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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