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Inflammation and Atherothrombosis:An Update on Trials

Assessing New Anti-Inflammatory Agents

Paul M Ridker, MD, MPHEugene Braunwald Professor of Medicine

Harvard Medical SchoolDirector, Center for Cardiovascular Disease Prevention

Brigham and Women’s Hospital, Boston MA

Baptist Health South Florida CME2015 Cardiovascular Disease Prevention 13th Annual International Symposium

Dr Ridker has received investigator-initiated resea rch support from the NHLBI, NCI, American Heart Association, Do nald W Reynolds Foundation, Leduc Foundation, Doris Duke C haritable Foundation, AstraZeneca, Novartis, and SanofiAventi s.

Dr Ridker has served as a consultant to Vascular Bi ogenics, Merck, ISIS, and Genzyme.

Dr Ridker is listed as a co-inventor on patents hel d by the Brigham and Women’s Hospital (BWH) that relate to t he use of inflammatory biomarkers in cardiovascular disease a nd diabetes that have been licensed to Seimens and AstraZeneca. Dr. Ridker and the BWH receive royalties on sales of the hsCRP test. However, neither Dr. Ridker nor the BWH receives an y royalties attributable to sales of the hsCRP test used in con nection with the CIRT or CANTOS trials.

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0 2 4 6 8

Years of Follow-Up

0.96

0.97

0.98

0.99

1.00

Quintiles of LDL

0 2 4 6 8

Years of Follow-Up

0.96

0.97

0.98

0.99

1.00

CV

D E

vent

-Fre

e S

urvi

val P

roba

bilit

y

Quintiles of hsCRP

Ridker et al N Engl J Med. 2002;347:1157-1165.

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4

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2

1

5

4

3

2

1

Event-Free Survival According to Baseline Quintiles of hs-CRP and LDL Cholesterol

sICAM1VCAMP-selectinEselectinIL-6, IL-18IL1raTNF / YKL-40

CRP, IL-6 and the Risk for DevelopingType-2 Diabetes in the Women’s Health Study

Pradhan et al JAMA 2001; 286:327-34

0

2

4

6

8

10

12

14

16

1 2 3 40

2

4

6

8

10

12

14

16

1 2 3 4

Relative RiskIL-6

Relative RiskIL-6

Relative Riskhs-CRP

Relative Riskhs-CRP

Quartile of ILQuartile of IL--66 Quartile of hsQuartile of hs--CRPCRP

Fully adjustedFully adjusted BMIBMI--adjustedadjusted CrudeCrude

0 2 4 6 8Years of Follow-Up

0.95

0.96

0.97

0.98

0.99

1.00

CV

D E

vent

-Fre

eS

urvi

val P

roba

bilit

y

CRP < 1 mg/LCRP < 1 mg/L

CRP 1-3 mg/LCRP 1-3 mg/L

CRP >CRP >3 mg/L3 mg/L

CRP adds to the ATP-III Definition of the Metabolic Syndrome(N = 3,097 with ATP-III Metabolic Syndrome)

Ridker et alCirculation 2003;107:391-7

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Linear Relationship of Inflammation to Vascular Risk Across a Linear Relationship of Inflammation to Vascular Risk Across a Very Wide Range of ValuesVery Wide Range of Values

0

1

2

3

4

5

6

7

8

<0.5 0.5-1.0 1.0-2.0 2.0-3.0 3.0-4.0 4.0-5.0 5.0-10.0 10.0-20.0 >20

hsCRP (mg/L)

Rel

ativ

e R

isk

of F

utur

e C

V E

vent

s

“lower risk”< 1 mg/L

“moderate risk”1 – 3 mg/L

“higher risk”> 3 mg/L

Ridker et al Circulation 2004;109:1955-59

CR-8Emerging Risk Factor Collaborators, Lancet January 2010

0.5 1.0 1.2 1.4 1.8

hsCRP

Systolic BP

Total cholesterol

Non-HDLC

1.37 (1.27-1.48)

1.35 (1.25-1.45)

1.16 (1.06-1.28)

1.28 (1.16-1.40)

Risk Ratio (95%CI)

The magnitude of independent risk associated with i nflammation is at least as large, if not larger, than that of BP a nd cholesterol

Risk Ratio (95%CI) per 1-SD higher usual values

Adjusted for age, gender, smoking, diabetes, BMI, triglycerides, a lcohol, lipid levels, and hsCRP

Why do we treat individuals with a persistent pro-inflammatory response with statin therapy?

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4

Ridker et al Circulation. 1998;98:839–844.

Rel

ativ

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isk

Rel

ativ

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isk

PP Trend = 0.005Trend = 0.005

0

1

2

3

Pravastatin Placebo Pravastatin Placebo

PravastatinPravastatin

PlaceboPlacebo

Med

ian

hsM

edia

n hs

--CR

P (

mg/

dL)

CR

P (

mg/

dL)

--21.6% (21.6% (PP=0.004)=0.004)

0.18

0.19

0.20

0.21

0.22

0.23

0.24

0.25

Baseline 5 Years

Ridker et al Circulation. 1999;100:230-235.

Inflammation, Statin Therapy, and hsCRP: Initial Observations

Inflammation PresentInflammation Absent

10

Follow-Up (years)

0.0 0.5 1.0 1.5 2.0 2.5

0.00

0.02

0.04

0.06

0.08

0.10

hsCRP>2 mg/L

hsCRP<2 mg/L

0.0 0.5 1.0 1.5 2.0 2.5

0.00

0.02

0.04

0.06

0.08

0.10

Cum

ulat

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Rat

e of

Rec

urre

nt M

yoca

rdia

l Inf

arct

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or C

oron

ary

Dea

th (

perc

ent)

LDLC>70 mg/dL

LDLC<70 mg/dL

Clinical Relevance of Achieved LDL and Achieved CRP After ACS Treated with Statin Therapy

Ridker et al NEJM 2005;352:20-28.

0.0 0.5 1.0 1.5 2.0 2.50.0 0.5 1.0 1.5 2.0 2.50.0 0.5 1.0 1.5 2.0 2.50.0 0.5 1.0 1.5 2.0 2.5

0.00

0.02

0.04

0.06

0.08

0.10

0.02

0.04

0.06

0.08

0.10

Follow-Up (Years)

LDL > 70 mg/dL, CRP > 2 mg/L

LDL < 70 mg/dL, CRP > 2 mg/LLDL > 70 mg/dL, CRP < 2 mg/L

LDL < 70 mg/dL, CRP < 2 mg/L

Clinical Relevance of Achieved LDL and Achieved CRP After ACS Treatmed with Statin Therapy

Ridker et al NEJM 2005;352:20-28.

“dual targets for statin therapy”

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REVERSAL: Regression of Atherosclerosis On Statin T herapy Occurs REVERSAL: Regression of Atherosclerosis On Statin T herapy Occurs Primarily Among Those with Primarily Among Those with BothBoth LDL and CRP ReductionLDL and CRP Reduction

-4

-2

0

2

4

6

8

10

Nissen et al NEJM 2005; 352:29-38

LDLCRP

LDLCRP

LDLCRP

LDLCRP

+8mm3

+2mm3

- 1mm3

- 2mm3

Rosuvastatin 20 mg (N=8901)Rosuvastatin 20 mg (N=8901) MIMIStrokeStroke

UnstableUnstableAnginaAngina

CVD DeathCVD DeathCABG/PTCACABG/PTCA

44--week week runrun--inin

No Prior CVD or DMNo Prior CVD or DMMen Men >>50, Women 50, Women >> 6060

LDL <130 mg/dLhsCRP >2 mg/L

JUPITERTrial Design

Placebo (N=8901)Placebo (N=8901)

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mex ico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Afri ca, Switzerland,

United Kingdom, Uruguay, United States, Venezuela

Mean LDLC 104 mg/dL, Mean HDLC 50 mg/dL, hsCRP 4 mg /L

JUPITERMulti-National Randomized Double Blind Placebo Controlled Trial of

Rosuvastatin in the Prevention of Cardiovascular EventsAmong Individuals With Low LDL and Elevated hsCRP

Ridker et al NEJM 2008;359:2195-2207

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JUPITERPrimary Trial EndpointPrimary Trial EndpointPrimary Trial EndpointPrimary Trial Endpoint :::: MI, Stroke, UA/Revascularization, CV DeathMI, Stroke, UA/Revascularization, CV DeathMI, Stroke, UA/Revascularization, CV DeathMI, Stroke, UA/Revascularization, CV Death

Placebo Placebo Placebo Placebo 251 / 8901251 / 8901251 / 8901251 / 8901

Rosuvastatin Rosuvastatin Rosuvastatin Rosuvastatin 142 / 8901142 / 8901142 / 8901142 / 8901

HR 0.56, 95% CI 0.46HR 0.56, 95% CI 0.46HR 0.56, 95% CI 0.46HR 0.56, 95% CI 0.46----0.690.690.690.69P < 0.00001P < 0.00001P < 0.00001P < 0.00001

Number Needed to Treat (NNT5) = 25

---- 44 %44 %44 %44 %

0 1 2 3 4

0.00

0.02

0.04

0.06

0.08

Cum

ulat

ive

Inci

denc

e

Number at Risk Follow-up (years)

RosuvastatinPlacebo

8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 1578,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

Ridker et al NEJM 2008;359:2195-2207

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0

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hsC

RP

(mg/

L)

0

20

40

60

80

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LDL

(m

g/dL

)

Months0 12 24 36 48

JUPITERAchieved LDLC, Achieved hsCRP, or Both?

LDL decrease 50 percent at 12 months LDL decrease 50 percent at 12 months LDL decrease 50 percent at 12 months LDL decrease 50 percent at 12 months

hsCRP decrease 37 percent at 12 monthshsCRP decrease 37 percent at 12 monthshsCRP decrease 37 percent at 12 monthshsCRP decrease 37 percent at 12 months

Is the large benefit observed in the JUPITER trial due to lipid lowering, to inflammation inhibition, or to a combination of these two processes?

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CR-17

JUPITERAbsolute Risk Reduction Increases With Increasing Levels of hsCRP

0.20 0.5 1.0 2.0

Better Worse

Baseline hsCRP

>10 mg/L_

>9 mg/L_

>8 mg/L_

>7 mg/L_

>6 mg/L_

>5 mg/L_

>4 mg/L_

>3 mg/L_

>2 mg/L_

N

2,503

3,071

3,839

4,723

5,897

7,425

9,726

12,939

17,802

1.0 2.0 3.0 4.0 5.0

Placebo Event Rate

Ridker et al, Am J Card 2010;106:206-9

JUPITERLDL reduction, hsCRP reduction, or both?

N Rate

Placebo 7832 1.11LDL>70mg/dL,hsCRP> 2 mg/L 1384 1.11LDL<70mg/dL,hsCRP> 2 mg/L 2921 0.62LDL>70mg/dL,hsCRP<2 mg/L 726 0.54LDL<70mg/dL,hsCRP<2 mg/L 2685 0.38

Placebo 7832 1.11LDL>70mg/dL,hsCRP> 1 mg/L 1874 0.95LDL<70mg/dL,hsCRP> 1 mg/L 4662 0.56LDL>70mg/dL,hsCRP<1 mg/L 236 0.64LDL<70mg/dL,hsCRP<1 mg/L 944 0.24

1.00.50.25 2.0 4.0

P < 0.001

RosuvastatinBetter

Rosuvastatin Worse

P < 0.001

Full Adjusted Hazard Ratio0.21, 95% CI 0.09-0.52, P < 0.0001

Ridker et al Lancet 2009;373:1175-82

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7

Puri R et al for the SATURN Investigators. Circulation 2013;128:2395-2403.

Hazard Ratio for Time to First MACE

JUPITERTotal Venous Thromboembolism

0 1 2 3 4

0.00

00.

005

0.01

00.

015

0.02

00.

025

Cum

ulat

ive

Inci

denc

e

Number at Risk Follow-up (years)

RosuvastatinPlacebo

8,901 8,648 8,447 6,575 3,927 1,986 1,376 1,003 548 1618,901 8,652 8,417 6,574 3,943 2,012 1,381 993 556 182

HR 0.57, 95%CI 0.37HR 0.57, 95%CI 0.37HR 0.57, 95%CI 0.37HR 0.57, 95%CI 0.37----0.860.860.860.86P= 0.007P= 0.007P= 0.007P= 0.007

Placebo Placebo Placebo Placebo 60606060 / 8901/ 8901/ 8901/ 8901

Rosuvastatin Rosuvastatin Rosuvastatin Rosuvastatin 34 / 890134 / 890134 / 890134 / 8901

---- 43 %43 %43 %43 %

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Glynn et al NEJM 2010

Can Targeted Anti-Inflammatory Therapy Reduce Cardiovascular Event Rates and Prolong Life?

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Ridker P Luscher T Eur Heart Journal 2014

Targeting Inflammatory Pathways for the Treatment o f Cardiovascular Disease

P=0.01P=0.003

P=0.3

Quartile of IL-6 (range, pg/dL)

P Trend = 0.001

≤1.04 1.04-1.46 1.47-2.28 ≥2.28

Rel

ativ

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isk

of M

I

Ridker et al, Circulation 2000;101:1767-1772

0

1

2

3

1 2 3 4

IL-6 and Risk of Future MI in Apparently Healthy Men

Relationship of IL-6 and Future Cardiovascular Events

Kaptoge et al, Eur Heart J 2013

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Mendelian Randomization and the IL-6 Regulatory Pat hway

Lancet 2012;379;1214-24Lancet 2012;379;1205-13

0

-5

-10

-15

-20

1/1 1/2 2/2

CR

P R

educ

tion

(%)

C/C C/T T/T

1.00

0.95

0.90

CRP Reduction (%) Hazard Ratio CHD

Haz

ard

Rat

io fo

r C

HD

rs2228145 rs7529229

Effects of Polymorphism in the IL-6 Receptor Signal ing Pathway On Downstream CRP Levels and Risks of Coronary Hear t Disease

Swerdlow et al, Lancet 2012;379;1214-24Sawar N et al, Lancet 2012;379;1205-13

0

-5

-10

-15

-20

1/1 1/2 2/2

CR

P R

educ

tion

(%)

C/C C/T T/T

1.00

0.95

0.90

CRP Reduction (%) Hazard Ratio CHD

Haz

ard

Rat

io fo

r C

HD

rs2228145 rs7529229

Effects of Polymorphism in the IL-6 Receptor Signal ing Pathway On Downstream CRP Levels and Risks of Coronary Hear t Disease

Swerdlow et al, Lancet 2012;379;1214-24Sawar N et al, Lancet 2012;379;1205-13

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Drug Target Trial Size Sponsor Status

A. Agents That Primarily Target the IL-6 Signaling Pathway

Canakinumab IL-1β CANTOS 10,000 Novartis EnrollingMethotrexate IL-6,TNF CIRT 7,000 NHLBI EnrollingAnakinra IL-1Ra IL-HEART 190 UK-MRC CompletedColchicine multiple LoDoCo 532 HRS, Aus PositiveTocilizumab IL-6 ENTRACTE 3,080 Hoffmann EnrollingInfliximab TNF ENTRACTE 3,080 Hoffmann Enrolling

B. Agents That Do Not Primarily Target the IL-6 Signaling Pathway

Succinobucol Ox-LDL ARISE 6,144 AtheroGenics NegativeVarespladib sPLA2 VISTA-16 5,000 Anthera NegativeDarapladib Lp-PLA2 STABILITY 15,000 GSK NegativeDarapladib Lp-PLA2 SOLID-TIMI-52 13,000 GSK NegativeInclacumab P-Selectin SELECT-ACS 544 Roche Completed Inclacumab P-Selectin SELECT-CABG 380 Roche Enrolled

Differentiating Anti-Inflammatory Agents ThatDo and Do Not Target the Central IL-6 Signaling Pathway

Ridker P Luscher T Eur Heart Journal 2014

TC

LDL

HDL

TG

Chylo

CRP / IL-6

Statins TNFinhibition

IL-6Inhibition

Issues in the Selection of Anti-inflammatory Agents forTrials of Cardiovascular Inflammation Inhibition

LDM IL-1ββββinhibition

For More Information :

theCIRT.org theCANTOS.org

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• To directly test the inflammatory hypothesis of atherothrombosis

• To evaluate in a randomized, double-blind, placebo-controlled trial whether MTX given at a target dose of 20 mg po weekly over a three year period will reduce rates of recurrent myocardial infarction, stroke, or cardiovascular death among patients with a prior history of myocardial infarction and either type 2 diabetes or metabolic syndrome.

Cardiovascular Inflammation Reduction Trial (CIRT)(Ridker PI) Primary Aims

N = 7,000 NHLBI-SponsoredEnrollment to Start June 2013350 US and Canadian Sites

Stable CAD (post MI)On Statin, ACE/ARB, BB, ASA

Persistent Evidence of InflammationDiabetes or Metabolic Syndrome

MTX 15-20 mgWeekly

Placebo

Nonfatal MI, Nonfatal Stroke, Cardiovascular Death

MTX Control

Bulgarelli et al, J Cardiovasc Pharmacol 2012;59:308-14

H & E

Anti-VSMC

Anti-rabbitmacrophage

Anti-rabbitMMP-9

MTX Control

Methotrexate Inhibits Atherogenesis in Cholesterol- fed Rabbits

Cohort Group HR* (95 % CI) Endpoint Exposure

Wichita RA 0.4 (0.2 - 0.8) Total Mortality LDMChoi 2002 0.3 (0.2 - 0.7) CV Mortality LDM

0.4 (0.3 – 0.8) CV Mortality LDM < 15 mg/wk

Netherlands RA 0.3 (0.1 – 0.7) CVD LDM onlyvan Helm 2006 0.2 (0.1 – 0.5) CVD LDM + SSZ

0.2 (0.1 – 1.2) CVD LDM + HCQ0.2 (0.1 – 0.5) CVD LDM + SSZ + HCQ

Miami VA PsA 0.7 (0.6 – 0.9) CVD LDMPradanovich 2005 0.5 (0.3 – 0.8) CVD LDM < 15 mg/wk

RA 0.8 (0.7 – 1.0) CVD LDM0.6 (0.5 – 0.8) CVD LDM < 15 mg/wk

CORRONA RA 0.6 (0.3 – 1.2) CVD LDMSolomon 2008 0.4 (0.2 – 0.8) CVD TNF-inhibitor

QUEST-RA RA 0.85 (0.8 – 0.9) CVD LDMNarango 2008 0.82 (0.7 – 0.9) MI LDM

0.89 (0.8 - 1.0) Stroke LDM

UK Norfolk RA, PsA 0.6 (0.4 – 1.0) Total Mortality LDM2008 0.5 (0.3 – 1.1) CV Mortality LDM

LDM and CVD: Observational Evidence

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Cardiovascular Inflammation Reduction Trial (CIRT)theCIRT.org website

The Balance of IL-1 and IL-1Ra :Key Regulatory Proteins for Innate Immunity

IL-1Ra

IL-1R

Pro-Inflammatory Anti-Inflammatory

IL-1ααααIL-1ββββ

Application of IL-1β promotes arterial intimal thickening in porcine coronary artery

Shimokawa et al. (1996) J Clin Invest 97:769

Lack of IL-1β decreases severity of atherosclerosis in ApoE-deficient mice

Kirii et al. (2003) Arterioscler Thromb Vasc Biol 23:656

ApoE KO ApoE KO, IL-1β KO

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Drenth JPH, et al, NEJM 2006; 355:730-732

NLRP3 Cryopyrin Inflammasome, Caspase-1, and IL-1 B MaturationEndogenous Danger Signals in Vascular Biology?

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Courtesy Eicke Latz Phase transition from soluble to crystalline as a “danger signal”

Courtesy, George S. Abela, MD.

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Canakinumab (Ilaris, Novartis)

• high-affinity human monoclonal anti-human interleukin-1 ββββ (IL-1ββββ) antibody currently indicated for the treatment of IL-1 ββββ driven inflammatory diseases (Cryopyrin-Associated Period Syndrome [CAPS], Muckle-Wells Syndrome)

• designed to bind to human IL-1 ββββ 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

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5 15

-70

-60

-50

-40

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-10

0

0 50 100 150

Canakinumab Dose (mg/month)

Me

dia

n R

ed

uct

ion

(%

)

Fibrinogen

Interleukin-6

C-reactive Protein

- 64.6 %

Ridker PM, et al; Circulation 2012; 126:2739-2748

Stable CAD (post MI)On Statin, ACE/ARB, BB, ASA

Persistent Elevation of hsCRP (> 2 mg/L)

RandomizedCanakinumab 150 mg

SC q 3 months

RandomizedPlacebo

SC q 3 months

Primary Endpoint: Nonfatal MI, Nonfatal Stroke, Cardiovascular Death

RandomizedCanakinumab 300 mg

SC q 3 months

Canakinumab Anti-inflammatory Thrombosis Outcomes S tudy(CANTOS) (Ridker PI)

Secondary Endpoints: Total Mortality, New Onset Diabetes , Other Vascular Events

Exploratory Endpoints: DVT/PE; SVT; hospitalization s for CHF; PCI/CABG; biomarkers42

RandomizedCanakinumab 50 mg

SC q 3 months

N = 10,000Novartis

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Tabas I, Glass CK. Anti-inflammatory therapy In Chronic Di sease: Challenges and OpportunitiesScience 2013;339:166-172

“The challenges in targetinginflammation in any chronicinflammatory disease lie in three properties that arecritical for evolutionary survival:redundancy, compensation, and necessity.”

Monitor for infection, TB, cancer

Balance potential vascular benefitswith probable risks

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34

0

1

2

3

4

PlaceboAspirin

Relative RiskMyocardial Infarction

Quartile of C-Reactive Protein

Ridker et al N Engl J Med 1997;336:973-9

hsCRP, Aspirin, and Risks of Future Myocardial Infarction

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Nidorf, SM, et al; JACC 2013; 61:404-10.

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Are the antiAre the anti--inflammatory effects of lipidinflammatory effects of lipid--lowering lowering relevant for clinical practice?relevant for clinical practice?

Agent Event Reduction ? LDL-Lowering? CRP-Lowering?

Statins Yes Yes Yes

Ezetimibe + Statin Yes Yes Yes

Fibrates No Yes No

Niacin No Yes No

CETP-inhibitors No/?* Yes No

HRT No Yes No

PCSK9-inhibitors ?? Yes No

For More Information : theCIRT.org

pridker@partners.org

Elaine Zaharris (617) 278-0893

Past history of multivessel CAD or MI and either diabetes or metabolic syndrome