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Novel Therapeutic Approaches to Elevate HDL-C and

Modulate HDL Functionality

Daniel J. Rader, MDPerelman School of Medicine

University of Pennsylvania Philadelphia, PA

Novel HDL Therapeutics

• Elevate plasma HDL-C • Enhance cholesterol efflux and

reverse cholesterol transport


• Elevate plasma HDL-C – CETP inhibition

CETP as a Therapeutic Target

Cholesteryl Ester Transfer Protein

CETP is a 74 kDa plasma protein that circulates in plasma mainly associated with HDL

It is a member of the LPS-binding and lipid transport protein family

It is expressed mainly in liver and adipose tissueCETP exchanges neutral lipids (cholesteryl esters

and triglycerides) among lipoprotein particlesCETP has a net effect of transferring CE out of

HDL in exchange for TGHayek T, et al. JCI 1995;96:20714.Okamoto H, et al. Nature 2000;406:2037.Jiang XC, et al. JBC 1993;268:2740612.

Mechanism of action of CETPTwo hypotheses have been proposed for the mechanism by which CETP transfers neutral lipids between plasma lipoproteins.

(i) a shuttle mechanism that involves CETP collecting cholesteryl esters from one lipoprotein and delivering them through the aqueous phase to another lipoprotein.

(ii) a tunnel mechanism in which CETP bridges two lipoproteins to form a ternary complex, with lipids flowing from the donor to acceptor lipoprotein through the CETP molecule

Barter et al; Biochem J. 1982; 208:1.Ihm et al. J. Lipid Res.1982;23:1328. Swenson et al. J. Biol. Chem. 1988; 263:5150. Tall. J. Lipid Res.1993;34:1255.Zhang et al. Nature Chem Biol. 2012; 8:342.

CETG

CE

HDL TRL

LDL

CETG

CETG

CETG

CETG

CE TG

TG

CETP CETP

CETP

CETP

Barter et al; Biochem J. 1982; 208:1. Swenson et al. J. Biol. Chem. 1988; 263:5150.Tall. J. Lipid Res.1993; 34:1255.

Shuttle Mechanism

CECE

CE

CE

CE

CE

CEHDL

VLDL/LDL

CETP

Binarycomplex

Ternarycomplex

TunnelVLDL/LDL

HDL

Tunnel Mechanism

Ihm et al. J. Lipid Res.1982; 23, 1328. Zhang et al. Nature Chem Biol. 2012; 8:342.

CETP

CECETG

CECE

TG

HDL

Excretion through kidney

TGR-LP

TGCE

CECETG

HDL

Small, dense HDL

Lipid-free/poorapoA-I

HLTG FFA

Role of CETP in the Remodelling of HDL

Rye et al Atherosclerosis, 1999,145:227.Rye et al Arterioscler Thromb Vasc Biol, 2004, 24: 421.

Brown ML, Inazu A, Hesler CB, et al. Nature. Nov 23 1989;342(6248):448-451.Maruyama T, Sakai N, Ishigami M, et al. Atherosclerosis. Jan 2003;166(1):177-185.Nagano M, Yamashita S, Hirano K, et al. J Lipid Res. Jul 2002;43(7):1011-1018.Ritsch A, et al. Arterioscler Thromb Vasc Biol. Dec 1997;17(12):3433-3441.Teh EM, Dolphin PJ, Breckenridge WC, Tan MH. J Lipid Res. Feb 1998;39(2):442-456.

Evidence that Activity of CETP Impacts on Plasma Lipoprotein ConcentrationsThe first genetic deficiency of CETP was identified in Japan in 1989 in patients with markedly elevated HDL-C

57% of Japanese subjects with levels of HDL-C > 100 mg/dL have mutations of the CETP gene

37% of Japanese subjects with levels of HDL-C between 75-100 mg/dL have mutations of the CETP gene

CETP mutations have also been identified outside Japan in association with elevated HDL

Common variants at the CETP locus are strongly associated with variation in HDL-C levels

Relationship of CETP and Atherosclerosis

CETP and Atherosclerosis Human epidemiology

Honolulu Heart Study 7-year prospective dataThere was no statistically significant relation between heterozygous mutations of CETP and CHD or strokeHowever, it was concluded that a deficiency of CETP is athero-protective, so long as it is accompanied by an HDL-C level > 60 mg/dL

Moriyama et al. Prev Med. 1998;27:659–667.

• A meta-analysis has been conducted of studies investigating relationships between CETP polymorphisms and cardiovascular disease in humans

• 46 studies had data on 27,196 coronary cases and 55,338 controls.

• Those polymorphisms that were associated with lower CETP mass and lower CETP activity had higher levels of HDL-C and a significantly reduced coronary risk.

CETP Polymorphisms and Cardiovascular Risk in Humans

Thompson et al JAMA2008;299:2777-2788.

A prospective cohort of 18,245 initially healthy American women

Polymorphisms near or in the CETP gene were associated with both HDL cholesterol concentration and risk of myocardial infarction

It was concluded that decreased CETP activity is associated with an increased level of HDL-C and a decreased risk of myocardial infarction.

CETP Genotypes and CHD in Humans

Ridker et al. Circ Cardiovasc Genet 2009; 2: 26.

CETP and Atherosclerosis in Rodents

Rodents naturally deficient in CETP

Rodents naturally resistant to development of atherosclerosis

Expression of CETP in transgenic mice and rats increases atherosclerosis in most (but not all) models

Marotti et al. Nature.1993;364:73. Plump et al. ATVB.1999;19:1105.

Rabbits have high level of activity of CETP

Rabbits naturally highly susceptible to the development of atherosclerosis

Inhibition of CETP in rabbits decreases atherosclerosis in all models, including genetic manipulation to inhibit CETP, use of an anti-CETP vaccine or by administration of small molecule CETP inhibitors (including dalcetrapib and torcetrapib)

CETP and Atherosclerosis in Rabbits

Sugano et al. J Biol Chem.1998;273:5033. Rittershaus et al. ATVB. 2000;20:2106.Okamoto et al. Nature. 2000;406:203. Morehouse et al. J Lipid Res. 2007;48:1263.

CETP inhibition in Humans

HDL

VLDL/LDL

CE

Liver

Bile

CE

SR-B1

LDL-R

CE

FC

FC

SR-B1

LCATExtrahepatic Tissues

(including the artery wall

Free Cholesterol

CETP

Effect of CETP Inhibition on Plasma Cholesterol Transport

Torcetrapib

CF3

F3C

N O

O

N

OO

CF3

Dalcetrapib

S

O

O

HN

Anacetrapib

O

F3C

O

N

O

F3C

F

CETP Inhibitors

Evacetrapib

Cao et al. J Lipid Res 2011; 52:2169.

Lipid efficacy of CETP inhibitors(% change from baseline)

CETPinhibitor

Dosemg/d

HDL-C%

LDL-C%

TG%

Torcetrapib 60 61 -24 -9

Adapted from Cannon C, JAMA 306:2154; 2011

Torcetrapib

Torcetrapib was an effective CETP inhibitor that was shown in humans to increase the concentration of HDL-C by more than 60% while reducing the concentration of LDL-C by more than 20% over and above the changes achieved by using high doses of statins.

Torcetrapib was the first CETP inhibitor to be tested in human imaging trials and in a large cardiovascular clinical end point trial

Barter et al, NEJM 2007;357:2109.

Coronary IVUS Trial - ILLUSTRATE

• 910 patients with angiographic coronary artery disease treated with torcetrapib 60 mg or placebo in addition to background atorvastatin for 24 months

• Change in coronary atheroma burden was determined in matched arterial segments by intravascular ultrasound

• Relationship between changes in biochemical parameters and plaque burden with treatment was determined

Nissen et al. NEJM. 2007;356:1304. Nicholls et al. Circulation 2008;118:2506.

ILLUSTRATE: Primary Efficacy Parameter

Change in Percent Atheroma Volume

0.19

0.12

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

Changein percentatheromavolume

Atorvastatinmonotherapy

Torcetrapib-atorvastatin

p = 0.72†

Nissen et al. NEJM. 2007;356:1304.

ILLUSTRATE: Secondary Efficacy ParametersChange in Normalized

Atheroma Volume (mm3)Change in 10 mm Most

Diseased Segment (mm3)

Nissen et al. NEJM. 2007;356:1304.

Atheroma Regression at Highest HDL-C Levels with Torcetrapib in the ILLUSTRATE

trial

-0.75

-0.50

-0.25

0.00

0.25

0.50

0.75

P=0.004 for trend

LS M

ean

Cha

nge

Per

cent

A

ther

oma

Volu

me

Q1 (<56)

Q3 (69.5-86)

Q2 (56-69)

Q4 (>86)

Quartiles of Achieved HDL Cholesterol (mg/dL)

Nicholls et al. Circulation 2008; 118:2506.

ILLUSTRATE Conclusions

• Torcetrapib 60 mg in combination with atorvastatin increased HDL-C by 61% and lowered LDL-C by 20%, compared with atorvastatin monotherapy.

• However, torcetrapib also increased systolic blood pressure by an average of 4.6 mmHg.

• Torcetrapib-atorvastatin did not reduce the progression of coronary atherosclerosis for the primary efficacy parameter, compared with atorvastatin alone.

• More regression was observed with greater torcetrapib-induced elevations of HDL-C

Carotid IMT trials: RADIANCE 1 and 2B-mode ultrasound every 6 months

SCREENING 24-month double-blind treatment

Atorvastatin only run-inTarget: LDL-C to goal

Torcetrapib/atorvastatin

Atorvastatin

RADIANCE 2

RADIANCE 1

Study Name

904HeFH; eligible for statin treatment8 countries (US, CAN, FRA, ITA, NL, FIN, CZ, S.AFR) 752Mixed hyperlipidemia; eligible for

statin treatment

NSubject PopulationClinical Sites

Dose titration (mg): 10 20 40 80

Kastelein et al. NEJM, 2007; 356:16; Bots et al. Lancet. 2007; 370:153.

RADIANCE 1 Lipids

HDL-C (mg/dL)

Weeks of treatment

40

50

60

70

80

T/AA

110

120

130

140

Weeks of treatment

LDL-C (mg/dL)

0 24 48 72 96 0 24 48 72 96

T/AA

T/A: torcetrapib plus atorvastatin A: atorvastatin alone

Kastelein et al. NEJM, 2007; 356:16.

RADIANCE 1 Imaging primary EndpointMaximum Carotid Intima-Media Thickness

(mm)

2418 126 0

Means +/- SD

1.126 1.1321.133 1.1481.134

1.1631.149 1.1621.1501.152

0

0.5

1

1.5

2

Months of Treatment

T/AA

Average Over 12 Carotid Segments Combined

Max

Car

otid

IMT

(mm

)


RADIANCE 1Systolic Blood Pressure (mmHg)

242118151296310

119.0116.0

121.7

116.6

100

105

110

115

120

125

130

Months of treatment

T/AAS

ysto

lic B

P (m

mH

g)


RADIANCE 1 Conclusions

• In heterozygous FH, T/A, when compared to A alone– Did not result in regression of atherosclerosis

as assessed by a combined measure of carotid arterial wall thickness

– Caused progression of disease in the common carotid segment

• These effects occurred despite a 52% increase in HDL-C and a 21% decrease in LDL-C

Kastelein et al. NEJM, 2007; 356:16 .

RADIANCE 2 Lipids

40

50

60

70

80

Months of treatment

70

80

90

100

110

0 1 6 12 18 24

HDL-C (mg/dL) LDL-C (mg/dL)

Months of treatment 0 1 6 12 18 24

T/AA

T/AA

T/A: torcetrapib plus atorvastatin A: atorvastatin alone

Bots et al. Lancet. 2007; 370:153.

RADIANCE 2 Imaging Primary EndpointMaximum Carotid Intima-Media Thickness

(mm) Average Over 12 Carotid Segments Combined

Means +/- SD

1.3210 1.35921.31501.36341.3260

1.36801.3319 1.34691.30791.3002

0.60

0.80

1.00

1.20

1.40

1.60

1.80

Months of Treatment

T/AA

2418 126 0

Max

Car

otid

IMT

(mm

)


RADIANCE 2 Systolic Blood Pressure

126.2126.8

125.5

127.3 127.7126.9

120.8 120.8 121.2 121.3122.1 122.2

122.9121.2

126.7

123.7

128.7

119.5119.6120.8

115

120

125

130

Months of Treatment

T/AA

Sys

tolic

BP

(mm

Hg)

242118151296310


RADIANCE 2 Conclusions

• In mixed dyslipidemia, torcetrapib plus atorvastatin, when compared to atorvastatin alone did not result in regression of atherosclerosis as measured by carotid arterial wall thickness

• These effects occurred despite a 63% increase in HDL-C and an 18% decrease inLDL-C


ILLUMINATE: Investigation of Lipid Level Management to Understand its Impact in

Atherosclerotic Events

Torcetrapib 60 mg + titrated atorvastatin dose

Titrated atorvastatin dose

15 067 patients

Primary End Point Composite of fatal CHD, nonfatal MI,

stroke (fatal and non-fatal and unstable angina requiring hospitalization

Men and women Aged 45-75 years 250 sites in 7 countries CHD or risk equivalent, any

HDL-C level, statin eligible

Planned 4.5-year follow-up or 1820

events whichever is later


48.5 48.2 48.9 49.2 48.9

79.3 80.5 80.5 80.7

128 127 128 130 129

79.9

0

20

40

60

80

100

120

140

Baseline 1 3 6 12

Study Month

Lipi

ds (m

g/dL

)On Trial Lipid Levels By Study Month

Atorvastatin only Group (Post Run-In)

HDL-C

LDL-C

TG


48.6

71.8 77.5 80.9 82.979.7

127115 112 112 112

58.358.259.359.7

0

20

40

60

80

100

120

140

Baseline 1

HDL-C

LDL-C

TG

ILLUMINATE: On Trial Lipid LevelsTorcetrapib/ Atorvastatin Group (Post Run-In)

Study Month

Lipi

ds (m

g/dL

)

-9% (-27,+13)*

+72.1% (34.7) †

-24.9% (28.5) †

3 6 12


ILLUMINATE: Primary Endpoint: Time to First MCVE*: Kaplan-Meier Plot

*Major cardiovascular event: CHD death, non-fatal MI, stroke or hospitalization for unstable angina


ILLUMINATE: Secondary EndpointTime to Death: Kaplan-Meier Plot


Causes of Death

Fatal stroke

44Reason unknown34Trauma/suicide/homicide42Other non-cardiovascular90Infection

2414Cancer4020Any non-cardiovascular32Other vascular death/procedure related MI21Fatal heart failure41Other cardiac death6086Fatal MI - not procedure related2625Sudden cardiac death4935Any cardiovascular death

Torcetrapib/ Atorvastatin (n=93)

Atorvastatin (n=59 )


What was the Reason for the Adverse Outcome with Torcetrapib in the

ILLUMINATE Trial?Possible explanations• Inhibiting CETP is pro-atherogenic

• Inhibiting CETP generates dysfunctional HDL

• Torcetrapib had an adverse off-target pharmacology unrelated to CETP

What was the Reason for the Adverse Outcome with Torcetrapib in the

ILLUMINATE Trial?Possible explanations

• Inhibiting CETP is pro-atherogenic

• Inhibiting CETP generates dysfunctional HDL

• Torcetrapib had an adverse off-target pharmacology unrelated to CETP

In patients receiving torcetrapib in the ILLUSTRATE, RADIANCE 1 & 2 and ILLUMINATE studies there was a significant:

• Increase in blood pressure• Decrease in serum potassium• Increase in serum bicarbonate• Increase in serum sodium• Increase in serum aldosterone

Off-target Pharmacological Effects of Torcetrapib

Barter et al, NEJM 2007;357:2109. Nissen et al. NEJM. 2007;356:1304.Kastelein et al. NEJM, 2007; 356:16. Bots et al. Lancet. 2007; 370:153.

ILLUMINATE: On-Trial Blood Pressure By Study Month

Atorvastatin Group

122.9 128.2*

73.7 75.7*

0 1 3 6 9 12Study Month

40

60

80

100

120

140

Blo

od P

ress

ure

(mm

Hg)

123.0 123.9

73.9 73.7

0 1 3 6 9 12

Torcetrapib plusAtorvastatin Group

* p<0.001 vs atorvastatin at month 12


Torcetrapib increases blood pressure in rats, a species that does not have CETP.

Analogues of torcetrapib that do not inhibit CETP raise blood pressure to an extent similar to that observed with torcetrapib

Other CETP inhibitors such as dalcetrapib, anacetrapib and evacetrapib do not raise blood pressure

Off-target Pharmacological Effects of Torcetrapib Unrelated to CETP Inhibition

Forrest et al. Br J Pharmacol. 2008;154:1465. Hu et al. Endocrinology 2009;150:2211.Nicholls et al. JAMA. 2011; 306:2099.

Torcetrapib induces synthesis and secretion of both aldosterone and cortisol from human adrenal cells in tissue culture.

Torcetrapib reduces expression of endothelial nitric oxide synthase mRNA and protein, reduces nitric oxide release, increases expression of endothelin-1 and induces endothelial dysfunction animals independent of CETP inhibition

Other CETP inhibitors such as dalcetrapib and anacetrapib do not have these off-target effects

Forrest et al. Br J Pharmacol. 2008;154:1465-1473. Hu et al. Endocrinology 2009;150:2211-2219. Capponi et al. Circulation 2008;118:S:452. Connelly et al. J Cardiovasc Pharmacol 2010; 55:459.Simic et al. Eur Heart J. 2012 [In Press].

Off-target Pharmacological Effects of Torcetrapib Unrelated to CETP Inhibition

There were 6101 patients with type 2 diabetes in the ILLUMINATE trial

Treatment with torcetrapib resulted in a highly significant improvement in diabetic control

Effects on Diabetic Control in ILLUMINATE

Barter et al. Circulation 2011; 124:555.

A

A

AA

7.4

7.6

7.8

8.0

8.2

8.4

Pla

sma

gluc

ose

(mm

ol/L

)

0 1 3 6Months of treatment

Effects of Atorvastatin (A) vs Atorvastatin Plus Torcetrapib (T/A) in Diabetics in ILLUMINATE

(N = 6661)Glucose

T/A

T/AT/A

T/A

(p<0.0001 for all)

(ns)


A A

A A

6.8

6.9

7.0

7.1

7.2

7.3

0 1 3 6


(N = 6661)HbA1C

Months of treatment

HbA

1C (%

)

T/A

T/A T/A

T/A

(p<0.0001 for all)

(ns)


A A

120

125

130

135

140

145

0 3


(N = 6661)Insulin

Months of treatment

Insu

lin

U/m

l

T/A

T/A

(ns) (p=0.0007)


A

A

46

47

48

49

50

51

0 3


(N = 6661)HOMA-IR

Months of treatment

HO

MA

-IR T/A

T/A

(ns)(p<0.0001)

52



CETPinhibitor

Dosemg/d

HDL-C%

LDL-C%

TG%


Dalcetrapib 600 31 -2 -3


dal-HEART Program: dalcetrapib HDL Evaluation, Atherosclerosis &

Reverse Cholesterol Transport

Double-blind, randomized, placebo-controlled studies

dal-OUTCOMES

15,872 patients recently

hospitalized for ACS

CV outcomes

Fully recruited

1. Schwartz et al. Am Heart J. 2009;158:896–901.2. Kastelein et al. Curr Med Res Opin. 2011;27:141–150.3. http://clinicaltrials.gov/ct2/show/NCT00655473; Accessed 21st April 2009.4. http://clinicaltrials.gov/ct2/show/NCT01059682; Accessed February 2nd 2010.5. Roche, data on file.

dal-VESSEL

476 patients with CHD or

CHD risk equivalent

endothelial function and

blood pressure

Completed

dal-PLAQUE

130 patients with CHD

inflammation, plaque size and burden, measured by PET/CT and

MRI

Completed

dal-PLAQUE 2

906 patients with CAD

on atherosclerotic

disease progression, assessed by

imaging

Fully recruited

dal-ACUTE

300 patients hospitalized

for ACS <1 week after

ACS

treatment initiated within 1 week of an

ACSFully

recruited

dal-OUTCOMES 2

20,000 patients with stable

CHD, CHD risk equivalents or at elevated risk

for CVD

CV outcomes

FPI (Feb 2012)

Dal-PLAQUE

dal-PLAQUE was the first multicentre study using novel non-invasive multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary endpoints.

Co-primary endpoints were MRI-assessed indices (total vessel area, wall area, wall thickness, and normalised wall index [average carotid]) after 24 months and 18F-fluorodeoxyglucose PET/CT assessment of arterial inflammation within an index vessel (right carotid, left carotid, or ascending thoracic aorta) after 6 months, with no-harm boundaries established before unblinding of the trial.

Fayad et al. Lancet, 2011;378:1547.

130 patients (men and women) aged 18–75 years, with CHD or CHD equivalent

dal-PLAQUE Trial

Dalcetrapib 600 mgTherapy to LDL-C <100 mg/dL

Placebo

Co-primary endpoints were MRI-assessed indices (total vessel area, wall area, wall thickness, and normalised wall index [average carotid]) after 24 months and 18F-fluorodeoxyglucose PET/CT assessment of arterial inflammation within an index vessel (right carotid, left carotid, or ascending thoracic aorta) after 6 months

24 Month follow-up


Dal-PLAQUE- Results

189 patients were screened and 130 randomly assigned to placebo (66 patients) or dalcetrapib (64 patients).

There was no evidence of harm in dalcetrapib treated subjects, with a possible beneficial vascular effects as evidenced by a reduction in total vessel enlargement over 24 months.

Dalcetrapib did not increase blood pressure and thefrequency of adverse events was similar between groups.

It was concluded that these results provided comfort with a decision to proceed with a longer and much larger clinical endpoint trial.


Dal-VESSEL

This trial investigated the effects of dalcetrapib on endothelial function, blood pressure, inflammatory markers and lipids in patients with, or at risk of, coronary heart disease (CHD) in a double-blind randomised placebo-controlled trial

Luscher et al. European Heart J, 2012;33:857.

476 patients with CHD or equivalentHDL-C < 50 mg/dL

dal-VESSEL Trial

Dalcetrapib 600 mgTherapy to LDL-C <100 mg/dL

Placebo

The primary outcome measures were change from baseline of flow-mediated dilatation of the right brachial artery at 12 weeks and the 24-hour ambulatory blood pressure at week 4.

36 week follow-up


Dal-VESSEL- Results

476 patients were randomised. Change in FMD was not significantly different from placebo after 12 and 36 weeks of treatment with dalcetrapib.

After 4, 24 and 36 weeks of treatment with dalcetrapib, CETP activity decreased by 51, 53 and 56% while at weeks 4, 12 and 36 HDL-C increased by 25, 27 and 31%. Dalcetrapib had no effect on LDL-C levels

Ambulatory blood pressure was unaffected by dalcetrapib up to 36 weeks.

Biomarkers of inflammation, oxidative stress and coagulation were unaffected by dalcetrapib up to 36 weeks, although Lp-PLA2 levels increased by 17%.


Objective of the dal‐OUTCOMES trial

• To compare the effects of dalcetrapib with placebo, added to evidence‐based background therapy, on cardiovascular risk in patients with recent acute coronary syndrome

15,600 patients 4-12 weeks

after an index ACS event

dal-OUTCOMES Trial

Dalcetrapib 600 mgStatin therapy to optimal LDL-C level

Placebo

Primary End PointCHD death, non-fatal MI, atherothrombotic stroke, unstable angina requiring hospitalization or resuscitated cardiac arrest

2.5-year follow-up(Likely to report at

ACC in 2013)

Schwartz et al. Am Heart J. 2009;158:896.

Entry criteria

• Age 45 years• Acute coronary syndrome• Evidence‐based management of LDL‐C• No restriction on entry level of HDL‐C• Key exclusions: Triglycerides >400 mg/dl; treatment with niacin, fibrates, or bile acid sequestrants.

Outcome measures• Primary outcome composite (time to first

occurrence):– Coronary heart disease death– Non-fatal MI– Ischemic stroke– Hospitalization for unstable angina (with

objective evidence of acute myocardial ischemia)– Cardiac arrest with resuscitation

• Secondary outcome measures:– All cause mortality– Coronary revascularization

Flow of patients in the trial• 19,005 entered single blind run-in

• 15,871 patients randomized

• Withdrawal of consent or loss to follow-up: dalcetrapib 3.9%, placebo 3.3%

• At the 2nd pre-specified interim analysis, including 1135 (71% of projected) primary endpoint events, the DSMB recommended termination of the trial for futility.

• At termination, median follow-up 31 mo.

Baseline characteristics(all balanced between treatment groups)

Mean age (years) 60

Female 19%Caucasian 88%

Region

Europe or Israel 50%

North America 32%

Cardiovascular risk factors

Hypertension 68%Metabolic syndrome 63%

Diabetes 24%

Current smoker 21%

Cardiac biomarker‐positive qualifying (index) event 87%

Time from index event to randomization (days) 61

Concurrent treatments(all balanced between treatment groups)

PCI or CABG for index event (before randomization) 91%

Statin 97%

Aspirin 97%

Clopidogrel, ticlopidine or prasugrel 89%

Beta blocker 88%

ACE inhibitor or ARB 79%

Baseline lipids (mean)(all balanced between treatment groups)

mg/dl mmol/L

LDL cholesterol 76 1.96

HDL cholesterol 42 1.09

Triglycerides 134 1.51

HDL‐C and LDL‐C by treatment group

Data aremean ± 95% CI

PlaceboDalcetrapib

PlaceboDalcetrapib

HD

L ch

oles

tero

l (m

g/dl

)LD

L ch

oles

tero

l (m

g/dl

)

Primary outcome* by treatment group

* Coronary heart disease death, non‐fatal MI, ischemic stroke, hospitalization for unstable angina, resuscitated cardiac arrest

Hazard ratio 1.04(95% CI 0.93-1.16)

Risk of primary and secondary outcomesEvent Dalcetrapib

(% at 3 years)Placebo

(% at 3 years)Hazard Ratio (95% CI)

P‐valuePrimary composite 9.2 9.1 1.04 (0.93‐1.16)

0.52CHD death 1.6 1.8 0.94 (0.73‐1.21)

0.66

Non‐fatal MI 5.9 6.0 1.02 (0.89‐1.17)0.80

Unstable angina 1.3 1.3 0.91 (0.68‐1.22)0.54

Resuscitatedcardiac arrest

0.2 0.1 1.41 (0.63‐3.18)0.40

Ischemic Stroke 1.4 1.0 1.25 (0.92‐1.70)0.16

All cause mortality 3.1 3.4 0.99 (0.82‐1.19)0.90

Coronary revascularization

9.5 9.6 1.00 (0.87‐1.11)0.97

Systolic blood pressure and hs‐CRP were slightly higher with dalcetrapib than placebo

With dalcetrapib, compared with placebo:

•Mean systolic blood pressure was 0.6 mm Hg higher (P<0.001)•No effect on plasma aldosterone, bicarbonate, or potassium•No difference in number of anti-hypertensive medications

•At 3 months of assigned treatment, median hs-CRP was 0.2 mg/L higher (P<0.001, based on ANOVA after log transformation)

Conclusions• In patients with recent ACS, the CETP inhibitor dalcetrapib raised HDL‐C by ~30% with minimal effect on LDL‐C and had no effect on the risk of major cardiovascular events.

• HDL‐C concentration did not predict risk in this study population.

• Slightly higher systolic blood pressure and C‐reactive protein with dalcetrapib might reflect an adverse effect of inhibiting CETP.

The two most obvious explanations are:

(i) The increase in HDL-C concentration induced by dalcetrapib is not accompanied by an enhancement of the protective functions of HDL or

(ii) that the inverse relationship between HDL-C concentration and cardiovascular risk observed in population studies is an epiphenomenon rather than being reflective of an ability of HDL to protect against cardiovascular disease.

Why did Dalcetrapib fail to Reduce CV Events?


CETPinhibitor

Dosemg/d

HDL-C%

LDL-C%

TG%



Anacetrapib 100 138 -40 -7


1620 patients with CHD or CHD risk

equivalents

DEFINE TrialDetermining the EFficacy and Tolerability of

CETP INhibition with AnacEtrapib

Anacetrapib 100 mgStatin therapy to achieve LDL-C <100 mg/dL

Placebo

Primary End PointLipid efficacy and the safety

76 week follow-up

Cannon et al. NEJM. 2010; 363:2406.

DEFINE Trial

Study Week

O 24 760

20

40

60

80

100

120

Anacetrapib

Placebo

LDL-C (mg/dL)

Study Week

0 24 760

20

40

60

80

100

Anacetrapib

Placebo


HDL-C (mg/dL)

DEFINE TrialApoA-I (mg/ml)

Study Week

O 24 760

40

80

120

160

200

240 Anacetrapib

Placebo

ApoB (mg/ml)

Study Week

0 24 760

20

40

60

80

100

Anacetrapib

Placebo


DEFINE Trial

Study Week

O 24 760

20

40

60

80

100

120

Anacetrapib

Placebo

Study Week

0 24 760

30

60

90

120

150

Anacetrapib

Placebo

Non-HDL-C (mg/dL)TG (mg/dL)


DEFINE Trial

Study Week

O 24 760

0.5

1.0

1.5

2.0

2.5

3.0

Anacetrapib

Placebo

Study Week

0 24 760

10

20

30

40

50

Anacetrapib

Placebo

CRP (mg/L)Lp(a) (nmol/L)


Anacetrapib had no Effect on BP

SBP

DBP

mm

Hg

mm

Hg

Week

AnacetrapibPlacebo

20016012080400

120

80

40

00 6 12 18 24 30 38 46 54 62 70 76

0 6 12 18 24 30 38 46 54 62 70 76


Adjudicated CV Events and Death

Anacetrapib N=808n (%)

Placebo N=804n (%)

Hazard ratio (95% CI) P value

Pre-specified adjudicated CV Safety endpoint 16 (2.0) 21 (2.6) 0.76 (0.39, 1.45) 0.40

Cardiovascular Death 4 (0.5) 1 (0.1)Non-fatal MI 6 (0.7) 9 (1.1)Unstable Angina 1 (0.1) 6 (0.7)Non-fatal Stroke 5 (0.6) 5 (0.6)

Death from any Cause 11 (1.4) 8 (1.0)Revascularization 8 (1.0) 28 (3.5) 0.29 (0.13, 0.64) 0.001Death or major CV event (Death/MI/UA/S/Revasc)** 27 (3.3) 43 (5.3) 0.62 (0.38, 1.01) 0.048


Primary Bayesian analysis revealed that the event distribution in DEFINE indicates a 94% predictive probability of dismissing a torcetrapib type increase in CV Events

DEFINE trial


0.5 1.0 1.5

Primary endpoint: MCVE

Revascularization

0.75 1.25CETP-I Better CETP-I worse

DEFINE trial (2010) N = 1,623 (anacetrapib)

ILLUMINATE Trial (2007) N=15,067 (torcetrapib)

Primary endpoint: MCVE

Revascularization

0.25

ILLUMINATE Trial 2007 (torcetrapib)1

DEFINE Trial 2010 (anacetrapib)2

1. Barter et al, NEJM 2007;357:2109.2. Cannon et al. NEJM. 2010; 363:2406.

30,000 patients aged > 50 with with occlusive

arterial disease

REVEAL TrialRandomized Evaluation of the Effects of Anacetrapib

through Lipid-modification

Anacetrapib 100 mgAtovastatin to achieve LDL-C target

Placebo

Primary End PointCoronary death, myocardial infarction or

coronary revascularization

4 year follow-up

www.revealtrial.org

Sites in North America, Europe and Asia

Planned completion in 2017


CETPinhibitor

Dosemg/d

HDL-C%

LDL-C%

TG%



Anacetrapib 100 138 -40 -7

Evacetrapib 500 129 -36 -17


Study Design

• Subjects with elevated LDL-C or low HDL-C

• Up to 8 week dietary lead-in period and withdrawalof lipid-modifying therapies

• 12 week treatment period

– Evacetrapib (30, 100 or 500 mg) or placebo

– Evacetrapib 100 mg or placebo in combination with statin therapy (simvastatin 40 mg, atorvastatin 20 mg, rosuvastatin 10 mg)

• Co-primary endpoints: Percent change in HDL-C and LDL-C

Nicholls et al. JAMA. 2011; 306:2099.

Percent Change in HDL-C and LDL-C

* P<0.001 compared with placeboNicholls et al. JAMA. 2011;306:2099.

Percent Change in HDL-C: Evacetrapib Plus Statin


Percent Change in LDL-C: Evacetrapib Plus Statin


Evacetrapib Conclusions• Evacetrapib monotherapy produced a dose-dependent

increase in HDL-C up to 128.8% and decrease in LDL-C up to 35.9%.

• Significant incremental HDL-C and LDL-C changes were observed when evacetrapib 100 mg was administeredin combination with statins.

• Evacetrapib was well tolerated with no evidence of adverse blood pressure or mineralocorticoid effects.

• The impact of evacetrapib on cardiovascular events remains to be determined.

Nicholls et al. JAMA. 2011; 306:2099.

• There is still a compelling case for further testing the hypothesis that inhibiting CETP by will be anti-atherogenic in humans so long as the hypothesis is tested using potent CETP inhibitors that more than double the level of HDL-C and reduce LDL-C by more than 30%.

• This hypothesis is currently being tested in large CV clinical endpoint trials.

Future of CETP Inhibition as a Strategy to Reduce CV Risk

A-I

Liver

CECE

FCLCAT

FC

Bile

SR-BI

A-I

Macrophage

CEB

LDLR

VLDL/LDL

CETP

TG

ABCA1

ABCG1

XCETP inhibitor

CETP Inhibition: Effect on RCT?


• Elevate plasma HDL-C • Enhance cholesterol efflux and

reverse cholesterol transport

HDLAnti-oxidant

Anti-thrombotic

Anti-inflammatory

Anti-atherogenic HDL functions

NO-promoting

HDLAnti-oxidant

Anti-thrombotic

Anti-inflammatory

Cholesterol efflux and reverse cholesterol transport

Anti-atherogenic HDL functions

NO-promoting

Reverse Cholesterol Transport

A-I

Liver

CECE

FCLCATFC

Bile

SR-BI

A-I

Macrophage

FCABCA1

ABCG1FC

Quantitation of macrophage reverse cholesterol transport in vivo

Plasma 3H-cholesterol,AcLDL

3H-Chol

Bile

Feces

3H-FC

3H-chol

3H-BA

3H-BA

3H-BA 3H-FC

3H-FC

Macrophage

Genetic and pharmacologic interventions

3H‐Cholesterol

MACROPHAGES

HDL % cholesterol efflux

cAMP

Measuring HDL Cholesterol Efflux Capacity

After George Rothblat, et al

A-I

Liver

CECE

FCLCATFC

Bile

SR-BI

A-I

Macrophage

FCABCA1

ABCG1FC

Promoting Cholesterol Efflux and Reverse Cholesterol Transport

• apoA-I infusion

Normal Apo A1 and Apo A1 Milano Dimer

A1m/A1m

A1

1 1

243243

173173ss

1

25

35

66 121 165209 220

243

18714399

Lipid Binding In Vivo Catabolism

LCAT Activation Cholesterol

Efflux

“Receptor”Binding

Franceschini G. Eur J Clin Invest 1996;26:733–746.

A1=apolipoprotein A1A1m=apolipoprotein A1 MilanoLCAT=lecithin cholesterol acyl-

transferase

Can reconstituted HDL remove cholesterol from plaque?

Recombinant apoA-I Milano Produced Regression of Coronary Atherosclerosis

Nissen SE, et al. JAMA. 2003;290(17):2292-2300. Copyright © 2003 American Medical Association.

ETC-216: apoA-Imilano/phospholipids

Reconstituted HDL: The ERASE Trial

Tardif JC et al. JAMA 2007;297:1675–1682.Tardif JC et al. JAMA 2007;297:1675–1682.

Percent Change in Atheroma Volume from Baseline to 6 weeks

Plasma Selective Delipidation: LS-001 Study

Waksman et al. JACC. 2010:55;2727.

Effects of apoA-I vs LDL Interventions on Coronary Atherosclerosis by IVUS

Intensive Statin Treatment Up to 53% reduction LDL-C for 2 years

apoA-I Milanoor r-HDL

for 4-5 weeks

60 70 90 100 120

0

-5.00

-2.50

+2.50

+5.00

REVERSALpravastatin 40 mg540 days

REVERSALatorvastatin 80 mg540 days

ASTEROID rosuvastatin 40 mg720 days

Progression

Med

ian

Ch

ang

e in

% A

ther

om

a V

olu

me

Courtesy of Dr. Jan Johansson

80 11050Mean LDL-C

ERASEJAMA 2007

VSapoA-I milanoJAMA 2003

Nissen SE, et al. JAMA. 2003;290(17):2292-2300.Tardif JC, et al. JAMA. 2007;297(15):1675-1682.Nissen SE, et al. JAMA. 2006;295(13):1556-1565.Nissen SE, et al. JAMA. 2004;291(9):1071-1080.

Delipidated HDL

A-I

Liver

CECE

FCLCATFC

Bile

SR-BI

A-I

Macrophage

FCABCA1

ABCG1FC


• apoA-I infusion• apoA-I upregulation

***

Nicholls SJ, et al. J Am Coll Cardiol. 2011;57(9):1111-1119.Copyright © 2011 American College of Cardiology Foundation.

**P < 0.001*P < 0.01

PlaceboRVX-208 50 mgRVX-208 100 mgRVX-208 150 mg

Efficacy of RVX-208 Time Course of Changes in HDL and

Large Particle HDLHDL Cholesterol Large HDL Particles

1086420

-2Med

ian

Perc

ent C

hang

e

*

25201510

50

-5Med

ian

Perc

ent C

hang

e

Regulation of Macrophage Cholesterol Efflux

A1FC LXR/RXR

PPARPPARPPAR

ABCA1

ABCA1=ATP-binding cassette transporter A1; A1=apolipoprotein A1; FC=free cholesterol; LXR=liver X receptor; RXR=retinoid X receptor; PPAR= peroxisome proliferator-activated receptor; TZD=thiazolidinedione

Oxysterols

FC

A-I

Liver

CECE

FCLCATFC

Bile

SR-BI

A-I

Macrophage

FCABCA1

ABCG1FC


• apoA-I infusion• apoA-I upregulation• LXR agonism

Targeting LXR

A1FC LXR/RXR

New agents

PPARPPARPPAR

ABCA1

ABCA1=ATP-binding cassette transporter A1; A1=apolipoprotein A1; FC=free cholesterol; LXR=liver X receptor; RXR=retinoid X receptor; PPAR= peroxisome proliferator-activated receptor; TZD=thiazolidinedione

Effect of LXR Agonist on Macrophage to Feces Reverse Cholesterol Transport

Bile

Feces 3H-BA

3H-BA 3H-FC

3H-FC

3H cholesterol,AcLDL

3H-FC3H-BA

3H cholesterol

LXR agonist

Plasma3H cholesterol

LXR=liver X receptor; BA=bile acid; FC=free cholesterol; AcLDL=acetylated low-density lipoprotein

% C

PM In

ject

ed

An LXR Agonist Significantly Increased Macrophage-to-Feces Reverse Cholesterol Transport in vivo

0.0

0.5

1.0

1.5

2.0

2.5

*

Control LXR Agonist

* P < 0.05 vs vehicle-treated group

Adapted from Naik SU, et al. Circulation. 2006;113(1):90-97.

A-I

Liver

CECE

FCLCATFC

Bile

SR-BI

A-I

Macrophage

FCABCA1

ABCG1FC


• apoA-I infusion• apoA-I upregulation• LXR agonism• miR-33 antagonism

Targeting miR-33

A1FC LXR/RXR

miR-33

ABCA1Anti-

miR-33

A-I

Liver

CECE

FCLCATFC

Bile

SR-BI

A-I

Macrophage

FCABCA1

ABCG1FC


• apoA-I infusion• apoA-I upregulation• LXR agonism• miR-33 antagonism• LCAT infusion/activation

The HDL flux hypothesis

A-I

CECE

FCLCATFC

Bile

SR-BI

A-I

ABCA1

Macrophage

FC

ABCG1

HL, EL

CEB

LDLR

VLDL/LDL

CETP

TG

novel therapeutic approaches to elevate hdl-c and modulate ... · novel therapeutic approaches to...

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