1. Slide 1 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Factorial Coadministration Studies

2. Slide 2 Downloaded from www.ezetrol.aewww.ezetrol.ae Rationale for Coadministration of Ezetimibe and Statins Cholesterol homeostasis depends on the balance between cholesterol biosynthesis and cholesterol absorption Statins primarily affect hepatic production of cholesterol by blocking HMG CoA reductase –Reduces hepatic stores –Leads to up-regulation of LDL receptors and removal of cholesterol from circulation –Enterohepatic recirculation of cholesterol into the bile with transport to the intestine Ezetimibe inhibits intestinal absorption of cholesterol –Reduces amount of cholesterol delivered to the liver –Leads to up-regulation of LDL receptors, facilitating removal of cholesterol from circulation Dual inhibition of cholesterol absorption and synthesis by coadministration of ezetimibe and statins provides greater LDL-C lowering efficacy than inhibition of either pathway alone

3. Slide 3 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Factorial Coadministration Studies Four multicenter, randomized, double-blind, placebo-controlled trials Entry criteria –LDL-C 145–250 mg/dl (3.75–6.50 mmol/L) –Triglycerides  350 mg/dl (4.00 mmol/L) Design –2- to 12-week screening phase: washout of lipid-modifying therapy, NCEP Step I diet –4-week prerandomization phase: placebo run-in, NCEP Step I diet –12-week double-blind phase: treatment with ezetimibe alone, statin alone, or coadministration of ezetimibe with a statin Adapted from Ballantyne CM et al Circulation 2003;107:2409–2415; Davidson MH et al J Am Coll Cardiol 2002;40:2125–2134; Melani L et al Eur Heart J 2003;24:717–728,1381; Kerzner B et al Am J Cardiol 2003;91:418–424.

4. Slide 4 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Coadministration Studies: Factorial Design *Only atorvastatin and simvastatin were given in an 80 mg dose. Adapted from Ballantyne CM et al Circulation 2003;107:2409–2415; Davidson MH et al J Am Coll Cardiol 2002;40:2125–2134; Melani L et al Eur Heart J 2003;24:717–728,1381; Kerzner B et al Am J Cardiol 2003;91:418–424. Placebo Ezetimibe 10 mg StatinStatinStatinStatin Placebo 10 mg20 mg40 mg80 mg* Statins: atorvastatin,* simvastatin,* pravastatin, and lovastatin >2300 patients; ~65 patients per group Primary endpoint: % reduction from baseline in LDL-C –Pooled statin alone vs. pooled ezetimibe + statin –Pairwise comparisons between treatment groups

5. Slide 5 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Coadministered with Atorvastatin

6. Slide 6 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Coadministered with Atorvastatin: Pooled Results for LDL-C *p<0.01 coadministration therapy vs. statin alone Adapted from Ballantyne CM et al Circulation 2003;107:2409–2415. –50 –40 –30 –20 –10 0 Mean % change in calculated LDL-C from baseline at 12 weeks Atorvastatin (10–80 mg) (n=248) 4.69 mmol/L Ezetimibe + atorvastatin (10–80 mg) (n=255) 4.70 mmol/L Baseline LDL-C –56.3 –44.2 –12.1%* Pooled doses –60

7. Slide 7 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Coadministered with Atorvastatin: LDL-C Lowering Efficacy Adapted from Ballantyne CM et al Circulation 2003;107:2409–2415. 10 mg Ezetimibe 10 mg + atorvastatin 10 mg 80 mg40 mg20 mg Atorvastatin –50 –40 –30 –20 –10 0 –60 –54 –45 –42 –37 –53 Mean % change in calculated LDL-C from baseline at 12 weeks p<0.01

8. Slide 8 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Coadministered with Atorvastatin: LDL-C Lowering Efficacy *p<0.01 coadministration vs. statin alone Adapted from Ballantyne CM et al Circulation 2003;107:2409–2415. Mean % change in calculated LDL-C from baseline at 12 weeks –50 –40 –30 –20 –10 0 –70 Ezetimibe + atorvastatin 10 mg (n=65) Atorvastatin 10 mg (n=60) Ezetimibe + atorvastatin 20 mg (n=62) Atorvastatin 20 mg (n=60) Ezetimibe + atorvastatin 80 mg (n=63) Atorvastatin 80 mg (n=62) Ezetimibe + atorvastatin 40 mg (n=65) Atorvastatin 40 mg (n=66) –53* –37 –54* –42 –61* –54 –56* –45 –60

9. Slide 9 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Coadministered with Atorvastatin: Pooled Results for LDL-C, TG, and HDL-C *Calculated LDL-C **Median % changes shown ***p<0.01 coadministration vs. statin alone Adapted from Ballantyne CM et al Circulation 2003;107:2409–2415. –56* 7*** –44 4 –24 –33* Mean % change from baseline at 12 weeks LDL-C*HDL-CTG** –60 –50 –40 –30 10 0 20 –20 –10 Atorvastatin (n=248) Ezetimibe + atorvastatin (n=255)

10. Slide 10 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Coadministered with Simvastatin

11. Slide 11 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Coadministered with Simvastatin: Pooled Results for LDL-C –60 –40 –30 –20 –10 0 Mean % change in calculated LDL-C from baseline at 12 weeks Simvastatin (10–80 mg) (n=263) 4.66 mmol/L Ezetimibe + simvastatin (10–80 mg) (n=274) 4.60 mmol/L Baseline LDL-C –51.3 –36.5 –14.8%* Pooled doses *p<0.01 coadministration vs. statin alone Adapted from Davidson MH et al J Am Coll Cardiol 2002;40:2125–2134. –50

12. Slide 12 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Coadministered with Simvastatin: LDL-C Lowering Efficacy Adapted from Davidson MH et al J Am Coll Cardiol 2002;40:2125–2134. –46 –45 –27 –37 –38 Mean % change in calculated LDL-C from baseline at 12 weeks 10 mg Ezetimibe 10 mg + simvastatin 10 mg 80 mg40 mg20 mg Simvastatin –50 –40 –30 –20 –10 0 –60 p<0.01

13. Slide 13 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Coadministered with Simvastatin: LDL-C Lowering Efficacy *p<0.01 coadministration vs. statin alone Adapted from Davidson MH et al J Am Coll Cardiol 2002;40:2125–2134. Mean % change in calculated LDL-C from baseline at 12 weeks –50 –40 –30 –20 –10 0 –60 Ezetimibe + simvastatin 10 mg (n=67) Simvastatin 10 mg (n=70) Ezetimibe + simvastatin 20 mg (n=69) Simvastatin 20 mg (n=61) Ezetimibe + simvastatin 80 mg (n=65) Simvastatin 80 mg (n=67) Ezetimibe + simvastatin 40 mg (n=73) Simvastatin 40 mg (n=65) –46* –27 –46* –37 –58* –45 –56* –38

14. Slide 14 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Coadministered with Simvastatin: Pooled Results for LDL-C, TG, and HDL-C *Calculated LDL-C **p<0.01 coadministration vs. statin alone ***p=0.03 coadministration vs. statin alone Adapted from Davidson MH et al J Am Coll Cardiol 2002;40:2125–2134. –51* 9*** –37 7 –17 –24** Mean % change from baseline at 12 weeks Simvastatin (n=263) Ezetimibe + simvastatin (n=274) –60 –50 –40 –30 10 0 20 –20 –10 LDL-C*HDL-CTG

15. Slide 15 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Coadministered with Simvastatin: Effect on CRP *p<0.01 coadministration vs. statin alone **p<0.05 coadministration vs. statin alone ***p=0.09 coadministration vs. statin alone CRP=C-reactive protein Adapted from Sager P et al Am J Cardiol 2003;92:1414–1418. Median % change from baseline at 12 weeks (n=227)(n=232) 10 mg (n=57) (n=62) 20 mg (n=54) 20 mg (n=55) –35* –18 –27** –12 –40** –24 –31*** –13 –20 –10 0 10 20 –40 –30 (n=54) 10 mg (n=57) 40 mg (n=60) 80 mg (n=54) 80 mg (n=60) 40 mg (n=62) Simvastatin Placebo Ezetimibe Ezetimibe + simvastatin –36** –29 1 12 PooledIndividual Dose Groups

16. Slide 16 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Coadministered with Pravastatin

17. Slide 17 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Coadministered with Pravastatin: Pooled Results for LDL-C –45 –20 –15 –10 –5 0 Mean % change in calculated LDL-C from baseline at 12 weeks Pravastatin (10–40 mg) (n=205) 4.6 mmol/L Ezetimibe + pravastatin (10–40 mg) (n=204) 4.6 mmol/L Baseline LDL-C –38.6 –25.2 –13.4%* Pooled doses *p<0.01 coadministration vs. statin alone Adapted from Melani L et al Eur Heart J 2003;24:717–728,1381. –25 –35 –30 –40

18. Slide 18 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Coadministered with Pravastatin: LDL-C Lowering Efficacy Adapted from Melani L et al Eur Heart J 2003;24:717–728,1381. –34 –31 Mean % change in calculated LDL-C from baseline at 12 weeks –21 10 mg Ezetimibe 10 mg + pravastatin 10 mg 40 mg –23 20 mg Pravastatin –50 –40 –30 –20 –10 0 –60 p<0.01

19. Slide 19 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Coadministered with Pravastatin: LDL-C Lowering Efficacy *p<0.01 coadministration vs. statin alone Adapted from Melani L et al Eur Heart J 2003;24:717–728,1381. Mean % change in calculated LDL-C from baseline at 12 weeks –40 –30 –20 –10 0 –60 Ezetimibe + pravastatin 10 mg (n=71) Pravastatin 10 mg (n=66) Ezetimibe + pravastatin 20 mg (n=66) Pravastatin 20 mg (n=69) Ezetimibe + pravastatin 40 mg (n=67) Pravastatin 40 mg (n=70) –34* –21 –40* –23 –42* –31 –50

20. Slide 20 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Coadministered with Pravastatin: Pooled Results for LDL-C, TG, and HDL-C *p<0.01 coadministration vs. statin alone Adapted from Davidson MH et al J Am Coll Cardiol 2002;40:2125–2134. –39* 8 –25 7 –8 –18* Mean % change from baseline at 12 weeks Pravastatin (n=205) Ezetimibe + pravastatin (n=204) –40 –30 0 10 –20 –10 Calculated LDL-C HDL-CTG

21. Slide 21 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Coadministered with Statins

22. Slide 22 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Coadministered with Statins: Efficient Control of LDL-C One-step coadministration of ezetimibe similar to doubling the statin dose 3 times Adapted from Stein E Eur Heart J Suppl 2001;3(suppl E):E11-E16. 060 The “rule of 6” One-step coadministration Statin 10 mg + Ezetimibe 10 mg 50 +6% 302010 20 mg 40 mg 80 mg % Reduction in LDL-C +6% +25% 40

23. Slide 23 Downloaded from www.ezetrol.aewww.ezetrol.ae *p<0.01 ezetimibe + pooled statin doses vs. pooled statin doses alone Adapted from Ballantyne CM et al Circulation 2003;107:2409–2415; Davidson MH et al J Am Coll Cardiol 2002;40:2125–2134; Melani L et al Eur Heart J 2003;24:717–728,1381; Kerzner B et al Am J Cardiol 2003;91:418–424. Ezetimibe Coadministered with Statins: Results for LDL-C Mean % change in calculated LDL-C from baseline at 12 weeks –60 –50 –40 –20 0 Ezetimibe 10 mg + atorvastatin (n=255) Atorvastatin (n=248) Ezetimibe 10 mg + simvastatin (n=274) Simvastatin (n=263) Ezetimibe 10 mg + lovastatin (n=192) Lovastatin (n=220) Ezetimibe 10 mg + pravastatin (n=204) Pravastatin (n=205) –56* –44 –51* –37 –40* –25 –39* –25 –30 –10

24. Slide 24 Downloaded from www.ezetrol.aewww.ezetrol.ae *p<0.01 ezetimibe + pooled statin doses vs. pooled statin doses alone; **p=0.03 ezetimibe + pooled statin doses vs. pooled statin doses alone Adapted from Ballantyne CM et al Circulation 2003;107:2409–2415; Davidson MH et al J Am Coll Cardiol 2002;40:2125–2134; Melani L et al Eur Heart J 2003;24:717–728,1381; Kerzner B et al Am J Cardiol 2003;91:418–424. Ezetimibe Coadministered with Statins: Results for HDL-C Ezetimibe 10 mg + atorvastatin (n=255) Atorvastatin (n=248) Ezetimibe 10 mg + simvastatin (n=274) Simvastatin (n=263) Ezetimibe 10 mg + lovastatin (n=192) Lovastatin (n=220) Ezetimibe 10 mg + pravastatin (n=204) Pravastatin (n=205) Mean % change in HDL-C from baseline at 12 weeks 2 4 6 8 10 0 4 7* 9** 7 9* 4 8 7

25. Slide 25 Downloaded from www.ezetrol.aewww.ezetrol.ae *Median change; **p<0.01 ezetimibe + pooled statin doses vs. pooled statin doses alone Adapted from Ballantyne CM et al Circulation 2003;107:2409–2415; Davidson MH et al J Am Coll Cardiol 2002;40:2125–2134; Melani L et al Eur Heart J 2003;24:717–728,1381; Kerzner B et al Am J Cardiol 2003;91:418–424. Ezetimibe Coadministered with Statins: Results for TG Mean % change in TG from baseline at 12 weeks –35 –30 –25 –20 –10 0 Ezetimibe 10 mg + atorvastatin (n=255) Atorvastatin (n=248) Ezetimibe 10 mg + simvastatin (n=274) Simvastatin (n=263) Ezetimibe 10 mg + lovastatin (n=192) Lovastatin (n=220) Ezetimibe 10 mg + pravastatin (n=204) Pravastatin (n=205) –33*, ** –25* –24** –17 –22** –11 –18** –8–8 –15 –5–5

26. Slide 26 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Coadministered with Statins: Tolerability and Safety Profile Tolerability profile of ezetimibe + statin similar to that of statin alone Tolerability profile of ezetimibe monotherapy similar to that of placebo No increased risk of hematologic or blood chemistry abnormalities over statin alone No clinically significant ezetimibe–statin pharmacokinetic interactions Ezetimibe PlaceboEzetimibeStatin+ statin (n=259)(n=262)(n=936)(n=925) Treatment-related AE (%)18.115.616.919.5 Discontinuation due to 3.9 2.7 2.5 3.7 treatment-related AE (%) Serious treatment-related AE (%)0 0.4 0.1 1.1 AE=adverse event Adapted from Kosoglou T et al. Presented at the European Atherosclerosis Society Meeting, 2004; Summary of Product Characteristics, EZETROL TM, MSP; Data from Registration File, MSP.

27. Slide 27 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Coadministered with Statins: Pooled Safety Data *All asymptomatic and reversible with drug continuation or discontinuation ULN=upper limit of normal; ALT=alanine aminotransferase; AST=aspartate aminotransferase; GGT=gamma-glutamyl transpeptidase; CPK=creatine phosphokinase Adapted from Data from Registration File, MSP. Ezetimibe Placebo 10 mg Statin + statin (n=259) (n=262) (n=936) (n=925) Liver function tests (  3  ULN)* ALT, %—total 0 0 0.4 1.3 ALT, %—normal baseline 0 0 0.30.4 AST, % 0 0 0.3 0.5 GGT, % 1 3.5 3 3.6 CPK (  10  ULN), % 0 0 <1 0 Myalgia, % 5 5 4 4.5

28. Slide 28 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Coadministered with Statins: Summary Coadministration of ezetimibe and a statin for dual inhibition of cholesterol absorption and synthesis provides greater LDL-C lowering than a statin alone –Coadministration of ezetimibe with each statin dose provided significantly greater reductions in LDL-C than the corresponding statin dose alone (p<0.01) Coadministration of ezetimibe and a statin also improves HDL-C and TG –7%–9% increase in HDL-C –18%–33% reduction in TG Coadministration of ezetimibe and a statin is well tolerated –Safety profile comparable to statin therapy alone Adapted from Ballantyne CM et al Circulation 2003;107:2409–2415; Davidson MH et al J Am Coll Cardiol 2002;40:2125–2134; Melani L et al Eur Heart J 2003;24:717–728,1381; Kerzner B et al Am J Cardiol 2003;91:418–424.

29. Slide 29 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe: Dosage and Administration Recommended ezetimibe dosage: 10 mg once daily, coadministered with a statin or as monotherapy –No dosage adjustment required in children and adolescents  10 years or in the elderly May be taken at any time of day, with or without food May be taken at same time as statin Adapted from Summary of Product Characteristics, EZETROL TM, MSP.

30. Slide 30 Downloaded from www.ezetrol.aewww.ezetrol.ae References Please see notes page

31. Slide 31 Downloaded from www.ezetrol.aewww.ezetrol.ae Ezetimibe Factorial Coadministration Studies Before prescribing, please consult the manufacturers’ prescribing information. MSP does not recommend the use of any product in any different manner than as described in the prescribing information. Copyright © 2004 MSP Singapore Company, LLC. All rights reserved.6-05 EZT 2004-W-6159-SSPrinted in USA VISIT US ON THE WORLD WIDE WEB AT http://www.ezetrol.com