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 SYNOPSIS Name of Sponsor: Takeda Europe Research & Development Centre Ltd. Name of Active Ingredient: Lapaquistat acetate Name of Finished Product: Not applicable Investigators/Study Centers: 73 sites in the Russian Federation, Lithuania, Latvia, Germany, the United Kingdom, Estonia, Serbia and Montenegro, Finland, Poland, and Hungary. Publication: None Study Period: 26 October 2005 to 09 January 2007 Phase of Development: Phase 3 OBJECTIVES Primary: The primary objective of this study was to evaluate the reduction in low-density lipoprotein cholesterol (LDL-C) in subjects with primary dyslipidemia when treated with lapaquistat acetate 100 mg once daily (QD) vs ezetimibe 10 mg QD for 24 weeks. Secondary: The secondary objectives of this study were: To evaluate the reduction in LDL-C in subjects with primary dyslipidemia when treated with ezetimibe 10 mg vs lapaquistat acetate 100 mg administered in combination with ezetimibe 10 mg for 24 weeks. To evaluate safety and tolerability (adverse events, safety laboratory tests, physical examination, vital signs, best corrected visual acuity [BCVA], and electrocardiogram [ECG]) and changes in lipid variables: total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), very-low-density lipoprotein cholesterol (VLDL-C), apolipoprotein A1 (Apo A1), apolipoprotein B (Apo B), and non HDL-C. The percentages of subjects achieving LDL-C levels of <3.37 mmol/l (130 mg/dl) and <2.59 mmol/l (100 mg/dl) were also evaluated. The effects of lapaquistat acetate 100 mg QD and lapaquistat acetate 100 mg QD administered in combination with ezetimibe 10 mg QD vs ezetimibe 10 mg QD for 24 weeks on other lipid variables were also evaluated.

3 METHODOLOGY This was a double-blind, randomized, double-dummy, parallel group, multicenter, phase 3 study to evaluate the reduction in LDL-C in subjects with primary dyslipidemia when treated with lapaquistat acetate 100 mg QD or lapaquistat acetate 100 mg administered in combination with ezetimibe 10 mg QD vs ezetimibe 10 mg QD for 24 weeks. The study consisted of a Screening Visit, a 6-week Dietary Run-In Period, and a 24-week Treatment Period. Subjects who initially met study eligibility criteria entered a 6-week diet stabilization period (on a standardized diet such as the therapeutic lifestyle change diet) and returned to the site at Weeks -2 and -1 (and at an optional visit 1 week later if necessary) for repeat qualifying lipid tests. Qualifying subjects were randomized to treatment after stratification by their Baseline TG level ( mmol/l or >1.695 mmol/l [ 150 mg/dl or >150 mg/dl]). Subjects self-administered study drug (lapaquistat acetate 100 mg QD, ezetimibe 10 mg QD, or coadministration of lapaquistat acetate 100 mg with ezetimibe 10 mg QD) from Day 1 through Week 24, and returned to the site at Weeks 2, 4, 8, 12, 16, 20, and 24 for study procedures. Number of Subjects: Planned: 1035 subjects (460 in each of the lapaquistat acetate 100 mg and ezetimibe 10 mg groups, and 115 in the lapaquistat acetate 100 mg/ezetimibe 10 mg coadministration group). Analyzed: Full analysis set: 1263 subjects (561 lapaquistat acetate 100 mg, 561 ezetimibe 10 mg, 141 lapaquistat acetate 100 mg/ezetimibe 10 mg coadministration). Safety analysis set: 1263 subjects (561 lapaquistat acetate 100 mg, 561 ezetimibe 10 mg, 141 lapaquistat acetate 100 mg/ezetimibe 10 mg coadministration). Diagnosis and Main Criteria for Inclusion: To qualify for study participation, a subject must have been a man or woman, aged at least 18 years, with a documented history of dyslipidemia who met the following lipid criteria prior to randomization: (1) mean fasting LDL-C levels 3.36 mmol/l ( 130 mg/dl) and 5.6 mmol/l ( 220 mg/dl) from 2 consecutive samples taken no less than 1 week apart, with the difference between the 2 values not exceeding 15% of the higher value, and (2) mean TG value 4.52 mmol/l ( 400 mg/dl) from 2 consecutive samples taken no less than 1 week apart, with the upper value for either sample 5.0 mmol/l ( 450 mg/dl). Test Product Dose and Mode of Administration Lot Numbers Lapaquistat acetate Matching placebo 100 mg tablet, oral, QD tablet, oral, QD Z , Z Z , Z Reference Therapy Dose and Mode of Administration Lot Numbers Ezetimibe Matching placebo 10 mg capsule, oral, QD capsule, oral, QD , , Duration of Treatment: The treatment duration was 24 weeks, which followed a 6- to 7-week Run-in Period. Criteria for Evaluation: Efficacy: The primary efficacy variable was fasting plasma direct LDL-C concentration based on direct measurement. The secondary efficacy variables were the fasting plasma concentrations of calculated LDL-C, non HDL-C (derived as TC minus HDL-C), TC, Apo B, TG, HDL-C, Apo A1, VLDL-C, derived ratios (TC/HDL-C, LDL-C/HDL-C, and Apo B/Apo A1), high-sensitivity C-reactive protein (hs-crp), and the proportion of subjects who achieved direct fasting plasma LDL-C concentrations of <3.37 and <2.59 mmol/l (<130 and <100 mg/dl) at the Week 24 (or early withdrawal) Visit.

4 Safety: Safety variables included adverse events, clinical laboratory results (chemistry, hematology, and urinalysis), physical examination findings, ECG assessments, BCVA results, and vital signs. 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. For the primary treatment comparison, a sequential test of superiority first and noninferiority of lapaquistat acetate 100 mg vs ezetimibe 10 mg was performed. If the upper limit of the 95% confidence interval (CI) for the difference in least square (LS) treatment means (lapaquistat acetate 100 mg minus ezetimibe 10 mg) was less than zero, superiority of lapaquistat acetate 100 mg over ezetimibe 10 mg was claimed. If the upper limit of the 95% CI was less than or equal to the noninferiority margin of 3%, then noninferiority of lapaquistat acetate 100 mg to ezetimibe 10 mg was claimed. 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, using ANCOVA models similar to the model used in the primary analysis. For TG, additional analysis was performed using the Wilcoxon rank-sum test; treatment differences in median percent change from Baseline and 95% confidence intervals were calculated based on the Hodges-Lehmann method and a distribution-free confidence interval method. For hs-crp, treatment differences in median change from Baseline and 95% confidence intervals were calculated based on the Hodges- Lehmann method and a distribution-free confidence interval method. Treatment groups were compared with an ANCOVA model using Tukey normalized ranks. The proportions of subjects who achieved LDL-C concentrations of <3.37 and <2.59 mmol/l (<130 and <100 mg/dl) at Week 24 (or time of early withdrawal) were summarized; no formal statistical analysis was performed. Numbers of subjects reaching LDL-C goals at the Final Visit determined with a risk-based algorithm devised by the National Cholesterol Education Program (NCEP) were also analyzed using a logistic regression model with terms for treatment, risk category, and Baseline LDL-C. Additional post hoc analyses of the primary and secondary efficacy variables were conducted within subgroups of subjects with Baseline TG values above and above mmol/l (150 and 200 mg/dl). 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: There were 1267 subjects randomized to treatment: 562 in the lapaquistat acetate 100 mg group, 564 in the ezetimibe 10 mg group, and 141 in the lapaquistat acetate/ezetimibe coadministration group. A total of 1096 subjects completed the study, 167 subjects (14.1% receiving lapaquistat acetate 100 mg, 11.5% receiving ezetimibe 10 mg, and 16.3% receiving lapaquistat acetate/ezetimibe coadministration) prematurely discontinued the study, and 4 subjects failed to receive study drug (1 in the lapaquistat acetate 100 mg group and 3 in the ezetimibe 10 mg group). The most common reasons for discontinuation were adverse events and voluntary withdrawal. All subjects were White, and the study population was predominantly female (63.1%), with a mean age of 55.4 years. There were no important differences between treatment groups in any of the Baseline demographic characteristics or Baseline efficacy parameters.

5 Efficacy Results: Summary of Primary and Secondary Lipid Variables: Change From Baseline at Week 24 (LOCF) % Change From Baseline, LS Mean (SE) LAP 100 mg/ Variable LAP 100 mg (n=561) Ezetimibe 10 mg (n=561) Ezetimibe 10 mg (n=141) Difference Between LAP and Ezetimibe (95% CI) Direct LDL-C (0.626) (0.627) (1.247)* (-5.99, -2.52) Calculated LDL-C (0.638) (0.638) (1.273)* (-5.99, -2.45) Non HDL-C (0.601) (0.600) (1.199)* (-5.78, -2.45) TC (0.481) (0.480) (0.959)* (-5.16, -2.50) Apo B (0.610) (0.610) (1.217)* (-6.49, -3.11) TG (a) * (-8.04, -1.66) P=0.003 HDL-C 1.74 (0.626) 3.79 (0.624) 3.05 (1.247) (-3.79, -0.32) P=0.020 Apo A (0.520) 6.63 (0.520) 7.07 (1.037) (-2.73, 0.16) P=0.082 VLDL-C (1.345) (1.344) (2.681)* (-8.30, -0.84) P=0.016 *P<0.05 vs lapaquistat acetate 100 mg and ezetimibe 10 mg. (a) For TG, changes from Baseline are medians, not means. LAP = lapaquistat acetate. The efficacy results for the primary and main secondary variables are presented in the above table. In addition, in direct LDL-C reductions, the difference between lapaquistat acetate 100 mg and ezetimibe 10 mg was statistically significant at all visits throughout the 24-week Treatment Period. In subgroup analyses of the primary variable, all differences between lapaquistat acetate 100 mg and ezetimibe 10 mg were statistically significant in subgroups based on age, body mass index, Baseline TG value, and among female subjects. All differences between lapaquistat acetate/ezetimibe coadministration and either monotherapy were highly statistically significant. Of subjects with a Baseline direct LDL-C value 3.37 mmol/l, 59.7% of lapaquistat acetate 100 mg subjects achieved levels below 3.37 mmol/l by the Week 24 (or early withdrawal) Visit, compared with 46.1% of ezetimibe 10 mg subjects. Of this same subgroup, 16.7% of lapaquistat acetate 100 mg subjects and 5.8% of ezetimibe 10 mg subjects achieved levels below 2.59 mmol/l by the Week 24 (or early withdrawal) Visit. Corresponding proportions of subjects in the lapaquistat acetate/ezetimibe coadministration group were 86.3% and 60.4%, respectively. Of subjects above their target LDL-C level at Baseline based on risk-modified NCEP criteria, 67.3% of those receiving lapaquistat acetate 100 mg, 58.8% receiving ezetimibe 10 mg, and 88.9% receiving lapaquistat acetate/ezetimibe coadministration were below the goal at the Final Visit. In this analysis, the difference between lapaquistat acetate 100 mg and ezetimibe 10 mg was statistically significant. In the lipid ratios LDL-C/HDL-C, TC/HDL-C, and Apo B/Apo A1, reductions seen with lapaquistat acetate 100 mg were statistically significantly larger than those with ezetimibe 10 mg at all time points. The largest reductions were seen with lapaquistat acetate/ezetimibe coadministration. Median hs-crp changes at Week 24 were % for lapaquistat acetate 100 mg, 0.00% for ezetimibe 10 mg, and % for lapaquistat acetate/ezetimibe

6 coadministration. The differences between lapaquistat acetate and ezetimibe monotherapy were statistically significant at all post-baseline visits. Results of post hoc analyses of primary and secondary efficacy variables in subgroups of subjects with Baseline TG values above and above mmol/l were similar to those of the main analyses. Safety Results: Of the 1267 subjects enrolled in this study, 1263 were exposed to study drug. A total of 438 subjects (34.7%) experienced an adverse event during the study (36.5% of lapaquistat acetate subjects, 32.8% of ezetimibe subjects, and 34.8% of lapaquistat acetate/ezetimibe coadministration subjects). Adverse events considered possibly, probably, or definitely related to study drug occurred in 214 subjects (16.9%): 19.4% of lapaquistat acetate 100 mg subjects, 13.2% of ezetimibe 10 mg subjects, and 22.0% of lapaquistat acetate/ezetimibe coadministration subjects. Twenty-four subjects (1.9%) experienced a severe event (2.1%, 1.6%, and 2.1% of subjects in the lapaquistat acetate 100 mg, ezetimibe 10 mg, and lapaquistat acetate/ezetimibe coadministration groups, respectively). Adverse events that occurred in at least 3% of subjects in any treatment group were nausea, nasopharyngitis, increased ALT, and increased AST. Two subjects died during the study, 1 of glioblastoma multiforme and 1 of colon carcinoma; the events leading to death occurred too soon after the beginning of study medication to suggest a possible effect of lapaquistat acetate. Twenty-five subjects (12 lapaquistat acetate 100 mg, 9 ezetimibe 10 mg, and 4 lapaquistat acetate/ezetimibe coadministration) experienced a total of 31 treatment-emergent serious adverse events, and all but 8 of these events were judged by the investigator to be not related to study drug. There were 93 subjects (54 [9.6%] of lapaquistat acetate 100 mg subjects, 22 [3.9%] of ezetimibe 10 mg subjects, and 17 [12.1%] of lapaquistat acetate/ezetimibe coadministration subjects) who either withdrew from the study (79 subjects) or temporarily discontinued study drug (14 subjects) because of an adverse event. Elevations in liver function values, and adverse events representing such elevations, occurred at higher incidences with lapaquistat acetate 100 mg and lapaquistat acetate/ezetimibe coadministration than with ezetimibe 10 mg. ALT elevations to >3xULN at consecutive visits occurred in 16 (2.9%) subjects receiving lapaquistat acetate 100 mg, 4 (0.7%) subjects receiving ezetimibe 10 mg, and 10 (7.1%) subjects receiving lapaquistat acetate/ezetimibe coadministration. No pattern of time to onset was evident, and none of the elevations was accompanied by increases in bilirubin. Most of the subjects experiencing such elevations withdrew from the study. In all cases where subsequent values were available, the elevations resolved either to the normal range or to 3xULN or below. Five subjects, 2 (0.4%) receiving lapaquistat acetate 100 mg and 3 (2.1%) receiving lapaquistat acetate/ezetimibe coadministration, had ALT elevations above 10xULN at least once during the study. No subject receiving lapaquistat acetate 100 mg experienced a CPK elevation to >10xULN. One subject in the ezetimibe 10 mg group experienced an elevation of CPK to 1783 IU/L on Day 1, before taking the first dose of study medication. No other CPK value >10xULN was seen in this study. Sixteen subjects had CPK elevations that were reported as adverse events: 7 (1.2%) lapaquistat acetate 100 mg subjects, 6 (1.1%) ezetimibe 10 mg subjects, and 3 (2.1%) lapaquistat acetate/ezetimibe coadministration subjects. Two of these elevations, both in the lapaquistat acetate 100 mg group, led to the subject s withdrawal. Thirteen subjects (8 [1.4%] lapaquistat acetate 100 mg, 2 [0.4%] ezetimibe 10 mg, and 3 [2.1%] lapaquistat acetate/ezetimibe coadministration) had muscle-related adverse events that led to withdrawal. There were no major findings in hematology, urinalysis, vital signs, ECGs, physical examination, or BCVA results.

7 CONCLUSIONS: Administration of lapaquistat acetate 100 mg QD for 24 weeks was consistently more effective than ezetimibe 10 mg QD in reducing LDL-C levels in subjects with primary dyslipidemia. Statistically significant differences in favor of lapaquistat acetate were seen in effects on mean direct and calculated LDL-C, non HDL-C, TC, Apo B, and VLDL-C; median hs-crp and TG; and all of the lipid ratios. Throughout the efficacy variables, coadministration of the 2 agents together provided significant additive effects over either monotherapy. In this study, lapaquistat acetate and ezetimibe, and the coadministration of both therapies, were generally safe and well tolerated. However, hepatic enzyme elevations and adverse events representing such elevations occurred at higher incidences in the coadministration group than with either monotherapy. Date of Report: 26 February 2008