the apparent clearance of the drug. METHODOLOGY This was a phase 3, randomized, double-blind, placebo-controlled, multicenter, parallel-group study designed to evaluate the efficacy and safety of lapaquistat acetate 50 mg or 100 mg coadministered with a stable dose of simvastatin (20 or 40 mg) compared with simvastatin monotherapy for 24 weeks in subjects with primary dyslipidemia. Subjects who had been taking a previously prescribed dose of simvastatin (20 or 40 mg) for at least 4 weeks and who initially met study eligibility criteria entered a 4-week diet stabilization period (on the therapeutic lifestyle change diet) and returned to the site at Weeks -2 and -1 for repeat qualifying lipid tests.

TAK 475 EC302 CSR 23rd October 2007

Title of Study: A Placebo-Controlled, Double-Blind, Randomized Study to Evaluate the Efficacy and Safety of TAK-475 50 mg and 100 mg Versus Placebo, When Coadministered With Simvastatin 20 mg or 40 mg in Subjects With Primary Dyslipidemia Qualifying subjects were randomized to treatment after stratification on the basis of the subject’s simvastatin dose (20 or 40 mg) and Baseline triglyceride (TG) level (”1.695 or >1.695 mmol/L [”150 or >150 mg/dL]). Subjects self- administered study drug (lapaquistat acetate 50 mg QD, lapaquistat acetate 100 mg QD, or matching placebo) from Weeks 1 through 24 and returned to the site at Weeks 2, 4, 8, 12, 16, 20, and 24 for study procedures. Number of Subjects: Planned: 522 subjects in a 1:1:1 ratio (174 in each treatment group). Analyzed: 517 Diagnosis and Main Criteria for Inclusion: To be eligible for study participation, subjects were required to be men or women, 18 years of age or older with documented stable primary dyslipidemia (within 4 weeks of Screening), who had elevated LDL-C •100 to ”190 mg/dL (•2.59 to ”4.92 mmol/L) and mean TG levels ”400 mg/dL (”4.5 mmol/L) within the 6 months prior to Screening (Visit 1). In addition, it was required that subjects be on a stable dose of simvastatin (either 20 or 40 mg) for at least 4 weeks prior to Screening. In order to be randomized, subjects were required to have mean LDL-C levels •100 to ”170 mg/dL (•2.59 to ”4.40 mmol/L) and mean TG levels ”400 mg/dL (”4.5 mmol/L), based on calculations made from measurements at Visit 2 (Week -2) and Visit 3 (Week -1). To be randomized, for each subject the difference between the 2 individual values was not to differ by more than 15% of the upper value for LDL-C, and the upper value for TG (for either sample) was to be ”450 mg/dL (5.1 mmol/L). Test Product Dose and Mode of Administration Lot Numbers Lapaquistat acetate 100 mg tablet, oral, QD Z5537111 Lapaquistat acetate 50 mg tablet, oral, QD Z553B031 Matching placebo Z5535071 Duration of Treatment: This study comprised a 4 (+1)-week Run-in Period followed by a 24-week treatment period (ie, approximately 29 weeks). Criteria for Evaluation: Efficacy: The primary efficacy variable was fasting plasma LDL-C concentration based on direct measurement. The secondary efficacy variables were the fasting plasma concentrations of calculated LDL-C, non–high-density lipoprotein cholesterol (non–HDL-C) (derived as total cholesterol [TC] minus HDL-C), TC, apolipoprotein B (Apo B), TG, HDL-C, apolipoprotein A1 (Apo A1), very-low-density lipoprotein cholesterol (VLDL-C), derived ratios (LDL-C/HDL-C, TC/HDL-C, and Apo B/Apo A1), and hs-CRP. Safety: Safety variables included adverse events, clinical laboratory results (chemistry, hematology, and urinalysis), physical examination findings, electrocardiogram (ECG) assessments, best corrected visual acuity (BCVA) results, and vital signs.

TAK 475 EC302 CSR 23rd October 2007

Title of Study: A Placebo-Controlled, Double-Blind, Randomized Study to Evaluate the Efficacy and Safety of TAK-475 50 mg and 100 mg Versus Placebo, When Coadministered With Simvastatin 20 mg or 40 mg in Subjects With Primary Dyslipidemia Statistical Methods: All statistical analyses were based on the statistical analysis plan, which was finalized before unblinding. The primary efficacy analysis was based on the percent change from Baseline to Week 24 (or time of early withdrawal) in direct fasting plasma LDL-C value. Treatment groups were compared using an analysis of covariance (ANCOVA) model with treatment as factor and Baseline value as covariate. To control the type 1 error in the primary analysis, a step-wise procedure was employed. If the P-value for lapaquistat acetate 100 mg vs placebo was not statistically significant at the 0.05 level, then the comparison of lapaquistat acetate 50 mg with placebo was not needed. However, if the P-value was statistically significant at the 0.05 level, the P-value for lapaquistat acetate 50 mg vs placebo was examined. Secondary variables were analyzed using the same analysis model as the primary analysis. For time-effect displays, primary and secondary variables were summarized and analyzed by study visit. ANCOVA models similar to the model used in the primary analysis were used in these analyses. For TG, the assumption of normality was assessed using the Shapiro-Wilk statistic. If the assumptions were found not to hold, a nonparametric analysis based on the Wilcoxon Rank-Sum test was used to corroborate or supersede the parametric analysis. The estimate of treatment differences in median and 95% confidence intervals (CIs) was based on the Hodges-Lehmann method and the distribution-free CI, respectively. The proportions of subjects who achieved LDL-C concentrations of less than 1.813, 2.590, and 3.367 mmol/L (<70, 100, and 130 mg/dL) at Week 24 (or time of early withdrawal) were summarized in a shift table; no formal statistical analysis was performed. To control the type 1 error across all efficacy variables intended to be included in the labeling, the efficacy variables were summarized and analyzed in the following order: direct LDL-C, non–HDL-C, TC, Apo B, TG, and HDL-C. If a variable in this sequence was not statistically significant at the alpha level of 0.05, the testing procedure was stopped for the subsequent variables. The number of subjects who reached the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) LDL-C goals at Week 24 (or Early Termination) were analyzed using a logistic regression model with terms for treatment, NCEP ATP III risk category (three levels based on the target LDL-C goals), and baseline LDL-C. A similar analysis was also performed for those subjects who were not at their LDL-C goal at Baseline. Summary statistics including P-values, estimates of odds-ratios, and 95% CI for the odds-ratio were presented. In the safety analyses, adverse events were coded using the Medical Dictionary for Regulatory Activities (Version 8.1) and summarized using descriptive statistics. Clinical laboratory test results were summarized descriptively by treatment. Markedly abnormal laboratory values were summarized by treatment group, including the number and percentage of subjects in each laboratory parameter group. Shift tables were produced that included the number of subjects per group with low, normal, or high values with respect to the reference ranges, and the number and percentage of subjects in each shift combination. Descriptive statistics of vital signs, ECG intervals, and BCVA evaluations were produced for each treatment group. SUMMARY OF RESULTS Subject Disposition: A total of 449 subjects completed the study. Within the placebo, lapaquistat acetate 50 mg, and lapaquistat acetate 100 mg groups, 13.6%, 11.0%, and 17.2% of subjects, respectively, discontinued from the study. Both overall and within each treatment group, the most common reasons for discontinuation were adverse events (30 subjects overall) and voluntary withdrawal (23 subjects overall); 1 placebo-treated subject withdrew due to pregnancy. The study population was predominantly White (94.4%) and female (62.5%), with a mean age of 59.1 years. There were no important differences between treatment groups in any of the Baseline demographic characteristics or Baseline efficacy parameters.

TAK 475 EC302 CSR 23rd October 2007

Title of Study: A Placebo-Controlled, Double-Blind, Randomized Study to Evaluate the Efficacy and Safety of TAK-475 50 mg and 100 mg Versus Placebo, When Coadministered With Simvastatin 20 mg or 40 mg in Subjects With Primary Dyslipidemia Efficacy Results: Summary of Primary and Secondary Lipid Variables: Change From Baseline at Week 24 (LOCF) % Change From Baseline, Least Squares Means % Difference From Placebo (SE) (95% CI) Placebo LAP 50 mg LAP 100 mg Variable (n=174) (n=171) (n=172) LAP 50 mg LAP 100 mg Direct 0.85 (1.380) -15.08 (1.388) -19.58 (1.400) -15.94 (-19.780, -12.091) -20.43 (-24.295, -16.571) LDL-C P<0.001 P<0.001 Calculated 2.85 (1.488) -14.00 (1.496) -20.36 (1.510) -16.84 (-20.986, -12.697) -23.21 (-27.375, -19.046) LDL-C P<0.001 P<0.001 Non–HDL-C 2.94 (1.309) -11.89 (1.318) -17.64 (1.329) -14.83 (-18.479, -11.180) -20.58 (-24.243, -16.913) P<0.001 P<0.001 TC 2.83 (0.962) -8.42 (0.969) -12.64 (0.977) -11.25 (-13.929, -8.564) -15.48 (-18.169, -12.781) P<0.001 P<0.001 Apo B 6.82 (1.300) -6.49 (1.307) -11.94 (1.326) -13.31 (-16.93, -9.68) -18.76 (-22.41, -15.11) P<0.001 P<0.001 TG -1.559 -7.773 -6.944 -5.68 (-11.293, 0.034) -6.68 (-12.358, -0.826) (median) P=0.051 P=0.026 HDL-C 2.93 (0.987) 2.25 (0.993) 2.21 (1.002) -0.68 (-3.430, 2.073) -0.73 (-3.489, 2.038) P=0.628 P=0.606 Apo A1 3.64 (0.865) 2.08 (0.870) 3.22 (0.883) -1.56 (-3.97, 0.85) -0.41 (-2.84, 2.01) P=0.204 P=0.738 VLDL-C 5.01 (2.437) -0.35 (2.451) -2.97 (2.472) -5.36 (-12.152, 1.434) -7.98 (-14.803, -1.163) P=0.122 P=0.022 LAP=lapaquistat acetate. Efficacy Results: The efficacy results for the primary and main secondary variables are presented in the above table. Statistically significant LDL-C reductions were first observed at Week 2 in both lapaquistat acetate treatment groups and were maintained throughout the 24-week Treatment Period. Of subjects with a Baseline direct LDL-C value •3.367 mmol/L, 28.3% of lapaquistat acetate 50 mg subjects, 35.1% of lapaquistat acetate 100 mg subjects, and 1.9% (1 subject) of placebo subjects achieved levels <2.590 μmol/L. Statistically significant and consistent differences in LDL-C reductions were observed between both lapaquistat acetate groups and placebo in all subgroups based on baseline simvastatin dose, TG value, age, gender, body mass index, and—among lapaquistat acetate 100 mg subjects—ethnicity. The reductions in LDL-C and in most secondary parameters observed with lapaquistat acetate 100 mg were numerically larger than those seen with lapaquistat acetate 50 mg. Clinically meaningful and statistically significant differences favoring lapaquistat acetate (at either dose) over placebo were seen in calculated LDL-C, non–HDL-C, TC, and Apo B; statistically significant differences between lapaquistat acetate 100 mg and placebo were also noted for changes from Baseline, favoring lapaquistat acetate, in median TG and mean VLDL-C. For changes within the lapaquistat acetate groups, the magnitude of reduction from Baseline to Week 24 in lipid variables appeared to be dependent on dose. Safety Results: Of the 522 subjects randomized to treatment, 517 were exposed to study drug. Adverse event incidences were generally similar among the 3 treatment groups, both in the overall incidence (64.4% placebo, 64.9% lapaquistat acetate 50 mg, and 59.9% lapaquistat acetate 100 mg) and in the incidence of most events. The most common adverse event was nasopharyngitis (6.0% overall). The majority of adverse events were mild or moderate in intensity.

TAK 475 EC302 CSR 23rd October 2007

Title of Study: A Placebo-Controlled, Double-Blind, Randomized Study to Evaluate the Efficacy and Safety of TAK-475 50 mg and 100 mg Versus Placebo, When Coadministered With Simvastatin 20 mg or 40 mg in Subjects With Primary Dyslipidemia Two subjects died of treatment-emergent adverse events during the study, 1 of cerebrovascular accident (placebo) and 1 of myocardial infarction (lapaquistat acetate 50 mg); both events were considered by the investigator to be unrelated to study drug. Treatment-emergent serious adverse events (SAEs) occurred more frequently in placebo-treated subjects than in subjects treated with lapaquistat acetate 50 mg or 100 mg (9, 5, and 3 subjects, respectively). In the presence of lapaquistat acetate, none of the SAEs was experienced by more than 1 subject, and with the exception of 1 event of possibly-related cholelithiasis in the 100 mg group, all SAEs were considered by the investigator to be unrelated to study drug. Nearly twice as many subjects in the lapaquistat acetate 100 mg group (15 subjects; 8.7%), compared with the placebo (8 subjects; 4.6%) or lapaquistat acetate 50 mg groups (8 subjects; 4.7%), had study drug withdrawn in response to an adverse event. Myalgia, the most frequently reported adverse event resulting in withdrawal of study drug, occurred in 24 subjects (8 in each group) and led to the withdrawal of study drug in 2 placebo subjects (1.1%) and in 4 subjects (2.3%) in each lapaquistat acetate group. Discontinuations due to hypertension (2 subjects) and elevated function tests (2 subjects, both with alanine aminotransferase [ALT] and aspartate aminotransferase [AST] abnormalities) occurred only in the presence of the higher lapaquistat acetate dose. Only in the lapaquistat acetate 100 mg group were ALT and/or AST values >3×ULN noted at consecutive visits, occurring in 2 subjects. For both of these subjects, elevations were reported as adverse events; 1 subject was withdrawn from the study in response. One additional subject (lapaquistat acetate 100 mg group) was withdrawn from the study, as specified in the protocol, due to an ALT elevation >3×ULN (103 IU/L) associated with total bilirubin values >2×ULN (55.2 μmol/L). There were no major findings in hematology, urinalysis, vital signs, ECGs, physical examination, or BCVA results. CONCLUSIONS: Treatment with lapaquistat acetate at doses of 50 or 100 mg QD for up to 24 weeks, in combination with simvastatin 20 mg or 40 mg QD, was effective in reducing LDL-C levels in subjects with primary dyslipidemia. Clinically meaningful and statistically significant differences favoring lapaquistat acetate (at either dose) over placebo were seen in calculated LDL-C, non-HDL-C, TC, and Apo B—the improvements showing a clear dose-dependency favoring the 100 mg dose of lapaquistat acetate. Statistically significant differences between lapaquistat acetate 100 mg and placebo were also noted for changes from Baseline, favoring lapaquistat acetate, in median TG and mean VLDL-C. The magnitude of reduction from Baseline to Week 24 in lipid variables appeared to be dose dependently affected. Lapaquistat acetate in combination with simvastatin was generally safe and well tolerated during this study; however, hepatic enzyme elevations occurred at a higher incidence in the lapaquistat acetate 100 mg group. Date of Report: 23 October 2007