new targets in lipid management · new targets in lipid management john j.p. kastelein, md phd...
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New Targets in Lipid Management
John J.P. Kastelein, MD PhD
Academic Medical Center / University of Amsterdam
The Netherlands
Novel Approaches to Modify Lipids and Lipoproteins
� Low Density Lipoprotein
� High Density Lipoprotein
� Triglyceride Rich Lipoproteins
2
� Triglyceride Rich Lipoproteins
� Inflammation
� Lipoprotein a
Statin Prescription in the UK
500,000
600,000
700,000
800,000
Net
Ingr
edie
nt C
ost (
000s
)
40,000
50,000
60,000
Pre
scrib
ed It
ems
(000
s)
3
0
100,000
200,000
300,000
400,000
500,000
91/9
2
92/9
3
93/9
4
94/9
5
95/9
6
96/9
7
97/9
8
98/9
9
99/0
0
00/0
1
01/0
2
02/0
3
03/0
4
04/0
5
05/0
6
06/0
7
07/0
8
08/0
9
Net
Ingr
edie
nt C
ost (
000s
)
0
10,000
20,000
30,000
Pre
scrib
ed It
ems
(000
s)
Statins – Prescribed Statins – Cost (£000s)
Percentage of the UK-population with TC > 5 mmol/l
70
80
90
100
% o
f th
e P
op
ula
tio
n
1994
1998
2003
4
0
10
20
30
40
50
60
16–24 25–34 35–44 45–54 55–64 65–74 75+ 16–24 25–34 35–44 45–54 55–64 65–74 75+
Men Women
% o
f th
e P
op
ula
tio
n
1994
1998
2003
2006
Year2006
All-Cause Mortality in the UK in those < 75 Years
115350
400
450
All
Cau
ses
-
397
296
5
8942
52
32
141
114
115
107
0
50
100
150
200
250
300
P Ave 95-97 P Ave 06-08
Mor
talit
y -
DS
R p
er 1
00,0
00 -
Other Cancer Other Circulatory CHD
Data
1995-1997 2006-2008
296
53% reduction
New Approaches to LDL Reduction
What is in development?
• Cholesterol Absorption Inhibitors
• Squalene Synthase (SSI) inhibitors
• Apo B mRNA antisense drugs
6
• Apo B mRNA antisense drugs
• Microsomal Triglyceride Transfer Protein (MTP) inhibitors
• Thyroxin Receptor Agonists
• PCSK9 Inhibitors
New Approaches to LDL Reduction
What is in development?
• Cholesterol Absorption Inhibitors
• Squalene Synthase (SSI) inhibitors
• Apo B mRNA antisense drugs
7
• Apo B mRNA antisense drugs
• Microsomal Triglyceride Transfer Protein (MTP) inhibitors
• Thyroxin Receptor Agonists
• PCSK9 Inhibitors
New Approaches to LDL Reduction
What is in development?
• Cholesterol Absorption Inhibitors
• Squalene Synthase (SSI) inhibitors
• Apo B mRNA antisense drugs
8
• Apo B mRNA antisense drugs
• Microsomal Triglyceride Transfer Protein (MTP) inhibitors
• Thyroxin Receptor Agonists
• PCSK9 Inhibitors
Mipomersen: Apo B-100 as a Target
Cholesterol
Apo B Triglyceride
VLDL� Apo B-100 is an important structural
and functional component of lipoproteins
� Blocking Apo B-100 production blocks VLDL and LDL production
Mipomersen
9
Apo B Triglyceride
VLDL IDL
LDL1LDL2 LDL3
Lp(a)
Apo A
� A 20-mer phosphorothioate antisense oligonucleotide that is complementary in sequence to a segment of the human Apo B mRNA
Overview of Mipomersen
10Kastelein JJ, et al. Circulation. 2006;114(16):1729-1735.
G C C T C A G T C T G C T T C G C A C C
PhosphorothioateBackbone
2′ MOE2′ MOE2′ Deoxy
(Supports RNase H Activity)
OB
O
O
B
O
O
OP
O
S
OP
O OCH3
O OCH3
5'
Antisense: A Novel Approach to Drug Discovery by Inhibition of Translation of a Specific Targeted Pr otein
Antisense Strand
Cell Membrane
2nd Generation Antisense Drugs
� ~20X more potent
� 1X/week to 1X/quarter dosing
� Better tolerated
RNase H Dependent Mechanism of Action
11
O
O
B
O
O
BO
OP
S
O
OP
S
OP
S
3'
Sense-Antisense Duplex
RNase H
DNA
mRNA
Nucleus Cytoplasm
Membrane
� Lower cost of therapy
Heterozygous Familial HypercholesterolemiaStudy Design
� Patients were randomized 2:1 to receive weekly subcutaneous injections of mipomersen 200 mg or placebo for 26 weeks
Active treatment
12
Active treatment
Placebo
R 2:1 active:placebo
Screening
≤4 weeks
Treatment period
26 weeks
Safety follow-up
24 weeks
Safety follow-up(for patients not entering OLE study)
225 patientsscreened;
124 patientsenrolled
Cromwell W, et all, [poster]. American Heart Association Scientific Sessions; Nov 14-18; Orlando, FL; 2009
Mipomersen Significantly Reduced LDL-C
Reduction in LDL-C over 28 weeks(full analysis set)
5.2%PET
13
–28.0%
Distribution of LDL-C % Change From BaselineC
fro
m b
asel
ine
at P
ET
14
% c
han
ge
in L
DL
-C f
rom
bas
elin
e at
PE
T
PET, primary efficacy time point, 2 weeks after final dose. Data on file.
New Approaches to LDL Reduction
What is in development?
• Cholesterol Absorption Inhibitors
• Squalene Synthase (SSI) inhibitors
• Apo B mRNA antisense drugs
15
• Apo B mRNA antisense drugs
• Microsomal Triglyceride Transfer Protein (MTP) inhibitors
• Thyroxin Receptor Agonists
• PCSK9 Inhibitors
1616
The Rationale
� Thyroid hormone receptors modulate lipid metabolism and energy expenditure through transcriptional effects
� The liver is the target organ for thyroid hormone-mediated regulation of lipid metabolism
16
of lipid metabolism
� Association between thyroid status and atherosclerosis clearly demonstrated
� The thyroid hormone receptor is a well known target
1717
Selective Thyroid Receptor Agonist Provides New Treatment Opportunities
Selective thyroid agonist
17
� Heart
� Bone
� Skeletal muscle
� Cholesterol
� Triglycerides
� Lipoprotein(a)
� Reverse cholesterol transport
� Metabolic rate
Side effects Metabolic effects
1818
Eprotirome is…
� a small molecule
� a thyroid receptor agonist
� acting in the liver
18
� as potent as T3
� for once daily oral administration
1919
Eprotirome Monotherapy Efficiently Lowers LDL-C
Placebo25 µg50 µg100 µg
LDL cholesterol
125
150
mg/
dL
LDL-cholesterolBaseline to week 12
-6
-10
0
% c
hang
e
19
100
125
750 4 8 12 16
Time (weeks)p <0.0001Mean ± 95% CI
-21-26
-32
-40
-30
-20
% c
hang
e
New Approaches to LDL Reduction
What is in development?
• Cholesterol Absorption Inhibitors
• Squalene Synthase (SSI) inhibitors
• Apo B mRNA antisense drugs
20
• Apo B mRNA antisense drugs
• Microsomal Triglyceride Transfer Protein (MTP) inhibitors
• Thyroxin Receptor Agonists
• PCSK9 Inhibitors
23
24
LDL-C Mean % Change from Baseline in Subjects Treated with IV REGN727/SAR236553
or PlaceboLS
ME
AN
S P
erce
nt C
hang
e (%
)
2727
Swergold G. J Clin Lipidol 2011;5(3):219. Study R727-CL-0902
LSM
EA
NS
Per
cent
Cha
nge
(%)
27
Novel Approaches to Modify Lipids and Lipoproteins
� Low Density Lipoprotein
� High Density Lipoprotein
� Triglyceride Rich Lipoproteins
28
� Triglyceride Rich Lipoproteins
� Inflammation
� Lipoprotein a
New Approaches for Raising HDL
What is in development?
• Cholesterol Ester Transfer Protein (CETP) inhibitors
• ER-Niacin / Laropiprant combination
• ApoA1 based strategies
29
• ApoA1 based strategies
• LCAT replacement strategies
• ABCA1 agonists
Future DirectionsPost-Torcetrapib Era
30Newsweek, March 26th, 2007
Odds ratio for future CAD
2
3
4
CETP Levels and CAD risk:CETP Levels and CAD risk:The EPIC The EPIC –– Norfolk studyNorfolk study
31
CETP quintile 1 2 3 4 5
Odds ratio for future CAD
0
1
2Trig>1.7 mmol/L
Boekholdt et al. Circulation 2004
Trig<1.7 mmol/L
Range, mg/L <2.4 2.4–2.9 3.0–3.7 3.8–4.9 >4.9
LDL-C
60
80
100
120
140
160
Per
cent
Cha
nge
from
Bas
elin
ein
HD
L-C
HDL-C
Per
cent
Cha
nge
from
Bas
elin
ein
LD
L-C
-40
-20
0
20
Anacetrapib Dose Ranging Study
32Bloomfield et al. Am Heart J 2009;157:352-60
PlaceboAnacetrapib 10 mgAnacetrapib 40 mgAnacetrapib 150 mgAnacetrapib 300 mg
Weeks on Treatment
-20
0
20
40
60
0 2 4 8
Per
cent
Cha
nge
from
Bas
elin
ein
HD
L
Per
cent
Cha
nge
from
Bas
elin
ein
LD
L
Weeks on Treatment0 2 4 8
-80
-60
-40
FutureFuture
33
�� 30,000 patients with occlusive arterial disease in North America, 30,000 patients with occlusive arterial disease in North America, Europe and AsiaEurope and Asia
�� Background LDLBackground LDL--lowering with atorvastatinlowering with atorvastatin
�� Randomized to anacetrapib 100 mg vs. placeboRandomized to anacetrapib 100 mg vs. placebo
�� Primary outcome: Coronary death, myocardial infarction or Primary outcome: Coronary death, myocardial infarction or coronary revascularizationcoronary revascularization
www.revealtrial.org. www.revealtrial.org.
The Verdict is Still Out on CETP Inhibition as a Mechanism
34
New Approaches for Raising HDL
What is in development?
• Cholesterol Ester Transfer Protein (CETP) inhibitors
• ER-Niacin / Laropiprant combination
• ApoA1 based strategies
35
• ApoA1 based strategies
• LCAT replacement strategies
• ABCA1 agonists
Niacin-Induced Flushing Limits Niacin Utilization
36
Niacin Flushing Pathway: Two Separate Steps and Sites of Action
1. Epidermal Langerhans Cells
• Niacin binds
• PGD2 is produced and released
37
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.
2. Dermal Blood Vessels
• PGD2 binds to DP1
• Vasodilation results
An Overview of the Niacin-Induced Flushing Pathway
Niacin
NiacinReceptor
(+)
Phospholipids
PLA
Arachidonic Acid Pathway
Epidermal Langerhans Cells Dermal Blood Vessel
PGD2
Prostaglandin D2 Receptor 1 (DP1) Pathway
38
Arachidonic Acid
PGG2
PGH2
PGF2α
PGI2PGE2
TXA2
PLA2
PGD Synthase
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.
PGD2
Vasodilationand Flushing
Factorial Study: Lipid Efficacy
Primary end point
HDL-C27.5
23.4
0 4 8 12
% C
hang
e
0
10
20
30
6.0-17.0
% C
hang
e
-30
-20
-10
0
39
� ER niacin/laropiprant (n = 160)
� Simvastatin (all doses pooled; n = 565)
� ER niacin/laropiprant + simvastatin (all doses pooled; n = 520)
TG-33.3
-21.6
-14.7
0 4 8 12
% C
hang
e-40
-30
-20
-10
0
Weeks on Treatment
Weeks on Treatment
LDL-C
-37.0
-47.9
0 4 8 12
% C
hang
e
-60
-50
-40
-30
Weeks on Treatment
ER niacin/laropiprant 2 g/40mg
Placebo
All patients receive either simvastatin 40mg or ezetimibe/simvastatin 10/40 mg
HPS2-THRIVE (Heart Protection Study 2 – Treating HDL to Reduce V ascular Events)
40
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)
New Approaches for Raising HDL
What is in development?
• Cholesterol Ester Transfer Protein (CETP) inhibitors
• ER-Niacin / Laropiprant combination
• ApoA1 based strategies
41
• ApoA1 based strategies
• LCAT replacement strategies
• ABCA1 agonists
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.
42
� Reconstituted HDL, CSL Ltd.
� ApoA1 Milano, The Medicines Company
� Trimeric ApoA1, Borean Pharma and now Roche
� RVX-208, as developed by Resverlogix
CERCER--001001
43
Cerenis HDL (CER-001)Homogeneous Drug Product
Traditional rHDL complexes
HDL
44
Proprietary charged CerenisrHDL complexes
Validated, scaleable GMP process for producing proprietary charged lipoprotein complexes
HDL
GMP run
CER-001 Mobilizes Cholesterol in Rabbits: Comparison with ETC-216
Total Cholesterol1.0
0 mg/kg2.5 mg/kg5 mg/kg10 mg/kg20 mg/kgETC-216 (100 mg/kg) *
CER-001 is at least 10 to 20 time more potent to mobilize cholesterol than ETC-216
45
2 4 6 80.0
0.5
Time (h)
Co
nce
ntr
atio
n (
g/L
)
* ETC-216 data were extracted from Marchesi M. et al (2004) J Pharmacol Exp Ther, 311(3): p. 1023-31
CHI SQUARE Study Design
�4 Treatment Groups
�Placebo
� Low dose CER-001
�Mid dose CER-001
46
�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
N = 126 Placebo
N = 126 Low dose
N = 126 Mid dose504
Su
bje
cts
Ran
do
miz
ed
50 SitesCanada, US, France,
Netherlands
Core IVUS LabMontreal Heart
Up to 1000 SubjectsScreened w/
Baseline IVUS
CHI-SQUARE Study Design
47
N = 126 High dose
Observation Period2 to 5 weeks
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
DelipidationDelipidation
48
Step 1Step 1Collected~1 litreCollected~1 litre
of plasmaof plasma
Step 2Step 2Plasma enrichedPlasma enrichedthrough processthrough process
Step 3Step 3ReRe--infused preinfused preββenriched plasmaenriched plasma
IVUS clinical trial using selective delipidated HDL
49
•• Used patients own HDLUsed patients own HDL•• Cholesterol removed fromCholesterol removed fromαHDLαHDL to yield to yield preβpreβ--HDLHDL
•• PreβPreβ enriched plasma isenriched plasma isrere--infused into patientinfused into patient
WalksmanWalksman R, R, et al. J Am et al. J Am CollColl CardiolCardiol 2010; 55 : 27272010; 55 : 2727--35.35.
Treatment arm (N=14)Treatment arm (N=14)
Control arm (N=Control arm (N=1414))
1:1 randomization1:1 randomization
(N=28)(N=28)
IVUS Clinical Trial Using Selective Delipidated HDL
50
Day 0Day 0 11 22 33 44 55 66 77 88
WeekWeek
IVUSIVUS IVUSIVUS
Treatment or control plasma infusionTreatment or control plasma infusion
WalksmanWalksman R, R, et al. J Am et al. J Am CollColl CardiolCardiol 2010; 55 : 27272010; 55 : 2727--35.35.
44
22
00
--22--1.731.73
2.82.8
volu
me
(mm
volu
me
(mm
33 ))
Results of the IVUS Clinical Trial Using Selective Delipidated HDL
51
--1414
Change in totalChange in totalatheromaatheroma volumevolume
Change in 10mm most Change in 10mm most diseased segmentdiseased segment
--44
--66
--88
--1010
--1212--12.1812.18
--6.246.24
Cha
nge
in
Cha
nge
in a
ther
oma
athe
rom
avo
lum
e (m
mvo
lum
e (m
m
PrePreββ--HDL infusionHDL infusion
ControlControl infusioninfusion
Waksman R, Waksman R, et al. J Am Coll Cardiolet al. J Am Coll Cardiol 2010; 55 : 27272010; 55 : 2727--35.35.
Conclusion
In the next five years, we will prove or disprove that additional LDL lowering with other agents than statins is
effective
and
52
we will show or not show that the HDL hypothesis is true
and
that lowering of triglycerides in patients on statins and inhibiting inflammation leads to a reduction of CVD events
Novel Approaches to Modify Lipids and Lipoproteins
� Low Density Lipoprotein
� High Density Lipoprotein
� Triglyceride Rich Lipoproteins
53
� Triglyceride Rich Lipoproteins
� Inflammation
� Lipoprotein a
VRN Dashboard
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VRN Website - Frontpage
55
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56
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57