Introduction: utilization of surrogate markers of atherosclerosis for the clinical development of pharmaceutical agents

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<ul><li><p>Introduction: Utilization of SurrogateMarkers of Atherosclerosis forthe Clinical Development of</p><p>Pharmaceutical AgentsMichael H. Davidson, MD</p><p>Low-density lipoprotein cholesterol (LDL-C) is cur-rently the primary established therapeutic targetfor cardiovascular disease (Table 1).1 However, re-search indicates that other lipoproteins (high-densitylipoprotein [HDL], apolipoprotein-B, and lipopro-tein[a]) may also be useful for stratifying patients atrisk for cardiovascular disease for drug therapy. Overthe past 5 years, advances in the understanding oflipoprotein metabolism and the pathogenesis of ath-erosclerosis have led to a significant increase in thepotential for therapeutic targets. This has further led toa large number of new drugs and genetic targets in thedevelopment pipeline (Figure 1, Table 2). To advancethese drugs through the US Food and Drug Adminis-tration (FDA) approval process for clinical use willmost likely require surrogate markers.</p><p>During a satellite meeting at the International Sym-posium on Atherosclerosis in Stockholm, Sweden, onJune 27, 2000, leading researchers discussed the useof surrogate markers of atherosclerosis for clinicaldevelopment of pharmaceutical agents. The session,which I organized and introduced entitled The Utili-zation of Surrogate Markers of Atherosclerosis for theClinical Development of Pharmaceutical Agents.</p><p>What is a surrogate marker? Surrogate markershave to predict risk of coronary disease, and improve-ment in the marker must correlate with improvementin the atherosclerotic process. However, we have toask, ideally, whether it is required that the markercorrelate with a reduction in cardiovascular events.</p><p>What is the rationale for using surrogate markers?Primarily it is a result of increasing ethical concernsabout long-term morbidity/mortality trials that includea placebo group. Surrogate markers can reduce thetime and cost of evaluating certain therapies that maybenefit populations at risk. Surrogate markers are alsouseful in evaluating the impact of other lipoproteinson the atherosclerotic process (e.g., triglycerides,HDL, lipoprotein[a]) or novel mechanisms to lowerLDL low-density lipoprotein (LDL) (e.g., microsomaltriglyceride transfer protein [MTP] inhibitors, squalenesynthase, or cyclase inhibitors). They are also usefulfor identifying antiatherosclerotic drugs that do not</p><p>significantly affect lipoproteins (e.g., cholesterol acyl-transferase inhibitors, matrix metalloprotease inhibi-tors).</p><p>Table 3 outlines under what circumstances surro-gate endpoints are required for FDA approval of var-ious drugs. The FDA presently requires a minimum15% decrease in LDL, non-HDL, or apolipoprotein Bfor systemic drugs.</p><p>Use of surrogate risk predictors of improvement inatherosclerosis will enhance the ability to do clinicaltrials by enabling researchers to accumulate a higher-risk population and conduct trials in a shorter timeframe with fewer patients. One of the best models forpredicting risk is the adapted Framingham Global</p><p>From the Chicago Center for Clinical Research, Chicago, Illinois,USA; and Department of Preventive Cardiology, Rush-PresbyterianSt.Lukes Medical Center, Chicago, Illinois, USA.</p><p>Address for reprints: Michael H. Davidson, MD, Chicago Centerfor Clinical Research, 515 North State Street, Suite 2700, Chicago,Illinois 60610-4324.</p><p>TABLE 1 National Cholesterol Education Program TreatmentRecommendations and Goals According to Risk Status*</p><p>Treatment/Risk StatusLDL-C Goal</p><p>(mg/dL)</p><p>Dietary therapyWithout CAD and ,2 risk factors ,160Without CAD and $2 risk factors ,130With known CAD #100</p><p>Drug treatmentWithout CAD and ,2 risk factors ,160Without CAD and $2 risk factors ,130With known CAD #100</p><p>CAD 5 coronary artery disease; LDL-C 5 low-density lipoprotein cholesterol.*Adapted from JAMA.1</p><p>Michael H. Davidson, MD</p><p>1A2001 by Excerpta Medica, Inc. 0002-9149/01/$ see front matterAll rights reserved. PII S0002-9149(01)01418-7</p></li><li><p>FIGURE 1. Lipoprotein metabolism. ABC 5 adenosine triphosphate binding cassette protein; ABCG 5 adenosine triphosphate bindingcassette protein G1 transport; Apo A1 5 apolipoprotein A1; CE 5 cholesteryl ester; CETP 5 cholesterol ester transfer protein; FC 5free cholesterol; HDL 5 high-density lipoprotein; HL 5 Hepatic lipase; HMG-CoA 5 3-hydroxy-3-methylglutaryl coenzyme A; IBAT 5illeal bile acid transport; LCAT 5 lecithin cholesterol acyl transferase; LDL 5 low-density lipoprotein; MTP 5 microsomal transfer pro-tein; SR-A 5 scavenger receptor A; SR-B1 5 scavenger receptor B1; VLDL 5 very-low-density lipoprotein.</p><p>TABLE 2 Current Status of Potential Therapeutic Targets</p><p>Potential Therapeutic Targets Status</p><p>Upregulate ABC-1 Animal testingInfuse nascent HDL or Apo A-I/Apo A-I Milano Early human testingUpregulate LCAT Animal testingInhibit hepatic lipase Animal testingInhibit CETP Phase 2</p><p>c Oral CETP inhibitorc Anti-CETP immunization</p><p>Upregulate SR-B1 Animal testingInhibit MTP and VLDL assembly Early human testingUpregulate ABCG1 Animal testingInhibit bile acid reabsorption FDA approved: cholestyramine, colestipol, colesevelamInhibit cholesterol absorption or reabsorption Phase 3</p><p>c EzetimibeInhibit IBAT Phase 3Upregulate LDL receptors</p><p>c Inhibit HMG-CoA reductase (statins) FDA approved: lovastatin, pravastatin, simvastatin, cerivastatin, fluvastatin, atorvastatinPhase 3: rosuvastatinPhase 2: NK104</p><p>c Inhibit squalene synthase Early human testingc Inhibit squalene cyclase Early human testing</p><p>Inhibit VLDL secretion FDA approved: Niaspan, gemfibrozil, fenofibrateActivate LPL FDA approved: gemfibrozil, fenofibrate</p><p>Phase 2: NO-1896Inhibit ACAT Phase 2: avisimbeIncrease HDL synthesis FDA approved: Niaspan</p><p>Phase 2: CI-1027PPAR -a, -g, -d (multiple potential effects) Phase 2</p><p>ABC-1 5 adenosine triphosphate binding cassette protein; ABCG1 5 adenosine triphosphate binding cassette G1 transport; ACAT 5 acyl coenzyme A: cholesterolacyltransferase; Apo 5 apolipoprotein; CETP 5 cholesterol ester transfer protein; FDA 5 US Food and Drug Administration; HDL 5 high-density lipoprotein;HMG-CoA 5 3-hydroxy-3-methylglutaryl coenzyme A; IBAT 5 ileal bile acid transport; LCAT 5 lecithin cholesterol acyltransferase; LDL 5 low-density lipoprotein;LPL 5 lipoprotein lipase; MTP 5 microsomal triglyceride transfer protein; PPAR 5 peroxisome proliferator-activated receptor; SR-B1 5 scavenger receptor B1; VLDL 5very-low-density lipoprotein.</p><p>2A THE AMERICAN JOURNAL OF CARDIOLOGYT VOL. 87 (4A) FEBRUARY 16, 2001</p></li><li><p>Risk Score (Tables 4 and 5).2 The question is, Willother surrogates, such as electron beam computedtomography, anklebrachial index, carotid ultrasound,magnetic resonance imaging, and brachial artery re-activity, improve on the predictability of the Framing-ham Global Risk Score? For example, anklebrachialindex appears to enhance our predictability for pa-tients at risk for both coronary artery disease andstroke (Figure 2).3</p><p>We also have to consider what are the best surro-gates. Is LDL the best predictor of risk, or is apoli-poprotein B preferred for assessing the effects of drugtherapy? Because non-HDL correlates very closelywith apolipoprotein B, perhaps non-HDL is more pre-dictive than LDL for patients at risk for cardiovascularevents. Figure 3 compares major coronary events ontreatment non-HDL versus LDL in the ScandinavianSimvastatin Survival Study (4S) trial.4 As demon-strated in Figure 3, non-HDL appears at least as ef-fective, and perhaps more linear, than LDL as a pre-dictor of cardiovascular events.4 As further demon-strated in Figure 4, apolipoprotein B appears quitelinear in its relation to cardiovascular mortality in the4S trial.4 Figure 5 demonstrated in overlap analysisthat lovastatin-treated patients in the Air Force/TexasCoronary Atherosclerosis Prevention Study (AF-CAPS/TexCAPS) had a lower event rate than patientsin the placebo group with the same LDL-C value atyear 1.5 In Figure 6, using apolipoprotein B versusLDL as the variable, the overlapping difference be-</p><p>tween lovastatin and placebo was significantly nar-rowed, and the estimated percentage of patients withendpoints was related to apolipoprotein B in a morelinear fashion than LDL-C. Apolipoprotein B/apoli-poprotein A-I was the most predictive variable in theAFCAPS/TexCAPS trial (Figure 7).5 Further, to sup-port the hypothesis that apolipoprotein B rather thanLDL-C should be the primary endpoint for FDA ap-proval, the Heart Estrogen Progesterone ReplacementStudy (HERS) failed to demonstrate a decrease inclinical events in women with coronary artery diseasedespite reductions in LDL-C (Figure 8).6 Althoughapolipoprotein B has yet to be measured in the HERScohort, other studies have indicated that apolipopro-tein B is only slightly decreased with hormone re-placement therapy and in patients with hypertriglyc-eridemia (pattern B), estradiol may increase apoli-poprotein B levels (Figure 9).69 In a post-hoc analysisof the HERS cohort, patients with increased lipopro-tein(a) and decreased triglyceride values appeared tobenefit from hormone replacement therapy, but pa-tients with increased triglycerides and decreased li-poprotein(a) appeared at increased cardiovascular riskwith hormone replacement therapy.7 Therefore, thefailure of hormone replacement therapy to decreaseapolipoprotein B may partially explain the lack ofclinical benefit in cardiovascular event reduction inpostmenopausal women with coronary artery disease.</p><p>The articles in this supplement to The AmericanJournal of Cardiology address the following issues:</p><p>FIGURE 2. Percentage of elderly men with coronary artery disease (CAD) and stroke bypresence or absence of abnormal anklebrachial index. (Adapted from Arterioscler ThrombVasc Biol.3)</p><p>TABLE 3 Surrogate Endpoints Required for US Food and Drug Administration DrugApproval</p><p>Yes No Uncertain</p><p>LDL, non-HDL, Apo B by known mechanism of action XLDL, non-HDL, Apo B, by novel mechanism of action XApo B/A-I XTriglycerides XHDL or Apo A-I XLp(a) XEmerging risk factors (homocysteine, fibrinogen, CRP) X</p><p>Apo 5 apolipoprotein; CRP 5 C-reactive protein; HDL 5 high-density lipoprotein; LDL 5 low-density lipopro-tein; Lp(a) 5 lipoprotein (a).</p><p>A SYMPOSIUM: SURROGATE MARKERS OF ATHEROSCLEROSIS 3A</p></li><li><p>TABLE 4 Scoring for Global Risk Assessment (Adjusted Framingham Points for RiskFactors)</p><p>Risk Factor</p><p>Risk Points</p><p>Men Women</p><p>Age (yr),34 21 293539 0 244044 1 04549 2 35054 3 65559 4 76064 5 86569 6 97074 7 10</p><p>Total cholesterol (mg/dL),160 23 22160199 0 0200239 1 1240279 2 2$280 3 3</p><p>Blood pressure (mm Hg),120 0 23120129 0 0130139 1 1140159 2 2.160 3 3</p><p>SmokerNo 0 0Yes 2 2</p><p>HDL cholesterol (mg/dL),35 2 53544 1 24549 0 15059 21 0$60 22 23</p><p>Plasma glucose (mg/dL),110 0 0110126 1 2.126 2 4</p><p>Adding Up the Points</p><p>Age Total cholesterolPlasma glucose (diabetes) HDL cholesterolSmoker Blood pressure</p><p>Total</p><p>Reprinted with permission from Am J Cardiol.2</p><p>TABLE 5 Absolute Risk Estimates for Hard Coronary Artery Disease According toFramingham Points</p><p>Framingham Risk Points</p><p>Absolute 10-Year Risk (%)</p><p>Men Women</p><p>1 2 12 3 23 4 24 5 25 6 26 7 27 9 38 13 39 16 3</p><p>10 20 411 25 712 30 813 35 1114 45 1315 1516 1817 20</p><p>Reprinted with permission from Am J Cardiol.2</p><p>4A THE AMERICAN JOURNAL OF CARDIOLOGYT VOL. 87 (4A) FEBRUARY 16, 2001</p></li><li><p>FIGURE 3. Major coronary events on treatment nonhigh-density lipoprotein (HDL) versuslow-density lipoprotein (LDL): the Scandinavian Simvastatin Survival Study. (Adapted fromCirculation.4)</p><p>FIGURE 4. The relation of mortality in the Scandinavian Simvastatin Survival Study to thedecrease in apolipoprotein B. C 5 control. (Adapted from Circulation.4)</p><p>FIGURE 5. Logistic regression models adjusted for age, sex, marital status, hypertension,smoking, and family history of relation between acute myocardial coronary event and year1 on treatment low-density lipoprotein cholesterol (LDL-C). (Adapted from Circulation.5)</p><p>A SYMPOSIUM: SURROGATE MARKERS OF ATHEROSCLEROSIS 5A</p></li><li><p>FIGURE 6. Logistic regression models adjusted for age, sex, marital status, hypertension,smoking, and family history of relation between acute myocardial coronary event and year1 on treatment apolipoprotein B (Apo B). (Adapted from Circulation.5)</p><p>FIGURE 7. Logistic regression models adjusted for age, sex, marital status, hypertension,smoking, and family history of relation between acute myocardial coronary event and year1 on treatment apolipoprotein B/A-I (Apo B/A-I). (Adapted from Circulation.5)</p><p>FIGURE 8. The Heart and Estrogen-Progesterone Replacement Study (HERS): Dyslipidemiareduced with hormone replacement therapy. HDL 5 high-density lipoprotein; LDL 5 low-density lipoprotein; Trigs 5 triglycerides. (Adapted from JAMA.6)</p><p>6A THE AMERICAN JOURNAL OF CARDIOLOGYT VOL. 87 (4A) FEBRUARY 16, 2001</p></li><li><p>Can apolipoprotein B or apolipoprotein B/A-I be sub-stituted for LDL as the primary endpoint for drugapproval? What is the process for including surrogatemarkers in the drug development plan? How manysurrogate markers are necessary for drug approval? Ifmultiple markers are positively modified, are morbid-ity/mortality trials still required? How will the FDArespond to new technologies that assess atheroscle-rotic development?</p><p>Dr. Jacques D. Barth presents information on ca-rotid ultrasound, endothelial function, and magneticresonance imaging as risk markers. Dr. Steven Nissenpresents data on coronary angiography and intravas-cular ultrasound. Laboratory surrogates, including lip-ids (HDL, lipoprotein[a], triglycerides), apolipopro-teins, procoagulants, inflammatory changes, adhesionmolecules, and lesion lytic enzymes are discussed byDr. Evan Stein. Appearance of coronary calcium inelectron beam computed tomography imaging as asurrogate marker of coronary artery disease is dis-cussed by Dr. Paolo Raggi. In the final article, Dr.David G. Orloff discusses the FDA view of surrogatemarkers and the process for including surrogates in theclinical development of pharmaceutical agents.</p><p>The goal of the meeting was to identify additionalmarkers to enable recruitment of higher-risk popula-tions and surrogates to assess potential clinical benefitfor trials of new therapies to advance clinical research.As cardiovascular disease continues to be an enor-mous health problem, finding new techniques foridentifying and treating the disease is vital. New sur-rogate markers will greatly expand our abilities tomeet this challenge.</p><p>Acknowledgements: We would like to thank KateIngram for coordinating the symposium and for writ-ing and editorial support of the supplement. We wouldalso like to thank the Illinois chapter of the AmericanCollege of Cardiology for their additional unrestrictedlimited funding for the symposium.</p><p>1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Choles-terol in Adults. Summary of the second report of the National CholesterolEducation Program (NCEP) expert panel on detection, evaluation, and treatmentof high blood cholesterol in adults (Adult Treatment Panel II). JAMA 1993;269:30153023.2. Grundy SM. Cholesterol management in the era of managed care. Am JCardiol 2000;85(suppl 3A):3A9A...</p></li></ul>