1. Dov Gavish MD הטיפול בחולים בסיכון גבוה לאור המלצות ESC2011-2012 מאי 2013 ההסתדרות הרפואית בישראל – החברה לחקר, מניעה וטיפול בטרשת עורקים Israel Medical Association-Society for Research, Prevention and Treatment of Atherosclerosis

2. עורקים חולים עם משקעי כולסטרול

3. עורק לפני טיפול ואחריו

5. 5 2006 AHA/ACC guidelines for patients with CHD 2,b <100 mg/dL: Goal for all patients with CHD 2,a <70 mg/dL: A reasonable goal for all patients with CHD 2,a ESC/EAS 2011 -2012 <100 mg/dL: Patients with High CHD risk equivalents (10-year risk >20%) 1 <70 mg/dL: Therapeutic goal for very high-risk patients 1, a LDL-C Goals for High-Risk Patients <100 mg/dL <70 mg/dL a Factors that place a patient at very high risk are established CVD plus: multiple major risk factors (especially diabetes); severe and poorly controlled risk factors (eg, cigarette smoking); metabolic syndrome (TG ≥200 mg/dL + non–HDL-C ≥130 mg/dL with HDL-C <40 mg/dL); and ACS. 1 b And other forms of atherosclerotic disease. 2 ATP = Adult Treatment Panel; AHA = American Heart Association; ACC = American College of Cardiology; CVD = coronary vascular disease; TG = triglycerides; ACS = acute coronary syndrome. 1. Grundy SM et al. Circulation. 2004;110:227–239; 2. Smith SC Jr et al. Circulation. 2006;113:2363–2372. If it is not possible to attain LDL-C 50% with more intensive LDL-C–lowering therapy, including drug combinations 2

6. Good News Regarding Very Low LDLs

7. The Reduction in CHD Risk is Proportional to the % LDL-C Lowering 0.4 0.2 0 -0.2 -0.4 -0.6 -0.8 0 5 10 15 20 25 30 35 40 45 % Change in LDL-Cholesterol ALLHAT-LLT LIPID WOSCOPS HPS CARE % Change in CHD Event Rate LIPS 4S Adapted from JAMA. 2002;288:2998-3007 and Circulation 2005; 111: 2280-2281. Prove-It ASCOT TNT A to Z LRC-CPPT

8. Relative Risk for CHD (Log Scale) 3.7 2.9 2.2 1.7 1.3 1.0 LDL-C (mg/dL) 4070100130160 190 0 1 Grundy SM et al. Circulation 2004;110:227–239. 1988 1993 2001 2004 Lower is Better, But How Low?

9. Hazard Ratio of the Primary Endpoint Compared with Achieved LDL-C < 100 PROVE-IT (TIMI 22) Substudy* *Adjusted for age, gender, baseline LDL-C, diabetes mellitus, and prior MI. Lower better Higher worse 0 1 2 > 80-100 > 60-80 > 40-60  40 Referent 0.80 (0.59, 1.07) 0.67 (0.50, 0.92) 0.61 (0.40, 0.91) Hazard Ratio Achieved LDL-C (mg/dL) n = 256 n = 631 n = 576 n = 193 Wiviott SD et al. JACC. 2005;46:1411-1416. Atorvastatin 80 mg vs pravastatin 40 mg in 2099 ACS patients for 24 months Endpoint: CHD death, nonfatal MI, CVA, recurrent ischemia, revascularization

10. JUPITER: Event* Reduction Among Subjects Attaining LDL-C <50 mg/dL *Events: MI, stroke, revascularization, UA, and CV death. ** P = 0.0001. 0 0.1 1 10 Placebo LDL-C not <50 vs Placebo LDL-C <50 † vs Placebo LDL-C <50 vs not <50 0.76 (0.57, 1.00) 0.35 (0.25, 0.49)** 0.39 (0.26, 0.59)** Hazard Ratio Hsia J et al. JACC. 2011;57:1666-1675. Rosuvastatin 40 mg vs placebo in 17,802 patients with LDL-C 2.0 n = 8150 n = 4000 n = 4154 † Median 44 mg/dL Range 38-50 mg/dL

11. Target : New Rx To reduce LDL מחקרים חדשים על הורדת LDL לא על ידי סטטינים. חולים בסיכון בינוני עד גבוה על מקסימום טיפול נסבל. דב גביש וולפסון

13. 13 3 Genes Affecting LDL Uptake Can Cause FH Apo B: acts as ligand binding LDL particle to receptor (APOB gene, 1:1,000) LDL Particle Liver cell Circulation LDLR: on hepatocyte, binds to Apo B on LDL particle, inducing endocytosis of LDL (LDLR mutations, 1:500 ) PCSK9 Enzyme: degrades LDL receptors (PCSK9 mutations, 1:2,500) 1,000+ mutations identified to date 1.Kumar V, Abbas AK, Fausto N, et al. Robbins and Cotran Pathologic Basis of Disease. 2009. 2.Rader DJ, Cohen J, Hobbs HH. J Clin Invest. 2003;111:1795–1803. Image reproduced from: http://www.dls.ym.edu.tw/ol_biology2/ultranet/Endocytosis.html.

14. 14 FH-related Genes Affect Uptake of LDL Particles LDL Particle Liver cell Circulation Apo B: acts as ligand binding LDL particle to receptor LDLR induces endocytosis of LDL into hepatocyte PCSK9: enzyme that degrades LDL receptors 14 1.Kumar V, Abbas AK, Fausto N, et al. Robbins and Cotran Pathologic Basis of Disease. 2009. 2.Rader DJ, Cohen J, Hobbs HH. J Clin Invest. 2003;111:1795–1803. Image reproduced from: http://www.dls.ym.edu.tw/ol_biology2/ultranet/Endocytosis.html.

15. 15 Apo B LDL Particle LDLR LDLR binding site prevents binding of ApoB Normal FH: LDLR LDLR Mutations Change the Shape of Receptors, Preventing Binding of LDL Particles 1.Kumar V, Abbas AK, Fausto N, et al. Robbins and Cotran Pathologic Basis of Disease. 2009. 2.Rader DJ, Cohen J, Hobbs HH. J Clin Invest. 2003;111:1795–1803. Image reproduced from: http://www.dls.ym.edu.tw/ol_biology2/ultranet/Endocytosis.html.

16. 16 APOB Mutations Affect the Shape of Apo B and Ability to “Grab” the LDL Receptor Apo B LDLR Mutation impairs Apo B binding ability to LDL receptor LDL Particle Normal FH: Apo B 1.Kumar V, Abbas AK, Fausto N, et al. Robbins and Cotran Pathologic Basis of Disease. 2009. 2.Rader DJ, Cohen J, Hobbs HH. J Clin Invest. 2003;111:1795–1803. Image reproduced from: http://www.dls.ym.edu.tw/ol_biology2/ultranet/Endocytosis.html.

17. 17 PCSK9 Mutations Increase Degradation of the LDLR, Preventing Binding and Endocytosis Apo B PCSK9 LDLR LDLR are degraded at a faster rate by increased PCSK9 activity LDL Particle Normal FH: PCSK9+ 1.Kumar V, Abbas AK, Fausto N, et al. Robbins and Cotran Pathologic Basis of Disease. 2009. 2.Rader DJ, Cohen J, Hobbs HH. J Clin Invest. 2003;111:1795–1803. Image reproduced from: http://www.dls.ym.edu.tw/ol_biology2/ultranet/Endocytosis.html.

18. Inherited Syndromes of Extremes of LDL-C: Story of PCSK9 Frequency (%) LDL-C Gain of function mutations in PCSK9 Loss of function mutations in PCSK9

20. Concept of Lifetime Cumulative LDL-C Exposure and Vascular Risk Age (years) 020406080 Horton, Cohen, Hobbs Journal of Lipid Research 2009 Cumulative LDL Exposure HoFH HeFH Normal HoFH HeFH Normal

21. Concept of Lifetime Cumulative LDL-C Exposure and Vascular Risk Age (years) 020406080 Horton et al, J Lipid Res 2009: 50: S172-S177 Cumulative LDL Exposure HoFH HeFH High Risk Mod Risk PCSK9 LOF PCSK9 GOF

22. % LDL-C Change at 2 Weekly Intervals from Baseline to Week 12 with SAR236553 22 Mean % change in LDL-C from baseline to weeks 2, 4, 6, 8, 10, and 12, by Q2W treatment group. LDL-C Mean (  SE) % Change from Baseline ∆ - 8.5% ∆ - 30.5% ∆ - 53.6% ∆ - 62.9% ∆ - 64.2% ∆ - 5.1% ∆ - 39.6% ∆ - 72.4% McKenney et al. J Am Coll Cardiol 2012;59 2344-2353

23. -100 The Impact of Atorvastatin Dose on % LDL-C Change With SAR236553 LS mean (±95% CI) percentage change in calculated LDL-C from baseline to Week 12 for each dose/regimenSAR236553 50 mg Q2W200 mg Q4W300 mg Q4W100 mg Q2W150 mg Q2W LDL-C Mean (+/- 95% CI) % Change from Baseline to Week 12 vs. Placebo 0 -20 -40 -60 -80 Atorvastatin 10 mg (N=66) Atorvastatin 20 mg (N=69) Atorvastatin 40 mg (N=44) McKenney et al. J Am Coll Cardiol 2012;59 2344-2353

24. Changes in Apo B, nonHDL-C, and Lp(a) from Baseline to Week 12 with SAR236553 (“565” Study”) % Change from Baseline to Week 12 1 LS mean (SE) 2 median (Q1-Q3) * p < 00001 † p = 0.0022 McKenney et al. J Am Coll Cardiol 2012;59 2344-2353 10 0 -10 -20 -30 -40 -50 -60 -70 Apo B nonHDL-C Lp(a) -2% -34%* -56%* -63%* -0% -13% † -26%* -29%* -27%* -48%* -56%*

25. ApoB & LDL-C Response Mean % Change from Baseline, Day 57 % * P < 0.0001 vs. Placebo † P < 0.01 vs. Placebo * * * * * * † * * * * * * Stein et al NEJM 2012; 366:1108-18

26. AMG 145 Effect of Multiple Doses on Lp(a) vs Placebo Dias et al Presented at ACC, Chicago. March 25, 2012

27. LDL-C Mean (  SE) % Change from Baseline BSL 120.6 mg/dL WK8 40.4 mg/dL ∆ - 66.2% BSL 121.1 mg/dL WK8 100.0 mg/dL ∆ - 17.3% BSL 126.9 mg/dL WK8 36.8 mg/dL ∆ - 73.2% * * *P<0.0001 vs PL + A80mg % LDL-C Change at 2 Weekly Intervals from Baseline to Week 12 with SAR236553 Roth EM et al. N Engl J Med, Published online Oct 31, 2012

28. Antisense Technology as a New Approach for Drug Discovery

29. Mechanism of Action Antisense Oligonucleotide DNAmRNADisease-Associated Protein TranscriptionTranslation Antisense Drug (Oligonucleotide) Transcription Traditional Drug No Disease-Associated Proteins Produced RNaseH Degrades RNA No Translation Goldberg AC. J Clin Lipidol. 2010;4:350-6.

30. Inhibition of Apo B-100 production Cholesterol Apo B Triglyceride VLDL IDL LDL1 LDL2 LDL3 Lp(a) ► Apo B-100 is an important structural and functional component of lipoproteins ► Blocking Apo B-100 production blocks VLDL, LDL and Lp(a) production Apo B antisense (Mipomersen)

31. Inhibition of Apo B-100 production Cholesterol Apo B Triglyceride VLDL ► Apo B-100 is an important structural and functional component of lipoproteins ► Blocking Apo B-100 production blocks VLDL, LDL and Lp(a) production Apo B antisense (Mipomersen)

32. Mipomersen Monotherapy: Dose Ranging Phase 2 Trials Kastelein et al Circulation 2006; 114:1729-1735

33. Mipomersen in Homozygous FH: Early Studies ApoB and LDL-C Reductions* ApoB LDL-C *300 mg per week

34. Inhibition of MTP Cholesterol Apo B Triglyceride VLDL ► MTP is an important enzyme required for lipidation of Apo B and formation of VLDL in liver and chylos in gut ► Blocking MTP reduces hepatic VLDL, LDL and Lp(a) production and intestinal chylomicron formation MTPi (lomitapide) VLDL IDL LDL2 LDL1 LDL3 Lp(a)

35. Inhibition of MTP Cholesterol Apo B Triglyceride VLDL ► MTP is an important enzyme required for lipidation of Apo B and formation of VLDL in liver and chylos in gut ► Blocking MTP reduces hepatic VLDL, LDL and Lp(a) production and intestinal chylomicron formation MTPi (lomitapide)