Raising HDL Cholesterol 20/09/2018 Raising HDL Cholesterol

Guideline recommended HDL-C targets (mmol/L) 20/09/2018 Guideline (year) Recommended target Canadian Cardiovascular Society (2009) Ratio: Total/HDL-C <4.0 American Diabetes Association (2009) > 1.0 (40 mg/dL) men; >1.3 (50 mg/dL) women NCEP/ATP III (2002/04) - in women (2004/07) HDL-C >1.55 (60 mg/dL) is a negative risk factor; low HDL-C <1.0 (<40 mg/dL) - >1.3 (50 mg/dL) 4th Joint Task Force Markers of increased cardiovascular risk: <1.0 (40 mg/dL) in men, <1.2 (45 mg/dL) in women ESC/EASD (2007) Markers of increased cardiovascular risk: <1.0 (39 mg/dL) in men, <1.2 (46 mg/dL) in women CHD Task Force (2003) >0.91 (35 mg/dL)

Effect of lifestyle interventions on HDL cholesterol 20/09/2018 Effect of lifestyle interventions on HDL cholesterol Intervention Increase in HDL Cholesterol Aerobic exercise 5-10% Stopping smoking Losing weight 0.35mg/dL per kg weight lost Healthy diet (rich in omega-3 fatty acids or monosaturated fatty acids) Up to 5% Moderate alcohol intake 5-15% Singh IM et al. JAMA 2007: 298: 786-98.

Pharmacotherapy of low HDL cholesterol 20/09/2018 Pharmacotherapy of low HDL cholesterol 15-35 5-15 10-15 % Change from baseline 5-20 5-25 7-30 20-50 20-50 18-55 LDL-C Triglycerides HDL-C

20/09/2018 Niacin

Dose-related efficacy of extended-release (ER) niacin 20/09/2018 Dose-related efficacy of extended-release (ER) niacin Recommended daily dose -50 -40 -30 -20 -10 10 20 30 40 Change from baseline (%) 30 29 24 HDL-C 21 16 10 -3 -8 -13 -5 -16 -12 -22 -21 -17 LDL-C -14 -25 Lp(a) -21 -26 -30 At the recommended therapeutic dose of 2000 mg daily, extended-release (ER) niacin raises HDL cholesterol by about 20-30%. Reference 1. Chapman MJ et al. Pharmacol Ther 2010;126:314-345 -32 -44 -39 TG 500 1000 1500 2000 2500 3000 Daily dose of ER Niacin (mg) Sprecher DL. Am J CardiolL 2000;86(12A):46L-50L

20/09/2018 Niacin monotherapy outcomes trial: 15-year follow-up in Coronary Drug Project 11% Reduction p=0.0004 Placebo (n = 2008) Niacin (n = 827) 12% Reduction p<0.05 Event Rate, % The Coronary Drug Project (CDP) is so far the only published outcomes study with niacin (nicotinic acid, immediate-release formulation) monotherapy. At 15 years (nearly 9 years after termination of the trial) total mortality in the niacin group was 11% lower than in the placebo group (p=0.0004). CHD mortality was also significantly decreased in the niacin group (12% reduction, p<0.05). However, mortality at 15 years was not an original end point of the CDP, patients had not received niacin for approximately 9 years, and confounding variables such as concomitant medication use and medical or surgical treatments, were not controlled in this follow-up study. Results from this follow-up study indicated that early treatment with niacin may provide a mortality benefit over subsequent years, even after discontinuation of niacin. Reference Canner PL et al. J Am Coll Cardiol 1986;8:1245-55. . Total Mortality CHD Mortality Canner PL, et al. J Am Coll Cardiol. 1986;8:1245-1255.

COMPELL: combination ER niacin/statin therapy 20/09/2018 Atorvastatin 40 mg + Niacin ER 2 g Rosuvastatin 20 mg + Niacin ER 1 g Lp(a) * Simvastatin 40 mg + Ezetimibe 10 mg * * Rosuvastatin 40 mg Change From Baseline, % * COMPELL: Comparative Effects of Combination Therapy Versus Statin Monotherapy. The COMPELL study evaluated comparative effects on lipid levels of combination therapy with ER niacin and low to moderate doses of a statin (atorvastatin or rosuvastatin), simvastatin plus ezetimibe, and rosuvastatin monotherapy. This was an open-label, multicentre, 12-week study in 292 patients (50% women) who qualified for lipid-modifying therapy based on a number of coronary risk factors. Doses of statins and niacin were titrated up over the 12 weeks. At 12 weeks, all groups lowered LDL cholesterol by more than 50%, with no significant differences among treatment groups. Statin/ER niacin combination regimens increased HDL cholesterol and lowered triglycerides and lipoprotein(a) significantly more than the other regimens (p<.001 for analysis of variance across groups). In summary, low to moderate dose combination therapy with a statin and ER niacin provided broad control of lipids and lipoproteins independently associated with coronary heart disease. Reference McKenney JM et al. Atherosclerosis. 2007;192:432-437. * LDL-C HDL-C TG *P<.05 versus atorvastatin + niacin ER McKenney JM, et al. Atherosclerosis. 2007. 192(2):432-7

SEACOAST: Trial design 20/09/2018 After a run-in phase (treatment with simvastatin, variable dose), patients were randomly assigned to either: SEACOAST I: ER niacin 1 g/simvastatin 20 mg; ER niacin 2 g/simvastatin 20 mg; or Simvastatin 20 mg. OR SEACOAST II: ER niacin 2 g/simvastatin 40 mg; ER niacin 1 g/simvastatin 40 mg; or Simvastatin 80 mg. The duration of treatment was 24 weeks. The SEACOAST trial evaluated the effects of combination therapy with a statin and two doses of ER niacin in dyslipidemic patients. Patients were initially enrolled in a run-in phase during which they discontinued all other lipid-modifying therapy and were treated with simvastatin (variable dose), in addition to a standard cholesterol-lowering diet. Following this phase more than 600 patients were randomly assigned to either the low-dose (20 mg) or high-dose (40 mg) simvastatin arm. Patients in the low-dose group (SEACOAST I) were randomized to: ER niacin 1 g/simvastatin 20 mg; ER niacin 2 g/simvastatin 20 mg; or Simvastatin 20 mg. Patients in the high-dose group (SEACOAST II) were randomized to: ER niacin 2 g/simvastatin 40 mg; ER niacin 1 g/simvastatin 40 mg; or Simvastatin 80 mg. Patients in the simvastatin monotherapy groups received a 50 mg dose of immediate-release niacin to maintain study blinding. Reference Ballantyne CM et al. Am J Cardiol 2008;101:1428-36. Ballantyne CM, Davidson MH, McKenney J, et al. Am J Cardiol 2008;101:1428-36

SEACOAST I: Median % change in lipids from baseline 20/09/2018 Lipid SIM 20 mg ER Niacin 1 g + SIM 20 mg ER Niacin 2 g + SIM 20 mg Non-HDL-C -7.4 -13.9* -22.5** LDL-C -7.1 -13.1 14.2 HDL-C 6.7 18.3** 24.9** Lp(a) -7.6 -16.7* -25.0** TG -15.3 -26.5* -38.0** *p<0.01; **p<0.001 vs. SIM ; SIM simvastatin; ER extended-release; Lp(a) lipoprotein(a); TG triglycerides SEACOAST I was aimed at demonstrating the superiority of ER niacin/simvastatin vs simvastatin monotherapy in patients already at NCEP ATP III coronary heart disease risk-adjusted target LDL cholesterol levels. Patients receiving niacin-statin combination treatment achieved 18% (1 g/20 mg) and 25% (2 g/20 mg) increases in HDL cholesterol vs 7% reduction with simvastatin 20 mg alone. Combination treatment also significantly reduced LDL cholesterol, non-HDL cholesterol, lipoprotein(a) and triglycerides compared with simvastatin monotherapy. Reference Ballantyne CM et al. Am J Cardiol 2008;101:1428-36. Ballantyne CM, Davidson MH, McKenney J, et al. Am J Cardiol 2008;101:1428-36

SEACOAST II: Median % change in lipids from baseline 20/09/2018 Lipid SIM 80 mg ER Niacin 1 g + SIM 40 mg ER Niacin + 2 g SIM 40 mg Non-HDL-C -10.1 -11.3 -17.1 LDL-C -12.7 -8.6 -11.6 HDL-C -1.0 14.8* 21.9* Lp(a) 0.0 -16.7* -21.0** TG 0.3 -22.8* -31.88 *p<0.01; **p<0.001 vs. SIM SIM simvastatin; ER extended-release; Lp(a) lipoprotein(a); TG triglycerides In SEACOAST II, combination therapy showed non-inferiority in reducing non-HDL cholesterol, with decreases of about 11% (1 g/40 mg) and 17% (2 g/40 mg) compared with a 10% reduction with simvastatin 80 mg alone. Both combination treatment doses were associated with significant improvements in HDL cholesterol, triglycerides, lipoprotein(a) and apolipoprotein A-1. Reference Ballantyne CM et al. Am J Cardiol 2008;101:1428-36. Ballantyne CM, Davidson MH, McKenney J, et al. Am J Cardiol 2008;101:1428-36

20/09/2018 Frequency of flushing >2x as many patients on ER-niacin/laropiprant than ER-niacin had no flushing (47% vs. 22%) Flushing is the main tolerability issue with niacin therapy. The combination of niacin with laropiprant, an inhibitor of the prostaglandin D2 receptor, was developed in attempt to manage this. In this study, patients treated with ER-niacin/laropiprant had significantly less flushing than those treated with ER-niacin over the 16-week period. Overall, more than twice as many patients reported no episodes of moderate, severe or extreme flushing with ER-niacin/laropiprant than ER-niacin (47% vs. 22%). Additionally, treatment with ER-niacin/laropiprant was associated with significantly less severe/extreme flushing (24.4% vs. 50.8%, p<0.001). Reference Maccubbin D et al. Am J Cardiol 2009;104:74-81. No. of days/week with at least moderate flushing Maccubbin D et al. Am J Cardiol 2009;104:74-81

HDL Atherosclerosis Treatment Study (HATS): Mean change in stenosis 20/09/2018 HDL Atherosclerosis Treatment Study (HATS): Mean change in stenosis Mean change in stenosis (% of diameter) Regression Progression Statin/niacin + antioxidants 0.7%* Statin/niacin 0.4%** Antioxidants 1.8%* HATS: HDL Atherosclerosis Treatment Study HATS evaluated the effect of combination treatment with simvastatin plus niacin in 160 patients with coronary heart disease and low HDL cholesterol levels and normal LDL cholesterol levels. Combination therapy resulted in a 29% increase in plasma levels of HDL cholesterol (versus 6% with placebo) together with reductions of 38% (versus 3%) in triglycerides and 43% (versus 9%) in LDL cholesterol. After 3 years, there was significant angiographic regression of stenosis by 0.4% on average, compared with placebo (p<0.001); the addition of anti-oxidants had no influence on this effect. However, HATS did not include a separate simvastatin treatment arm and therefore the incremental benefit of nicotinic acid over statin alone could not be discerned.   Reference Brown BG et al. N Engl J Med 2001;345:1583-92. * p<0.01 vs placebo **p<0.001 vs placebo Placebo 3.9%* Brown BG et al. N Engl J Med. 2001;345:1583

ARBITER 2: Change in carotid intima-media thickness at 12 months 20/09/2018 ARBITER 2: Change in carotid intima-media thickness at 12 months Niacin plus statin stabilized progression of atherosclerosis BUT Significant progression of atherosclerosis with statin alone Taylor et al . Circulation 2004; 110:3512-7. ARBITER-2: ARterial Biology for the Investigation of the Treatment Effects of Reducing cholesterol study ARBITER 2 included 167 patients with known coronary heart disease, moderately low HDL cholesterol (< 45 mg/dl [1.2 mmol/l]) and well-controlled LDL cholesterol (< 100 mg/dl [2.6 mmol/l]), who had been treated with a statin (93% with simvastatin) for an average of 4.8 years. Patients were randomised to treatment with ER niacin (500 mg for the first 30 days and 1000 mg daily thereafter) or placebo in addition to statin therapy for 12 months. The primary endpoint of the study was the change in carotid intima-media thickness (CIMT) at 12 months, as measured by B-mode ultrasonography, which is a meaningful and validated surrogate cardiovascular endpoint. Combination therapy raised HDL cholesterol by 21% (p=0.002) and reduced triglycerides, versus statin monotherapy. At 12 months, there was no significant change in CIMT in the statin/ER niacin combination group (+0.014  0.104 mm, p=0.23) whereas in patients treated with statin alone there was a significant increase in CIMT (+0.044  0.100 mm, p<0.001), indicative of increased progression of atherosclerosis. Reference Taylor AJ et al. Circulation 2004;110:3512-7.

ARBITER 6-HALTS Change from baseline in mean carotid IMT at 14 months 20/09/2018 ARBITER 6-HALTS Change from baseline in mean carotid IMT at 14 months  from baseline p-value Between groups p-value Niacin (n=97) -0.0142 (0.0041) p=0.001 0.003 Ezetimibe (n=111) -0.0007 (0.0035) p=0.84 This study tested two strategies in high-risk statin-treated patients at LDL cholesterol goal (<100 mg/dL or 2.6 mmol/L): 1. Raising HDL-C with extended-release (ER) niacin (target dose 2 g/day) 2. Further lowering LDL-C levels with ezetimibe (10 mg/day) The primary endpoint was the change in carotid intima-media thickness (IMT), a measure of atherosclerosis. The study was terminated 4 months early on the recommendation of an independent data advisory board on the basis of efficacy, according to a pre-specified interim analysis of carotid IMT 8 and 14-month data. At this time 208 (of 363 enrolled) patients had completed the study. Treatment with niacin led to significant reduction in mean carotid IMT at both 8 and 14 months (p=0.001 at each time point). In contrast, no significant changes were observed in patients treated with ezetimibe. The change from baseline to 14 months in the primary endpoint was significantly different between the niacin and ezetimibe groups (p=0.003). Reference Taylor AJ et al. N Engl J Med 2009;361:2113-22. Taylor AJ et al. N Engl J Med 2009;361: 2113-22

Fibrates

% change from baseline to week 24 Fenofibrate monotherapy vs. combination with atorvastatin in type 2 diabetes 20/09/2018 Atorvastatin 20 mg (n = 40) Fenofibrate 200 mg (n = 40) Atorvastatin 20 mg + fenofibrate 200 mg (n = 40) 22 20 16 9 % change from baseline to week 24 -20 -15 -16 In this study, 120 type 2 diabetes patients with mixed dyslipidemia but without coronary heart disease were randomized to treatment with atorvastatin (20 mg/day, n=40), micronized fenofibrate (200 mg/day, n=40) or a combination of both (n=40) for 24 weeks. Fenofibrate alone significantly raised HDL cholesterol by 16%, and also reduced triglycerides by 41% and LDL cholesterol by 15%. Changes in HDL cholesterol and triglycerides were greater in combination with atorvastatin. Reference Athyros VG et al. Diabetes Care 2002;25:1198-202. -31 -30 -40 -37 -40 -41 -46 -50 -60 LDL-C TC TG HDL-C Athyros VG et al. Diabetes Care 2002;25:1198-202.

DAIS Investigators. Lancet 2001;357:905–910. 20/09/2018 DAIS: Fenofibrate slows progression of atherosclerosis (coronary angiography) Angiographic changes from baseline mm Change (%) mm 4.00 -0.10 -0.10 -40% -42% -0.08 -25% -0.08 -0.06 -0.06 2.00 Progression of CAD -0.04 -0.04 The Diabetes Atherosclerosis Intervention Study (DAIS) was specifically designed to investigate the effect of fenofibrate treatment on angiographic progression of coronary atherosclerosis. In total, 418 patients with type 2 diabetes mellitus and at least one angiographically confirmed coronary lesion were included. Treatment with fenofibrate produced a significant increase in HDL cholesterol (p<0.001), together with significant reductions in LDL cholesterol and triglycerides (p<0.001) versus placebo. These lipid changes were associated with significantly less progression in markers of focal coronary artery disease, specifically minimum lumen diameter (p=0.029) and percent stenosis (p=0.02), as well as a non-significant trend for less progression in mean segment diameter, a marker of diffuse disease, compared with placebo. Reference Diabetes Atherosclerosis Intervention Study Investigators. Lancet 2001;357:905-10 p = 0.029 p = 0.020 p = 0.171 -0.02 -0.02 0.00 0.00 0.00 Minimum lumen diameter Percent stenosis Mean Segment Diameter Fenofibrate Placebo DAIS Investigators. Lancet 2001;357:905–910.

VA-HIT: Outcome benefits from raising HDL-C 20/09/2018 VA-HIT: Outcome benefits from raising HDL-C Non-fatal MI or CHD death CHD death Stroke -22% p=0.006 p=0.07 -29% p=0.04 -40 -30 -20 -10 Risk reduction vs. placebo (%) The Veterans Affairs HDL Intervention Trial (VA-HIT) included 2,531 men with known coronary heart disease (CHD), low HDL cholesterol (mean baseline 32 mg/dl or 0.83 mmol/l) and moderate LDL cholesterol levels (mean baseline 111 mg/dl or 2.87 mmol/l). Treatment with gemfibrozil was associated with a 6% increase in HDL cholesterol levels and 31% decrease in fasting triglyceride levels compared with placebo at one year, with no appreciable change in LDL cholesterol levels. At the median follow-up of 5.1 years, raising HDL cholesterol (together with reduction of triglycerides) was associated with a 22% reduction in the primary endpoint (nonfatal MI and CHD death, p=0.006), as well as 22% reduction in CHD death (p=0.07) and 29% reduction in stroke (p=0.04). Reference Rubins HB et al. N Engl J Med 1999;341:410-8. Rubins HB et al. N Engl J Med 1999; 341:410-8.

ACCORD Lipid: Combination fenofibrate/simvastatin in Type 2 diabetes 20/09/2018 Hazard ratio for primary outcome P-value for interaction P=0.01 All patients HDL-C ≤34 mg/dL + TG ≥204 mg/dL P=0.06 The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid population comprised a cohort of 5,518 high-risk type 2 diabetic patients at goal for LDL cholesterol. The key question addressed by the trial was whether in the context of good glycemic control, fenofibrate plus simvastatin was more effective in reducing cardiovascular events than simvastatin monotherapy. ACCORD Lipid randomized 5,518 high-risk type 2 diabetes patients at target for LDL cholesterol (100 mg/dL or 2.6 mmol/L at baseline decreasing to 80 mg/dL or ~2.0 mmol/L on simvastatin, mean dose 22 mg/day) to fenofibrate plus simvastatin or simvastatin alone. ACCORD Lipid did not show any significant clinical benefit for any of the primary or secondary cardiovascular outcomes in the total study population. However, in a pre-defined subgroup analysis in patients with HDL cholestesterol levels <34 mg/dL and triglycerides ≥204 mg/dL at baseline (17% of the total population), there was suggestion of benefit. Adding fenofibrate resulted in 31% reduction versus simvastatin treatment alone, although this was not statistically significant. Reference The ACCORD Study Group. N Eng J Med 2010:362:1563-74. 0 1 2 Fenofibrate better Simvastatin alone better ACCORD Lipid NEJM 2010:362:1563-74.

Reduction in CV events*: fibrate studies 20/09/2018 Study (fibrate) Primary endpoint (all patients) Lipid criteria (mmol/L) Primary endpoint (Lipid subgroup) ACCORD (fenofibrate/ simvastatin) -8% (p=0.32) TG≥2.3 + HDL-C ≤0.88 -31% FIELD (fenofibrate) -11% (p=0.16) TG≥2.3 + Low HDL-C§ -27% (p=0.005) BIP (bezafibrate) -7.3% (p=0.24) TG≥2.3 + HDL-C ≤0.9 -39.5% (p=0.02) HHS (gemfibrozil) -34% (p<0.02) TG>2.3 + LDL/HDL >5.0 -71% (p<0.005) The ACCORD Lipid predefined subgroup analysis was consistent with other subgroup analyses in patients with elevated TG and low HDL-C, from other fibrate trials.1-6 However, for balance, it should be noted that the findings from the ACCORD Lipid subgroup were not as positive as observed with other fibrates. References 1. The ACCORD Study Group. N Eng J Med 2010:362:1563-74. 2. Scott R et al. Diabetes Care 2009;32:493-8. 3. Manninen V et al. Circulation 1992;85:37-45. 4. Rubins HB et al. Arch Intern Med 2002;162:2597-2604. 5. Tenkanen L, Mantarri M, Manninen V. Circulation 1995; 92: 1779-85. 6. Tenenbaum A et al. Arch Intern Med 2005; 165: 1154-60. *Comparator treatments: simvastatin in ACCORD Lipid and placebo in other studies; §<1.03 in men and <1.29 in women

Developmental treatments for raising HDL cholesterol Cholesteryl ester transfer protein (CETP) inhibitors Recombinant apolipoprotein A-I Reconstituted HDL

CETP inhibitors

Cholesteryl ester transfer protein (CETP) 20/09/2018 Cholesteryl ester transfer protein (CETP) Promotes re-distribution of cholesteryl esters (CE) between HDL and triglyceride-rich lipoproteins

20/09/2018 CETP-mediated exchanges of lipids between HDLs and triglyceride-rich lipoproteins (TRLs) TGR-LP HDL CE TG TG CETP CE CE

CETP : a pharmacological target 20/09/2018 NY-160626.038/020131YlsjoLS1 CETP Action in Atherogenic Dyslipidaemia Cardioprotective HDL High CETP Activity Atherogenic LPs CETP : a pharmacological target

CETP and Atherosclerosis in Rodents NY-160626.038/020131YlsjoLS1 CETP and Atherosclerosis in Rodents Rodents naturally deficient in CETP Rodents naturally resistant to development of atherosclerosis Expression of CETP in transgenic mice and rats increases atherosclerosis in most (but not all) models

CETP and Atherosclerosis in Rabbits NY-160626.038/020131YlsjoLS1 CETP and Atherosclerosis in Rabbits Rabbits have high level of activity of CETP Rabbits naturally highly susceptible to the development of atherosclerosis Inhibition of CETP in rabbits decreases atherosclerosis in all models

ILLUMINATE trial - torcetrapib 20/09/2018 NY-160626.038/020131YlsjoLS1 ILLUMINATE trial - torcetrapib Terminated 2nd December 2006 Excess of deaths in patients treated with torcetrapib and atorvastatin vs. atorvastatin alone: 93 vs. 59, p=0.006 Excess of major cardiovascular events in patients treated with torcetrapib and atorvastatin vs. atorvastatin alone: 464 vs. 373, p=0.001 Outcome effects associated with the use of torcetrapib may have been due to off-target pharmacology. However, the possibility of an adverse effect of CETP inhibition cannot be excluded. Barter P, et al. N Engl J Med 2007; 357:2109-22.

20/09/2018 NY-160626.038/020131YlsjoLS1 Off-target pharmacological effects of torcetrapib unrelated to CETP inhibition In patients receiving torcetrapib/atorvastatin (but not in those receiving atorvastatin alone) there was a significant: Increase in blood pressure Reduction in serum potassium Increase in serum bicarbonate Increase in serum sodium Increase in serum aldosterone These changes are consistent with activation of the renin-angiotensin-aldosterone system Barter P, et al. N Engl J Med 2007; 357:2109-22.

Lipid effects with dalcetrapib 20/09/2018 *p<0.0001 %change from baseline *p<0.01 *p=0.002 Treatment with dalcetrapib led to significant increases in plasma HDL cholesterol levels (by 33%) and apolipoprotein A-I (by 11-16%) at weeks 24 and 48, together with about 50% reduction in CETP activity (54% at 24 weeks and 57% at 48 weeks, p<0.0001 at each time point). There was negligible effect on LDL cholesterol levels. Reference 1. Stein EA, Stroes ESG, Steiner G et al. Am J Cardiol 2009;104:82-91 D Dalcetrapib 900 mg/day * D 48 weeks vs. placebo Stein EA et al. Eur Heart J 2010;31(4):480-8

DEFINE Trial: anacetrapib 20/09/2018 DEFINE Trial: anacetrapib Primary endpoint: Reduction in LDL-C at 24 weeks Secondary endpoint: Change in HDL-C Adverse events Clinical and laboratory test findings The primary endpoint is the percent change in LDL cholesterol levels. Secondary endpoints include the change in HDL cholesterol levels and the safety and tolerability of anacetrapib. Pre-planned interim analyses at 6- and 12-months will investigate the effects on anacetrapib on safety endpoints including blood pressure and electrolytes. Cannon CP, et al. Am Heart J 2009;158:513-19.

Fig 1. DEFINE: Change from baseline lipids (mg/dL) HDL-C LDL-C TG Lp(a) 138% vs. placebo  60 vs. 6 mg/dL - 39.8% - 6.8% - 36.4% vs. placebo HDL Forum November 2010 Cannon CP et al. N Engl J Med 2010: published on-line November 17.

DEFINE: Frequency of adverse events of interest Anacetrapib (n=811) Placebo (n=812)  Systolic BP ≥10 mmHg 62.6% 64.5%  Systolic BP ≥15 mmHg 44.1% 47.3% Sodium >ULN 10.8% 10.5% Chloride >ULN 2.9% 3.4% Bicarbonate >ULN 1.4% 2.1% Potassium <LLN 4.8% ULN upper limit of normal range; LLN lower limit of normal range HDL Forum November 2010 Cannon CP et al. N Engl J Med 2010: published on-line November 17.

DEFINE: Cardiovascular safety Frequency of the composite cardiovascular outcome* was similar in anacetrapib and placebo groups (2.0% vs. 2.6%, p=0.40) Prespecified Bayesian analysis provided a 94% probability that anacetrapib would not be associated with a 25% increase in CV events (as seen in ILLUMINATE) * Defined as the composite of cardiovascular death, nonfatal MI, nonfatal stroke, hospitalisation for unstable angina HDL Forum November 2010 Cannon CP et al. N Engl J Med 2010: published on-line November 17.

Recombinant apoA-I

Apo A-I protects against atherosclerosis 20/09/2018 NY-160626.038/020131YlsjoLS1 Apo A-I protects against atherosclerosis The human apo A-I transgenic mouse model Atherosclerotic lesions Normal mouse Lipid rich diet - 95 % Human apo A-I transgenic mouse Normal mouse Transgenic mouse The human apo A-I transgenic rabbit model Atherosclerosis lesions (% of total thoracic aortic surface) Normal rabbit 30 p<0,0001 Lipid rich diet 20 10 Human apo A-I transgenic rabbit

Apo A-I Milano Carriers of the mutant have: NY-160626.038/020131YlsjoLS1 Carriers of the mutant have: Low levels of HDL cholesterol Moderate hypertriglyceridemia Carriers of the mutant have an increased protection against vascular disease

With Acute Coronary Syndromes NY-160626.038/020131YlsjoLS1 Effect of recombinant apo A-I Milano on Coronary Atherosclerosis in Patients With Acute Coronary Syndromes A Randomized Controlled Trial Steven E. Nissen, Taro Tsunoda, E. Murat Tuzcu, et al. JAMA. 2003;290:2292-2300

Atheroma Regression in a patient who NY-160626.038/020131YlsjoLS1 Atheroma Regression in a patient who received High-Dose ETC-216 (45mg/kg) Atheroma Area 8.1 mm2 Atheroma Area 5.35 mm2 ETC-216 : Apo A-IMilano / Phospholipids Nissen S et al. JAMA. 2003; 290:2292-2300.

Raising HDL cholesterol - Conclusions NY-160626.038/020131YlsjoLS1 Raising HDL cholesterol - Conclusions ‘Given that there is a continuum of clinical benefit associated with raising HDL cholesterol, we should be aiming to increase levels by at least 50%, well above current targets. It is clear that we need new therapeutic agents to achieve this and await with interest ongoing developments.’ - Professor M John Chapman, HDL Forum Editor Director, Dyslipoproteinemia and Atherosclerosis Research Unit, INSERM, Paris, France