Plaque Profilingq gPursuing VP Signatures & New Therapeutic Agents

Cheol Whan Lee, MDCheol Whan Lee, MD

Professor of Medicine, University of Ulsan College of Medicine,, y g ,Heart Institute, Asan Medical Center, Seoul, Korea

iiPresentationPresentation

Established Targets• Established Targets- HMGCoA reductase- P2Y receptor- P2Y12 receptor

• Emerging TargetsEmerging Targets- Lipid metabolism- ECM proteases- ECM proteases- Inflammation

T G t DKing

of CV Medicine

Two Great DrugsStatins and Anti-platelet AgentsStatins and Anti platelet Agents

HMGCoA reductase: statins

P2Y12 receptor: clopidogrel, prasugrel, ticagrelor

HMGCoA reductase: statins

12 ecepto : p g , p g , t g

…the only proven medicine

Landmark Statin TrialsLandmark Statin TrialsLandmark Statin TrialsLandmark Statin Trials

So Luxurious …So Luxurious …So Luxurious …So Luxurious …Clinical EndClinical End--Point Trials: Point Trials: “The Only “The Only One_StatinOne_Statin Trials”Trials”yy __AFCAPS/AFCAPS/TexCapsTexCaps, WOSCOPS, ALLHAT, CARE, LIPID, PROSPER, 4S, HPS, A, WOSCOPS, ALLHAT, CARE, LIPID, PROSPER, 4S, HPS, A--toto--Z, Z, MIRACL, CARDS, PROVEIT, ALLIANCE, 4D, ASCOTLLA, IDEAL, TNT, SPARCL, MIRACL, CARDS, PROVEIT, ALLIANCE, 4D, ASCOTLLA, IDEAL, TNT, SPARCL, AURORA CORONA GISSIAURORA CORONA GISSI--HF JUPITER SEAS SHARP IMPROVEHF JUPITER SEAS SHARP IMPROVE--IT (ongoing)IT (ongoing)

StatinStatin is an antiis an anti‐‐atherosclerotic drug.atherosclerotic drug.AURORA, CORONA, GISSIAURORA, CORONA, GISSI HF, JUPITER, SEAS, SHARP, IMPROVEHF, JUPITER, SEAS, SHARP, IMPROVE IT (ongoing).IT (ongoing).

Rapid Effects of Statin TherapyBackground

Rapid Effects of Statin Therapy

12 h12 h 11 4 th4 th 66 12 month12 month7 d7 d 15 d15 d 24 month24 month12 hour12 hour 11--4 month4 month 66--12 month12 month

Ultrafast

7 day7 day

Fast

15 day15 day

Very Early Early Late

24 month24 month

Very Late

ARMYDA - ACS ARMYDA PROVE-IT MIRACL A to Z

4S/HPS

HPS-DM

LIPIDARMYDA -RECAPTURE

NAPLES II

ARMYDA -CAMs

ARMYDA 3

ASCOT

AVERT/CARDS

4S/HPSWOSCOPS

PROSPER

LIPID

CARE

ALHATNAPLES II ARMYDA 3

LIPS

JUPITERCORONA

LRC-CPPTPOSCH

Mechanisms of early benefits are not fully understood.

Inside Plaques

Expression of HMGExpression of HMG--CoAR in Human CoronaryCoAR in Human Coronaryxpxp yyPlaques & Plaques & RelationshipRelationship to Plaque Destabilizationto Plaque Destabilization

Heart 2011;97:715‐20

We investigated the expression of HMG‐CoAR We investigated the expression of HMG CoAR in coronary atherectomy tissues retrieved from 43 patients with unstable & stable angina, & examined p g ,the relationship of HMG‐CoAR with plaque instability. 

Results

ImmunohistochemistryImmunohistochemistry

Unstable angina(n=22)

Stable angina(n=21)

p-value( )

α-SM actin (%)

( )

21.4±18.7 33.6±28.7 0.103

CD31 (%) 3.4±4.1 0.3±0.5 0.002

CD68 (%)

HMG CoA R (%)

10.9±16.2

3 0±4 5

1.8±1.7

0 4±0 7

0.016

0 014HMG-CoA R (%) 3.0±4.5 0.4±0.7 0.014

Data are shown as % positive area (immunostaining area/total plaque area×100)  Data are shown as % positive area (immunostaining area/total plaque area×100). 

PositiveControl

UnstableAngina

NegativeC t l

StableA i ControlAngina

HMG-CoAR Mφ

Merge

HMGCoAR Filipin staining

Negative control Colocalization

R l ti hi B t CD68 P iti A

Results

Relationship Between CD68-Positive Areas& HMG-CoA Reductase-Positive Areas (mm2) 

2 )

40

2 )

40

ctas

e (m

m2

30r= 0.018, p=0.937

tase

(mm

2

30r= 0.721, p<0.001

CoA

redu

c

10

20

CoA

redu

ct

10

20

0 20 40 60 80 100 120H

MG

C

0HM

GC

0

10

Unstable Angina Stable Angina

CD68 (mm2)

0 20 40 60 80 100 120

CD68 (mm2)

0 20 40 60 80 100 120

g g

Beyond CholesterolSummary

Beyond Cholesterol

Statin

HMGCoA ReductaseLiver: cholesterol Plaque: inflammation

Plaque StabilizationPlaque Stabilization

These findings support a potential role of the HMGThese findings support a potential role of the HMG--CoARCoAR in the in the g pp pg pp ppathogenesis of ACS, and may help explain the early benefits of pathogenesis of ACS, and may help explain the early benefits of statinstatin therapy in patients with ACS. therapy in patients with ACS.

T G t DKing

of CV Medicine

Two Great DrugsStatins and Anti-platelet AgentsStatins and Anti platelet Agents

HMGCoA reductase: statins

P2Y12 receptor: clopidogrel, prasugrel, ticagrelor

HMGCoA reductase: statins

12 ecepto : p g , p g , t g

P2Y12 Receptor: A Key Player12 p y y

Curr Pharm Des 2006;12:1255Circulation 2010;121:171

PLATO: Major Outcomesj

HR 0.84(0.77-0.92)P=.0003NNT=54

CV Death / MI / StrokeClopidogrel

9.8

11.7

%)

10

12

NNT 54

Ticagrelor

cide

nce(

%

8

HR 0.79(0 69-0 91)

CV deathClopidogrel

5.1

ativ

e In

c

6

(0.69-0.91)P=.001NNT=90Ticagrelor

4.0

Cum

ula

2

4

0

Definite ST33%p=0.009

Total death 22%↓ (NNT )

Days After Randomization120 1800 60 p<0.0001 (NNT70)

Bleeding Tax4

) Non‐procedural Bleeding

g

3pe

r yea

r) Non procedural Bleeding

3.06Ticagrelor

2

rate

(%

2.31Clopidogrel

1

stim

ated

p g

0HR 1.31 (95% CI 1.08-1.60), p=0.006

K-M

es

0 60 120 180 240 300 360

No. at riskDays from first IP dose

TicagrelorClopidogrel

9,2359,186

7,6417,718

7,2477,371

6,9797,134

5,4965,597

4,0674,147

3,6983,764

“More Bleeding = More Death”More Bleeding = More DeathImpact of Bleeding on Mortality after PCI

17,393 patients from REPLACE-2, ACUITY and Horizons

TIMI Bleed All 3 17 [2 51 4 0] <0 001

HR [95%CI] P-value

TIMI Bleed-All

TIMI Bleed-Nonaccess Site

3.17 [2.51-4.0]

3.94 [3.07-5.15]

<0.001

<0.001

TIMI Bleed-Access Site Only

[ ]

1.82 [1.17-2.83] 0.008

0.1 81

Adjusted Risk for 1-Year Mortality

Inside Plaques

Differential Expression of P2YDifferential Expression of P2Y1212 Receptor in Culprit Receptor in Culprit Pl f P ti t ith AMI & St bl A iPl f P ti t ith AMI & St bl A iPlaques from Patients with AMI & Stable AnginaPlaques from Patients with AMI & Stable Angina

Am J ardiol 2011;108:799‐803

W   d  h   i   f P Y    We compared the expression of P2Y12 receptors in coronary atherectomy tissues retrieved from   i   i h AMI ( )    bl   i  ( )54 patients with AMI (n=35) or stable angina (n=19).

Results

ImmunohistochemistryImmunohistochemistryAMI

(n=35)Stable angina

(n=19)p-

value

α-SM actin (%) 2.9±2.7 12.3±14.4 0.011

CD31 (%)

CD68 (%)

1.1±1.6

15 5±13 6

0.2±0.2

7 0±14 6

0.001

0 038CD68 (%)

P2Y12 Receptor (%)

15.5±13.6

1.1±0.9

7.0±14.6

0.5±0.4

0.038

<0.001P2Y12 Receptor (%) 1.1±0.9 0.5±0.4 0.001

Data are shown as % positive area (immunostaining area/total plaque area×100).AMI  STEMI   NSTEMI    AMI: STEMI 27, NSTEMI 8  

AMIP2Y12R SMC CD31

P2Y12R SMC CD31

Stable anginaStable angina

Beyond PlateletsSummary

Beyond Platelets

ADP

P2Y12 ReceptorpPlatelets Endothelial Cells VSMCs

Acute Coronary SyndromeAcute Coronary Syndrome

P2Y12 receptor inhibitors may have a dual antiP2Y12 receptor inhibitors may have a dual anti--ischemic effectischemic effectP2Y12 receptor inhibitors may have a dual antiP2Y12 receptor inhibitors may have a dual anti ischemic effect ischemic effect by inhibiting both platelet activation and plaque destabilization.by inhibiting both platelet activation and plaque destabilization.

iiPresentationPresentation

Established Targets• Established Targets- HMGCoA reductase- P2Y receptor- P2Y12 receptor

• Emerging TargetsEmerging Targets- Lipid metabolism- ECM proteases- ECM proteases- Inflammation

Residual CV Risk in Statin Treated PatientsUnmet Medical Need

Residual CV Risk in Statin-Treated Patients

0

161615

272431

24 22

ction,

%

10

20

30

363737

3137

Ris

k Reduc

40

50

60

Rela

tive

R

60

70

80

90

Despite optimal treatment the residual risk of another

90

100

Despite optimal treatment, the residual risk of another MACE in these patients is estimated to be 70–80%.

On-Treatment HDL-C and CV RiskRed Flag Sign? 

HDL: not predictive of residual vascular risk

On Treatment HDL C and CV Riskp

- JUPITER: Lancet2010;376:333- TNT: NEJM2007; 357: 1301- PROVEIT: ATVB2009; 29: 424

Futile Strategies?The Story So Far …HDL-Targeted Therapies

We have reached the limit of what we can do by lowering LDL-C?

The Story So Far …

Estrogen (↑15%): WHI trialFibrates (↑15%): ACCORD Lipid trial

We have reached the limit of what we can do by lowering LDL-C?.

Fibrates (↑15%): ACCORD Lipid trial

Nicotinic acids (↑20%)Nicotinic acids (↑20%)Extended release niacin: AIM‐HIGH trialTredaptive (nicotinic acid/laropiprant) : HPS‐2 trialTredaptive (nicotinic acid/laropiprant) : HPS 2 trial

CETP inhibitors (↑30%-140%)(↑ )Torcetrapib: Illuminate trial (↑death: discarded) Anacetrapib: Define trial (safe), HPS‐3 (REVEAL) trialDalcetrapib: Dal‐Plaque (promising), Dal‐Outcomes trial

New TargetsA Potential Game Changer

Biologic Wows for LDL-C Lowering

PCSK9: a key regulator of the LDL receptorGain-of-function mutations result in hypercholesterolemiaGain of function mutations result in hypercholesterolemiaLoss-of-function mutations associated with low LDL-C & low prevalence of CHD events

SAR236553/REGN727 is a highly specific, fully human monoclonal antibody (mAb) to PCSK9

Monoclonal Antibody to PCSK9, SAR236553/REGN727, Adjunct to Statin

0S

Monoclonal Antibody to PCSK9, SAR236553/REGN727, in Patients with Primary Hypercholesterolemia

Baselin

e

20

-10

BASELINE WEEK 2 WEEK 4 WEEK 6 WEEK 8 WEEK 10 WEEK 12∆ - 5.1%

ange fro

m

-30

-20

±SE)

% C

h

-50

-40

∆ - 47.7%

∆ - 39.6%

∆ - 43.2%

-C

Mean (±

-70

-60

∆ - 64.2%

∆ 47.7%

LD

L

-80

-70

Placebo SAR236553 50 mg Q2W SAR236553 100 mg Q2WSAR236553 200 mg Q4W SAR236553 300 mg Q4W SAR236553 150 mg Q2W

∆ - 72.4%

It was generally safe & well tolerated. SQ every two weeks dropped LDL by 40% to 72%There is some risk of immunity with an agent like this & we need longer-term outcome studies.

iiPresentationPresentation

Established Targets• Established Targets- HMGCoA reductase- P2Y receptor- P2Y12 receptor

• Emerging TargetsEmerging Targets- Lipid metabolism- ECM proteases- ECM proteases- Inflammation

ECM Proteases Hypothesis f Pl R tof Plaque Rupture

M i l i (MMP )Matrix metaloproteinases (MMPs)Elevated: MMP1, MMP2, MMP3, MMP8, MMP9, MMP10, MMP13 

ADAMTS proteasesOthers: serine proteases (elastase) cysteine proteases (cathepsins)Others: serine proteases (elastase), cysteine proteases (cathepsins)

Tragic Failure

MMP-Based Therapy

MMPs have been heralded as promising targets for cancer therapy on the basis of their massive up-regulation in malignant tissues and their

i bili d d ll f h ll l iunique ability to degrade all components of the extracellular matrix.

Many of these trials turned out to be major failures. y jOwing to serious complications, the trials were terminated early.

MMPs are vital for immune regulation. Some MMPs are the good guysMMPs are vital for immune regulation. Some MMPs are the good guys in disease. To overcome the danger of off-target effects, it is essential to either thoroughly characterize the biological roles or understand the degree of cross-reactivity of inhibitors before drug developmentdegree of cross-reactivity of inhibitors before drug development.

Science 2002;295:2387

ADAMTS ProteasesAMI Stable Angina AMI Stable Angina

ADMTS1 ADMTS2

ADMTS4 ADMTS3

ADMTS5 ADMTS13

J Clin Pathol 2011;64:399 J Thromb Thrombolysis 2012 (in press)

Target for futuredrug development

LimitationsIt remains uncertain whether ADAMTS It remains uncertain whether ADAMTS It remains uncertain whether ADAMTS It remains uncertain whether ADAMTS proteases are a cause or consequence of proteases are a cause or consequence of plaque instability  plaque instability  plaque instability. plaque instability. 

Y      fi fi ht   t   fl i  Y      fi fi ht   t   fl i  You can see firefighters at every flaming You can see firefighters at every flaming building, but they  did not set the blazes.building, but they  did not set the blazes.

iiPresentationPresentation

Established Targets• Established Targets- HMGCoA reductase- P2Y receptor- P2Y12 receptor

• Emerging TargetsEmerging Targets- Lipid metabolism- ECM proteases- ECM proteases- Inflammation

Inflammation AKey Player

The contribution of inflammation to the development of atherosclerotic plaques is now well-understood and several promising targets have been identified.

Nonspecific Inflammatory Genes

I fl t G t R t d PlThe proper study of mankind is man

Inflammatory Genes at Ruptured PlaquesThe proper study of mankind is man.

HG-U133 Plus 254,675 probes

Inflammation is caused by complex interactions involving multiple cell types & multiple mediators. It is not yet clear which targets will yield the greatest effect in atherosclerosis.

PLA2 i hibit ↓ d d l lAnti-inflammatory Drugs Cooling Down

Burning Plaques

PLA2 inhibitors (↓ oxidized LDL, multiple isozymes) Darapladib (Lp‐PLA2): STABILITY trial (Phase 3)Varespladib (sPLA2): VISTA 16 trial (Phase 3)Varespladib (sPLA2): VISTA‐16 trial (Phase 3)

Experimental DrugsA ii flAntiinflammatory agents‐Methotrexate: Cardiovascular Inflammation Reduction Trial ‐ Others:Others:

It is not yet clear which anti-inflammatory targets will yield the greatest effect in preventing, reversing or delaying this process.

Strong DesireLittle Hope

Summary

There are no therapies specifically to target       • e e a e o t e ap es spec ca y to ta getthe inflammatory component of atherosclerosis.

There is a critical need to identify key markers & local mediators of the atherosclerotic process  

•& local mediators of the atherosclerotic process  so that new therapeutics can be developed.