Agents to Raise HDL - · PDF fileAgents to Raise HDL Do we have the right Biomarker of HDL function? The Case for HDL ... ATI-5261, CS-6253

Jacques Genest MD

Cardiovascular Research Laboratories

McGill University Health Center

Agents to Raise HDL

Do we have the right Biomarker of HDL

function?

The Case for HDL

The clinical equipoise

HDL-C as a biomarker of CAD, CVD

HDL Functions and biomarkers

Where do we go from here?

Hazard Ratios for Coronary Heart Disease or Ischemic Stroke Across Quantiles HDL-C

JAMA 2009;302:1993-2000

Figure 3. Hazard Ratios for Coronary Heart Disease Across Fifths of Usual Lipids or

Apolipoproteins

JAMA 2009;302:1993-2000

Copyright restrictions may apply.

Human Serum Lipoproteins

Blaha MJ et al., J Clin Lipidol 2008;2:267-273

Yin and Yang of HDL

The epidemiological association between HDL-C and CVD is strong and coherent.

HDL-C still predicts events if LDL-C is low

Animal data is unequivocal: HDL protect against atherosclerosis

Strong biological plausibility for HDL as a therapeutic target

Mendelian Randomization does not support HDL-Cholesterol as a causal risk factor

The Clinical trial data is neutral (and, in some cases, there is harm)

Boekholdt MS. Circulation. 2013;128:1504-1512

HDL Modulators

Fibrates. (Fenofibrate: Accord)

Niacin (Aim High, HPS-2 THRIVE)

CETP inh. Torcetrapib; Dalcetrapib

rHDL: CER, CSL-112

Apolipoprotein mimetics

BET modulators (RVX208; 222)

Fibrates

Gemfibrozil, Bezafibrate

Fenofibrate

HDL3 HDL2

CETP

EL/HL CE

LCAT

VLDL

LDL

LDLR

SR-BI

ApoA-I

ABCA1

ABCG1

ABCA1

ABCG5/8

ApoA-I

PLTP

Lipid-poor ApoA-I

Nascent HDL

Kidney

Macrophages Intestine

TG

HDL Metabolism

Cholesterol bilary excretion

Bile acid

Fibrates

Effects of Combination Lipid Therapy on Cardiovascular Events in Type 2 Diabetes Mellitus: The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Trial

Henry C. Ginsberg, MD College of Physicians & Surgeons , Columbia University, New York For The ACCORD Study Group

Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus The ACCORD Study Group Published at www.nejm.org March 14, 2010 (10.1056/NEJMoa1001282)

ACCORD Study www.nejm.org March 14, 2010 (10.1056/NEJMoa1001282)

Niacin

Aim-HIGH

HPS2-THRIVE

HDL3 HDL2

CETP

EL/HL CE

LCAT

VLDL

LDL

LDLR

SR-BI

ApoA-I

ABCA1

ABCG1

ABCA1

ABCG5/8

ApoA-I

PLTP

Lipid-poor ApoA-I

Nascent HDL

Kidney


TG

HDL Metabolism


Bile acid

Niacin

AIM-HIGH : Results 50

40

30

20

10

0 0 1 2 3 4

P=0.79 by log-rank best

Niacine plus statine

Placebo plus statine

Années

Po

urc

en

tage

cu

mu

lé d

e p

atie

nts

ave

c d

es

résu

ltat

s p

rim

aire

s

No. à risque

Placebo plus statine 1695 1581 1381 910 436

Niacin plus statine 1718 1606 1366 903 428

Effect of ERN/LRPT on MAJOR VASCULAR EVENTS

0 1 2 3 4

Years of follow-up

0

5

10

15

20

Pati

ents

su

ffer

ing

even

ts (

%)

15.0% 14.5%

Placebo ERN/LRPT

Logrank P=0.29

Risk ratio 0.96 (95% CI 0.90 – 1.03)

Effect of ERN/LRPT on SERIOUS adverse events

0 2 4 6 8 10 12

Skin

Bleeding

Heart failure

Musculoskeletal

Gastrointestinal

Infection

New onset diabetes

Diabetic complication

Active

Placebo

Percentage of patients

Excess p value

3.7% <0.0001

1.8% <0.0001

1.4% <0.0001

1.0% <0.0001

0.7% 0.0008

0.4% 0.05

0.7% 0.0002

0.3% 0.0026

ERN/LRPT

CEPTinh

Torcetrapib; Dalcetrapib

Anacetrapib, Evacetrapib

HDL3 HDL2

CETP

EL/HL CE

LCAT

VLDL

LDL

LDLR

SR-BI

ApoA-I

ABCA1

ABCG1

ABCA1

ABCG5/8

ApoA-I

PLTP

Lipid-poor ApoA-I

Nascent HDL

Kidney


TG

CETP inh.

HDL Metabolism


Bile acid

Inhibiting CETP

Anacetrapib (REVEAL TIMI 55)

Evacetrapib (ACCELERATE)

Anacetrapib: Effects on LDL-C and HDL-C

HDL-C

Study Week

Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76

HD

L-C

(m

g/d

L)

(SE

)

0

20

40

60

80

100

120

Anacetrapib

Placebo

Anacetrapib n = 776 757 718 687 647 607 572 543

Placebo n = 766 761 741 744 736 711 691 666

LDL-C

Study Week

Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76

LD

L-C

(m

g/d

L)

(SE

)

0

20

40

60

80

100

Anacetrapib

Placebo

Anacetrapib n = 804 771 716 687 646 604 568 540

Placebo n = 803 759 741 743 735 711 691 666

-39.8% (p<0.001) +138.1% (p<0.001)

Increasing Apo AI and HDL

Biogenesis

Reconstituted HDL infusions in man

HDL3 HDL2

CETP

EL/HL CE

LCAT

VLDL

LDL

LDLR

SR-BI

ApoA-I

ABCA1

ABCG1

ABCA1

ABCG5/8

ApoA-I

PLTP

Lipid-poor ApoA-I

Nascent HDL

Kidney


TG

HDL Metabolism


Bile acid

rHDL

Apo AI Proteoliposomes

POPC:Chol:Apo AI

200:20:2

ApoA-I

+

SR-BI

Oxysterol

Mitochondria Nucleus Cholesterol pool

Passive

Diffusion

LCAT LCAT

RXR LXR

+ABCA1

+ABCG1

ABCG1 ABCA1

Discoidal HDL

Cholesterol

Efflux

Hafiane A. Cholesterol 2013

Cholesterol Efflux

Nascent HDL structure and Composition

rHDL: Lipid composition resembles raft domains.

Sorci-Thomas MG JLR 2012

Physicochemical properties and lipid class composition of HDL particle subpopulations.

Kontush A et al. J. Lipid Res. 2013;54:2950-2963

©2013 by American Society for Biochemistry and Molecular Biology

Specifically, the content of phosphatidylserine revealed positive correlations with all metrics of HDL functionality, reflecting enrichment of phosphatidylserine in small, dense HDL3.

ERASE Trial: Primary Endpoint

-3.4%

-1.6%

-4%

-3%

-2%

-1%

0%

1%

Percent Change in Atheroma Volume from Baseline to 6 weeks

• The primary endpoint of

percent change in

atheroma volume from

baseline to 6 weeks did

not differ between

treatment groups (-

3.4% in the CSL-111

group vs. -1.6% in the

placebo group, p=0.48)

Placebo CSL-111

Ch

ange

in a

ther

om

a vo

lum

e (%

)

ACC 2007

p = 0.48

HDL Mimetics

Apolipoprotein Mimetics

D-4F, rD-4F

5A, 6F

FAMPS, ELK-2A2K2E

ATI-5261, CS-6253

►The purpose of this study is to investigate

apolipoprotein-mimetic peptides for their ability to

mimic the functionality of HDL particles

►We therefore investigated compound ATI-5261 in the

process of HDL biogenesis

HDL Mimetic Peptide ATI-5261 Promotes Nascent HDL

Formation and Reverse Cholesterol Transport in vitro

Creation of α-helix peptide ATI-5261

Major lipid-binding motif

270 238

EVRSKLEEWFAAFREFAEEFLARLKS

aa238-266

ATI-5261

263

260 299

Hydrophobic segment

237 216

Acidic residues

Segrest et al. J. Lipid Res., 33(1992), pp.141–166

ATI-5261 (squares)

Km= 1.04±0.16 ug/ml (0.37±0.05 uM)

Vmax=14.48±0.29% efflux/6h

Vmax/Km=13.92

CS-6253 (triangles)

Km= 2.27±0.16 ug/ml (0.37±0.18 uM)


Vmax/Km= 6.71

ApoA-I (circles)

Km= 4.53±0.67 ug/ml (0.15±0.02 uM)


Vmax/Km=3.27

Cholesterol efflux in BHK-ABCA1 cells

Summary

1

2

3

4

5

6

7

Increasing Apo AI and HDL

Biogenesis

RVX-208

RVX-208 (BET Bromodomain inh.)

RVX-208 Sub-Group Analysis (ACC 2014)

40

Conclusion: In ASSURE potentially more favorable effects of the apoA-I inducer, RVX-208, on coronary disease progression and MACE were observed in patients with higher levels of systemic inflammation.

Why does this NOT work?

HDL might not be causal in protection against atherosclerosis

HDL-cholesterol is a biomarker of CV health

Need for better biomarkers of HDL function

This does not fit the biology

Most likely

Yes, but which one?

Cellular Cholesterol Efflux

Anti-oxidant

Anti-inflammatory

Vascular Endothelial function

Anti-thrombotic

The Challenge

Develop Biomarkers of HDL Function

That can be tested in outcome studies, be reproducible and brought to high throughput.

HDL3 HDL2

CETP

EL/HL CE

LCAT

VLDL

LDL

LDLR

SR-BI

ApoA-I

ABCA1

ABCG1

ABCA1

ABCG5/8

ApoA-I

PLTP

Lipid-poor ApoA-I

Nascent HDL

Kidney


TG

CETP inh.

HDL Metabolism


Bile acid

Fibrates

rHDL

Niacin

Apo Mimetics RVX

The Need to Study HDL Function: Potential Novel Therapeutic Approaches.

Dalcetrapib Anacetrapib Evacetrapib

LxR agonists

Apo AI Prod RVX208

PPARα agonists (Fibrates)

LxR agonists FxR agonists BAR agonists PPARα agonists

Niacin

The HDL pathway remains a sound therapeutic target.

HDL-C is not a good biomarker of therapeutic success

HDL biogenesis, lipidome and proteome may hold the key to novel therapies.

Conclusions

Documents

Agents to Raise HDL - · PDF fileAgents to Raise HDL Do we have the right Biomarker of HDL function? The Case for HDL ... ATI-5261, CS-6253