1. De-risking the development programs of CETP inhibitors after the torcetrapib failure: Endothelial function & blood pressure Prof. John Deanfield University College London United Kingdom

2. HDL : a novel target in prevention ? HDL

3. Relationship Between Changes in LDL-C and HDL-C Levels and CHD Risk Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm 1% decrease in LDL-C reduces CHD risk by 1% 1% increase in HDL-C reduces CHD risk by 3%

4. The Emerging Risk Factors Collaboration. JAMA 2009;302:1993-2000 Coronary Heart Disease and HDL-C0.8 1.0 1.5 2.0 2.5 3.0 3.5 Hazard Ratio 406080 HDL-C (mg/dL) N = 302,430 305070

5. Reduced HDL is associated with increased CV risk – despite intense statin therapy Barter P N Engl J Med 2007; 357: 1301-10 Quintile of HDL-C level (mg/dL) Q1 (<37) Q2 (37 to <42) Q3 (42 to <47) Q4 (47 to <55) Q4 (≥55) 0 1 2 3 4 5 6 7 8 9 10 5-yr risk of major CV events (%)

6. ApoAI upregulation hyperTGemia Omega-3 FAs Reconstituted apoAI/HDL ; HDL delipidation pre-β HDL HDL apoCIII ABCA1 induction / LXR agonists HDL-Raising Therapies on the Horizon sPLA2 HL EL LCAT SR-B1 ApoAI upregulation ApoAI mimetics Niacin analogues CETP Inhibitors PPAR agonists apoAII apoE

7. Schematic Overview of Lipoprotein Metabolism Courtesy of Brian Brewer

8. Torcetrapib in High-risk Patients : ILLUMINATE Study Barter PJ: NEJM 2008 -30 -20 -10 0 10 20 30 40 50 60 70 80 TC HDL LDL * * * % change 0180360540720 Atorvastatin Atorvastatin + Torcetrapib p=0.001 Days 100 98 96 94 92 90 0 without an event (%) CV Events Lipid Levels

9. Torcetrapib causes Endothelial Dysfunction independent of CETP inhibition Connelly J Cardiovasc Pharmacol 2010 55; 459-468 Arterial diameter (mm) 1. 0 0. 9 0. 8 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 BLBL Post NE 1017 30 56 15 min post Acetylcholine infusions (µg/min for 15 min) Vehicle Torcetrapib, 30 mg/kg x 4d Torcetrapib 2-wk washout

10. CETP Inhibition and Endothelial Function FMD (%) HDL-C <1.19 mmol/L HDL-C >1.19 mmol/L Dalcetrapib 600 mg Placebo Total population Dalcetrapib-treated patients by baseline HDL- C 0 1 2 3 4 BL +2 +4 weeks BL +2 +4 weeks 0 1 2 3 4 5 FMD (%) Herman Thrombosis Research 2009 123 460-465

11. dal-VESSEL : Study Design ; 27:141-150 Placebo Randomisation FMD, ABPM 36 weeks FMD, ABPM Dalcetrapib 600 mg Pre- randomisatio n phase 8 weeks 476 patients randomised 4 weeks ABPM 12 weeks FMD, ABPM Double-blind randomised, placebo-controlled, parallel-group multicentre FMD/ABPM study in patients with CHD or CHD-risk equivalent

14.  Firm epidemiological link to CV outcome  Exciting therapeutic opportunity  HDL is complex particle with multiple functions  First CETP inhibitor Torcetrapib caused increased mortality  Current trials will define clinical role for HDL elevation HDL as a Therapeutic Target