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 2 years from Amgen, Aegerion, Astra Zeneca Biolab, BMS, Boehringer Ingelheim Genzyme, Merck, Praxis Pfizer, Eli Lilly, Novartis, Nestlé, Unilever Sanofi/Regeneron 2

3 Agents do reduce LDL Epidemiology Current options Statins Ezetimibe Resins Niacin Recently approved and future treatments Lomitapide Mipomersen CETP inhibitors PCSK9 inhibitors 3

4 Epidemiology 4

5 Lancet 2007; 370: Cholesterol and CHD Mortality N=900,000

6 Non-HDL-cholesterol, CHD and Ischemic Stroke N= N= CAD Stroke JAMA 2009;302:

7 Statins

8 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

9 Effects of Statins on LDL-C: STELLAR (% 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.

10 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%

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

12 Statins: Side Effects Muscle Liver (??) Diabetes Hemorrhagic stroke (???) Cognitive functions??????????? 12

13 Ezetimibe

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

15 Fr ac t i ona l Cho l es t e r o l Abso r p t i on (%) Ezetimibe reduces cholesterol absorption in humans Mild Hypercholesterolemic Pure Vegetarians 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,

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

17 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;

18 IMPROVE-IT vs. CTT: Ezetimibe vs. Statin Benefit IMPROVE-IT CTT Collaboration. Lancet 2005; 366: ; Lancet 2010;376: Cannon C. AHA Presentation 2014

19 Ezetimibe: Side Effects Gastro intestinal 19

20 Bile acid binding resins

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

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

23 Bile Acid Resins: Side effects Gastro intestinal (much less with colesevelam) Increase in TG levels Binding to other medications 23

24 Niacin 24

25 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

26 Extended release Niacin Changes vs. baseline (Mean %) Treatment Duration n TC LDL-c HDL-c TG Lp(a) ApoB ER Niacin 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

27 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:

28 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:

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

30 Recently Approved Drugs for Homozygous Familial Hypercholesterolemia 30

31 MTP inhibitors Lomitapide

32 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.) Lomitapide causes a higher rate of gastrointestinal side p0300 Moriarty effects & Santos and aminotransferase In Clinical elevations Lipidology: than does ezeti- A companion the upper limito ofbraunwald s normal. Approximately Heart 14% ofdisease study 2015 one liver enzyme to greater than or equal to three times 32

33 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

34 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

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

36 Antisense Oligonucleotides Mipomersen

37 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:

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

39 Pooled Population Homozygous FH Santos RD et al ATVB 2015 e pub 39

40 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 2013;eurheartj.eht549

41 Change from baseline in ALT levels and liver fat fraction over time. ALT Liver Fat Santos R D et al. Eur Heart J 2013;eurheartj.eht549

42 Antibodies against PCSK9

43 Effect of PCSK9 antibodies in increasing the expression of the LDLR

44 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:

45 45

46 % Change From Baseline Evolocumab Reduces Lp(a) in Heterozygous FH 0-5 Lp(a) 350 mg 420 mg Raal F et al. Circulation 2012;126:

47 CETP Inhibitors 47

48 CETP inhibition Forrester J et al. Circulation. 2005;111:

49 Changes in Cholesterol and Blood Pressure : Anacetrapib Cannon CP et al. N Engl J Med 2010;363:

50 Ongoing Phase III Trials Anacetrapib Evacetrapib Name (ID) REVEAL (NCT ) ACCELERATE (NCT ) Company Merck (Oxford trial Sponsor) Eli Lilly Dose 100mg daily 130mg daily Sample size 30,000 11,000 Inclusion 1) Age 50yrs 2) Hx of MI 3) Stroke or cerebr. revasc 4) PAD repair/revasc 5) DM with symptomatic CAD 1) Age 18yrs 2) Hx of ACS (30 to 365 days) 3) Cerebrovascular 4) PAD 5) DM with documented CAD PEP Study duration Coronary death, MI, or Coronary Revascularization 1) Median ~4 yrs 2) 1900 Primary endpoints CV death, MI, Stroke, Coronary Revascularization, or Hospitalization for UA 1) Median ~2yrs 2) 1136 Primary endpoints

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 51