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Emerging targets in HDL modification: Relevant data from development
programs
Prof. John KasteleinAcademic Medical Centre
Amsterdam, The Netherlands
2
Novel Approaches to Modify Lipids and Lipoproteins
Low Density Lipoprotein
High Density Lipoprotein
Triglyceride Rich Lipoproteins
Inflammation
Lipoprotein a
3
New Approaches for Raising HDL
What is in development?
• Cholesterol Ester Transfer Protein (CETP) inhibitors
• ER-Niacin / Laropiprant combination
• ApoA1 based strategies
• LCAT replacement strategies
• ABCA1 agonists
4
The Verdict is Still Out on CETP Inhibition as a Mechanism
5
New Approaches for Raising HDL
What is in development?
• Cholesterol Ester Transfer Protein (CETP) inhibitors
• ER-Niacin / Laropiprant combination
• ApoA1 based strategies
• LCAT replacement strategies
• ABCA1 agonists
6
Nicotinic AcidTreatment of Dyslipidemia and Atherosclerosis
First used as lipid-altering agent in 1955
Well understood safety profile
Broad spectrum of lipid effects*
↓LDL-C (15%–25%)
↑HDL-C (20%–35%)
↓TG (20%–40%)
↓Apo B, non-HDL-C, Lp(a)
Cardiovascular (CV) benefits
↓ CV events (Coronary Drug Project)
↓ Plaque progression (angiographic and IMT studies)
Niacin added to a statin may address residual CV risk
7
Most Patients on ER Niacin TherapyDo Not Reach a 2-g Dose
0
20
40
60
80
100
4 weeks N = 14,386
8 weeks
n = 6,349
12 weeks
n = 5,277
24 weeks
n = 5,402
1 year
n = 2,104
Use
rs,
%
> 1500 mg
1001–1500 mg
751–1000 mg
501–750 mg
500 mg
8
Effectiveness of 2 g vs 1 gof ER Niacin
Lipid-modifying efficacy generally seen with at least 1 g/day
Use of 2 g versus 1 g provides:
About twice the LDL-C reduction
About twice the HDL-C elevation
Several times the reduction of TG
LDL-C HDL-C TG
1 g/day –9 +15 –11
2 g/day –17 +26 –35
NIASPAN™ US Prescribing information.
Mean % change from baseline
9
Niacin Flushing Pathway: Two Separate Steps and Sites of Action
Illustrations are artistic renditions.PGD2=prostaglandin D2; PLA2=phospholipase A2; DP1=prostaglandin D2 receptor 1.Benyó Z et al. Mol Pharmacol. 2006;70:1844–1849; Morrow JD et al. J Invest Dermatol. 1992;98:812–815; Cheng K et al. Proc Natl Acad Sci USA. 2006;103:6682–6687.
1. Epidermal Langerhans Cells
• Niacin binds
• PGD2 is produced and released
2. Dermal Blood Vessels
• PGD2 binds to DP1• Vasodilation results
10
An Overview of the Niacin-Induced Flushing Pathway
Niacin
Niacin Receptor
(+)
Arachidonic Acid
Phospholipids
PGG2
PGH2
PGF2α
PGI2PGE2
TXA2
PLA2
PGD Synthase
Arachidonic Acid Pathway
Epidermal Langerhans Cells Dermal Blood Vessel
PGD2
DP1
PG=prostaglandin; PLA2=phospholipase A2; TXA2=thromboxane A2.Dashed arrows are normal parts of the arachidonic acid pathway that may or may not occur in Langerhans cells. Maciejewski-Lenoir D et al. J Invest Dermatol. 2006;126:2637–2646; Narumiya S et al. Physiol Rev. 1999;79:1193–1226; Cheng K et al. Proc Natl Acad Sci USA. 2006;103:6682–6687; Morrow JD et al. Prostaglandins. 1989;38:263–274.
Prostaglandin D2 Receptor 1 (DP1) Pathway
PGD2
Vasodilationand Flushing
11
Lipid/Flushing Study: Lower Incidence of Moderate or Greater Flushing vs ER Niacin
Percentage of patients with moderateor greater flushing symptoms
across weeks 1–24
Average number of days per weekwith moderate or greater flushing
symptoms across weeks 1–24
Weeks on Treatment
Num
ber
of
Day
s pe
r W
eek
dose advancement
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 250
1
2
% P
atie
nts
Weeks on Treatment
dose advancement
0 1 2 3 4 5 6 7 8 9 10 11 12131415161718192021222324250
10
20
30
40
50
60
ER niacin (n = 508) ER niacin/laropiprant (n = 763) O Placebo (n = 268)
12
-25
-20
-15
-10
-5
0
5
10
15
20
25
Placebo ER Niacin 2g ER Niacin/Laropiprant 2g
ER Niacin/Laropiprant Lipid Efficacy (Weeks 12-24)M
ean
% c
hang
e fr
om B
asel
ine
HDL-CLDL-C TG(median)
-1.2
19.818.8
-0.5
-18.1 -18.9
3.6
-21.2 -21.7
*
**
* p<0.001 vs. Placebo
Maccubbin et al. J Clin Lipidol 2007; 1: 323 Maccubbin et al. J Clin Lipidol 2007; 1: 323
13
Factorial Study: Lipid Efficacy
ER niacin/laropiprant (n = 160)
Simvastatin (all doses pooled; n = 565)
ER niacin/laropiprant + simvastatin (all doses pooled; n = 520)
Primary end point
TG-33.3
-21.6
-14.7
0 4 8 12
% C
hang
e
-40
-30
-20
-10
0
Weeks on Treatment
HDL-C 27.5
23.4
0 4 8 12
% C
hang
e
0
10
20
30
Weeks on Treatment
6.0
LDL-C
-17.0
-37.0
-47.9
0 4 8 12
% C
hang
e
-60
-50
-40
-30
-20
-10
0
Weeks on Treatment
14
ER niacin/laropiprant 2 g/40mg
Placebo
Patient Population Subjects Primary End Point
Age 50-80
• History of MI or cerebrovascular atherosclerotic disease or PAD or diabetes mellitus with any of the above or with other evidence of symptomatic CHD
25,000 UK
(n=8500), Scandinavia (n=6000) and China (n=10500)
Major vascular events (non-fatal MI or coronary death, non-fatal or fatal stroke or revascularisation)
All patients receive either simvastatin 40mg or ezetimibe/simvastatin 10/40 mg
HPS2-THRIVE (Heart Protection Study 2 – Treating HDL to Reduce Vascular Events)
15
New Approaches for Raising HDL
What is in development?
• Cholesterol Ester Transfer Protein (CETP) inhibitors
• ER-Niacin / Laropiprant combination
• ApoA1 based strategies
• LCAT replacement strategies
• ABCA1 agonists
16
Where to Intervene inHDL-C Metabolism?
Hovingh et al. Current Opinion in Lipidology 2005
17
ApoA1 Based Therapies
ApoA1 Mimetics, such as APL-180 Novartis
Full-length ApoA1, such as ApoA1 Cerenis Therapeutics
Pre-Beta HDL, as generated by delipidation, HDL Therapeutics Inc.
Reconstituted HDL, CSL Ltd.
ApoA1 Milano, The Medicines Company
Trimeric ApoA1, Borean Pharma and now Roche
RVX-208, as developed by Resverlogix
18
ApoA-I is made in the Liver and Small Intestines.
Liver
SmallIntestines
19
RVX-208 is an orally active, novel, and synthetic small molecule (<400 kDa) that shares similarities with the
Quinazoline family of compounds.
IT IS NOT RESVERATROL NOR A DERIVATIVE!
RVX-208
20
RVX-208 increases ApoA-I production, thus triggering HDL synthesis, especially pre-beta HDL known for its potent
cholesterol efflux activity. ApoA-
I
ApoA-IPool
a-HDL3
pre-bHDL
a-HDL2
RVX-208
Enhanced R.C.T.
21
Schematic of Phase 1a Protocol
Cohorts 1- 6 (42 treated and 14 placebo)
Cohort 7 (12 treated and 4 placebo)
Cohorts 8 - 9 (12 treated and 4 placebo)
Cohort 10 (6 treated and 2 placebo)
Single dose of RVX-208 (1-20 mg/kg), fasted
Single dose of RVX-208 (4 mg/kg), fed
Multiple doses x 7 days of RVX-208 (4 or 1 mg/kg), b.i.d., fasted
Single dose x 7 days of RVX-208 (3 mg/kg), q.d., fasted
A
B
C
D
80 S
ub
ject
s
This color denotes multiple day dosing of RVX-208
2222
Efficacy of RVX-208 in HumansPhase 1b/2a ApoA-I, % Change vs. Placebo
All Subjects Low HDL Normal HDL
DAY 8 Day 28 Day 8 Day 28 Day 8 Day 28
1mg/kg 5.11** 6.48* 5.7* 7.8* 4.53 5.2
3mg/kg 7.96*** 10.31*** 6.5** 10.6** 9.3*** 10.0*
* p<0.05, ** p<0.01, *** p<0.001
232323
RVX208 α1-HDL Comparison vs. High Dose Statins α1-HDL Strongest Predictor from Framingham Offspring Study
** p<0.008
0
10
20
30
40
50
60
70
Crestor 40mg Lipitor 80mg RVX208 1mg/kg RVX208 1mg/kgA
ll S
ub
ject
s
Lo
w H
DL
Su
bje
cts
**
**
24
Cerenis HDL (CER-001)Homogeneous Drug Product
Traditional rHDL complexes
Proprietary charged CerenisrHDL complexes
Validated, scaleable GMP process for producing proprietary charged lipoprotein complexes
HDL
HDL
GMP run
25
CER-001-CLIN-001 : 15 mg/kgLCAT Activation
26
CER-001 Mobilizes Cholesterol in Rabbits: Comparison with ETC-216
CER-001 is at least 10 to 20 time more potent to mobilize cholesterol than ETC-216
* ETC-216 data were extracted from Marchesi M. et al (2004) J Pharmacol Exp Ther, 311(3): p. 1023-31
27
CHI SQUARE Study Design
4 Treatment Groups Placebo
Low dose CER-001
Mid dose CER-001
High dose CER-001
6 doses per subject
125 subjects enrolled per group Estimated 75 - 80% completion rate
==> ~98 subjects w/ follow-up IVUS per group
28
N = 126 Placebo
N = 126 Low dose
N = 126 Mid dose
N = 126 High dose
Observation Period2 to 5 weeks
504
Su
bje
cts
Ran
do
miz
ed
50 SitesCanada, US, France,
Netherlands
Core IVUS LabMontreal Heart
Up to 1000 SubjectsScreened w/
Baseline IVUS following
Acute ACS Event
Screen Period2 weeks
IVUS VisitScreening
Follow-Up IVUS Visit
Infusion Visits InterimVisit
Therapy Period5 weeks
Long Term Follow-up6 months
Follow-UpVisit
CHI-SQUARE Study Design
29
CER-001-CLIN-001Overall Conclusions
Administration of a single intravenous infusion of CER-001 at doses up to 45 mg/kg over 1 or 2 hours has been safe and well-tolerated
CER-001 exhibits the desired effect of cholesterol mobilization and is significantly more effective than earlier complexes
30
Step 1Collected~1 litre
of plasma
Step 2Plasma enrichedthrough process
Step 3Re-infused preβenriched plasma
• Used patients own HDL• Cholesterol removed from
αHDL to yield preβ-HDL• Preβ enriched plasma is
re-infused into patient
IVUS clinical trial using selective delipidated HDL
Walksman R, et al. J Am Coll Cardiol 2010; 55 : 2727-35.
31
Treatment arm (N=14)
Control arm (N=14)
1:1 randomization
(N=28)
Day 0 1 2 3 4 5 6 7 8
Week
IVUS IVUS
Treatment or control plasma infusion
IVUS Clinical Trial Using Selective Delipidated HDL
Walksman R, et al. J Am Coll Cardiol 2010; 55 : 2727-35.
32
-14
Change in totalatheroma volume
Change in 10mm most diseased segment
4
2
0
-2
-4
-6
-8
-10
-12-12.18
-6.24
-1.73
2.8C
hang
e in
ath
erom
a vo
lum
e (m
m3 )
Preβ-HDL infusion
Control infusion
Results of the IVUS Clinical Trial Using Selective Delipidated HDL
Waksman R, et al. J Am Coll Cardiol 2010; 55 : 2727-35.
33
Conclusion
Therapies that raise levels of ApoA-I and pre-beta HDL carry a strong promise for the future of
cardiovascular disease prevention
34
New Approaches for Raising HDL
What is in development?
• Cholesterol Ester Transfer Protein (CETP) inhibitors
• ER-Niacin / Laropiprant combination
• ApoA1 based strategies
• LCAT replacement strategies
• ABCA1 agonists
35
LDL
Peripheral tissues
SR-BI
LDL-RCETP
mature HDL(large, α-HDL)
nascent HDL (small, preβ-HDL)
LCAT
Kidney
Liver
Small HDL Clearance
LCAT Product Gradient Drives Reverse Cholesterol Transport
36
>75 gene mutations have been described resulting in two phenotypes
>200 cases reported worldwide
Familial LCAT Deficiency (FLD)
• Complete absence of LCAT activity in plasma
• Corneal opacities, anemia, proteinuria, renal failure
• Glomerulosclerosis a major cause of morbidity and mortality
Fish Eye Disease (FED)
• Partial deficiency of LCAT activity in plasma
• Corneal opacities
Current TreatmentsDietary fat restriction
ACE inhibitor, ARB’s
Dialysis
Kidney transplantation
Corneal transplantation
LCAT Deficiency in Humans
37
LDL
Peripheral tissues
SR-BI
LDL-RCETP
mature HDL(α-HDL)
nascent HDL (Preβ-HDL)
LCAT
Lp-XKidney
Liver
Decreased
Increased
Impaired RCT in Familial LCAT Deficiency
38
Conclusion
In the next five years, we will prove or disprove that additional LDL lowering with other agents
than statins is effective
and
we will show or not show that the HDL hypothesis is true.