1. CETP inhibition: Where are we now? Prof. John Kastelein Academic Medical Centre Amsterdam, The Netherlands

2. Research contracts:None Consulting:Dezima Pharma, Eli Lilly, MSD, Roche, Boehringer Ingelheim, Novartis Employment in industry:None Stockholder of a healthcare company: Dezima Pharma, Vivus, Xenon Pharma, Uniqure Owner of a healthcare company:None Other:None Disclosure of Potential Conflicts of Interest

3. What do we know about the relationship between CETP and atherosclerosis?

4. Meta-analysis of studies investigating relationships between CETP polymorphisms and cardiovascular disease in humans. Meta-analysis of studies investigating relationships between CETP polymorphisms and cardiovascular disease in humans. 46 studies with data on 27,196 coronary cases and 55,338 controls. 46 studies with data on 27,196 coronary cases and 55,338 controls. Polymorphisms associated with lower CETP mass and lower CETP activity had higher HDL-C and a significantly reduced coronary risk. Polymorphisms associated with lower CETP mass and lower CETP activity had higher HDL-C and a significantly reduced coronary risk. Thompson et al JAMA2008;299:2777-2788 CETP Polymorphisms and Cardiovascular Risk in Humans

5. Torcetrapib CF 3 F3CF3CF3CF3C N O O N O O Dalcetrapib S O O HNHNHNHN Anacetrapib O F3CF3CF3CF3C O N O F3CF3CF3CF3C F CETP Inhibitors with Human Studies Evacetrapib Cao et al. J Lipid Res 2011; 52:2169

6. ILLUMINATE: Primary Endpoint: Time to First MACE: Kaplan-Meier Plot 090180270360450540630720810 Days from Randomization Event Free (%) 90 92 94 96 98 100 Atorvastatin events = 373 Torcetrapib/Atorvastatin events = 464 Hazard Ratio 1.25 P=0.001 Barter et al, NEJM 2007;357:2109

7. Reduced Cardiovascular Events with Increasing HDL-C with Torcetrapib HR for CHD Death or Non-fatal MI vs. Achieved Level of HDL-C Philip Barter Personal Communication

8. Dalcetrapib Inhibits CETP activity by about 50% Modest CETP inhibition produces a 30% increase in HDL-C with no effect on LDL-C Safety studies revealed no beneficial or adverse effect on endothelial function, plaque progression or plaque inflammation Luscher et al. European Heart J, 2012;33:857

9. 15,600 patients 4-12 weeks after an index ACS event Dal-Outcomes Trial Dalcetrapib 600 mg Statin therapy to reach optimal LDL-C level Placebo Primary End Point CHD death, non-fatal MI, atherothrombotic stroke, unstable angina requiring hospitalization or resuscitated cardiac arrest 2.5-year follow-up Schwartz et al. Am Heart J. 2009;158:896-901.

10. It was announced in early May 2012 that the dal-OUTCOMES trial had been terminated on the basis of futility. Dal-Outcomes Trial http://www.roche.com/media_releases/med-cor-2012-05-07.htm

11. Inhibiting CETP with a relatively weak inhibitor such as dalcetrapib may not be sufficient to have a favorable impact on CV events: Inhibiting CETP with a relatively weak inhibitor such as dalcetrapib may not be sufficient to have a favorable impact on CV events: − Only a 30% increase in HDL-C − No effect on LDL-C Why Did Dalcetrapib Fail to Reduce CV Events?

12. 1620 patients 1620 patients with CHD or CHD risk equivalents DEFINE trial Anacetrapib 100 mg Statin therapy to achieve LDL-C <100 mg/dL Placebo Primary End Point Lipid efficacy and the safety 76 week follow-up Cannon et al. Cannon et al. NEJM. 2010; 363:2406-2415

13. 0.51.01.5 Primary endpoint: MCVE Revascularization 0.751.25 CETP-I BetterCETP-I worse DEFINE trial (2010) N = 1,623 (anacetrapib) ILLUMINATE Trial (2007) N=15,067 (torcetrapib) Primary endpoint: MCVE Revascularization 0.25 ILLUMINATE Trial 2007 (torcetrapib) DEFINE Trial 2010 (anacetrapib) Cannon et al. Cannon et al. NEJM. 2010; 363:2406-2415 Barter et al, NEJM 2007;357:2109-2122

14. 30,000 patients aged > 50 with occlusive arterial disease 30,000 patients aged > 50 with with occlusive arterial disease REVEAL trial Anacetrapib 100 mg Atovastatin to achieve LDL-C target Placebo Primary End Point Coronary death, myocardial infarction or coronary revascularization 4 year follow-up www.revealtrial.org Sites in North America, Europe and Asia Planned completion in 2017

15. 11,000 patients at high CV risk ACCELERATE trial Evacetrapib 130 mg Treatment with a statin for at least 30 days Placebo Primary End Point CV death, MI, stroke, coronary revasc or hospitalization for UA 3 year follow-up Sites in North America, Europe and Asia- Pacific countries Planned completion in 2017

16. TA - 8995 Computational LogP predictions  Anacetrapib (9.34)  Evacetrapib (8.62)  TA-8995 (7.89)

17. TA - 8995: Multiple Ascending Dose phase 1 Results  Five groups of 12 received 1, 2.5, 5, 10 and 25mg or placebo as single dose  Followed by repeat dosing, starting 1 week later  5mg given for 28 days; steady state reached in < 21 days  1, 2.5, 10 and 25mg given for 21 days  t 1/2,SS approx. 130 hrs (=5,4 days)

18. 1mg* N=10 2.5mg N=10 5mg N=10 10mg N=10 25mg N=10 CETP activity-67%-90%-92%-98%-99% HDL-C+38%+95%+118%+140%+136% LDL-C-30%-39%-42%-44%-53% Efficacy relative to baseline after 21days Significant reduction in Lp(a) seen in all dose groups TA - 8995: Multiple Ascending Dose phase 1 Efficacy

19.  Safe and well tolerated  No serious adverse events  No dose related trends in TEAEs  No significant changes in vital signs, or safety lab parameters TA - 8995: Multiple Ascending Dose phase 1 Safety

20. TA - 8995 TULIP study N=45 placebo + placebo N=45 TA-8995 1mg + placebo N=45 TA-8995 2.5mg + placebo N=45 TA-8995 10mg+ Atorvastatin 20mg N=45 placebo +Atorvastatin 20mg N=45 TA-8995 10mg + placebo N=45 TA-8995 5mg + placebo N=45 placebo + Rosuvastatin 10mg N=45 TA-8995 10mg + Rosuvastatin 10mg Washout/ run in Double blind treatment 12 weeks Follow up 800 screened 400 randomised 360 evaluable No CVD LDL > 2.5mmol/l HDL < 1.8mmol/l 9 Groups

21. Summary Potent CETP inhibition has profound effects on HDL-C and LDL-C levels Off-target toxicities of torcetrapib and poor efficacy of dalcetrapib leave hope that a potent CETP inhibitor may benefit patients Early studies demonstrate safety, tolerability and lipid efficacy of anacetrapib, evacetrapib and TA - 8995 The ultimate outcome will be determined in large clinical event studies