John J'P' Kastelein, MD PhD

1
John J.P. Kastelein, MD PhD

• Professor and Chair of Vascular Medicine,
  University of Amsterdam
• Strategic Chair of the Genetics of Cardiovascular
  Disease at the Academic Medical Centre
• President of the Dutch Atherosclerosis Society
• Amsterdam, The Netherlands

2
Why have HDL raising drugs failed to demonstrate
improved patient outcomes?

• Prof. John J.P. Kastelein
• Department of Vascular Medicine
• Academic Medical Center / University of Amsteram
• Amsterdam, The Netherlands

3
LDL-lowering Insufficient of Events not Avoided
4

• CAD risk can be reduced to a maximum of
  approximately 35 with current statin and/or
  fibric acid derivates
• Leaving 65 risk reduction to be gained, HDL-C
  increasing strategies are becoming increasingly
  important1

1Duffy Rader Circulation 2006 113
5
Low HDL-C andCardiovascular RiskAn Independent
Frequent Risk Factor
4.0
4.0
3.0
Risk
2.0
2.0
1.0
1.0
0
1.68
0.65
1.17
HDL-C (mmol/L)
Kannel WB. AJC 1983 52 Framingham Study Genest
JJ et al. Am J Cardiol 1991 6711851189
6
Does the HDL level matter if the LDL-C is reduced
by statins and is very low?
7
TNT Events in HDL-C andLDL-C Quintiles
16
14
12
10
5-year K-M incidence of MCVE ()
8
6
4
gt100
2
70-100
LDL-C (mg/dL)
lt70
0
1 (lt38)
2 (38-lt43)
3 (43-lt48)
4 (48-lt55)
5 (?55)
HDL-C quintile (mg/dL)
Barter and Kastelein, NEJM in press, 2007
8
There exist no registered drugs that are
specifically developed to target HDL-C metabolism
to reduce CAD
9
Why Does HDL-C Protect?
HDL-C
10
Why Does HDL-C Protect?

cholesterylester donor

• Which of these function are most important in
  humans?
• How can we differentiate?
• What assays are needed to assess benefit?
• Are we left with waiting for data on surrogate
  endpoints?

11
Benefits of raising HDLAnimal studies

• Raising HDL-C either by infusing HDL or by
  increasing the synthesis of apoA-I by genetic
  manipulation greatly inhibits the development of
  atherosclerosis in both mice and rabbits.

12
HDL-C as Next Therapeutic Target What Does
HDL-C Add?

• Complementary to LDL-C lowering
• Atheroma reversal
• Anti-inflammatory effects

13
HDL-C Increase Reduces Events (HATS) Niacin on
Top of Statin
90 reduction
60 reduction
30
Plt0.01
Percentage MCE


0
No Antioxidants
Includes Antioxidants
Placebo vitamins
Placebo
Niacin/simvastatin vitamins
Niacin/simvastatin
Brown B.G. et al, NEJM 2001
14
HDL-C Increase and LDL-C Decrease Additive
Absolute change in LDLHDL
0
10
20
30
40
50
60
70
80
0
ALLHAT
BIP
10
PROSPER
CDP
20
CARE, HPS
VA HIT
DAIS
LIPID
30
4S
HHS
40
CV event RRR
WOSCOPS
AFCAPS/ TexCAPS
50
ASCOT
60
FATS F/U
70
80
FATS
HATS
90
100
LDL-C lowering HDL-C increase
LDL-C lowering
Brown, 2004
15
HPS2THRIVE Treatment of HDL to Reduce the
Incidence of Vascular Events
ER niacinMK-0524A combination tablet
Statin therapy to optimal LDL-C level
20 000 patients

• Men and women
• Aged 50-80 years
• History of MI, stroke, or PAD
• 7000 patients with diabetes
• Coordinating centers in UK, China, and Scandinavia

Placebo
4-year follow-up

• Primary End Point
• MI, stroke, revascularization procedures

Reports 2012
16
What Does HDL-C Add?

• Complementary to LDL-C lowering
• Atheroma reversal, rather than stabilization
• Anti-inflammatory properties

17
Reverse Cholesterol Transport
18
Infusion of rHDL or liposomes

• Means
• ApoAI-Milano PL complexes (ETC216)
• Sub acute use (Nissen, JAMA, 2003, 290)
• LUVs
• Liposome applications

19
Partial ABCA1 deficiency - Infusion of
rHDLNormalization of Endothelial Function
rHDL infusion
Bisoendial, Circulation 2003
20
Percent Change in Atheroma Volume with IVUS LDL-C
Reduction vs. HDL-C Increasing Therapy
P0.02
REVERSAL ASTEROID APOA-1 Milano
4
4
2.7
2
Median change in TAV ()
-0.3
-4.2
-0.8
0
Prava 40 mg 18 months
Atorva 80 mg 18 months
-2
Rosuva 40 mg 24 months
-4
ApoA-1 Milano 5 weeks
Progression
From no change to regression
Nissen SE et al. JAMA. 2003 and 2004
21
What Does HDL-C Add?

• Complementary to LDL-lowering
• Atheroma reversal, rather than stabilization
• Anti-inflammatory properties

22
HDL and Re-infarctionMIRACL Trial

• At time of presentation ACS
• LDL-C no relation with risk
• HDL-C predicts risk for future event

23
Inhibition of Inflammation Collar Model in Rabbits
Collar-induced arterial wall content of
neutrophils with (C) and without (D) pre-infusion
of rHDL
Collared Saline
Barter P. Circulation 2005
24
Sensitivity Towards Inflammation Genetic Low vs.
High HDL-C
Birjmohun Kastelein, ATVB 2007 May27(5)1153-8
25
Results Pro-Inflammatory Cytokines
P0.02
P0.01
900
140
600
IL-6 (pg/ml)
IL-8 (pg/ml)
70
300
0
0
0
2
4
6
8
24
0
2
4
6
8
24
Time (hr)
Time (hr)
Birjmohun Kastelein, ATVB 2007 May27(5)1153-8
26
Results Coagulation Activation
8
Plt0.01
4
F12 (nmol/L)
0
0
2
4
6
8
24
Time (hr)
Birjmohun Kastelein, ATVB 2007 May27(5)1153-8
27
Targeting HDL-C Metabolism
A new challenge
28
Targeting HDL-C Metabolism

• HDL remodeling
• HL, EL, PLTP?
• apoCI?
• CETP

• Improve lipidation
• maturation
• ABCA1
• ABCG1
• LCAT

• Modulate PL
• phosphatidyl inositol
• sPLA2

PL,FC,CE,apos

• Improve HDL function
• apoAI Milano
• apoAI mimetic peptides

• Increase HDL synth.
• or infuse rHDL
• apoM? ETC216
• LPL LUVs
• apoAI Delipidated HDL

Renal clearance

• Extend/reduce circulation
• Time Block clearance
• trimeric apoAI
• SR-BI

29
Apolipoprotein AI Clinical Relevance

• ApoAI is a very feasible target
• Compelling evidence of anti-atherogenic potential
  (Barter Rye, JIntMed,2006)
• How to increase apoAI levels?
• Upregulation of apoAI gene expression
• PPAR alpha and PPAR delta agonists
• need of apoAI specific upregulation
• Gene therapy (Belalcazar, Circ 2003 Pastore,
  Gene 2004)

30
Partial Apolipoprotein A-IDeficiency

• ApoAIL178P
• 51 heterozygotes

Hovingh et al. JACC, 200444
31
Heterozygosity for ApoAIL178PBiochemistry
Hovingh et al. JACC, 200444
32
Heterozygosity for ApoA-IL178P Event-free
Survival in Carriers vs. Non-carriers
ApoA-I (L178P) Carriers
100
Family controls
Log Rank P0.003
Event Free Survival ()
50
0
30
40
50
60
70
80
Age (years)
33
CETP Inhibition and Lipoprotein Metabolism
Brewer 2004
34
Associations Between the CETP I405V Allele
Particle Size and Longevity
Conclusions Individuals with exceptional
longevity have significantly larger HDL and LDL
particle sizes. This phenotype is associated with
a lower prevalence of hypertension,
cardiovascular disease, the metabolic syndrome
increased homozygosity for the I405V variant in
CETP and lower serum CETP concentrations .
(JAMA, !5 October, 2003)
35
CETP Plasma Levels and CAD Risk

• EPIC-Norfolk cohort, Cambridge, UK
• Prospective nested case-control design
• 735 cases vs 1400 matched controls
• Apparently healthy at baseline
• Outcome Fatal / non-fatal coronary artery disease

Boekholdt et al. Circulation 2004
36
CETP Levels and CAD risk
4
3
Odds ratio for future CAD
2
Triggt1.7 mmol/L
1
Triglt1.7 mmol/L
0
CETP quintile 1 2 3 4
5
Range, mg/L lt2.4 2.42.9
3.03.7 3.84.9 gt4.9
Boekholdt et al. Circulation 2004
37
RADIANCE 1 and 2 Study Designs
B-mode ultrasound every 6 months

S C R E E N I N G
Torcetrapib/atorvastatin (T/A)
R
Atorvastatin (A) only run-in Target LDL-C to CV
risk goal
Atorvastatin (A)
Dose titration (mg) 10 20 40 80
atorvastatin dose at end of titration period
RADIANCE 1 20 mg start no wash-out
periodRADIANCE 2 4 week wash-out, 416 wk run-in
24-month double-blind treatment
38
RADIANCE 2- Mixed Dyslipidemia1o Imaging
Endpoint
T/A
1.80
A
1.60
1.3680
1.3319
1.3469
1.3079
1.40
1.3002
1.3634
1.3592
1.3210
1.3260
1.3150
1.20
1.00
Means /- SD
0.80
0.60
Treatment Period
Kastelein et al, Lancet 2007
39
RADIANCE 2- Mixed Dyslipidemia Adverse Events
(All Causality)
Kastelein et al, Lancet 2007
40
Future DirectionsPost-Torcetrapib Era
Newsweek, March 26th, 2007
41
Conclusions

• Raising HDL-C is an attractive but hypothetical
  target in the prevention of CVD.
• Targeting HDL-C metabolism is infinitely more
  complex than lowering LDL-C.
• Increasing ApoA1 synthesis (early in the
  pathway), rather than CETP inhibition (late in
  the pathway) might be the best option to go
  forward.