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
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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
Macrophages Intestine
TG
HDL Metabolism
Cholesterol bilary excretion
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
Macrophages Intestine
TG
CETP inh.
HDL Metabolism
Cholesterol bilary excretion
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
Macrophages Intestine
TG
HDL Metabolism
Cholesterol bilary excretion
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=15.25±0.25% efflux/6h
Vmax/Km= 6.71
ApoA-I (circles)
Km= 4.53±0.67 ug/ml (0.15±0.02 uM)
Vmax=14.85±0.02% efflux/6h
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
Macrophages Intestine
TG
CETP inh.
HDL Metabolism
Cholesterol bilary excretion
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
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