Inflammation, the Inflammasome and CAD Do Cardiologists need to know this? Jacques Genest MD

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1 Inflammation, the Inflammasome and CAD Do Cardiologists need to know this? Jacques Genest MD Cardiovascular Research Laboratories Research Institute of the McGill University Health Center

2 Disclosure J. Genest MD 2013 Advisory Board, Speaker s Bureau, Consultant, Grants, Clinical Trials Merck * Pfizer Novartis AMGEN * Roche * AstraZeneca Stock ownership: none; Off label use: none * Scientific Advisory Sanofi/Regeneron Lilly Valeant Biotech: Danone Acasti Nutrasource Relevant disclosure: JUPITER, IMPROVE-IT, CANTOS, CAPREE steering Committees; REVEAL, ACCELERATE, AMG145 Clinical Trials.

3 Questions Are inflammatory diseases a risk factor for CVD? Do markers of inflammation predict risk? Should this influence screening and treatment? What is new in inflammation and CVD?

4 Inflammatory Diseases and CVD Can J Cardiol 2011;27:

5 Inflammatory Diseases and CVD MI CVD CVD deaths Lupus Erythomatosus Rheumatoid Arthritis Ankylosing Spondylitis Psoriatic Arthritis Polymyositis / Dermatomyositis Inflammatory Bowel Disease Roifman I et al. Can J Cardiol 2011;27:

6 Cardiovascular Mortality in Rheumatoid Arthritis

7 Rheumatoid Arthritis and CVD Libby P. Am J Med 2008

8 QUEST-RA Study Naranjo A. Arthritis Res Ther. 2008; 10(2): R30.

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10 Inflammation and Atherosclerosis

11 Proof in Pudding Concept -I Is a strategy based on hscrp risk determination and treatment effective? The JUPITER Study

12 JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death Cumulative Incidence HR 0.56, 95% CI P < Ridker et al NEJM 2008 Number Needed to Treat (NNT 5 ) = Placebo 251 / % Rosuvastatin 142 / 8901 Number at Risk Rosuvastatin Placebo Follow-up (years) 8,901 8,631 8,412 6,540 3,893 1,958 1, ,901 8,621 8,353 6,508 3,872 1,963 1,

13 Conclusion from JUPITER A screening strategy that includes hscrp influences therapeutic decisions and alters outcomes favorably. Few physicians are buying it

14 BIOMARKERS: Serum/Plasma Apolipoproteins* Atrial Natriuretic Peptide (ANP) hscrp HgA1c Lipoprotein-associated phospholipase A2 Inflammatory biomarkers (spla2, IL) Homocysteine Class III Class III Class IIa Class IIb Class IIb N/A N/A * Apo AI, apo B, LDL particle size by gel or NMR, HDL particle size, density JUPITER indications (Same as in Canada)

15 Is CRP Causal in Atherosclerosis? Epidemiological association does not imply causality Animal data Mendelian Randomization

16 Mendelian Randomization CRP Genetics and Outcome Zacko et al NEJM 2008;359:1897.

17 Conclusion: Human genetic data indicate that C reactive protein concentration itself is unlikely to be even a modest causal factor in coronary heart disease. Authors, Engert J et al. BMJ Feb 15;342:d548. doi: /bmj.d548.

18 The forest plots show the meta-analysis of the association of the CRP genetic risk score with MI (A) and CHD (B). Dehghan A et al. Circulation 2011;123: Copyright American Heart Association

19 Take Home Point Based on animal models and Mendelian randomization experiments, it is unlikely that CRP plays a causal role in atherosclerosis hscrp is a non-specific biomarker of inflammation

20 Gout: Uric acid crystalopathy

21 Questions / Objectives What is Cryopyrin-Associated Periodic Syndrome (CAPS)? Are cholesterol crystals only seen in latestage atherosclerosis? What is the inflammasome? Is this useful clinically?

22 Cholesterol Crystals in Plaques

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24 Duewell, P, et al, Nature 2010; 464: Rajamaki K et al, PLoS One 2010;5:e11765

25 Points to Take Home (1) Vascular Inflammation is triggered by many stimuli including cholesterol crystals Mononuclear cells accumulate at sites of inflammation Mediators of inflammation propagate the inflammatory response Biomarkers of inflammation increase in serum

26 The Inflammasome Inflammasomes are large, multimeric protein complexes that link the sensing of microbial products and metabolic stress to the proteolytic processing of prointerleukin (pro-il)-1β to its active form. NATURE CLINICAL PRACTICE RHEUMATOLOGY 2008 VOL 4 NO 1

27 NATURE CLINICAL PRACTICE RHEUMATOLOGY 2008 VOL 4 NO 1

28 Targeted Inactivation of IL-1b In Man The CANTOS Study

29 Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) To directly test the inflammatory hypothesis of atherothrombosis To determine whether long-term inhibition of interleukin-1b with canakinumab (50 mg,150 mg or 300 mg SQ every three months) as compared to placebo will reduce rates of recurrent cardiovascular events among stable post-myocardial infarction patients who remain at elevated vascular risk due to increased levels of hscrp (> 2 mg/l) despite usual care, including statin therapy. 29

30 What about secondary prevention? Clinical Relevance of Achieved hscrp in Stable ACS Patients After Treatment with Statin Therapy Cumulative Rate of Recurrent Myocardial Infarction or Coronary Death (percent) hscrp>2 mg/l hscrp<2 mg/l Ridker et al NEJM 2005;352: Follow-Up (years)

31 Immunomodulation by Inhibition of Cytokines TNF-a: IL-1b IL-1R Il-6 adalinumab (HUMIRA); infliximab (REMICADE); ethenercept (EMBREL) canakinumab (ILARIS) anakinra (KINERET) mimics IL-1RA tocilizumab (ACTEMRA) (elsilimumab in cancers)

32 Canakinumab high-affinity human monoclonal anti-human interleukin-1b (IL-1b) antibody currently indicated for the treatment of IL-1b driven inflammatory diseases (Cryopyrin-Associated Period Syndrome [CAPS], Muckle-Wells Syndrome) designed to bind to human IL-1b and functionally neutralize the bioactivity of this pro-inflammatory cytokine long half-life (4-8 weeks) with CRP and IL-6 reduction for up to 3 months

33 Issues in the Selection of Anti-inflammatory Agents for Trials of Cardiovascular Inflammation Inhibition Statins TNF inhibition IL-6 Inhibition IL-1b inhibition TC LDL HDL TG Chylo CRP / IL-6

34 Potential Strengths of IL-1b Antagonism in Atherothrombosis Selective: an important pro-inflammatory mediator, but not essential for host defense Leaves IL-1a signaling intact Implicated in atherothrombosis and plaque rupture in several preclinical and clinical studies Potentially beneficial effects without altering lipids or platelet function Safety, tolerability, and adverse effect profiles acceptable for a secondary prevention trial

35 Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) Event driven trial Sample size of 17,200 randomized participants assigned in a 1:1:1:1.5 allocation canakinumab 50, 150 and 300 mg quarterly, and placebo. Trial completion after 1400 primary endpoints ; estimated 4.0 year trial period. 90 %power to detect the superiority canakinumab compared to placebo, assuming a RR of 20 %. Data and Safety Monitoring Board (DSMB) will review unblinded safety data at least twice yearly. 35

36 Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) Stable CAD (post MI) On Statin, ACE/ARB, BB, ASA Persistent Elevation of hscrp (> 2 mg/l) 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 Endpoint: Nonfatal MI, Nonfatal Stroke, Cardiovascular Death Secondary Endpoints: Total Mortality, New Onset Diabetes, Other Vascular Events Exploratory Endpoints: DVT/PE; SVT; hospitalizations for CHF; PCI/CABG; biomarkers 36

37 CANTOS: Canakinumab Anti-inflammatory Thrombosis Outcomes Study Argentina Australia Brazil Canada China Colombia Germany Hungary India Italy Japan Korea Poland Romania Netherlands Russia Slovakia Sweden Taiwan United States

38 The Cardiovascular Inflammation Reduction Trial (CIRT) is a randomized clinical trial investigating whether taking low-dose methotrexate reduces heart attacks, strokes, or death in people with type 2 diabetes or metabolic syndrome that have had a heart attack. This trial is funded by the National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH). Estimated Enrollment: 7000 Study Start Date: March 2013 Estimated Study Completion Date: December 2018

39 Methotrexate and CVD: Meta-analysis Micha R Am J Cardiol. 2011; 108(9):

40 Conclusions The relationship between cholesterol and inflammation and atherosclerosis is better understood Cholesterol crystals activate the inflammasome In turn, IL-1b (and IL-18) are secreted by macrophages, initiating a local systemic reaction A low-grade systemic inflammation is also initiated by other cytokines (IL-6); this can be measured by biomarkers such as hscrp

41 Newsweek 14 May 2012