Transcript Diapositive 1 - Moodle Lille 2

Is there a future for VYTORIN?
or
The limits of surrogate markers
VYTORIN® ( Simvastatin + Ezetimibe)
CHARLES Chloé
MAHAMMED Halima
GOMBET Julienne
1
THE BEGINNING OF TROUBLES
January, 14 2008 MSP issues a press
release
ENHANCE RESULTS
Merck & Co simvastatin
-20% in 15 days
-40% and -50% in a year
Schering-plough ezetimibe
FALLS of Merck &
Schering-plough charts
Yahoo finance US
2
THE LONG-AWAITED ENHANCE TRIAL RESULTS
ENHANCE results:
-After 2 years of study period
-INEGY®/ VYTORIN® trial failed
-Non significative primary end-point
ENHANCE trials
-on public eyes since November 07
-publication of results had been delayed
-Discussion between investigators
3
EFFECTS OF ENHANCE ON VYTORIN PRESCRIBINGS
% patients
Three months later VYTORIN prescribing falls
4
EFFECTS OF ENHANCE ON VYTORIN PRESCRIBINGS
% patients
ENHANCE FOLLOW-UP: The loss of professionnal trust
5
SUMMARY
I) Medical care strategy for hypercholesterolemia
1) Cardiovascular diseases
2) Lowering LDL-C
II) ENHANCE trial
1) Presentation
2) Discussion
6
I) MEDICAL CARE STRATEGY FOR
HYPERCHOLESTEROLEMIA
1) Cardiovascular diseases
-
Epidemiology
Risk factors
7
CARDIOVASCULAR DISEASES ARE A WORLD ISSUE
• Cardiovascular diseases (CVD) made up 16.6 million or a third
of global deaths in 2001
• Around 80% of CVD deaths took place in low and middleincome country
• By 2010 CVD will be the leading cause of deaths in rich and
developping country
• At last 20 million of people
survive heart disease and strokes
every year, many require
continuing costly medical care
WHO SOURCES
8
CARDIOVASCULAR RISK FACTORS
Major non modifiable risk factors:
Sexes (Male)
Aging
Ethnicity
Genetics
Major modifiable risk factors:
Physical inactivity
Poor nutrition
Smoking
High pressure blood
Diabetes
Overweight and obesity (particularly central fat)
Dyslipidaemia ↗
LDL-C, ↗TG, ↙HDL-C
9
WHY LDL-C IS USED AS A MARKER?
• An increase in LDL-C leads to an
increase of cardiovascular risk
• Each decrease of 0.30 g/L LDL-C
Relative
risk
logarithm
scale
•↘30% RR of developping a
coronary pathology
LDL-C (g/L)
10
ATHEROSCLEROSIS TIME-LINE
Media
Phase I: Initiation
Unstable
LDL-C plays a major role in
initiating the development
of atherosclerotic plaque.
Intima
LDL-C
Phase II: Progression
Disease progression results
in the remodeling of the
vascular wall so that the
size of the lumen does
not change significantly.
Stable
Phase III: Complication
Extensive lipid accumulation
and a greater inflammatory
component can pose the
threat of plaque rupture.
Libby P. In: Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. Philadelphia, Pa: WB Saunders Co;
2001:995-1009;
Libby P. J Intern Med. 2000;247:349-358.
11
I) MEDICAL CARE STRATEGY FOR
HYPERCHOLESTEROLEMIA
1) Cardiovascular diseases
2) Lowering LDL-C
- Endogeneous source: statin
- Exogeneous source: ezetimibe
- Association simvastatin/ezetimibe
12
MECHANISM OF ACTION OF DRUGS
Exogenous
Ezetimibe
Bile Acid
Sequestrants
Diet
Dietary
Intestine
Cholesterol
Intake
Fecal Excretion
13
MECHANISM OF ACTION OF DRUGS
Extrahepatic
Tissue
Endogenous
VLDL
IDL
LDL
Fibrates
Chol
LDL-R
Biliary
Cholesterol
Chol
SC-BI
Statins
Acetyl
CoA
Bile
Acids
Exogenous
Diet
Cholesterol
Intake
Acetyl
CoA
Absorption
Chylomicrons
Ezetimibe
Dietary
HDL
Bile Acid
Sequestrants
Intestine
Fecal Excretion
14
MECHANISM OF STATIN
HMG COA
HMG COA reductase
Mevalonate
Squalene
Farnesyl pyrophosphate
Geranyl Geranyl
Pyrophosphate
Dolichol,
Ubiquinon
Cholesterol
Prenylated protein
15
HOW STATINS ACT ON LDL-C?
Increase LDL-R expression in liver
Increase hepatic clearance of plasmatic LDL-C
Decrease the plasmatic LDL-C concentration
16
PHARMACOLOGIC THERAPY STATIN DOSE RESPONSE
% of reduction in LDL-C
60
50
18
12
40
10
30
12
20
10
12
19
27
28
35
37
0
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
MINI DOSES
MAXI DOSES
17
CLINICAL TRIALS
18
P.DURIEZ Médicaments hypolipidémiants, Dijon 19-11-2008
STATINS: “RULE OF SIX”
Doubling the dose of statin used,
the reduction in LDL cholesterol attained (X-Y) = 6%
LDL
cholesterol
(mmol/L)
X
6%
Y
6%
10
Dose 1X
20
Dose 2X
40
6%
80
Statin dose (mg)
19
www.medic.usm.my/~chempath/Lipidsweb%2020May2004/Lipid%20Resources/drug/Ezetimibe.ppt
STATIN’S EFFICIENCY IS PROVED! BUT….
Agressive doses of statins gives side effects
MYOPATHY
HEPATHIC
DAMAGE
RHABDOMYOLYSE
SIDE
EFFECTS
20
STATINS PATENTS
Merck & Co., Inc.
Patent expiration
ZOCOR® simvastatin
2003: Germany,UK (1)
2006: USA (2)
(1)
(2)
EARL, J., KIRKPATRICK, P., 2003. Fresh from the pipeline. Nature reviews, Drug discovery, (2), 97-98
KIDD, J., 2006. Life after statin patent expiries. Nature reviews, Drug discovery, (5), 813-814
21
TWO SOURCES OF CHOLESTEROL:
SYNTHESIS AND ABSORPTION
Liver
Synthesis*
(~800 mg/day)
Biliary
cholesterol
(~1000 mg/day)
22
TWO SOURCES OF CHOLESTEROL:
SYNTHESIS AND ABSORPTION
Dietary
cholesterol
Liver
(~300–700 mg/day)
Synthesis*
(~800 mg/day)
Inhibition of
dietary
cholesterol
sources
Biliary
cholesterol
(~1000 mg/day)
Absorption
(~700 mg/day)
Intestine
Fecal bile acids and neutral
sterols (~700 mg/day)
23
EZETIMIBE
• First in class
• Approved by the FDA in
October 2002
• Selectively inhibits the
intestinal absorption of
cholesterol
• Distinct mechanism
complementary to that of
statins
24
EARL, J., KIRKPATRICK, P., 2003. Fresh from the pipeline. Nature reviews, Drug discovery, (2), 97-98
METABOLISM OF EZETIMIBE
• Rapidly metabolized to an
active glucuronide
metabolite
• Both parent drug and
metabolite inhibit
cholesterol absorption
Glucuronide
• Glucuronide metabolite
more potent than parent
drug in inhibiting
cholesterol absorption
25
NPC1L1
(Ezetimibe)
NPC1L1: Sterol Transporter Niemann-Pick C1-like 1
26
EFFECTS OF EZETIMIBE ON PLASMA LIPIDS
LDL-C
Triglycerides
HDL-C
-0,4
-15,7*
-18,5*°
* p < 0,05 vs placebo
° p < 0,05 vs 5 mg ezetimibe
27
THE SOLUTION
• Joint venture
- Merck & Co., Inc.: Simvastatin
- Schering-Plough Corporation.: Ezetimibe
• Develop and market new prescription medicines in
cholesterol management
• Collaboration worldwide markets (excluding Japan)
28
http://www.msppharma.com/msp_jv/msppharma/about_us/index.jsp
DUAL INHIBITION: EZETIMIBE AND STATIN
• VYTORIN®
• Patent n° RE37,721
• Expiration Oct 25, 2016
• Assignee Schering
corporation
• Code U-473 to reduce
plasma cholesterol levels in a
mammal
29
EZETIMIBE/SIMVASTATIN VYTORIN®
• Approved by FDA in July 2004
• Clinical studies showing that it
- reduces total C
- LDL-C
- Apo B
- TG
- increases HDL-C
• Patients with
hypercholesterolemia
30
http://pharmamkting.blogspot.com/2007/02/vytorin-ads-are-getting-old-and.html
VYTORIN® INDICATION
 Primary Hypercholesterolemia
Heterozygous familial and non-familial
Hypercholesterolemia or mixed hyperlipidemia
Homozygous Familial
Hypercholesterolemia (HoFH)
Adjunct to other lipid-lowering
treatments (e.g. LDL apheresis)
or if such treatments are unavailable
http://www.schering-plough.com/schering_plough/news/release.jsp?releaseID=1095943
31
32
SYNERGY STUDY (EZE/SIMVA)
• Multicenter
• Randomized
• Double-blind
• Versus placebo
Davidson and al.,2002.Ezetimibe Coadministration With Simvastatin in Patients With Primary Hypercholesterolemia.JACC.(40).2125-2134
33
SYNERGITICAL EFFECTS OF SIMVASTATIN AND EZETIMIBE ON
LIPIDS
Co administration of ezetimibe plus simvastatin was more effective than
simvastatin alone in
Reducing LDL-C
* p < 0.01, combination versus statin alone.
34
Davidson and al.,2002.Ezetimibe coadministration with simvastatin in patients with primary hypercholesterolemia.JACC.(40).2125-2134
SYNERGITICAL EFFECTS OF SIMVASTATIN AND EZETIMIBE ON
LIPIDS
Reducing TG
p=0,01
p=0,08
p=0,06
p=0,02
Davidson and al.,2002.Ezetimibe coadministration with simvastatin in patients with primary hypercholesterolemia.JACC.(40).2125-2134
35
SYNERGITICAL EFFECTS OF SIMVASTATIN AND EZETIMIBE ON
LIPIDS
 Increasing HDL-C
p=0,66
p=0,10
p=0,02
p=0,93
Davidson and al.,2002.Ezetimibe coadministration with simvastatin in patients with primary hypercholesterolemia.JACC.(40).2125-2134
36
II) ENHANCE trial
1) Presentation
- Design
- Primary outcome
- Results
37
ENHANCE: Ezetimibe and simvastatiN in Hypercholesterolemia
enhANce atherosClerosis rEgression
Ezetimibe reduces levels of LDL-C when added to
Statin treatment
However
The effect of Ezetimibe on the progression of
atherosclerosis remains unknown
38
PRIMARY OUTCOME
Mean change in the carotid-artery intima-media thickness (CA IMT)
• Assessed
by
B-mode ultrasound
39
PRIMARY OUTCOME
• 3 sites
- common carotid
- carotid bulbs
- internal carotid
40
PRIMARY OUTCOME: Interests
CORRELATION
Increasing in the Intima-MediaThickness in CAROTID Artery
INCREASING in the probability
to develop an atherosclerosis
plaque in CORONARY!
41
ENHANCE TRIAL DESIGN
Subjects
720 patients with heterozygous familial
hypercholesterolemia
Studied Period
August 2002 - April 2006
Treatment of 24 months
Methodology
Randomized,Double-blind,Multicenter Study
42
CRITERIA
Inclusion Criteria
o ≥30 to ≤75 years of age
o Clinical diagnosis of heterozygous familial hypercholesterolemia
o LDL-C ≥210 mg/dL (5.43 mmol/L)
Exclusion Criteria
o High-grade stenosis or occlusion of the carotid
o Homozygous familial hypercholesterolemia
o Recent cardiovascular events
43
Demographic and clinical characteristics of the
patients
44
J.P.Kastelein and al.2008.Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia.N Engl J Med.(358).1431-1442.
STUDY DESIGN OF ENHANCE TRIAL
R
Pre-Randominzation
phase
FH:
LDL-C ≥ 5.43mmol/L
Screening
and fibrate
wash-out
A
N
D
O
M
I
Z
A
T
I
O
Placebo
lead-in/
wash-out
Ezetimibe 10 / simvastatin 80
N= 357
simvastatin 80
N= 363
N
Intima-media thickness assessement
-10 to -7 -6
weeks
FH: familial cholesterolemia
0
3
6
9
12
15
Months
18
21
24
45
RESULTS FROM ENHANCE STUDY
KASTELEIN, J J.P. et al., 2008. Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia.
The new England journal of medicine, Vol., 358, No. 14, 1431-1443
46
RESULTS FROM ENHANCE STUDY
KASTELEIN, J J.P. et al., 2008. Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia.
The new England journal of medicine, Vol., 358, No. 14, 1431-1443
47
RESULTS FROM ENHANCE STUDY
KASTELEIN, J J.P. et al., 2008. Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia.
The new England journal of medicine, Vol., 358, No. 14, 1431-1443
48
ARE THESE LIPID PARAMETERS
REFLECTED IN PRIMARY OUTCOME?
49
RESULTS FROM ENHANCE STUDY
The change in the
average IMT over time
did not differ
significantly between the
two study groups
KASTELEIN, J J.P. et al., 2008. Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia.
The new England journal of medicine, Vol., 358, No. 14, 1431-1443
50
II) ENHANCE trial
1) Presentation
2) Discussion
- Theory n°1 Previous statin treatment
-Theory n°2 Pleiotropics effects
- Theory n°3 Intima-Media-Thickness
51
THEORY N°1
Previous statin treatment disturb surrogate marker evolution
80% of ENHANCE patients
had received statins
And
Their carotid Intima-MediaThickness was already low
at baseline
Difficulties to observe a significative change in IMT
Because IMT was very low at the beginnig!!
52
years
THEORY N°1
Previous statin treatment disturb surrogate marker evolution
0,7
ENHANCE
53
THEORY N°2
Ezetimibe may not have pleiotropic effects
54
Statins are not just a LDL-C lowering…
↘
INFLAMATORY
RESPONSE
CIRCULATIONAHA study
-Simvastatin help relaese of NO
-Ezetimibe doesn’t!!
RELEASE OF
NO ?
Statins
OTHER
PLEIOTROPiCS
EFFECTS….
These are statin’s pleiotropic effects
55
Statins are not just a LDL-C lowering…
↘
INFLAMATORY
RESPONSE
Statins
RELEASE OF
NO ?
OTHER
PLEIOTROPiCS
EFFECTS….
These are statin’s pleiotropic effects
56
Statins are not just a LDL-C lowering…
↘
INFLAMATORY
RESPONSE
CIRCULATIONAHA study
-Simvastatin help release of NO
-Ezetimibe doesn’t!!
RELEASE OF
NO ?
Statins
OTHER
PLEIOTROPiCS
EFFECTS….
These are statin’s pleiotropic effects
57
THEORY N°3
IMT does not reflect the true benefits of lowering LDL-C
• Some studies have shown that Carotid Intima-MediaThickness (CIMT) could be correlated with an increase of
the cardiovascular events
 ARIC: Atherosclerosis Risk In Communities study
↗0,1mm CIMT→ ↗ Risk of myocardial infarction by 11%
 KIHD: Kuopio Ischaemic Heart Disease risk factor study
↗0,19 mm CIMT→ ↗ Risk of death on myocardial infarction by 36%
• CIMT is a « SURROGATE MARKER » that predicts the rate
of progression of coronary atherosclerosis and coronary
events → Just a correlation!!
58
CIMT
a sound
WhyB mode
is CIMT
the most Imaging technic used ?
Non Invasive
Quick
Cheap to perform
Reproductible
Easily standardized
(multi-centres)
Ideal for serial
examination
59
CIMT
The limits of this imaging method
• Not focalize on atherosclerosis plaque
• No information about
-plaque component
-plaque evolution
Media
Intima
Change of plaque silhouette was not studied in ENHANCE
60
WHY NOT USE ANOTHER METHOD?
• Many imaging methods
can be used
• Most of them are:
 invasive
contrast and radiation
• No plaque composition
• 2 are recognized by FDA
 QCA: Quantative Coronary
Angiography
 CIMT: Carotid Intima Media
Thickness
61
EXPLANATIONS SUMMARY
• Study design
-
2-year is too short to see a favorable effect of cholesterol lowering on cIMT
Patient who had received prior statin therapy
Relatively normal cIMT values at baseline
Harder to demonstrate a reduction in cIMT
• Other unknown properties of ezetimibe that may negate
the beneficial effects of LDL lowering on cIMT
• No pleiotropic effects of ezetimibe
• Surrogate marker, only a correlation
WHAT’S NEXT FOR VYTORIN
FUTURE?
63
Simvastatin and Ezetimibe in patients with Aortic Stenosis
• Randomized, Double-blind trial
•
1873 patients with mild-to moderate asymptomatic aortic stenosis
• 40 mg Simvastatin + 10 mg Ezetimibe or placebo daily.
• Outcomes :
-composite of major cardiovascular events
-events related to Aortic Stenosis
-ischemic cardiovascular events
• No reduction of events related to aortic-valve stenosis and
composite events
• Reduction of the incidence of ischemic cardiovascular events
64
IMPROVE-IT TRIAL
IMProved Reduction of Outcomes: Vytorin Efficacy International Trial
• Study period: October 2005- June 2012
• Multicenter, Double-Blind, Randomized Study
• Up to 18000 subjects with stabilized high-risk acute coronary
syndrome
• ezetimibe/simvastatin 10/40 mg vs simvastatin 40 mg
• Cardiovascular clinical outcomes study
• Primary Outcome Measures:
- death due to any cardiovascular events
- non-fatal coronary events (heart attack)
- non-fatal strokes
65
A CLOUDY FUTURE FOR VYTORIN
• Instead of demonstrating a real efficiency on
cardiovascular events
• ENHANCE raises deep doubts about the use of CIMT
and general surrogate markers in clinical trial
• This study harms the commercial lifetime
of VYTORIN
- 2006: Prediction sales for 2010 7$ billion
- 2009: Prediction sales for 2009 1,2$ billion
• It’s realy difficult to relaunch a product in distress!
66
AN ALTERNATIVE AND A WAY TO REBOUND
New association ezetimibe and atorvastatin
Joint venture again
Atorvastatin patent ends in 2010
They hopefully will learn about their mistaskes
And rethink the design of the study
The clinical trial of this new association should be based on
morbimortality studies instead of surrogate markers
67
FDA statements
• January 8, 2009
→ ENHANCE results do not change FDA’s position:
« LDL cholesterol is a risk factor for cardiovascular disease.
Lowering LDL-C reduces the risk for cardiovascular disease »
→ Pending IMPROVE-IT results, patients should not stop Vytorin
• Mary Parks, director of the FDA’s Division of Metabolic and Endocrine Products
- Update guidance for developing cholesterol lowering agent
- No publication date set yet!!
- The original draft guidance was released in October 1990.
68
Merci de votre attention!
69
Hypolipidaemic market
• Combined sales 2007
ZETIA®/VYTORIN® (1)
more than US$5 billion
• Predicted sales (2)
VYTORIN® market is expected
to grow to some $7 billion by
2010
(1)
(2)
COUZIN, J., 2008. Cholesterol veers off script. Science, (322), 220-223
KIDD, J., 2006. Life after statin patent expiries. Nature reviews, Drug discovery, (5), 813-814
70
1 MDCT exposure = 15 chests radiographs!!!!
The significant radiations exposure cause by this technic make CT
unsuitable for serial examination!
COMPUTED TOMOGRAPHY OF THE
CORONARY ARTERY
Advantages :
Widely available
Images calcium
Disadvantages :
Significant radiation
exposure
Unsuitable for serial
examinations
Quantative Coronary angiography
• X-Ray arteriography use radio opaque contrast
• Provides 2-D projections of the lumen of the artery
• Automated vessels-edge detection is used to
estimate the degre of atherosclerosis
• Conversion to digital based storage decrease the
resolution
Quantative Coronary Angiography
Major weakness
 QCA only delinates the
silhouette, non
informations on the wall
composition
 Repeated radiations
exposure
 Invasive procedure can
always be risky
Major advantage
• Often indicated
as part of
clinical care
• Widely available
Optical Coherence Tomography
(OCT)
•
•
•
•
•
•
•
Invasive complex technique
Operator interface similar to IVUS
Small flexible wine-mounted infrared light
Speed of acquisition
High resolution images :10mm
endothelial and intimal structures
superficial macrophages
Limited tissue penetrance: 1-2mm
Deep structures not clearly seen
Positron Emission Tomography
(PET)
•
•
•
•
Nuclear imaging technique
Administration of radionuclides
Signal quantified by an external detector
18 F-fluorodeoxyglucose (FDG): signal
proportional to local glycolytic activity
• Coregistration with a second modality (CT,
MRI)
Positron Emission Tomography
(PET)
• Highly sensitive (picomolar range), established
molecular imaging technique, reproductible
over the short term
• Radiation exposure, requires radiotracer,
expensive, coronary arteries challenging, not
widely available
IVUS Intravascular ultrasound
Advantages and disadvantages
• Used to estimate total or
percentage atheroma
volume
• Widely available and
reproducible
• Can make serial
assessements of coronary
plaques, including plaque
that would not be
apparent using
angiographical
techniques.
• Invasive ( guidewire)
• Limited to the study of
patients in whom
coronary angiography is
clinically indicated
• is not the most accurate
method for quantifying
calcification.
• Images selected segments
only
MRI
Advantages and disadvantages
• Non- invasive method
of plaque measurment
• Has produced an
expanding range of in
vivo contrast agents
that can target
Macrophages, Platelets
and inflammatory cell
adhesion molecules.
• Inability to evaluate
systematically the walls
of the coronary arteries.
• Some patients with
metal devices excluded.
• Has relatively low
sensitivity.
THEORY N°1
Previous statin treatment affected the ENHANCE results
• 80% of ENHANCE
patients had received
statins
And
• Their carotid IntimaMedia-Thickness was
already low at baseline
Difficulties to observe a signifiative change in CIMT
80
150
150
310
THEORY N°1
Previous statin treatment disturb surrogate marker evolution
Atorvastatin 80 mg/day
ENHANCE
0,7
years
LDL-Cholesterol mg/dL