Contents:

ATHEROSCLEROSIS… STRATEGIC AUDIT OF MARKETPLACE ACTIVITY ISSUES AND IMPLICATIONS TABLE OF CONTENTS EXECUTIVE SUMMARY.........................................................................................................................................I SECTION 1 INTRODUCTION................................................................................................................................ 1 1.1 SCOPE AND OBJECTIVES OF RESEARCH INVESTIGATION........................................................... 1 1.2 METHODOLOGY OF INVESTIGATION................................................................................................ 2 1.3 LIMITATIONS OF INVESTIGATION ..................................................................................................... 4 SECTION 2 GENERAL ISSUES IN THE MANAGEMENT OF HYPERLIPIDEMIA AND ATHEROSCLEROSIS .................................................................................................................. 5 2.1 FUNDAMENTALS OF THE CONDITION .............................................................................................. 5 2.2 INCIDENCE AND PREVALENCE........................................................................................................... 8 2.3 ETIOLOGY AND PATHOPHYSIOLOGY ............................................................................................... 9 2.4 SCREENING AND DIAGNOSTIC CLASSIFICATION........................................................................ 12 2.5 MANAGEMENT OF BLOOD LIPID LEVELS IN THE PRIMARY PREVENTION OF CARDIOVASCULAR DISEASE............................................................................................................. 16 2.6 IMPACT AND CHALLENGES OF HYPERLIPIDEMIA AND ATHEROSCLEROSIS....................... 21 SECTION 3 CLINICAL MANAGEMENT OF HYPERLIPIDEMIA AND ATHEROSCLEROSIS .............. 27 3.1 PHARMACEUTICAL STRATEGIES FOR MANAGING THE CONDITION...................................... 27 3.2 PATIENT CARE STRATEGIES.............................................................................................................. 30 SECTION 4 PHARMACEUTICAL PRODUCT DEVELOPMENT FOR HYPERLIPIDEMIA AND ATHEROSCLEROSIS ................................................................................................................ 39 4.1 ISSUES IN CURRENT PHARMACEUTICAL APPROACHES ............................................................ 39 4.1.1 Statins............................................................................................................................................ 40 4.1.2 Bile Sequestrants ............................................................................................................................ 49 4.1.3 Fibrates.......................................................................................................................................... 54 4.1.4 Niacin (Nicotinic Acid) and Other Therapeutic Approaches ......................................................... 55 4.2 PHARMACEUTICAL TECHNOLOGIES IN DEVELOPMENT ........................................................... 56 SECTION 5 THE HYPERLIPIDEMIA/ATHEROSCLEROSIS MARKET:DELIVERY SYSTEM ISSUES 73 SECTION 6 NEEDS/GAPS ANALYSIS OF THE MANAGEMENT OF HYPERLIPIDEMIA AND ATHEROSCLEROSIS ................................................................................................................ 99 6.1 NEEDS/GAPS IN THE CURRENT MANAGEMENT OF HYPERLIPIDEMIA................................... 99 6.2 ASPECTS OF THE CURRENT MANAGEMENT OF HYPERLIPIDEMIA NOT CONSIDERED SUBSTANTIALLY PROBLEMATICAL.............................................................................................. 102 ADDENDUM A NATIONAL INSTITUTES OF HEALTH GUIDELINE: CHOLESTEROL LOWERING IN THE PATIENT WITH CORONARY HEART DISEASE..................................................... 107 ADDENDUM B NATIONAL INSTITUTES OF HEALTH GUIDELINE: EXECUTIVE SUMMARIES OF “RECOMMENDATIONS ON LIPOPROTEIN MEASUREMENT”................................... 131 ADDENDUM C INTERNATIONAL TASK FORCE FOR PREVENTION OF CORONARY HEART DISEASE: CORONARY HEART DISEASE: REDUCING THE RISK.............................. 163 C.1 FOREWORD......................................................................................................................................... 163 C.2 THE ECONOMIC BURDEN OF CHD.................................................................................................. 164 C.3 RISK FACTORS AS CAUSES OF CHD............................................................................................... 164 C.4 CHD AND STROKE............................................................................................................................. 171 C.5 STRATEGIES OF PREVENTION......................................................................................................... 173 C.6 THE PHYSICIAN’S CONTRIBUTION TO CHD PREVENTION....................................................... 173 C.7 THE CONCEPT OF GLOBAL RISK .................................................................................................... 174 C.8 THE ASSESSMENT OF GLOBAL RISK ............................................................................................. 174 C.9 PERSONAL AND FAMILY HISTORY................................................................................................ 175 C.10 PHYSICAL EXAMINATION................................................................................................................ 177 C.11 BIOCHEMICAL AND LABORATORY RISK FACTORS .................................................................. 179 C.12 THE RISK REVIEW .............................................................................................................................. 184 C.13 CLASSIFICATION AND CAUSES OF HYPERLIPIDEMIA.............................................................. 186 C.14 THE FUTURE OF RISK ASSESSMENT.............................................................................................. 187 C.15 MANAGEMENT OF CHD RISK FACTORS........................................................................................ 190 C.16 SMOKING CESSATION ....................................................................................................................... 190 C.17 MANAGEMENT OF OVERWEIGHT AND OBESITY....................................................................... 191 C.18 PHYSICAL EXERCISE ......................................................................................................................... 193 C.19 TREATMENT OF HYPERLIPIDEMIA................................................................................................ 194 C.20 THE ROLE OF ANTIOXIDANTS......................................................................................................... 204 C.21 FUTURE DIRECTIONS ........................................................................................................................ 205 ADDENDUM D AUDIT OF SELECTED PHARMACEUTICAL MANUFACTURERS THAT ARE STAKEHOLDERS IN HYPERLIPIDEMIA/ATHEROSCLEROSIS AND OTHER CARDIOVASCULAR INDICATIONS.................................................................................... 207 D.1 ABBOTT LABORATORIES ................................................................................................................. 207 D.2 AKZO NOBEL/ORGANON .................................................................................................................. 209 D.3 AMERICAN HOME PRODUCTS......................................................................................................... 210 D.4 ASTRAZENECA................................................................................................................................... 212 D.5 AVENTIS............................................................................................................................................... 213 D.6 BASF/KNOLL....................................................................................................................................... 214 D.7 BAYER.................................................................................................................................................. 215 D.8 BOEHRINGER INGELHEIM................................................................................................................ 216 D.9 BRISTOL-MYERS SQUIBB ................................................................................................................. 217 D.10 DUPONT ............................................................................................................................................... 220 D.11 ELI LILLY............................................................................................................................................. 221 D.12 FOREST................................................................................................................................................. 222 D.13 GLAXO WELLCOME.......................................................................................................................... 223 D.14 JOHNSON & JOHNSON ....................................................................................................................... 225 D.15 MERCK & CO....................................................................................................................................... 226 D.16 MONSANTO/SEARLE......................................................................................................................... 228 D.17 NOVARTIS ........................................................................................................................................... 229 D.18 PFIZER .................................................................................................................................................. 231 D.19 PHARMACIA CORP. ............................................................................................................................ 233 D.20 PROCTER & GAMBLE......................................................................................................................... 235 D.21 ROCHE.................................................................................................................................................. 236 D.22 SANOFI-SYNTHÉLABO ...................................................................................................................... 237 D.23 SCHERING AG/BERLEX ..................................................................................................................... 240 D.24 SCHERING-PLOUGH ........................................................................................................................... 241 D.25 SMITHKLINE BEECHAM.................................................................................................................... 242 D.26 WARNER-LAMBERT.......................................................................................................................... 244 ADDENDUM E AUDIT OF SELECTED BIOTECHNOLOGY DEVELOPMENT FIRMS THAT ARE STAKEHOLDERS IN HYPERLIPIDEMIA/ATHEROSCLEROSIS AND OTHER CARDIOVASCULAR INDICATIONS.................................................................................... 249 E.1 ACTELION............................................................................................................................................ 249 E.2 ALEXION.............................................................................................................................................. 250 E.3 AVANT.................................................................................................................................................. 250 E.4 AXYS..................................................................................................................................................... 251 E.5 BIOPROJET........................................................................................................................................... 252 E.6 BIO-TECHNOLOGY GENERAL.......................................................................................................... 252 E.7 BIOGEN ................................................................................................................................................ 252 E.8 CELL GENESYS................................................................................................................................... 252 E.9 CELLTECH GROUP............................................................................................................................. 253 E.10 CENTOCOR.......................................................................................................................................... 253 E.11 CHIRON ................................................................................................................................................ 254 E.12 COR THERAPEUTICS......................................................................................................................... 254 E.13 CORIXA ................................................................................................................................................ 255 E.14 CORVAS ............................................................................................................................................... 255 E.15 CV THERAPEUTICS............................................................................................................................ 256 E.16 DAIICHI SEIYAKU.............................................................................................................................. 256 E.17 EMISPHERE TECHNOLOGIES ........................................................................................................... 256 E.18 ENTREMED.......................................................................................................................................... 257 E.19 ESPERION THERAPEUTICS ............................................................................................................... 257 E.20 GELTEX PHARMACEUTICALS ......................................................................................................... 257 E.21 GENENTECH........................................................................................................................................ 257 E.22 GILEAD SCIENCES............................................................................................................................. 258 E.23 GUILFORD ........................................................................................................................................... 258 E.24 HUMAN GENOME SCIENCES............................................................................................................ 258 E.25 IMMUNEX............................................................................................................................................ 259 E.26 INCARA (INTERNEURON) ................................................................................................................. 259 E.27 LIGAND PHARMACEUTICAL............................................................................................................ 260 E.28 MEDIGENE........................................................................................................................................... 260 E.29 MILLENNIUM PHARMACEUTICALS ............................................................................................... 260 E.30 MITSUI.................................................................................................................................................. 261 E.31 NITROMED........................................................................................................................................... 261 E.32 PIERRE FABRE.................................................................................................................................... 262 E.33 PROTEIN DESIGN LABS..................................................................................................................... 262 E.34 PROTEUS.............................................................................................................................................. 262 E.35 SCIOS .................................................................................................................................................... 262 E.36 TEXAS BIOTECHNOLOGY................................................................................................................. 263 E.37 TRIGEN................................................................................................................................................. 264 E.38 VASCULAR GENETICS....................................................................................................................... 264 E.39 VICAL ................................................................................................................................................... 264 ADDENDUM F HISTORIC AND FORECAST SALES OF PRODUCTS FOR STROKE ............................ 265 ADDENDUM G TECHNOLOGIES AND COMPOUNDS IN DEVELOPMENT FOR HYPERLIPIDEMIA/ATHEROSCLEROSIS ......................................................................... 269 G.1 ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS ...................................................... 271 G.2 ADENOSINE RECEPTOR AGONISTS AND ANTAGONISTS ......................................................... 279 G.3 ALPHA BLOCKERS............................................................................................................................. 281 G.4 ALDOSTERONE ANTAGONISTS....................................................................................................... 283 G.5 ANGIOTENSIN II RECEPTOR ANTAGONISTS................................................................................ 284 G.6 ANTICOAGULANTS ............................................................................................................................ 285 G.7 ANTI-INFECTIVE AGENTS................................................................................................................. 290 G.8 ANTI-INFLAMMATORY AGENTS..................................................................................................... 291 G.9 ANTIPLATELET AGENTS................................................................................................................... 293 G.10 BETA BLOCKERS ............................................................................................................................... 295 G.11 CHOLESTEROL/LDL-REDUCING AGENTS..................................................................................... 297 G.12 CALCIUM CHANNEL BLOCKERS .................................................................................................... 299 G.13 CLASS I ANTI-ARRHYTHMIC AGENTS........................................................................................... 300 G.14 CLASS III ANTI-ARRHYTHMIC AGENTS........................................................................................ 301 G.15 DIURETICS........................................................................................................................................... 302 G.16 ENDOTHELIN ANTAGONISTS .......................................................................................................... 303 G.17 HDL-INCREASING AGENTS .............................................................................................................. 305 G.18 INOTROPIC AGENTS.......................................................................................................................... 306 G.19 METABOLIC MODULATORS............................................................................................................. 307 G.20 MOLECULAR THERAPIES ................................................................................................................. 309 G.21 NA/H EXCHANGE INHIBITORS ........................................................................................................ 310 G.22 NITRATES ............................................................................................................................................ 311 G.23 PHOTOSENSITIZERS.......................................................................................................................... 315 G.24 PPAR AGONISTS................................................................................................................................. 315 G.25 THROMBOLYTICS.............................................................................................................................. 316 G.26 VASOPEPTIDASE INHIBITORS ......................................................................................................... 319 G.27 VASOPRESSIN ANTAGONISTS......................................................................................................... 321 G.28 OTHER TECHNOLOGIES................................................................................................................... 322 LIST OF TABLES Table 1 WW Historic Sales Table - Atherosclerosis / Hyperlipidemia ..................................................... 266 Table 2 US Historic Sales Table - Atherosclerosis / Hyperlipidemia........................................................ 267 Table 3 Atherosclerosis Treatment Active WW Development Programs by Technology Platform and Clinical Status.............................................................................................................................. 272 Table 4 Atherosclerosis Treatment Active WW Development Programs by Company and Clinical Status ........................................................................................................................................... 273 Table 5 Product Development in Atherosclerosis ..................................................................................... 274

Summary:

The following is a summary of the major themes and issues that emerged from the interviews with the expert respondents in the field of hyperlipidemia and atherosclerosis who were interviewed for this marketplace audit. Simpler, less expensive technologies for screening populations for at-risk individuals, and stratifying those who would then be cost-effective targets for intervention for primary prevention. Several respondents noted that individuals who turn out to have high levels of arterial plaque are often asymptomatic, especially when below age 40. Genetic medicine was frequently raised in this context, as potentially being a way to identify (as contrasted with “treat”) at-risk individuals for further screening and possibly early intervention (see below for warnings about what can be, currently, an unproductive focus on the genetic risk element).