Novel therapies for the prevention of atherosclerotic vascular disease
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Transcript of Novel therapies for the prevention of atherosclerotic vascular disease
Novel therapies for the prevention of atherosclerotic vascular disease
Prof. John KasteleinAcademic Medical Centre
Amsterdam, The Netherlands
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Novel Approaches to Modify Lipids and Lipoproteins
•Low Density Lipoprotein•High Density Lipoprotein•Triglyceride Rich Lipoproteins•Inflammation•Lipoprotein a
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Statin Prescription in the UK
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Statins – Prescribed Statins – Cost ( £ 000s)
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Percentage of the UK-population with TC > 5 mmol/l
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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 the
Pop
ulati
on
1994
199820032006
Year
1994
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2006
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All-Cause Mortality in the UK in those < 75 Years
8942
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107
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P Ave 95-97 P Ave 06-08
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talit
y - D
SR p
er 1
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All C
ause
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Other Cancer Other Circulatory CHD
Data
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1995-1997 2006-2008
397
296
53% reduction
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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
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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
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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
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 patients screened;
124 patientsenrolled
Cromwell W, et all, [poster]. American Heart Association Scientific Sessions; Nov 14-18; Orlando, FL; 2009
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Mipomersen Significantly Reduced LDL-C
Reduction in LDL-C over 28 weeks(full analysis set)
–28.0%
5.2%PET
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Distribution of LDL-C % Change From Baseline
% c
hang
e in
LDL
-C fr
om b
asel
ine
at P
ET
PET, primary efficacy time point, 2 weeks after final dose. Data on file.
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MTPIs – Efficacy comes from its dual mechanism of action
Decreasesecretion to bloodstream
Liver source
cholesteroltriglyceride
Apo B-100
MTP
Diet Source
cholesteroltriglyceride
Apo B-48
MTPIntestinal cell
Liver cell
VLDL
ChylomicronX
X
MTP inhibition will limit secretion of cholesterol and triglycerides from the intestine and liver
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AEGR 733HoFH Phase II Study Design
AEGR 7330.03 mg/kg
AEGR 733 0.3 mg/kg
6 Patients
4 weeks 4 weeks 4 weeks
Patients:- Men/women aged
18-40- HoFH confirmed by
genetic analysis- Mean Baseline LDL
= 614 mg/dl
AEGR 7330.1 mg/kg
AEGR 7331.0 mg/kg
4 weeks
Cuchel, M. et al. NEJM 2007; 356:148-56.
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
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Change in Lipids Using Lomitapide with no Background Therapy
% C
hang
e fr
om B
asel
ine
Cuchel, M. et al. NEJM 2007; 356:148-56.
-5
-60
-31
-9-10
+10+12 0
-65
-34
-25
+4
-51
-25
-7-4
-70
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-10
0
10
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LDL-C TGs HDL-C nonHDL-C
0.03 mg/kg
0.1 mg/kg
0.3 mg/kg
1.0 mg/kg
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HoFH Phase 3: 6-Month Lipid Efficacy
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LDL Receptor Function and Life Cycle
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The Role of PCSK9 in the Regulation of LDL Receptor Expression
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Impact of an Anti-PCSK9 mAb on LDL Receptor Expression
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Study Design heFH study REGN727
WK -1 LDL-C ≥ 100 mg/dL (2.6 mmol/L) on stable
statin dose ezetimibe for ≥6 wks
Placebo Q2W
N=15
N=16REGN727 200 mg Q4W w/alt PBO
REGN727 300 mg Q4W w/alt PBO
N=15
N=15
N=16
Treatment Period (12 weeks) Follow-up Period (8 weeks)
Run-in/Screening Period (1–7 weeks)
Primary Endpoint% calculated LDL-C
from baseline to week 12
Secondary Endpoints% in other
lipoproteins and apolipoproteins and %
patients reaching prespecified LDL-C
levels
REGN727 150 mg Q4W w/alt PBO
REGN727 150 mg Q2W
Stein EA et al. Lancet on-line May 26, 2012
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InterventionBaseline
LDL-C mg/dL [mmol/L]
% ChangeLDL-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)*
Changes in LDL-C from Baseline to Week 12 by Treatment Group (mITT Population)REGN 727
*P<0.0001 for % change REGN727 vs. Placebo.1LS mean (SE), using LOCF method.
Stein EA et al. Lancet on-line May 26, 2012
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Change in Calculated LDL-C at 2 Weekly Intervals From Baseline to Week 20REGN727
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.
Mea
n (
SE) %
Cha
nge
in L
DL-C
from
Bas
elin
e
BASELINE WEEK 2 WEEK 4 WEEK 6 WEEK 8 WEEK 10 WEEK 12 WEEK 16 WEEK 20
-80
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-10
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Placebo 150 mg Q4W 200 mg Q4W 300 mg Q4W 150 mg Q2W
Stein EA et al. Lancet on-line May 26, 2012
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Attainment of Prespecified LDL-C Levelsat Week 12 (mITT Population) - REGN727
% P
atien
ts A
chie
ving
Pre
spec
ified
LDL
-C L
evel
*P=0.006; **P=0.007; †P<0.0001P-values obtained from the exact score test.
*
**
†
†
Stein EA et al. Lancet on-line May 26, 2012
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Novel Approaches to Modify Lipids and Lipoproteins
•Low Density Lipoprotein•High Density Lipoprotein•Triglyceride Rich Lipoproteins• Inflammation•Lipoprotein a
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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
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The dal-HEART Program tests a novel hypothesis: enhancing HDL efficacy through CETP modulation treats the underlying disease of atherosclerosis and will attenuate CV riskDouble blind, randomized, placebo-controlled studies
dal-OUTCOMES1
15,600 patients recently hospitalizedfor ACS
To evaluate the effect of dalcetrapib on CVoutcomesRECRUITMENT COMPLETE
dal-VESSEL2
450 patients withCHD or CHD riskequivalent
To evaluate the effect of dalcetrapib onendothelial function and blood pressure, measured by FMD and ABPMRECRUITMENT COMPLETE
dal-PLAQUE3
130 patients withCHD
To evaluate the effect of dalcetrapib oninflammation, plaque size and burden, measured by PET/CT and MRIRECRUITMENT COMPLETE
The Dal-HEART Programdalcetrapib HDL Evaluation, Atherosclerosis & Reverse cholesterol Transport
dal-PLAQUE 24
900 patients withCAD
To evaluate the effect of dalcetrapib onatherosclerotic disease progression, assessed by IVUS and carotid B-mode ultrasoundRECRUITING
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Effects on LDL-C and HDL-C
HDL-C
Base-line
6 12 18 24 30 46 62 76
HDL-
C (m
g/dL
) (SE
)
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AnacetrapibPlacebo
LDL-C
Study weekBase-line
LDL-
C (m
g/dL
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80
100
AnacetrapibPlacebo
-39.8% (p<0.001) +138.1% (p<0.001)
6 12 18 24 30 46 62 76
Study week
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Adjudicated CV Events and Death
Anacetrapib N=808n (%)
Placebo N=804n (%)
Hazard ratio (95% CI) P value
Pre-specified adjudicated CV safety endpoint 16 (2.0) 21 (2.6) 0.76 (0.39, 1.45) 0.40
Cardiovascular death4 (0.5) 1 (0.1) - -
Non-fatal MI6 (0.7) 9 (1.1) - -
Unstable Angina1 (0.1) 6 (0.7) - -
Non-fatal Stroke5 (0.6) 5 (0.6) - -
Death from any cause11 (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
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Anacetrapib N=808
(%)
Placebo N=804n (%)
Hazard ratio (95% CI) P value
Pre-specified adjudicated CV safety endpoint 16 (2.0) 21 (2.6) 0.76 (0.39, 1.45) 0.40
Cardiovascular death 4 (0.5) 1 (0.1) - -
Non-fatal MI 6 (0.7) 9 (1.1) - -
Unstable Angina 1 (0.1) 6 (0.7) - -
Non-fatal Stroke 5 (0.6) 5 (0.6) - -
Death from any cause 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
**Post hoc analysis.
Adjudicated CV Events and Death
Primary Bayesian Analysis: Event distribution indicates a 94% predictive
probability of dismissing a 25% increase (Torcetrapib-Type) in CV events
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• 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.
Future
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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
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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
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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
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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.