New Approaches to LDL Reduction

1. New Approaches to LDL Reduction Cholesterol Absorption Inhibitors

2. Liversynthesis Inhibition of Cholesterol Absorption and Production With Ezetimibe/Simvastatin Simvastatin Ezetimibe 1000 mg/day Dietarycholesterol ~300 mg/day–700 mg/day Biliary cholesterol ~1000 mg/day Intestine Extrahepatictissues Absorption Excretion

3. Cholesterol Balance in Mice (µmol/day.100 g body wt) Liver Peripheral cells 5 VLDL LDL Forward pathway LDL Reverse pathway Bile HDL 4 2 5 Feces Diet 10 7 Duodenum Jejunum Ileum

4. Ezetimibe Ezetimibe Ezetimibe Ezetimibe Control Control Control Control Ezetimibe strongly increases TICE bile TICE (re)absorption Feces Diet Control + Ezetimibe

5. Liver Peripheral cells 300 Cholesterol Fluxes in Humans(mg/day.70 kg body wt) VLDL LDL Forward pathway LDL Reverse pathway Bile HDL 700 1000 700 Feces Diet 1000 400 Duodenum Jejunum Ileum

6. Next Steps • Assessment of direct intestinal cholesterol excretion in vivo in humans. • Determine the contribution of TICE in low and high absorbers • Test the effect of pharmacologicalmanipulation in humans.

7. Cholesterol AbsorptionInhibitorsLower LDL-C and that is Enough in Itself

8. ENHANCE

9. ENHANCE - LogicalNext Step After ASAP - Timeline 1995 2000 2005 2010 ENHANCE LIPID (pediatric) ASAP Simvastatin 80 mg + Ezetimibe 10 mg Versus Simvastatin 80 mg Pravastatin 20-40 mg Versus Placebo Atorvastatin 80 mg Versus Simvastatin 40 mg Wiegman et al, Efficacy and Safety of Statin Therapy in ChildrenWith FH. JAMA 2004; 292(3):331-7 Smilde et al, Atorvastatin versus SimvastatinonAtheroscleroticProgressionstudy. Lancet 2001;357:577-81

10. ENHANCE Study Population Major inclusion criteria Major exclusion criteria • HeFH: • Genotyping • Diagnostic criteria WHO • Age 30-75 years • Untreated LDL-C levels > 210 mg/dL • (5.43 mmol/l) • Patients on lipid-lowering treatment • LDL-c after wash –out > 210 mg/dL • (5.43 mmol/l) • High-grade carotid stenosis • History carotid endarterectomy • Carotid stenting • Congestive heart failure III/IV NO MINIMAL CAROTID IMT ENTRY CRITERIA Kastelein et al, ENHANCE NEJM 2008;358 ;1431-43

11. ENHANCE Study Design Pre-randomization Phase RANDOMI ZAT I ON FH: LDL-c ≥ 210 mg/dL Placebo Lead-In/ Drug Washout Screening and Fibrate Washout Simvastatin 80 mg Ezetimibe 10 mg-Simvastatin 80 mg IMT assessment -6 -10 to -7 0 21 24 3 18 15 6 9 12 Weeks Months

12. Baseline Characteristics Kastelein et al, ENHANCE NEJM 2008;358 ;1431-43

13. Decrease(%) -40% Simva -56% Eze-Simva LDL-Cholesterol 10 0 -10 -20 P<0.01 -30 Percentage change from baseline -40 -16.5 % incremental reduction -50 -60 -70 0 6 24 18 12 Months Kastelein et al, ENHANCE NEJM 2008;358 ;1431-43

14. ENHANCEhsCRP 10 0 p < 0.01 Simva -10 Eze-Simva -20 Median percent change from Baseline -30 -26 % incremental reduction -40 -50 -60 -70 -80 12 6 18 3 24 Months

15. Mean cIMT During 24 Months of TherapyLongitudinal, Repeated Measures Analysis 0.80 Simva Eze-Simva 0.75 P=0.88 Mean IMT (mm) 0.70 0.65 0.60 12 18 6 24 Months Kastelein et al, ENHANCE NEJM 2008;358 ;1431-43

16. PossibleExplanationsfor the Absence of an Incremental Reduction in cIMT • Measurement Technique • Technique not accurate enough to reflect changes in atherosclerotic burden? • The Compound • Ezetimibe lacks vascular benefit despite the observed LDL-c and hsCRP reduction • The Population • At too low a risk to detect changes, which would limit the ability to detect a differential response

17. The Trial Design and Population To have any chance of success using cIMT to demonstrate that one treatment is better than another one of two critical factors must be present – preferably both: • The ‘control’ group must show significant progression – if not then only significant regression in the ‘test’ group can result in a positive trial • The population studied must have significant and quantifiable lipid rich intima – if minimal or no significant atherosclerosis is present then only possible change to be assessed is progression

18. P <0.05 ASAP Simva LDLc -40% Atorva LDLc -52% Critical Factors for Successful cIMT Trial ASAP - 1997 0.95 progression progression 0.90 0.85 cIMT mm 0.80 0.75 0.70 Simva/Control progressed; atorva/Test stable/regressed SUCCESS!! 0.65 regression regression 0 1 2 years

19. ASAP - 1997 0.95 ASAP progression 0.90 Simva LDLc -40% Atorva LDLc -52% 0.85 ENHANCE cIMT mm 0.80 Simva LDLc -40% Simva/Eze LDLc -57% 0.75 ENHANCE - 2003 P= ns 0.70 0.65 regression 0 1 2 years Critical Factors for Successful cIMT Trial progression regression

20. ASAP and ENHANCEBaseline cIMT in LIPID (Pediatric) ASAP ENHANCE LIPID (pediatric) Frequency 0.4 2.4 0.8 1.2 1.6 2.0 Mean CIMT (mm)

21. WhatAbout the Trial IndicatingPotential Harm fromIncreased CVD Events? • Although ENHANCE was a relatively small trial in low risk FH patients was there any evidence from the CVD events that addition of ezetimibe caused harm? • Can one even pick up such a signal from such small trials as ENHANCE in this FH population?

22. CVD Events – Recent FH cIMT Trials:RADIANCE I (CETPi) and CAPTIVATE (ACATi) RADIANCE I CAPTIVATE `p<0.02 `p<0.05 Thus even small studies (700-900 patients) in FH appear to be able to detect potential CVD harm *Kastelein et al NEJM 2007; 356:1620-30 **Meuwese MC et al JAMA in press

23. Conclusion from ENHANCE While the results of ENHANCE have been less than optimal for the sponsors of the trial they actually carry very good news for those with FH, and all patients on long term lipid lowering therapy, in that the data would seem to strongly indicate that even moderate, long term LDLc lowering dramatically reduces the atherosclerotic burden, at least in carotid arteries, and virtually halts progression of the underlying disease.