Agents to reduce LDL (and future developments) Raul D. Santos MD, PhD Heart Institute-InCor University of Sao Paulo Brazil

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1 Agents to reduce LDL (and future developments) Raul D. Santos MD, PhD Heart Institute-InCor University of Sao Paulo Brazil

2 Disclosure Honoraria for consulting and speaker activities on the last year from Amgen, Aegerion, Astra Zeneca, Akcea Biolab, Boehringer Ingelheim Genzyme, Merck, Praxis, Cerenis Pfizer, Eli Lilly, Kowa, Unilever Sanofi/Regeneron 2

3 Agents do reduce LDL Current options Statins Ezetimibe Resins Niacin Recently approved and future treatments (?) Lomitapide Mipomersen PCSK9 inhibitors CETP inhibitors ATP CL Inhibition 3

4 Statins

5 Statins: Mechanism of Action HMG-CoA redutase Statins inhibit HMG-CoA reductase Intrahepatic cholesteorl pool reduction Increment on LDL receptor expression Reduction of VLDL production Incrementof LDL catabolsim Less VLDL particles available to become LDL Reduction of : LDL-C, TC, non-hdl-c and TG

6 STELLAR LDL-c (% Changes vs. Baseline) RSV ATV SIN PRA % * -52 ** -55 *** Jones PH et al. AJC. 2003;93: *P<0.002 vs ATV 10 mg; PRA 10 mg, 20 mg, 40 mg; SIN 10 mg, 20 mg, 40 mg. **P<0.002 vs ATV 20 mg, 40 mg; PRA 20 mg, 40 mg; SIN20 mg, 40 mg, 80 mg. análise de mg.

7 Pravastatin Increases the Removal From Plasma of Chylomicron Remnants in CHD patients P = 0.01 % Santos RD et al. Am J Cardiol 2000; 85:1163-6

8 Impact of 1mmol/L reduction on LDL-C upon major cardiovascular events and mortality CTT 2010 Relative Risk (95% CI) All cause mortality CHD mortality Other cardiac deaths Stroke deaths Major vascular events Non-fatal MI Myocardial revascularization Ischemic stroke Cancer incidence Hemorrhagic stroke 0.90 ( ), p<0.0001** 0.80 ( ); p<0.0001** 0.89 ( ); p=0.002** 0.96 ( ); p= ( ); p< ( ); p< ( ); p< ( ); p< ( ); p= ( ); p=0.2 Adapted from The Lancet 2010.; 376: **- CI 99%

9 Non-Lipid Lowering Effects of Statins Jain MK, Ridker PM. Nature Rev Drug Discov, 2005

10 Statins: Side Effects Muscle Liver (??) Diabetes Hemorrhagic stroke (???) Cognitive functions??????????? 10

11 Ezetimibe

12 NPC1L1 Transports Intestinal Cholesterol and Phytosterols: Inhibition of NPC1L1 by Ezetimibe for Hypercholesterolemia and Sitosterolemia Cholesterol and Plant Sterols NPC1L1 Sitosterolemia

13 Ezetimibe reduces cholesterol absorption in humans Mild Hypercholesterolemic Pure Vegetarians Fr ac t i ona l Cho l es t e r o l Abso r p t i on (%) Mean = -54% Range: 0 to -94% LDL-C = % Mean = -58% LDL-C = -17.3% Sudhop et al. Circulation 106:1943, 2002 Clarenbach JJ et al. J Lipid Res. 47:2820,

14 Effects of ezetimibe, simvastatin and simvastatin/ezetimibe on pro-atherogenic lipids and apob Farnier M et al. Atherosclerosis 2013; 229:

15 Relative risk reduction of ischemic events (95% HF) CTT/SHARP: Effects on ischemic events in CKD 30% 25% 20% 15% Intensive hypolipidemia treatment vs. Conventional (5 studies) Statins vs. control (21 studies) SHARP 17% risk reduction 10% SHARP 32mg/dL 5% 0% Mean difference of LDL-C among treated groups (mg/dl) Baigent et al. Lancet 2011; 377;

16 Plot of the IMPROVE-IT Trial Data and Statin Trials for Change in Low-Density Lipoprotein (LDL) Cholesterol versus Clinical Benefit. Cannon CP et al. N Engl J Med 2015;372:

17 Ezetimibe: Side Effects Gastro intestinal 17

18 Bile acid binding resins

19 Bile Acid Binding Resins :Mechanism of Action Gotto AM and Pownall HJ: Manual of Lipid Disorders. 1992

20 The first study showing that cholesterol reduction prevents CVD was done with a resin JAMA 1984; 251:351

21 Bile Acid Resins: Side effects Gastro intestinal (much less with colesevelam) Increase in TG levels Binding to other medications 21

22 Niacin 22

23 Niacin: Mechanisms of Action Adipose tissue Hormone sensitive Lipase (GPR109A) FFA to the liver and TG and VLDL PPAR gamma ABCA1 Liver Production and Apo B degradation Apo A-I (?) Digby JE ATVB 2012;32:582-8 Lamon-Fava S et al. ATVB 2008;28:2672-8

24 Extended release Niacin Changes vs. baseline (Mean %) Treatment ER Niacin Duration n TC LDL-c HDL-c TG Lp(a) ApoB V. Baseline 723 Week Week ER Niacin + Statins Week Week All changes significant Capuzzi DM et al. Am J Cardiol 1998;82:74U-81U Guyton JR et al. Am J Cardiol 1998;82:82U-84U

25 Survivial (%) Coronary Drug Project: Long term mortality reduction in post AMI patients with niacin Placebo Niacin P = 0, Years of follow-up Canner PL et al. J Am Coll Cardiol 1986;8:

26 HPS 2 THRIVE: Niacin/Laropiprant not effective in patients with well controlled LDL-C The HPS2-THRIVE Collaborative Group. N Engl J Med 2014;371:

27 Niacin-ER: side effects Flushing Glucose intolerance/diabetes Skin infections Gout Peptic Ulcer

28 Recently Approved Drugs 28

29 MTP inhibitors Lomitapide

30 Special Pat ient Populat ions: FH and Ot her Severe Hypercholest erolemias Lomitapide: Mode of Action To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s), editor(s), reviewer(s), Elsevier and typesetter SPi. It is not allowed to publish this proof online or in print. This proof copy is the copyright property of the publisher and is confidential until formal publication. B , Cytoplasm ER Luman ApoB degraded MTP Liver cell Lower VLDL, LDL, chylomicrons, and chylomicron remnants TG Cytoplasm ER Luman Blood vessel ApoB48 degraded MTP Au1 Intestinal epithelial cell f0050 FIGURE 38-9 Effects of microsomal triglyceride transport protein (MTP) inhibition by lomitapide. ApoB, apolipoprotein B; LDL, low-density lipoprotein; TG, triglyceride; VLDL, very-low-density lipoprotein. (Modified from references 130,132,134,135.) p0300 Lomitapide causes a higher rate of gastrointestinal side effects and aminotransferase elevations than does ezetione liver enzyme to greater than or equal to three times the upper limit of normal. Approximately 14% of study Moriarty & Santos In Clinical Lipidology: A companion to Braunwald s Heart DIsease

31 Phase 3 Study in Patients with HoFH: LDL-C Reduction (Mean % Change) From Baseline to Week mg/dL 352mg/dL 40.1% reduction 44.0% reduction 38.4% reduction 50.2% reduction Baseline Week 26 Week 56 Week 78 0mg 44.6mg 0mg 38.4mg 40.2mg 40.7mg Adapted from Cuchel M et al. Lancet 2013; 381:40-46 (CA) (ITT) 3

32 HoFH Phase 3 Study Treatment Emergent Adverse Events Adverse Event Category n of subjects (%) weeks 0-26 N=29 n of subjects (%) weeks N=23 Any adverse event 27 (93.1) 21 (91.3) GI Disorders 27 (93.1) 17 (73.9) Diarrhea 23 (79) 8 (35) Nausea 18 (62) 7 (30) Lab abnormalities 15 (51.7) 10 (43.5) ALT elevation >5 x ULN 4 (13.8) 1 (4.3) Adapted from Cuchel M et al. Lancet 2013; 381:40-46

33 Figure 2 Lomitapide: Hepatic Safety Cuchel M et al. Lancet 2013; 381:40-46

34 Antisense Oligonucleotides Mipomersen

35 Antisense Therapy 1-3 Protein synthesis Proteins mrna mrna + Antisense Protein synthesis inhibited Fewer proteins Antisense molecules are short, single-stranded, synthetic analogues of natural nucleic acids that are complementary to, and thus bind with, a specific mrna to prevent disease-related protein synthesis mrna = messenger RNA. 1. Crooke RM, Graham MJ. Clin Lipidol. 2011;6, Koller E, et al. Trends Pharmacol Sci. 2000;21: Visser ME, et al. Eur Heart J. 2012;33:

36 Raal FJ, Santos RD et al. Lancet. 2010;375:

37 Pooled Population Homozygous FH Santos RD et al. Arterioscler Thromb Vasc Biol Mar;35(3):

38 Incidence of injection site reactions (ISRs) and flu-like symptom (FLS) events occurring at least once over time. All Subjects ISR = 1 in 10 FLS= 1 in 52 Completers Santos R D et al. Eur Heart J 2015; ;36:566-75

39 Change from baseline in ALT levels and liver fat fraction over time. ALT Liver Fat Santos R D et al. Eur Heart J 2015; ;36:566-75

40 Antibodies against PCSK9

41 PCSK9 Promotes Degradation of LDLRs PCSK9 LDLR protein LDL-C PCSK9 X LDLR protein LDL-C LDL-C=low-density lipoprotein cholesterol; LDLR=low-density lipoprotein receptor. 41

42 Percent Reduction from Baseline in Low-Density Lipoprotein (LDL) Cholesterol Levels in the Evolocumab Group, as Compared with the Placebo Group, at Weeks 12 and 52, According to Background Lipid-Lowering Therapy. N=901 Blom DJ et al. N Engl J Med 2014;370:

43 Alirocumab Reduces LDL-C in Familial Hypercholesterolemia John J.P. Kastelein et al. Eur Heart J 2015;eurheartj.ehv370

44 % Change From Baseline Evolocumab Reduces Lp(a) in Heterozygous FH Raal F et al. Circulation 2012;126:

45 Effects of PCSK9 inhibitors on All Cause Mortality Navarese et al. Ann Intern Med. 2015;163(1):40-51.

46 Outcomes Trials for Alirocumab and Evolocumab ODYSSEY OUTCOMES FOURIER Inclusion criteria Number of patients Primary endpoint ACS within the last 4 to 52 weeks; LDL-C 70 (on atorvastatin mg or rosuvastatin mg) 18,000 27,500 CV death, MI, stroke, and hospitalization for UA MI, stroke, or symptomatic PAD + at least 1 major RF or at least 2 minor RFs; LDL-C 70 (or non-hdl 100) (on atorvastatin 20 to 80 mg or equivalent) CV death, MI, stroke, coronary revascularization and hospitalization for UA Background Therapy Dosing regimen Max tolerated doses of atorvastatin and rosuvastatin 75 mg 150 mg Q2W (based on w8 LDL-C level) Atorvastatin: 20 (at least), 40 (recommended where locally approved), 80 mg (or equivalent) 140 Q2W (1 ml pen) or 420 QM (3 x 1 ml pen or 3.5 ml via personal injector (9 injection time) Schwartz et al. Am Heart J 2014;168:

47 Future Treatments? 47

48 ETC-1002 AMP-activated protein kinase (AMPK) activation and ATPcitrate lyase (ACL) inhibition ETC-1002 (Bempedoic Acid) 48

49 Dual mechanism of action of ETC-1002 AMP-activated protein kinase (AMPK) activation and ATP-citrate lyase (ACL) inhibition. Maria J. Gutierrez et al. Arterioscler Thromb Vasc Biol. 2014;34: Copyright American Heart Association, Inc. All rights reserved.

50 Use of ETC-1002 to treat hypercholesterolemia in patients with statin intolerance Thompson P et al. Journal of Clinical Lipidology, 9(3):

51 Conclusions LDL-C is an independent risk factor for atherosclerosis There are many proven therapies that reduce LDL-C and prevent CVD Statins are the cornerstone of LDL-C lowering Other drugs should be added to control LDL-C adequately Newer medications (PCSK9 inhibitors): cost effectiveness and safety needs to be proven 51