as PPT (PPTX 13.2MB)

Report
Novel therapies for the prevention
of atherosclerotic vascular disease
Prof. John Kastelein
Academic Medical Centre
Amsterdam, The Netherlands
Novel Approaches to Modify
Lipids and Lipoproteins
• Low Density Lipoprotein
• High Density Lipoprotein
• Triglyceride Rich Lipoproteins
• Inflammation
• Lipoprotein a
2
Statin Prescription in the UK
800,000
60,000
700,000
50,000
500,000
400,000
30,000
300,000
20,000
Statins –
200,000
Cost ( £ 000s)
Prescribed Items (000s)
40,000
Statins – Prescribed
10,000
100,000
08/09
07/08
06/07
05/06
04/05
03/04
02/03
01/02
00/01
99/00
98/99
97/98
96/97
95/96
94/95
93/94
0
92/93
0
91/92
Net Ingredient Cost (000s)
600,000
3
Percentage of the UKpopulation with TC > 5 mmol/l
% of the Population
100
90
1994
80
1998
70
2003
60
2006
Year
1994
1998
50
2003
40
2006
30
20
10
0
16–24
25–34 35–44
45–54 55–64
Men
65–74
75+
16–24 25–34
35–44 45–54
Women
55–64
65–74
75+
4
All-Cause Mortality in the UK in
those < 75 Years
-
Mortality - DSR per 100,000 - All Causes
450
397
400
350
115
296
300
250
200
107
141
150
100
50
Data
Other
Cancer
Other Circulatory
CHD
114
52
89
53% reduction
32
42
0
P Ave 95-97
1995-1997
P Ave 06-08
2006-2008
5
New Approaches to LDL Reduction
What is in development?
• Cholesterol Absorption Inhibitors
• Squalene Synthase (SSI) inhibitors
• Thyroxin Receptor Agonists
• Apo B mRNA antisense drugs
• Microsomal Triglyceride Transfer Protein (MTP) inhibitors
• PCSK9 Inhibitors
6
New Approaches to LDL Reduction
• Ezetimibe is and will be the only cholesterol absorption
inhibitor in clinical use
• Squalene synthase inhibitor development was discontinued
because of liver toxicity
• The thyroxine receptor agonist Eprotirome study in FH
(Akka) was halted for toxicity in animals
7
Heterozygous Familial
Hypercholesterolemia- Study Design
•
Patients were randomized 2:1 to receive weekly
subcutaneous injections of mipomersen 200 mg or
placebo for 26 weeks
Active treatment
225 patients
screened;
124 patients
enrolled
R
2:1 active:placebo
Safety follow-up
(for patients not entering OLE study)
Placebo
Screening
Treatment period
Safety follow-up
≤4 weeks
26 weeks
24 weeks
Cromwell W, et all, [poster]. American Heart Association Scientific Sessions; Nov 14-18; Orlando, FL; 2009
8
Mipomersen Significantly
Reduced LDL-C
Reduction in LDL-C over 28 weeks
(full analysis set)
PET
5.2%
–28.0%
9
% change in LDL-C from baseline at PET
Distribution of LDL-C %
Change From Baseline
PET, primary efficacy time point, 2 weeks after final dose.
Data on file. 10
MTPIs – Efficacy comes from its
dual mechanism of action
Intestinal cell
MTP
MTP inhibition
will limit secretion
of cholesterol and
triglycerides from
the intestine and
liver
Diet Source
X
Chylomicron
triglyceride
cholesterol
Apo B-48
Liver cell
MTP
X
Decrease
secretion to
bloodstream
Liver source
triglyceride
cholesterol
VLDL
Apo B-100
11
11
AEGR 733
HoFH Phase II Study Design
Patients:
- Men/women aged
18-40
6 Patients
- HoFH confirmed by
genetic analysis
- Mean Baseline LDL
= 614 mg/dl
AEGR 733
0.03 mg/kg
4 weeks
AEGR 733
0.1 mg/kg
4 weeks
AEGR 733
0.3 mg/kg
4 weeks
AEGR 733
1.0 mg/kg
4 weeks
Washout
4 weeks
 Open label, ascending dose trial
 Very low fat diet
 Visits: Screen, baseline, every 1, 2, and 4 weeks after
each new dose, end of washout period
Cuchel, M. et al. NEJM 2007; 356:148-56.
12
Change in Lipids Using Lomitapide
with no Background Therapy
20
10
% Change from Baseline
0
-10
+10+12 0
+4
-4
-7
-30
-9
-10
-20
-5
0.03 mg/kg
0.1 mg/kg
-25
-40
0.3 mg/kg
-31
-25
1.0 mg/kg
-34
-50
-51
-60
-60
-65
-70
LDL-C
TGs
HDL-C
nonHDL-C
Cuchel, M. et al. NEJM 2007; 356:148-56.
13
13
HoFH Phase 3: 6-Month Lipid Efficacy
14
LDL Receptor Function and Life Cycle
15
15
The Role of PCSK9 in the Regulation
of LDL Receptor Expression
16
16
Impact of an Anti-PCSK9 mAb
on LDL Receptor Expression
17
17
Study Design heFH study REGN727
Run-in/Screening Period (1–
7 weeks)
Treatment Period (12 weeks)
N=15
Placebo Q2W
N=15
REGN727 150 mg Q4W w/alt PBO
WK -1 LDL-C ≥ 100 mg/dL
(2.6 mmol/L) on stable
statin dose
 ezetimibe for ≥6 wks
N=16
N=15
N=16
Follow-up Period
(8 weeks)
Primary Endpoint
%  calculated LDL-C
from baseline
to week 12
REGN727 200 mg Q4W w/alt PBO
REGN727 300 mg Q4W w/alt PBO
REGN727 150 mg Q2W
Secondary Endpoints
%  in other
lipoproteins and
apolipoproteins and %
patients reaching
prespecified LDL-C
levels
Stein EA et al. Lancet on-line May 26, 2012
18
Changes in LDL-C from Baseline to Week
12 by Treatment Group (mITT Population)
REGN 727
Intervention
Baseline
LDL-C
mg/dL [mmol/L]
% Change
LDL-C1
Placebo
150.8 [3.9]
–10.7 (5.0)
REGN727 150 mg Q4W
166.7 [4.3]
–28.9 (5.1)*
REGN727 200 mg Q4W
169.8 [4.4]
–31.5 (4.9)*
REGN727 300 mg Q4W
139.6 [3.6]
–42.5 (5.1)*
REGN727 150 mg Q2W
147.2 [3.8]
–67.9 (4.9)*
*P<0.0001 for % change REGN727 vs. Placebo.
1LS
mean (SE), using LOCF method.
Stein EA et al. Lancet on-line May 26, 2012
19
Change in Calculated LDL-C at 2 Weekly
Intervals From Baseline to Week 20
REGN727
BASELINE
WEEK 2
WEEK 4
WEEK 6
WEEK 8
WEEK 10
WEEK 12
WEEK 16
WEEK 20
20
Mean (SE) % Change in LDL-C from Baseline
10
0
-10
-20
-30
-40
-50
-60
-70
-80
Placebo
150 mg Q4W
200 mg Q4W
300 mg Q4W
150 mg Q2W
Mean percentage change in calculated LDL-C from baseline to weeks 2, 4, 6, 8, 10, 12 , 16 and 20 in the modified intent-to-treat (mITT)
population, by treatment group.
Stein EA et al. Lancet on-line May 26, 2012
20
Attainment of Prespecified LDL-C Levels
at Week 12 (mITT Population) - REGN727
†
% Patients Achieving Prespecified LDL-C Level
†
*
**
*P=0.006; **P=0.007; †P<0.0001
P-values obtained from the exact score test.
Stein EA et al. Lancet on-line May 26, 2012
21
Novel Approaches to Modify
Lipids and Lipoproteins
• Low Density Lipoprotein
• High Density Lipoprotein
• Triglyceride Rich Lipoproteins
• Inflammation
• Lipoprotein a
22
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 / miR-33 inhibition
23
The Dal-HEART Program
dalcetrapib HDL Evaluation, Atherosclerosis &
Reverse cholesterol Transport
The dal-HEART Program tests a novel hypothesis: enhancing HDL efficacy through CETP
modulation treats the underlying disease of atherosclerosis and will attenuate CV risk
Double blind, randomized, placebo-controlled studies
dal-OUTCOMES
1
15,600 patients
recently
hospitalized
for ACS
To evaluate the
effect of dalcetrapib
on CV
outcomes
RECRUITMENT
COMPLETE
2
3
4
dal-VESSEL
dal-PLAQUE
dal-PLAQUE 2
450 patients with
CHD or CHD risk
equivalent
130 patients with
CHD
900 patients with
CAD
To evaluate the
effect of dalcetrapib
on
inflammation,
plaque size and
burden, measured
by PET/CT and MRI
To evaluate the effect
of dalcetrapib on
atherosclerotic
disease progression,
assessed by IVUS and
carotid B-mode
ultrasound
RECRUITMENT COMPLETE
RECRUITING
To evaluate the
effect of dalcetrapib
on
endothelial function
and blood pressure,
measured by FMD
and ABPM
RECRUITMENT
COMPLETE
24
25
Effects on LDL-C and HDL-C
LDL-C
HDL-C
120
100
80
HDL-C (mg/dL) (SE)
LDL-C (mg/dL) (SE)
100
-39.8% (p<0.001)
60
40
Anacetrapib
Placebo
20
0
Base- 6
line
12
18
24
80
+138.1% (p<0.001)
60
40
Anacetrapib
Placebo
20
30
46
Study week
62
76
0
Base- 6
line
12
18
24
30
46
62
76
Study week
26
Adjudicated CV Events and Death
Anacetrapib
N=808
n (%)
Placebo
N=804
n (%)
Hazard ratio
(95% CI)
P value
16 (2.0)
21 (2.6)
0.76 (0.39, 1.45)
0.40
4 (0.5)
1 (0.1)
-
-
6 (0.7)
9 (1.1)
-
-
1 (0.1)
6 (0.7)
-
-
5 (0.6)
5 (0.6)
-
-
11 (1.4)
8 (1.0)
-
-
Revascularization
8 (1.0)
28 (3.5)
0.29 (0.13, 0.64)
0.001
Death or major CV event
(Death/MI/UA/S/Revasc)**
27 (3.3)
43 (5.3)
0.62 (0.38, 1.01)
0.048
Pre-specified adjudicated CV safety
endpoint
Cardiovascular death
Non-fatal MI
Unstable Angina
Non-fatal Stroke
Death from any cause
**Post hoc analysis.
27
Adjudicated CV Events and Death
Anacetrapib
N=808
(%)
Placebo
N=804
n (%)
Hazard ratio
(95% CI)
P value
16 (2.0)
21 (2.6)
0.76 (0.39, 1.45)
0.40
4 (0.5)
1 (0.1)
-
-
Revascularization
8 (1.0)
28 (3.5)
0.29 (0.13, 0.64)
0.001
Death or major CV event
(Death/MI/UA/S/Revasc)**
27 (3.3)
43 (5.3)
0.62 (0.38, 1.01)
0.048
Pre-specified adjudicated CV
safety endpoint
Primary 6Bayesian
Analysis:(0.7)
9 (1.1)
Event
distribution1 (0.1)
indicates
6 (0.7) a 94% predictive
Unstable Angina
5 (0.6)
5 (0.6)a 25% increase
probability
of dismissing
Non-fatal
Stroke
11 (1.4)
8 (1.0)
(Torcetrapib-Type)
in CV events
Death from any cause
Cardiovascular death
Non-fatal MI
**Post hoc analysis.
28
Future
• 30,000 patients with occlusive arterial disease in North America,
Europe and Asia
• Background LDL-lowering with atorvastatin
• Randomized to anacetrapib 100 mg vs. placebo
• Primary outcome: Coronary death, myocardial infarction or
coronary revascularization
www.revealtrial.org.
29
New Approaches for LDL Reduction
and HDL Raising
• The real battle in the future will be between PCSK9 Mab’s
and CETP inhibitors
* oral versus sc
* every day versus bi-weekly or once monthly
* atherogenic lipoproteins with or without HDL increase
* time to efficacy
* cost
30
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
31
New Approaches for Reduction of
TG rich Lipoproteins
What is in development?
• Microsomal Triglyceride Transfer Protein (MTP) inhibitors
• DiacylGlycerol AcylTransferase (DGAT) inhibitors
• Marine Omega 3 Fatty Acids
• ApoCIII mRNA antisense drugs
• Lipoprotein lipase gene therapy
32
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.
33

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