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Pathway of Exogenous Cholesterol Metabolism

CE. Synthesis. Brush Border. ENTEROCYTE. FC biosynthesis. Cholesteryl Ester (CE). FC. ACAT. Pathway of Exogenous Cholesterol Metabolism. BILIARY TRACT. INTESTINAL LUMEN. Plaque formation. Bile acids. Free cholesterol. Remnants. DIET. Unstirred water layer. BLOOD.

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Pathway of Exogenous Cholesterol Metabolism

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  1. CE Synthesis Brush Border ENTEROCYTE FC biosynthesis Cholesteryl Ester (CE) FC ACAT Pathway of Exogenous Cholesterol Metabolism BILIARY TRACT INTESTINAL LUMEN Plaque formation Bile acids Free cholesterol Remnants DIET Unstirred water layer BLOOD Cholesterol CE Micelles Chylomicrons LYMPH

  2. Complementary Mechanisms of Action Lead to Broader Lipid Control VLDL IDL LDL Statins synthesis BILIARY SECRETION Absorption Cholesterol Absorption Inhibition INTESTINE Excretion DIETARY CHOLESTEROL

  3. Inhibition of Cholesterol Absorption

  4. Ezetimibe Phase III Pooled Monotherapy: Efficacy Results LDL-C HDL-C TG Placebo Placebo (n=409) Ezetimibe 10 mg (n=1234) Placebo (n=409) Ezetimibe 10 mg (n=1234) Placebo (n=409) Ezetimibe10 mg (n=1234) EZ 10 mg 3.5 0.3 1.0* 0 -5 -10 -15 -20 -1.6 Mean % Change in LDL from Baseline at Week 12 -4.2* -17.4* * p <0.01 vs. placebo

  5. Ezetimibe Phase III Monotherapy:Pooled Safety Results No. of Patients/Total (%) Placebo Ezetimibe (n=431) (n=1288) Adverse events 285 (66) 802 (62) Gastrointestinal 93 (22) 230 (18) DC 2° AE 11 (2.6) 51 (4) Liver function tests (3 x ULN) ALT 2 (<1) 7 (<1) AST 3 (<1) 6 (<1) GGT 10 (2) 20 (2) Total bilirubin 0 0 ALP 0 0 Creatine kinase (CK) elevations 5-10 x ULN 0 8 (<1) 10 x ULN 1 (<1) 3 (<1)

  6. Results: Added Efficacy Across the Lipid Profile Regardless of Statin Used * * ‡ * * * * * * * * Lovastatin Pravastatin Simvastatin Atorvastatin * *p<0.01 for EZE + statin vs statin alone; ‡p=0.22 for EZE + statin vs statin alone

  7. Ezetimibe Co-administered with Statins • Ezetimibe co-administered with low dose statins, offers broader lipid control than that achieved by increasing the dose of the statin alone Additional 5% 6% HDL–C TG 40% Additional -10% LDL–C 20% TG Additional -14 to 18 %

  8. Homozygous FH Study: Efficacy on LDL-C When Added to Ongoing 40 mg of Statin % Change From Baseline (Statin 40 mg) 14% 21% * * n=50 *P<0.01 vs statin 80 mg

  9. OH OH N F O F Structure of Ezetimibe (SCH 58235)

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