Preventing coronary artery disease: Cholesterol or inflammation?

Transcription

1 Preventing coronary artery disease: Cholesterol or inflammation? Alexis Baass MD, MSc, FRCPC, DABCL, FNLA Medical Biochemist and Lipidologist MUHC Clinical Researcher and Lipidologist IRCM

2 Disclaimers Grants/Research Support Amgen, Pfizer, Sanofi, Regeneron, Merck, Astra Zeneca, Ionis, Leducq Foundation Speakers Bureau/Honoraria Amgen, Sanofi, Aegerion Stock Ownership None Off Label Use None

3 Objectives Understand the LDL Hypothesis Reaffirm the importance of statin therapy Interpret the data concerning PCSK9 inhibitors Understand the link between inflammation and atherosclerosis

4 Outline Cholesterol and atherosclerosis Background Statins: Hope 3 Trial Evolocumab: Fourier Trial Inflammation and atherosclerosis Background Canakinumab: Canthos Trial

5 Cholesterol and atherosclerosis

6 A Brief History of Cholesterol 1760 François Poulletier de la Salle discovered cholesterol in solid form from gallstones Nikolai Anitschkow demonstrated that cholesterol caused rabbits to develop vascular lesions similar to atherosclerosis seen in humans Michel Eugène Chevreul isolated and purified the sterol from gallstones and named it cholesterol (Greek, chol for bile plus stereos for solid). Adapted From: Hoefner. M, The cholesterol controversy continues April 2008

7 A Brief History of Cholesterol 1985 Michael S. Brown and Joseph L. Goldstein received the Nobel Prize for their discoveries concerning the role of the LDL receptor in cholesterol metabolism and regulation Scandinavian Simvastatin Survival Study (4S) showed that statin treatment of patients with coronary heart disease lowered morbidity and mortality Lovastatin Mevacor was the first statin drug to be cleared for use by the FDA PCSK9 Inhibitor Approved in the US Adapted From: Hoefner. M, The cholesterol controversy continues April 2008

8 Cholesterol : Observational Studies Epidemiologic Data Serum Cholesterol Levels and CHD MRFIT trial: age-adjusted CHD death rate and serum cholesterol in 361,662 US men (aged years) Each 1% Increase in Total Cholesterol Level is associated with a 2% Increase in CHD Risk Martin MJ, et al. Lancet 1986;2:

9 Cholesterol : Prospective Data Individual records were supplied on 302,430 people without initial vascular disease from 68 long-term prospective studies, mostly in Europe and North America LDL-C, per 0.84 mmol/l Non-HDL-C, per 1.10 mmol/l Apo B, per g/l HDL-C, per 0.38 mmol/l Apo A-I, per g/l Non HDL-C/HDL-C, per 1.53 Unit Apo B/Apo A-I, per 0.27 Unit TG, per 60% change Adjusted for confounding factors and lipid markers HR % Cl The Emerging Risk factors Collaboration JAMA 2009;302;

10 LDL-C and Atherosclerosis in IVUS* Studies Interventional Studies Have Shown Linear Relationship Between LDL-C, and Atherosclerosis Progression Median Chamge in percent Atheroma Volume (%) E GLAGOV (PCSK9i) ASTEROID (statin) REVERSAL (statin) A-PLUS (placebo) REVERSAL (statin) ACTIVATE (placebo) CAMELOT (placebo) Mean LDL-C (mmol/l) * Intravascular Ultrasound (IVUS) Adapted from Sipahi I, et al. Cleve Clin J Med. 2006;10: and Nissen SE, et al. JAMA; 2006:295: ; Nissen SE, et al. Advance online publication. JAMA doi: /jama

11 Cholesterol : Statin RCT More intense LDL-C lowering associated with greater reduction of coronary heart disease events Updated from: LaRosa JC, et al. N Engl J Med 2005; 352(14): ; Pencina et al NEJM 2014

12 The LDL Hypothesis Linear Relationship Between Reduction of CV Events and LDL-C Reduction Independent of Method (Diet, Bile Acid Sequestrants, Surgery and Statins) Non-fatal MI and CHD death RRR (%) LDL-C reduction (%) Robinson JG, et al. J Am Coll Cardiol 2005; 46(10):

13 Hope-3 trial

14 Hope-3 Trial (Lipid Arm) Patients at intermediate risk of ASCVD No entry criteria based on lipid level No dose titration Rosuvastatin 10mg (n=6361) vs placebo (n=6344) Median follow up 5.6 years

15 Hope-3 Trial: CVD Outcomes Cumulative Hazard Rates CV Death, MI, Stroke, Cardiac Arrest, Revasc, Heart Failure HR (95% CI) = 0.75 ( ) P-value = Placebo Rosuvastatin Rosuva Placebo Years

16 Hope-3 Trial: Expected results

17 Hope-3 Trial: Conclusions Rosuvastatin 10mg/day reduced: LDL-C by 0.9 mmol/l CVD by 25% Consistent benefits regardless of: LDL-C SBP Risk CRP Ethnicity Excess in muscle pain/weakness (reversible) and perhaps cataract surgery No excess in rhabdomyolysis, myopathy or new diabetes 27

18 Fourier trial

19 PCSK9 rapid progress from discovery to bedside

20 Serum LDL-Cholesterol Binds to LDL-Receptors. Following Internalization, LDL is Degraded and the In the Presence of PCSK9, the LDL-R Is Degraded and Does Not Cycle Back to Cell Surface Receptor Recycled Plasma LDL PCSK9 LDL LDL-R LDL-R Endocytosis Hepatocyte Endocytosis LDL-R Recycling PCSK9 Self-procession Endosome Endosome Golgi Apparatus LDL Degradation LDL, LDL-R and PCSK9 Degradation Qian YW, et al. J Lipid Res. 2007;48: ; Horton JD, et al. J Lipid Res. 2009;50(suppl):S172-S177. Nucleus Endoplasmic Reticulum (ER) 2013 Amgen Canada Inc. All rights reserved.

21 Evolocumab: Fourier Trial

22 Fourier: Follow up Randomized 27,564 patients Evolocumab (N=13,784) Placebo (N=13,780) Follow-up median 26 months (IQR 22-30) 2907 patients experienced primary endpoint 1829 experienced key secondary endpoint Premature perm. drug discontinuation 5.6%/yr 5.8%/yr Withdrew consent 0.29%/yr 0.35%/yr Lost to follow-up 5 patients 13 patients Ascertainment for primary endpoint was complete for 99.5% of potential patient-years of follow up

23 Baseline Characteristics Characteristic Value Age, years, mean (SD) 63 (9) Male sex (%) 75 Type of cardiovascular disease (%) Myocardial infarction 81 Stroke (non-hemorrhagic) 19 Symptomatic PAD 13 Cardiovascular risk factor (%) Hypertension 80 Diabetes mellitus 37 Current cigarette use 28 Median time from most recent event ~3 yrs Pooled data; no differences between treatment arms

24 Baseline Characteristics Characteristic Value Statin use (%)* High-intensity 69 Moderate-intensity 30 Ezetimibe use (%) 5 Median lipid measures (IQR) mg/dl LDL-C 92 (80-109) Total cholesterol 168 ( ) HDL-C 44 (37-53) Triglycerides 133 ( ) 2.4 mmol/l 3.3 mmol/l 1.1 mmol/l 1.5 mmol/l *Per protocol, patients were to be on atorva 20 mg/d or equivalent. 1% were on low intensity or intensity data were missing. Statin intensity defined per ACC/AHA 2013 Cholesterol Guidelines. Pooled data; no differences between treatment arms

25 LDL-C 1.45 mmol/l (95% CI ) (Median 0.78 mmol/l IQR, mmol/l

26 Primary endpoint CV death, MI, stroke, hosp. for UA, or coronary revasc

27 Secondary endpoint CV death, MI or stroke (MACE)

28 Types of CV Outcomes Endpoint Evolocumab (N=13,784) Placebo (N=13,780) 3-yr Kaplan-Meier rate HR (95% CI) CV death, MI, or stroke ( ) Cardiovascular death ( ) Death due to acute MI ( ) Death due to stroke ( ) Other CV death ( ) MI ( ) Stroke ( )

29 Safety Evolocumab (N=13,769) Placebo (N=13,756) Adverse events (%) Any Serious Allergic reaction Injection-site reaction Treatment-related and led to d/c of study drug Muscle-related Cataract Diabetes (new-onset) Neurocognitive Laboratory results (%) Binding Ab 0.3 n/a Neutralizing Ab none n/a New-onset diabetes assessed in patients without diabetes at baseline; adjudicated by CEC

30 Neurocognitive substudy Placebo SC Q2W or QM RANDOMIZED DOUBLE BLIND Evolocumab SC 140 mg Q2W or 420 mg QM 2442 patients screened for EBBINGHAUS 1974 Enrolled (Full Analysis Pop) Median F/U 19.8 months MAJOR EXCLUSIONS 1. Not enrolled in FOURIER 2. >12 wk FOURIER visit 3. H/O dementia, cognitive impairment or other conditions interfering with participation Primary Analysis Cohort (N=1204) Baseline cognitive testing on/before 1 st dose of study drug and had f/u cognitive testing post dosing* Additional 770 pts w/ baseline assessment before week 12 visit *Cognitive tests performed at baseline; at 6, 12, 24 months; and end of study Giugliano RP et al. Clin Card 2017;40:59 65

31 Primary Endpoint Spatial Working Memory Strategy Index 25 Placebo Evolocumab Mean Number of boxes Baseline Post baseline Change

32 Cognitive assessment by LDL-C Mean D of boxes Primary CANTAB Endpoint*: Average Change from Baseline # pts <0.65 <25 mg/dl mmol/l mg/dl mmol/l > mmol/l mg/dl Nadir LDL-Achieved (mmol/l) P=NS across LDL values achieved and also between treatments Placebo Evolocumab

33 Self reported symptoms All Patients Placebo (N=781) Mean (SD) Evolocumab (N=800) Mean (SD) P-Value Memory 1.16 (0.39) 1.17 (0.39) 0.81 Executive functioning total score 1.11 (0.32) 1.12 (0.32) 0.28 Planning 1.08 (0.31) 1.10 (0.32) 0.20 Organization 1.09 (0.32) 1.10 (0.33) 0.57 Divided attention 1.15 (0.42) 1.16 (0.41) 0.54 Total Score 1.13 (0.33) 1.14 (0.33) 0.42 Patient self-report at end of study as compared to randomization, graded as 1. Better or no change 2. Questionable / occasionally worse 3. Consistently a little worse 4. Consistently much worse Lower scores represent better cognition Results shown are in the full study population

34 Summary LDL-C by 59% Consistent throughout duration of trial Median achieved LDL-C of 0.78 mmol/l IQR, mmol/l CV outcomes in patients already on statin therapy 20% MACE (CV death, MI, or stroke) Consistent benefit in all subgroups Long-term benefits consistent w/ statins per mmol/l LDL-C Safe and well-tolerated Similar rates of AEs, incl DM & neurocog events w/ EvoMab & pbo Rates of EvoMab discontinuation low and no greater than pbo No neutralizing antibodies developed

35 PCSK9 inhibitors in Canada Both Repatha and Praluent have been approved by Health Canada Familial Hypercholesterolemia 1. Patient has a confirmed diagnosis of HeFH 2. Patient is unable to reach the target LDL-C level specified in current guidelines 3. Patient is currently receiving optimally tolerated standard of care (maximally tolerated statins (MTS) with or without ezetimibe Secondary prevention 1. Patient is unable to reach the target LDL-C level specified in current guidelines Patient is currently receiving optimally tolerated standard of care (MTS with or without ezetimibe)

36 Administration Alirocumab Administration 1 injection SC q2wk, Doses: 75 mg or 150 mg Auto-injector ALIROCUMAB ALIROCUMAB *As per the product monograph, measure LDL-C levels within 4 to 8 weeks of initiation or titration to assess response and adjust dose if needed Evolocumab Administration 1 injection SC q2wk, Dose: 140 mg 3 injections SC q4wk Total Dose: 420 mg Auto-injector Patient Support Programs available for both: MyPraluent Coach and Repatha Ready

37 Inflammation and atherosclerosis

38 Rudolf Virchow Inflammation-based arterial changes is a mechanism of primary importance in atherosclerosis mid 19th century Virchow, R. Cellular Pathology. London: John Churchill;

39 The Antiatherogenic Effect of Cortisone Chow-fed (n=5) Cholesterol-fed (n=11) Cholesterol-fed + cortisone (n=8) Plasma cholesterol mg/dl Aortic cholesterol g/100g FRIEDMAN M et al. Arch Pathol. 77:142, 1964 Segments of ascending aorta (Intimal sudanophilic deposits in black) Atherosclerosis score Chol-fed + Cortisone Chowfed Cholesterolfed

40 Atherosclerosis: A Chronic Inflammatory Disease Stroke TIA Injury Endothelial dysfunction LDL Fatty streak Inflammation Infiltration Remodeling Plaque progression Plaque instability Rupture Thrombosis Occlusion Years of life Myocardial infarction Angina Hypertension Renal failure Peripheral arterial disease

41 Inflammatory Cascade CRP

42 < 1 mg/l 1 to 3 mg/l > 3 mg/l PHS 1997 WHS 2000 UK 2000 MONICA 2004 ARIC 2004 Iceland NHS 2004 HPFUS 2004 EPIC-N 2005 Strong 2005 Kuopio 2005 FHS CHS 2005 PIMA 2005 Fully Adjusted Relative Risk Observation studies: hscrp and CVD

43 Statin RCT: LDL and CRP effects Cumulative Rate of Recurrent Myocardial Infarction or Coronary Death (percent) LDLC> 1.8mmol/L LDLC< 1.8mmol/L hscrp>2 mg/l hscrp<2 mg/l Ridker et al NEJM 2005;352: Follow-Up (years)

44 Statins for Low LDL high hscrp patients? AFCAPS/TexCAPS Low LDL Subgroups Low LDL, Low hscrp Low LDL, High hscrp Statin Effective RR Statin Not Effective However, while intriguing and of potential public health importance, the observation in AFCAPS/TexCAPS that statin therapy might be effective among those with elevated hscrp but low cholesterol was made on a post hoc basis. Thus, a large-scale randomized trial of statin therapy was needed to directly test this hypotheses. Ridker et al, New Engl J Med 2001;344:

45 JUPITER Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hscrp No Prior CVD or DM Men >50, Women >60 LDL <3.4 mmol/l hscrp >2 mg/l 4-week run-in Rosuvastatin 20 mg (N=8901) Placebo (N=8901) MI Stroke Unstable Angina CVD Death CABG/PTCA Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland, United Kingdom, Uruguay, United States, Venezuela Ridker et al, Circulation 2003;108:

46 JUPITER Myocardial Infarction, Stroke, Cardiovascular Death Cumulative Incidence Number at Risk Rosuvastatin Placebo HR 0.53, 95%CI P < Follow-up (years) Placebo (N = 157) - 47 % Rosuvastatin (N = 83) 8,901 8,643 8,437 6,571 3,921 1,979 1, ,901 8,633 8,381 6,542 3,918 1,992 1,

47 JUPITER Secondary Endpoint All Cause Mortality Cumulative Incidence Number at Risk Rosuvastatin Placebo HR 0.80, 95%CI P= Follow-up (years) Placebo 247 / % Rosuvastatin 198 / ,901 8,847 8,787 6,999 4,312 2,268 1,602 1, ,901 8,852 8,775 6,987 4,319 2,295 1,614 1,

48 Ridker PM. Eur Heart J 2016;37: Residual Cardiovascular Risk Known Cardiovascular Disease LDL 150 mg/dl (3.8 mmol/l) hscrp 4.5mg/L High Intensity Statin Residual Cholesterol Risk LDL 110 mg/dl (2.8 mmol/l) hscrp 1.8 mg/l Residual Inflammatory Risk LDL 70 mg/dl (1.8 mmol/l) hscrp 3.8 mg/l Additional LDL Reduction IMPROVE-IT : Ezetimibe 6% RRR FOURIER/SPIRE: PCSK9 Inhibition q2 weeks 15% RRR Additional Inflammation Reduction No Prior Proof of Concept

49 Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) Stable CAD (post MI) On Statin, ACE/ARB, BB, ASA Persistent Elevation of hscrp (> 2 mg/l) N = 10, Countries April June Primary Events Randomized Canakinumab 50 mg SC q 3 months Randomized Canakinumab 150 mg SC q 3 months Randomized Canakinumab 300 mg SC q 3 months* Randomized Placebo SC q 3 months Primary CV Endpoint: Nonfatal MI, Nonfatal Stroke, Cardiovascular Death (MACE) Key Secondary CV Endpoint: MACE + Unstable Angina Requiring Unplanned Revascularization (MACE+) Critical Non- Cardiovascular Safety Endpoints: Cancer and Cancer Mortality, Infection and Infection Mortality

50 Canakinumab (Novartis) Monoclonal anti-interleukin-1β (IL-1 β) antibody indicated for the treatment of IL-1 β driven inflammatory diseases Binds to human IL-1β and functionally neutralize the bioactivity of this proinflammatory cytokine Long half-life (4-8 weeks) with CRP and IL- 6 reduction for up to 3 months

51 CANTOS: Baseline Clinical Characteristics Characteristic Placebo (N=3347) Canakinumab SC q 3 months 50 mg (N=2170) 150 mg (N=2284) 300 mg (N=2263) Age (years) Female (%) Current smoker (%) Diabetes (%) Lipid lowering therapy (%) Renin-angiotensin inhibitors (%) Prior Revascularization (%) LDL cholesterol (mg/dl) HDL cholesterol (mg/dl) Triglycerides (mg/dl) hscrp (mg/l) mmol/l

52 Placebo Canakinumab 50 Canakinumab 150 Canakinumab 300 CANTOS: Biomarkers Placebo SC q 3 mth Percent Change from Baseline (median) hscrp LDLC HDLC Canakinumab 50mg SC q 3 mth Canakinumab 150mg SC q 3 mth Canakinumab 300mg SC q 3 mth 10 TG Months

53 CANTOS: CVD CV death, MI or stroke (MACE)

54 CANTOS: Adverse Effets Adverse Event Placebo (N=3347) Canakinumab SC q 3 months 50 mg (N=2170) 150 mg (N=2284) 300 mg (N=2263) P-trend Any SAE Leukopenia Any infection Fatal infection /0.02* Injection site reaction Any Malignancy Fatal Malignancy Arthritis Osteoarthritis Gout ALT > 3x normal Bilirubin > 2x normal (per 100 person years of exposure) * P-value for combined canakinumab doses vs placebo

55 CANTOS: Cancer Incidence

56 CANTOS: Cancer mortality

57 Conclusions Cholesterol and atherosclerosis Statins remain the first line therapy to reduce LDL-C and CVD risk Ezetrol and PCSK9 inhibitors confer additional cardiovascular benefit to statin therapy These drugs are all very well tolerated Inflammation and atherosclerosis Canakinumab will significantly decrease CVD risk on top of statin therapy An increase in the incidence of fatal infections was observed Canakinumab was associated with a decreased incidence of lung cancer and decreased cancer mortality Novel and safer inhibitors of inflammation could be developed in the future

58 Questions?