1. HDL-cholesterol versus apoA-I and Atherosclerosis Regression
Prof. Erik Stroes
Academic Medical Centre
Amsterdam, The Netherlands

2. HDL-c decreases CV-risk via ‘Reverse cholesterol transport’
4.0
3.0
2.0
1.0
0.65
1.17
1.68
HDL-c (mmol/L)
Kannel WB AJC 52, 1983 – Framingham Study
Risk
INTESTINE
LIVER
PERIPHERAL TISSUES
HDL
VLDL
LDL
Chylo-microns
Exogenous cholesterol
Bile
excretion
MACROPHAGE

3. HDL-c concentration and CV-risk No association ‘genetic’ HDL-c increase and risk
Epidemiology
OR / 0.03 mmol/L HDLc increase
Genetics
OR / 0.03 mmol/L HDLc increase
Cohort Atherosclerosis Risk in Communities Study Copenhagen City Heart Study Malmo Diet and Cancer Study, Cardiovascular Cohort Framingham Heart Study Heart Professionals Follow up Study Danish Diet, Cancer, and Health Study Meta-analysis of cohort studies Per 0.03 mmol/L (1 mg/dL) increase in plasma HDL-c Per 0.39 mmol/L (15 mg/dL) increase in plasma HDL-c
0.97 ( )
0.98 ( )
0.96 ( ) -
0.98 ( )
0.70 ( )
7x10-18
6x10-13
1x10-6
4x10-6 -
4x10-36
0.96 ( )
1.09 ( )
0.82 ( )
1.17 ( )
1.84 ( )
1.05 ( )
1.02 ( )
1.28 ( )
0.44
0.21
0.06
0.16
0.71
0.64
Voight, Lancet 2012

4. HDL-c concentration and CV-risk No association ‘drug-induced’ HDL-c increase and risk
ILLUMINATE Torcetrapib:
HDLc  +72% : CV-death OR +1.25
DALOUTCOMES Dalcetrapib:
HDLc  +35% : CV-events no change
HPS2-THRIVE Nicotinic acid:
HDLc  % : CV-events no change
Meta-analysis Briel et al
HDLc  +2-15% : CV-events no change
HDL-c change no longer valid as surrogate
for future CV-risk.
Barter, New Engl J Med 2007; Schwartz GG, New Engl J Med Eur Heart J 2013; Briel, BMJ 2009

5. HDL-c and Reverse cholesterol transport No association between HDLc and fecal chol. excretion
HDL-c concentration no longer valid as surrogate
for RCT capacity.
Broussea, ATvB 2005

6. Is apoA-I/HDL involved in RCT?

7. Decreased ‘Tissue cholesterol efflux’ in apoA-I/L178P heterozygotes
Holleboom, Stroes J Lipid res 2013

8. Increased ‘Vessel-wall thickening’ in ABCA1 & LCAT- heterozygotes
ABCAI heterozygotes
LCAT heterozygotes
Mean wall area outer wall area
Duivenvoorden, Stroes, JACC 2010;
Bochem, Stroes, J Lip Res 2013

9. Number of HDL particles more relevant than HDL-c concentration
Mackey et al., JACC 2012

10. DO APOA-I - INCREASING STRATEGIES WORK?

11. apoA-I increase and RCT effect of rHDL particle infusion (≈ 45mg/kg)
After Infusion
35% peak Increase
Before Infusion
Bile Acids
400
Neutral Sterols
HDL-C (mg/dl)
41±7
300
Intestinal Excretion mg/day
200
100
0.0 SG GG LM IN
Eriksson, Circ 1999

12. apoA-I increase and Plaque regression effect of rHDL particle infusion (40mg/kg) on peripheral atheroma
Shaw, Circ Res 2008

13. apoA-I and Plaque regression Effect of ApoAI milano on coronary atheroma
REVERSAL
ASTEROID
APOA-1 Milano 4 4
2.7* 2
Median change in TAV (%)
-0.3†
-0.8
-4.2
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 and 2004
Reference
1. Nissen SE, et al. JAMA. 2004;291:

14. apoA-I and Plaque regression rHDL& delipidated HDL and coronary atheroma
Reconstituted HDL (CSL-111)
Delipidated HDL (LS-001)
Tardiff, JAMA 2007; Waksman, JACC 2010

15. New apoA-I therapies CER-001
CER-001: recombinant human apoA-I preB HDL particle
composed of recombinant human Apolipoprotein A-I and phospholipid containing Sphingomyelin and dipalmitoyl phosphatidylglycerol
reconstituted charged pre-beta High Density Lipoprotein, mimicking biological properties of natural HDL

16. Preliminary results SAMBA study CER-001 infusion in Subjects with Familial HDL-C deficiency
Trial design:
Baseline Evaluations
Lipoprotein profile
Cholesterol Flux
MRI
Initial Dosing Period
CER-001 Day 1
Lipoprotein profile
PK and PD
Cholesterol Flux
Induction Period
CER-001 q3 days
Day 8 through Day 29
Lipoprotein profile
PK and PD
MRI Day 29
Maintenance Period
CER-001 q2 weeks
Week 6 through Week 24
Final Dosing Period
CER-001 Week 26
Lipoprotein profile
PK and PD
MRI
Study Drug Dosing
First dose
CER-001 8mg/kg
Infusions every 3 days
CER-001 8mg/kg,
Day 1 to Day 29, 9 doses total
Infusions every 2 weeks
CER001 8mg/kg, 10 doses
Final dose
Methods:
Safety & lipid profiles
Cholesterol flux: 2H4-sitostanol (oral) C2-cholesterol (iv)
Vessel wall dimension: 3T-carotid & aorta MRI

17. Summary Both HDL-chol & apoAI are inversely related to CVD-risk
Recent drug trials & genetic studies challenged the protective role of HDL
Novel concept: HDL particle number better predictor of CV risk?
CER-001, a recombinant human ApoA-I particle:
Promotes plasma efflux capacity
Promotes fecal cholesterol excretion
Reduces carotid wall thickness in patients with genetic low-HDLc levels
Ongoing clinical trials with HDL-c & apoAI elevators will help us determine the value of HDL vs. ApoA-I therapy