200R9ep ort M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke

PRESENTED BY AMERICA ’ S PHARMACEUTICAL RESEARCH COMPANIES More Than 300 Medicines in Testing for Two Leading Causes of Death in Americans

harmaceutical and biotechnology researchers are MEDICINES IN DEVELOPMENT FOR HEART DISEASE AND STROKE * working on 312 medicines for two of the three Pleading causes of death in Americans—heart disease Acute Coronary Syndrome 21 and stroke—keeping up the momentum of drug discovery Adjunctive Therapies 5 Angina 2 that has helped cut deaths from these diseases by more Arrhythmia/Atrial Fibrillation 20 than a quarter between 1999 and 2005. All of the medicines Atherosclerosis 18 are either in clinical trials or awaiting approval by the Coronary Artery Disease 11 Heart Attack 16 Food and Drug Administration. Heart Failure 33 Hypertension 36 According to the National Center for Health Statistics, Imaging Agents 10 heart disease has topped the list of killer diseases every Ischemic Disorders 18 Lipid Disorders 26 year but one since 1900. (The exception was 1918, Peripheral Vascular Disease 27 when an influenza epidemic killed more than 450,000 Pulmonary Vascular Disease 16 Stroke Americans.) In 2002, cancer surpassed heart disease as 22 Thrombosis 40 the top killer of Americans under age 85, who account Other 39 for 98.4 percent of the U.S. population. Stroke is the *S ome medicines are listed in more than one category. third leading cause of death.

Thanks in large part to new drug treatments, death rates cost of these diseases to American society is more than from heart disease and stroke are falling. According to the $448 billion a year. National Heart, Lung and Blood Institute (NHLBI), if death The medicines in development include 36 for high rates were the same as those of 30 years ago, 815,000 blood pressure, 33 for heart failure, 16 for heart attacks, more Americans would die of heart disease annually and and 22 for stroke. Many of the potential medicines use 250,000 more would die of stroke. This reduction in cutting-edge technologies and new scientific approaches. death rates is “one of the great triumphs of medicine in For example: the past 50 years,” according to cardiologist Dr. Eugene Braunwald of Brigham and Women’s Hospital at • Human stem cells that may restore cardiac function by Harvard University. forming new heart muscle.

Much of the progress is due to the development of • A new anticoagulant that regulates clot formation to effective medicines to control both blood pressure and prevent deep vein thrombosis. cholesterol, according to officials at the NHLBI. In • A gene therapy that uses a patient’s own cells to treat addition, treatment of heart attacks has vastly improved. heart failure. Twenty-five years ago, the treatment for heart attacks was simply bed rest. Today, doctors have medicines that can These new medicines promise to continue the already stop a heart attack in mid-stream as well as other high- remarkable progress against heart disease and stroke and tech treatments. to raise the quality of life for patients suffering from these diseases. But, experts warn, the war against heart disease and stroke is not yet won. According to the American Heart Association, every 37 seconds an American dies of cardiovascular disease, and nearly 80 million Americans have one or more types of cardiovascular disease. Many Billy Tauzin people who survive heart attacks develop heart failure, a President and CEO chronic disease that affects 5.3 million Americans. The PhRMA Medicines in Development for Heart Disease and Stroke

A CUTE C ORONARY S YNDROME Product Name Sponsor Indication Development Status*

Angiomax ® The Medicines Company acute coronary syndrome application submitted bivalirudin Parsippany, NJ (973) 656-1616 apixaban Bristol-Myers Squibb acute coronary syndrome Phase III (factor XA Princeton, NJ (see also stroke, thrombosis) (212) 546-4000 inhibitor) Pfizer (860) 732-5156 New York, NY Arixtra ® GlaxoSmithKline acute coronary syndrome application submitted fondaparinux Rsch. Triangle Park, NC (888) 825-5249 cangrelor The Medicines Company acute coronary syndrome Phase III Parsippany, NJ (800) 388-1183 DX9065a Daiichi Sankyo acute coronary syndrome Phase II Parsippany, NJ (see also coronary artery disease, (973) 359-2600 thrombosis) E5555 Eisai Medical Research acute coronary syndrome/chronic Phase II Ridgefield Park, NJ atherothrombotic disease (888) 422-4743 factor IIa/Xa Bayer HealthCare acute coronary syndrome Phase I inhibitor Pharmaceuticals (888) 842-2937 Wayne, NJ Integrelin ® Schering-Plough early acute coronary syndrome Phase III eptifibatide Kenilworth, NJ (908) 298-4000 M118 Momenta Pharmaceuticals acute coronary syndrome Phase II Cambridge, MA (617) 491-9700 otamixaban sanofi-aventis acute coronary syndrome Phase II (XRP0673) Bridgewater, NJ (800) 633-1610 prasugrel Eli Lilly acute coronary syndrome application submitted (CS-747) Indianapolis, IN (800) 545-5979 Daiichi Sankyo (973) 359-2600 Parsippany, NJ ------acute coronary syndrome Phase II (combination therapy) (800) 545-5979 (973) 359-2600 PRT060128 Portola Pharmaceuticals acute coronary syndrome Phase II South San Francisco, CA (see also heart attack) rivaroxaban Bayer HealthCare acute coronary syndrome Phase II Pharmaceuticals (see also stroke, thrombosis) (888) 842-2937 Wayne, NJ Johnson & Johnson Pharmaceutical Reseach & Development Raritan, NJ SCH-530348 Schering-Plough acute coronary syndrome Phase III Kenilworth,NJ (908) 298-4000

* For more information about a specific medicine in this report, please call the telephone number listed.

2 M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 A CUTE C ORONARY S YNDROME Product Name Sponsor Indication Development Status TAK-442 Takeda Pharmaceuticals acute coronary syndrome Phase II North America (see also thrombosis) (877) 582-5332 Deerfield, IL Thelin ™ Encysive Pharmaceuticals acute coronary disorders Phase I sitaxentan Houston, TX (see also heart failure, (713) 796-8822 pulmonary vascular disease) ticagrelor AstraZeneca acute coronary syndrome Phase III Wilmington, DE (see also thrombosis) (800) 236-9933 varespladib Anthera Pharmaceuticals acute coronary syndrome Phase II San Mateo, CA (see also atherosclerosis) (510) 277-0356 VIA-2291 VIA Pharmaceuticals acute coronary syndrome Phase II San Francisco, CA (see also atherosclerosis) (415) 283-2200 VT-111 Viron Therapeutics acute coronary syndrome Phase II London, ON (see also atherosclerosis, (519) 858-5109 coronary artery disease) Vytorin ™ Merck acute coronary syndrome Phase III ezetimibe/ Whitehouse Station, NJ (800) 672-6372 simvastatin Schering-Plough (908) 298-4000 Kenilworth, NJ

A DJUNCTIVE T HERAPIES ; R EVASCULARIZATION Product Name Sponsor Indication Development Status CCX140 ChemoCentryx treatment of vascular restinosis Phase I Mountain View, CA following angioplasty or stenting (650) 210-2900 fibrin patch Omrix Biopharmaceuticals surgical blood loss Phase II New York, NY (212) 887-6500 Ethicon, a Johnson & Johnson Company Somerville, NJ NovoSeven ® Novo Nordisk post-operative hemorrhage in Phase II eptacog alfa Princeton, NJ cardiac surgery (800) 727-6500 rFXIII Novo Nordisk post-operative hemorrhage in Phase I Princeton, NJ cardiac surgery (800) 727-6500 Trinam ® Ark Therapeutics prevention of vascular restinosis Phase III (EG004) London, England following vascular graft surgery

A NGINA Product Name Sponsor Indication Development Status ACCLAIM ™ Angiogenix angina pectoris Phase II isosorbide Burlingame, CA (650) 579-6685 mononitrate/ arginine

M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 3 A NGINA Product Name Sponsor Indication Development Status FGF-1 CardioVascular angina pectoris Phase II (fibroblast growth BioTherapeutics (see also peripheral vascular disease) (702) 248-1174 factor 1) Las Vegas, NV

A RRHYTHMIA , A TRIAL F IBRILLATION Product Name Sponsor Indication Development Status Amio-Aqueous ™ Academic Pharmaceuticals supraventricular arrhythmia, Phase III aqueous Lake Bluff, IL ventricular tachycardia (847) 735-1170 amiodarone ATI-2042 ARYx Therapeutics atrial fibrillation Phase II Fremont, CA (510) 585-2200 ATPace ™ Duska Therapeutics diagnosis of bradycardia, Phase II adenosine La Jolla, CA treatment of paroxysmal (858) 551-5700 triphosphate supraventricular tachycardia injection Avapro ® sanofi-aventis atrial fibrillation Phase III irbesartan Bridgewater, NJ (see also heart failure) (800) 633-1610 AZD1305 AstraZeneca atrial fibrillation, left ventricular Phase II Wilmington, DE dysfunction (800) 236-9933 ------atrial flutter Phase I/II (800) 236-9933 ------arrhythmia Phase I (800) 236-9933 capadenoson Bayer HealthCare atrial fibrillation Phase II Pharmaceuticals (888) 842-2937 Wayne, NJ celivarone sanofi-aventis atrial fibrillation Phase II (SSR149744) Bridgewater, NJ (800) 633-1610 GAP-134 Wyeth Pharmaceuticals arrhythmia Phase I Collegeville, PA (800) 934-5556 idrabiotaparinux sanofi-aventis atrial fibrillation Phase III Bridgewater, NJ (see also thrombosis) (800) 633-1610 idraparinux sanofi-aventis atrial fibrillation Phase III Bridgewater, NJ (see also thrombosis) (800) 633-1610 Lipitor ® Pfizer atrial fibrillation Phase II/III atorvastatin New York, NY (860) 732-5156 Lovaza ® GlaxoSmithKline atrial fibrillation Phase III omega-3 ethylester Rsch. Triangle Park, NC (888) 825-5249 concentrate Multaq ® sanofi-aventis atrial fibrillation application submitted dronedarone Bridgewater, NJ (800) 633-1610 nifekalant Mitsui Chemicals America arrhythmia Phase II Rye Brook, NY (914) 253-0777

4 M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 A RRHYTHMIA , A TRIAL F IBRILLATION Product Name Sponsor Indication Development Status

Pulzium ® Solvay Pharmaceuticals atrial fibrillation application submitted tedisamil Marietta, GA (770) 578-9000 sematilide Bayer HealthCare arrhythmia Phase III Pharmaceuticals (888) 842-2937 Wayne, NJ Stedicor ® Procter & Gamble atrial fibrillation, atrial flutter, application submitted azimilide Pharmaceuticals supraventricular arrhythmia (513) 983-1100 Cincinnati, OH (see also heart attack) ------arrhythmia Phase III (513) 983-1100 tecadenoson CV Therapeutics paroxysmal supraventricular Phase III Palo Alto, CA tachycardia (650) 384-8500 ------acute atrial fibrillation, atrial flutter Phase II (650) 384-8500 vernakalant Astellas Pharma atrial fibrillation (intravenous) application submitted Deerfield, IL (800) 727-7003 Cardiome Pharma (800) 330-9928 Vancouver, BC ------atrial flutter (intravenous) Phase III (800) 727-7003 (800) 330-9928 ------atrial fibrillation (oral) Phase II (800) 727-7003 (800) 330-9928 YM-758 Astellas Pharma atrial fibrillation Phase II Deerfield, IL (800) 727-7003

A THEROSCLEROSIS Product Name Sponsor Indication Development Status 568859 GlaxoSmithKline atherosclerosis Phase I (lipoprotein- Rsch. Triangle Park, NC (888) 825-5249 associated phospholipase AZ [Lp-PLA2] inhibitor) 681323 GlaxoSmithKline atherosclerosis Phase II (p38 kinase Rsch. Triangle Park, NC (888) 825-5249 inhibitor) 856553 GlaxoSmithKline atherosclerosis Phase I (p38 kinase Rsch. Triangle Park, NC (combination therapy) (888) 825-5249 inhibitor) anacetrapib Merck atherosclerosis Phase III (MK-0859) Whitehouse Station, NJ (see also lipid disorders) (800) 672-6372

M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 5 A THEROSCLEROSIS Product Name Sponsor Indication Development Status CER002 Cerenis Therapeutics atherosclerosis Phase I Ann Arbor, MI (734) 769-1110 CP-800569 Pfizer atherosclerosis Phase I New York, NY (860) 732-5156 darapladib GlaxoSmithKline atherosclerosis Phase III (Lp-PLA2 Rsch. Triangle Park, NC (888) 825-5249 inhibitor) Human Genome Sciences Rockville, MD K-604 Kowa Research Institute atherosclerosis Phase I Morrisville, NC www.kowa.co.jp liver XR agonist Bristol-Myers Squibb atherosclerosis in clinical trials Princeton, NJ (212) 546-4000 Exelixis San Francisco, CA MK-1903 Merck atherosclerosis Phase I Whitehouse Station, NJ (800) 672-6372 MLN1202 Millennium atherosclerosis Phase II Pharmaceuticals (800) 390-5663 Cambridge, MA niacin receptor Arena Pharmaceuticals atherosclerosis Phase I agonist San Diego, CA (858) 453-7200 Merck (800) 672-6372 Whitehouse Station, NJ PF-3185043 Pfizer atherosclerosis Phase I New York, NY (860) 732-5156 PSI-697/ Wyeth Pharmaceuticals atherosclerosis Phase I WAY-197697 Collegeville, PA (see also thrombosis) (800) 934-5556 rilapladib GlaxoSmithKline atherosclerosis Phase I (Lp-PLA2 Rsch. Triangle Park, NC (888) 825-5249 inhibitor) Human Genome Sciences (301) 309-8504 Rockville, MD varespladib Anthera Pharmaceuticals atherosclerosis Phase II San Mateo, CA (see also acute coronary syndrome) (510) 277-0356 VIA-2291 VIA Pharmaceuticals atherosclerosis Phase II San Francisco, CA (see also acute coronary syndrome) (415) 383-2200 VT-111 Viron Therapeutics atherosclerosis Phase I London, ON (see also acute coronary syndrome, (519) 858-5109 coronary artery disease)

C ORONARY A RTERY D ISEASE Product Name Sponsor Indication Development Status APL180 Novartis Pharmaceuticals coronary heart disease Phase I/II East Hanover, NJ (888) 669-6682

6 M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 C ORONARY A RTERY D ISEASE Product Name Sponsor Indication Development Status coronary artery BioCardia coronary artery disease Phase II disease gene South San Francisco, CA (650) 624-0900 therapy Coroxane ™ Abraxis BioScience coronary artery restenosis Phase II albumin-bound Los Angeles, CA (see also peripheral vascular disease) (310) 437-7700 paclitaxel DX9065a Daiichi Sankyo coronary artery restenosis Phase II Parsippany, NJ (see also acute coronary syndrome, (973) 359-2600 thrombosis) K-134 Kowa Research Institute arteriosclerosis obliterans Phase II Morrisville, NC www.kowa.co.jp LT-1951 Lumen Therapeutics coronary artery restenosis Phase I/II Mountain View, CA (650) 641-0084 mycophenolic Avantec Vascular coronary artery restinosis in clinical trials acid Sunnyvale, CA (408) 329-5400 myolimus Elixir Medical coronary artery restenosis in clinical trials Sunnyvale, CA (408) 636-2000 Resten-MP ™ AVI BioPharma coronary artery restenosis Phase I Portland, OR (503) 227-0554 Resten-NG ® AVI BioPharma coronary artery restenosis Phase II Portland, OR (503) 227-0554 VT-111 Viron Therapeutics coronary artery restenosis Phase I London, ON (see also acute coronary syndrome, (519) 858-5109 atherosclerosis)

H EART A TTACK (M YOCARDIAL I NFARCTION ) Product Name Sponsor Indication Development Status AMR-001 Amorcyte myocardial infarction Phase I Hackensack, NJ (201) 883-5300 Progenitor Cell Therapy (201) 883-5303 Hackensack, NJ BVI-007 BioVascular myocardial infarction Phase I San Diego, CA (see also stroke) (858) 455-5000 caldaret Mitsubishi myocardial infarction Phase II Pharma America (908) 607-1950 Warren, NJ KAI-9803/ Bristol-Myers Squibb prevention of reperfusion injury Phase II BMS-875944 Princeton, NJ following acute myocardial (212) 546-4000 (PKC-Delta KAI Pharmaceuticals infarction (650) 244-1100 inhibitor) South San Francisco, CA MultiStem ® Athersys myocardial infarction Phase I stem cell therapy Cleveland, OH (216) 431-9900 NEU2000 Amkor Pharma myocardial infarction Phase I Seattle, WA (see also stroke) (206) 332-5587

M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 7 H EART A TTACK (M YOCARDIAL I NFARCTION ) Product Name Sponsor Indication Development Status NX CP-105 Neuronyx myocardial infarction Phase I Malvern, PA (610) 240-4150 PL2100 PLx Pharma myocardial infarction Phase I (aspirin/ Houston, TX (see also stroke) (713) 842-1249 phosphatidyl- choline) Prochymal ™ Osiris Therapeutics acute myocardial infarction Phase II mesenchymal Baltimore, MD (410) 522-5005 stem cell therapy (human) PRT060128 Portola Pharmaceuticals myocardial infarction Phase II South San Francisco, CA (see also acute coronary syndrome) (650) 246-7000 ReoPro ® Centocor myocardial infarction Phase III completed abciximab Horsham, PA (see also peripheral vascular disease) (610) 651-6000 Eli Lilly (800) 545-5979 Indianapolis, IN Stedicor ® Procter & Gamble post-myocardial infarction Phase III azimilide Pharmaceuticals (see also arrhythmia) (513) 983-1100 Cincinnati, OH Tekturna ® Novartis Pharmaceuticals myocardial infarction Phase III aliskiren East Hanover, NJ (see also heart failure) (888) 669-6682 thymosin beta-4 ReGeneRx myocardial infarction Phase I Biopharmaceuticals (301) 280-1992 Bethesda, MD V10153 Vernalis Pharmaceuticals myocardial infarction Phase II Morristown, NJ (see also stroke) (973) 867-5555 VMD-30283 VM Discovery myocardial infarction Phase I/II Fremont, CA (510) 661-6770

H EART F AILURE (C ONGESTIVE H EART F AILURE ) Product Name Sponsor Indication Development Status AC2592 Amylin Pharmaceuticals congestive heart failure Phase II San Diego, CA (858) 552-2200 Adentri ™ Biogen Idec acute heart failure Phase III Cambridge, MA (617) 679-2000 ------chronic heart failure Phase II (617) 679-2000 alagebrium Synvista Therapeutics heart failure Phase II chloride Montvale, NJ (201) 934-5000 (ALT-711) Anginera ™ Theregen heart failure Phase I epicardial San Francisco, CA (see also ischemic disorders) (415) 439-8320 angiogenesis patch

8 M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 H EART F AILURE (C ONGESTIVE H EART F AILURE ) Product Name Sponsor Indication Development Status autologous stem Aldagen heart failure Phase I cell therapy Durham, NC (see also ischemic disorders) (919) 484-2571 AVE3085 sanofi-aventis congestive heart failure Phase I Bridgewater, NJ (800) 633-1610 BAY 60-4552 Bayer HealthCare heart failure Phase II Pharmaceuticals (888) 842-2937 Wayne, NJ BB3 Angion Therapeutics prevention of congestive Phase II Manhasset, NY heart failure (516) 869-6400 Bidil XR ™ NitroMed heart failure Phase I hydralazine Lexington, MA (781) 266-4000 hydrochloride/ isosorbide dinitrate (extended-release) bucindolol ARCA biopharma heart failure application submitted Broomfield, CO (720) 940-2200 Cardeva ™ Teva Pharmaceuticals USA chronic heart failure Phase I/II B-type natriuretic North Wales, PA (215) 591-3000 peptide carperitide Asubio Pharmaceuticals heart failure Phase II Rochelle Park, NJ (201) 368-5020 CD-NP Niles Therapeutics heart failure Phase II San Francisco, CA (415) 875-7880 cinaciguat Bayer HealthCare heart failure Phase II (BAY 58-2667) Pharmaceuticals (888) 842-2937 Wayne, NJ CK-1827452 Cytokinetics heart failure Phase II South San Francisco, CA (650) 624-3000 daglutril Solvay Pharmaceuticals heart failure Phase II Marietta, GA (see also hypertension) (770) 578-9000 icodextrin solution Baxter Healthcare heart failure Phase II Deerfield, IL (800) 422-9837 INOmax ® Ikaria congestive heart failure Phase II nitric oxide Clinton, NJ (see also pulmonary vascular disease) (908) 238-6600 inhalation Mydicar ™ Celladon congestive heart failure Phase I/II AAV1/SERCA2a La Jolla, CA (858) 366-4288 gene therapy Targeted Genetics (206) 623-7612 Seattle, WA myoblast cell Advanced Cell Technology heart failure Phase I transplantation Los Angeles, CA (617) 242-9100 therapy Mytogen Charlestown, MA MyoCell ™ Bioheart congestive heart failure Phase II/III cell-based heart Sunrise, FL (954) 835-1500 damage therapy (tissue regeneration)

M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 9 H EART F AILURE (C ONGESTIVE H EART F AILURE ) Product Name Sponsor Indication Development Status

Natrecor ® Scios chronic heart failure (IV-infusion) Phase II nesiritide Mountain View, CA (650) 564-5000 ------heart failure (subcutaneous) Phase I (650) 564-5000 NeoFuse ™ Mesoblast prevention of heart failure Phase II mesenchymal Melbourne, Australia www.mesoblast.com stem cell therapy PL-3994 Palatin Technologies congestive heart failure Phase I Cranbury, NJ (see also hypertension) (609) 495-2200 recombinant Corthera acute heart failure Phase II/III relaxin San Mateo, CA (see also hypertension) (650) 235-3555 Renormax ® Schering-Plough heart failure application submitted spirapril Kenilworth, NJ (908) 298-4000 rolofylline NovaCardia congestive heart failure Phase III San Diego, CA (intravenous) (858) 509-0455 ------congestive heart failure Phase I (oral) (858) 509-0455 Samska ™ Otsuka America congestive heart failure application submitted tolvaptan Pharmaceutical (see also other) (800) 562-3974 Rockville, MD SLV320 Solvay Pharmaceuticals congestive heart failure Phase II Marietta, GA (770) 578-9000 Tekturna ® Novartis Pharmaceuticals congestive heart failure Phase III aliskiren East Hanover, NJ (see also heart attack) (888) 669-6682 Thelin ™ Encysive Pharmaceuticals congestive heart failure Phase II sitaxentan Houston, TX (see also acute coronary syndrome, (713) 796-8822 pulmonary vascular disease) ularitide EKR Therapeutics acute decompensated heart failure Phase I Bedminster, NJ (877) 435-2524 urocortin 2 Neurocrine Biosciences congestive heart failure Phase II San Diego, CA (858) 617-7600

H YPERTENSION (H IGH B LOOD P RESSURE ) Product Name Sponsor Indication Development Status ADX415 Sciele Pharma hypertension Phase II Atlanta, GA (800) 461-3696 Altace HCT ® King Pharmaceuticals hypertension Phase III ramipril/hydro- Bristol, VA (800) 776-3637 chlorothiazide Angeliq ® Bayer HealthCare hypertension Phase III estradiol/ Pharmaceuticals (888) 842-2937 drospirenone Wayne, NJ

10 M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 H YPERTENSION (H IGH B LOOD P RESSURE ) Product Name Sponsor Indication Development Status AR9281 Arête Therapeutics hypertension Phase I Hayward, CA (510) 785-7060 CloniBID ® Adderex Pharmaceuticals hypertension application submitted clonidine Durham, NC (919) 941-0800 controlled-release Sciele Pharma (800) 461-3695 Atlanta, GA cobiprostone Sucampo Pharmaceuticals portal hypertension Phase II Bethesda, MD (301) 961-3400 Coreg ® CR GlaxoSmithKline hypertension Phase III carvedilol/ Rsch. Triangle Park, NC (888) 825-5249 lisinopril (fixed-dose combination) CS-8635 Daiichi Sankyo hypertension Phase III (olmesartan Parsippany, NJ (973) 359-2600 medoxomil/ amlodipine/ hydrochlorothiazide combination) CYT006 AngQb Cytos Biotechnology treatment of hypertension Phase II vaccine Zurich, Switzerland www.cytos.com daglutril Solvay Pharmaceuticals hypertension Phase II Marietta, GA (see also heart failure) (770) 578-9000 darusentan Gilead Sciences resistant hypertension Phase III Foster City, CA (800) 445-3235 DigiFab ™ and Protherics (BTG) severe preeclampsia Phase II Digibind ® Brentwood, TN (615) 327-1027 digoxin immune Fabs (ovine) combination imidapril Xanodyne Pharmaceuticals hypertension Phase II Newport, KY (859) 371-6383 LCI699 Novartis Pharmaceuticals hypertension Phase I East Hanover, NJ (888) 669-6682 LCZ696 Novartis Pharmaceuticals hypertension Phase II East Hanover, NJ (888) 669-6682 lercanidipine MR Forest Laboratories hypertension Phase II (modified-release) New York, NY (800) 678-1605 MK-1597 Merck hypertension Phase I Whitehouse Station, NJ (800) 672-6372 MK-3614 Merck hypertension Phase I Whitehouse Station, NJ (800) 672-6372 MK-8984 Merck hypertension Phase I Whitehouse Station, NJ (800) 672-6372 moxonidine Solvay Pharmaceuticals hypertension Phase III Marietta, GA (770) 578-9000

M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 11 H YPERTENSION (H IGH B LOOD P RESSURE ) Product Name Sponsor Indication Development Status naproxcinod NicOx hypertension Phase I Warren, NJ (908) 604-1070 NCX-899 Merck hypertension Phase I Whitehouse Station, NJ (800) 672-6372 NicOx (908) 604-1070 Warren, NJ PL-3994 Palatin Technologies hypertension Phase II Cranbury, NJ (see also heart failure) (609) 495-2200 PS433540 Pharmacopeia hypertension Phase II Cranbury, NJ (609) 452-3600 recombinant Corthera preeclampsia Phase I relaxin San Mateo, CA (see also heart failure) (650) 235-3555 sapropterin BioMarin Pharmaceutical hypertension Phase II completed Novato, CA (see also peripheral vascular disease, (415) 506-6700 pulmonary vascular disease) SPP635 Speedel Pharmaceuticals hypertension Phase I (Novartis) (732) 537-2290 Bridgewater, NJ SPP676 Speedel Pharmaceuticals hypertension Phase I (Novartis) (732) 537-2290 Bridgewater, NJ SPP1148 Speedel Pharmaceuticals hypertension Phase I (Novartis) (732) 537-2290 Bridgewater, NJ SPP1234 Speedel Pharmaceuticals hypertension Phase 0 (Novartis) (732) 537-2290 Bridgewater, NJ SPP2745 Speedel Pharmaceuticals hypertension Phase 0 (Novartis) (732) 537-2290 Bridgewater, NJ tadalafil Eli Lilly hypertension Phase II Indianapolis, IN (see also pulmonary vascular (800) 545-5979 disease) TAK-491 Takeda Pharmaceuticals hypertension Phase III (azilsartan North America (877) 582-5332 kamedoxomil) Deerfield, IL TAK-536 Takeda Pharmaceuticals hypertension Phase II (azilsartan) North America (877) 582-5332 Deerfield, IL TBC3711 Encysive Pharmaceuticals resistant hypertension Phase II Houston, TX (713) 796-8822 VNP489 Novartis Pharmaceuticals hypertension Phase I East Hanover, NJ (888) 669-6682

12 M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 I MAGING A GENTS Product Name Sponsor Indication Development Status AdreView ™ GE Healthcare diagnosis of heart failure Phase III 123I-mIBG Waukesha, WI (800) 345-2700 cardiac PET FluoroPharma diagnosis of coronary artery disease Phase I imaging agent Boston, MA (617) 482-2333 CorVue ™ King Pharmaceuticals imaging agent for cardiovascular application submitted binodenoson Bristol, TN disorders (800) 776-3637 Feraheme ™ AMAG Pharmaceuticals diagnosis of peripheral arterial Phase II ferumoxytol Lexington, MA disorders (617) 498-3300 gadobutrol Bayer HealthCare diagnosis of vascular disorders Phase II Pharmaceuticals (888) 842-2937 Wayne, NJ Imagify ™ Acusphere detection of coronary artery application submitted perflubutane Watertown, MA disease (617) 648-8800 myocardial FluoroPharma diagnosis of coronary disorders Phase I perfusion Boston, MA (617) 482-2333 imaging agent SHU 555C Bayer HealthCare imaging of ischemic heart disorders Phase III Pharmaceuticals (888) 842-2937 Wayne, NJ Stedivaze ™ PGx Health myocardial perfusion imaging Phase II apadenoson New Haven, CT (877) 274-9432 Zemiva ™ Molecular Insight diagnosis of myocardial ischemia Phase II completed iodofiltic acid Pharmaceuticals (617) 492-5554 I-123 Cambridge, MA

I SCHEMIC D ISORDERS Product Name Sponsor Indication Development Status acadesine Schering-Plough ischemia-reperfusion injury Phase III Kenilworth, NJ (908) 298-4000 ACY001 Arteriocyte ischemia Phase I (stem cell therapy) Cleveland, OH (216) 658-3970 adult stem cell Baxter Healthcare myocardial ischemia Phase II therapy Deerfield, IL (see also peripheral vascular (800) 422-9837 disorders) ------ischemic heart disease Phase I (800) 422-9837 Anginera ™ Theregen ischemic heart disease Phase I epicardial San Francisco, CA (see also heart failure) (415) 439-8320 angiogenesis patch Aricept ® Pfizer vascular dementia application submitted donepezil New York, NY (860) 732-5156 autologous cell BioCardia ischemic heart disease Phase I therapy South San Francisco, CA (650) 624-0900

M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 13 I SCHEMIC D ISORDERS Product Name Sponsor Indication Development Status autologous stem Aldagen critical limb ischemia Phase I/II cell therapy Durham, NC (see also heart failure) (919) 484-2572 CGT-2168 Cogentus Pharmaceuticals ischemic heart disorders Phase III (clopidogrel/ Palo Alto, CA (fixed combination) (650) 543-4730 omeprazole) Exelon ® Novartis vascular dementia Phase III rivastigmine East Hanover, NJ (888) 669-6682 Generx ™ Cardium Therapeutics myocardial ischemia Phase III alferminogene San Diego, CA (858) 436-1000 tadenovec HGF DNA plasmid AnGes ischemic heart disease Phase I Gaithersburg, MD (see also peripheral vascular disease) (973) 359-2600 Daiichi Sankyo Parsippany, NJ KAI-1455 KAI Pharmaceuticals prevention of ischemic injury Phase I South San Francisco, CA during surgical procedures (650) 244-1100 MEM 1003 Memory Pharmaceuticals vascular dementia Phase I Montvale, NJ (201) 802-7100 MLN-2222 Millennium post-ischemic reperfusion injury Phase I Pharmaceuticals (800) 390-5663 Cambridge, MA Ranexa ® CV Therapeutics myocardial ischemia Phase II ranolazine Palo Alto, CA (650) 384-8500 extended-release Reminyl ® Johnson & Johnson vascular dementia Phase III galantamine Pharmaceutical Research (800) 817-5286 (extended release) & Development Raritan, NJ tissue repair Aastrom Biosciences ischemia Phase I/II stem cell therapy Ann Arbor, MI (see also other) (734) 930-5555 VM-202 ViroMed ischemic heart disease Phase I (modified Seoul, Korea (see also peripheral vascular disease) www.viromed.co.kr hepatocyte growth factor gene therapy)

L IPID D ISORDERS Product Name Sponsor Indication Development Status 256073 GlaxoSmithKline dyslipidemia Phase I (high affinity Rsch. Triangle Park, NC (888) 825-5249 nicotinic acid receptor [HM74A] agonist) AEGR-427 Aegerion Pharmaceuticals primary hypercholesterolemia Phase II (implitapide) Bridgewater, NJ (908) 707-2100

14 M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 L IPID D ISORDERS Product Name Sponsor Indication Development Status AEGR-733 Aegerion Pharmaceuticals hyperlipoproteinemia type II Phase III Bridgewater, NJ (908) 707-2100 ------hypercholesterolemia Phase II (908) 707-2100 anacetrapib Merck hypercholesterolemia, Phase II (MK-0859) Whitehouse Station, NJ mixed hyperlipidemia (800) 672-6372 (see also atherosclerosis) atorvastatin/ LifeCycle Pharma dyslipidemia Phase II/III fenofibrate New York, NY (646) 200-8500 AVE5530 sanofi-aventis hypercholesterolemia Phase III Bridgewater, NJ (800) 633-1610 Crestor ® Abbott Laboratories hyperlipidemia Phase III rosuvastatin and Abbott Park, IL (847) 937-6100 Trilipix ™ AstraZeneca (800) 236-9933 choline fenofibrate Wilmington, DE combination Evista ® Eli Lilly hypercholesterolemia in clinical trials raloxifene Indianapolis, IN (see also other) (800) 545-5979 fenofibrate/ Sciele Pharma hyperlipidemia Phase III pravastatin Atlanta, GA (800) 461-3696 combination laropiprant/niacin/ Merck hyperlipidemia Phase III simvastatin Whitehouse Station, NJ (800) 672-6372 combination MB-07811 Metabasis Therapeutics hyperlipidemia Phase I La Jolla, CA (858) 587-2770 MBX-8025 Metabolex hyperlipidemia Phase II completed Hayward, CA (510) 293-8800 MD-0727 Ironwood Pharmaceuticals hypercholesterolemia Phase II Cambridge, MA (617) 621-7722 mipomersen Genzyme hypercholesterolemia Phase III Cambridge, MA (617) 252-7500 Isis Pharmaceuticals (760) 931-9200 Carlsbad, CA MK-6213 Merck hypercholesterolemia Phase II Whitehouse Station, NJ (800) 672-6372 MPC-028 URL Pharma hypercholesterolemia, application submitted Philadelphia, PA hyperlipidemia, (800) 523-3684 hypertriglyceridemia pitavastatin Daiichi Sankyo hypercholesterolemia, application submitted (NK-104) Parsippany, NJ hyperlipidemia (973) 359-2600 R1658 Roche hyperlipidemia Phase III Nutley, NJ (973) 235-5000 R7232 Roche hyperlipidemia Phase I Nutley, NJ (973) 235-5000

M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 15 L IPID D ISORDERS Product Name Sponsor Indication Development Status RBx10558 PPD hyperlipidemia Phase I Wilmington, DE (910) 251-0081 SLx-4090 Surface Logix dyslipidemia, Phase II Brighton, MA hypercholesterolemia (617) 746-8500 sobetirome QuatRx Pharmaceuticals dyslipidemia Phase I Ann Arbor, MI (734) 913-9900 sodelglitazar GlaxoSmithKline hyperlipidemia Phase II Rsch. Triangle Park, NC (888) 825-5249 Tredaptive ™ Merck hypercholesterolemia Phase III laropiprant/niacin Whitehouse Station, NJ (800) 672-6372 TriLipix ® Abbott Laboratories hyperlipidemia Phase III choline fenofibrate Abbott Park, IL (combination therapy) (847) 937-6100 Solvay Pharmaceuticals (770) 578-9000 Marietta, GA Uros ® Axcan Pharma US hypercholesterolemia Phase II ursodeoxycholic Bridgewater, NJ (908) 927-9600 acid

P ERIPHERAL V ASCULAR D ISEASE Product Name Sponsor Indication Development Status adult stem cell Baxter Healthcare critical limb ischemia Phase I/II therapy Deerfield, IL (see also ischemic disorders) (800) 422-9837 ANGX-1039 Angiogenix intermittent claudication Phase I Burlingame, CA (650) 579-6685 ataciguat sanofi-aventis peripheral arterial disease Phase II (HMR1766) Bridgewater, NJ (800) 633-1610 Coroxane ™ Abraxis BioScience peripheral arterial disease, Phase II albumin-bound Los Angeles, CA prevention of vascular restinosis (310) 437-7700 paclitaxel (see also coronary artery disease) CS-8080 Daiichi Sankyo arterial occlusive disorders Phase I Parsippany, NJ (973) 359-2600 EWA-401 Sangamo BioSciences intermittent claudication, Phase I Richmond, CA peripheral vascular disease (510) 970-6000 FGF-1 CardioVascular peripheral arterial disorder Phase I (fibroblast growth BioTherapeutics (see also angina) (702) 248-1174 factor 1) Las Vegas, NV HGF DNA plasmid AnGes peripheral arterial disease Phase II Gaithersburg, MD (see also ischemic disorders) (973) 359-2600 Daiichi Sankyo Parsippany, NJ HIF-1 alpha Genzyme peripheral arterial disease Phase II gene therapy Cambridge, MA (617) 252-7500 hypoxia Diffusion Pharmaceuticals arterial occlusive disorders Phase I/II therapeutic Charlottesville, VA (434) 220-0718 (TSC)

16 M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 P ERIPHERAL V ASCULAR D ISEASE Product Name Sponsor Indication Development Status iloprost Actelion peripheral vascular disorder application submitted Pharmaceuticals US (650) 624-6900 South San Francisco, CA INDI-702 Indigo Pharmaceuticals peripheral arterial occlusive Phase II completed New York, NY disorders (212) 554-4283 Liprostin ™ Endovasc peripheral arterial occlusive disease Phase II alprostadil Montgomery, TX (936) 582-5920 NV1FGF sanofi-aventis peripheral arterial disease Phase III (XRP0038 ) Bridgewater, NJ (800) 633-1610 paclitaxel Angiotech Pharmaceuticals vascular restenosis Phase III Vancouver, Canada (604) 221-7676 propionyl Sigma-Tau Pharmaceuticals peripheral arterial occlusive application submitted carnitine Gaithersburg, MD disorder (800) 447-0169 (ST-261) R1512 Roche peripheral vascular disorder Phase I Nutley, NJ (973) 235-5000 Remodulin ® United Therapeutics peripheral vascular disorder Phase II treprostinil Silver Spring, MD (see also pulmonary vascular disease) (301) 608-9292 ReoPro ® Centocor arterial occlusive disorders Phase II abciximab Horsham, PA (see also heart attack) (610) 651-6000 Eli Lilly (800) 545-5979 Indianapolis, IN RO4905417 Roche peripheral arterial disorder in Phase I Nutley, NJ elderly patients (973) 235-5000 sapropterin BioMarin Pharmaceutical peripheral arterial disorder, Phase II Novato, CA vascular disease (415) 506-6700 (see also hypertension, pulmonary vascular disease) sarpogrelate Mitsubishi arterial occlusive disorders Phase II Pharma America (908) 607-1950 Warren, NJ SL65.0472 sanofi-aventis peripheral arterial disease Phase II Bridgewater, NJ (800) 633-1610 SPP200 Speedel Pharmaceuticals prevention of vascular graft Phase II (PEG hirudin) (Novartis) occlusion (732) 537-2290 Bridgewater, NJ (see also thrombosis) TAL-0500018 Talecris Therapeutics peripheral arterial occlusive disorder Phase I/II Rsch. Triangle Park, NC (see also thrombosis) (919) 316-6300 Vascugel ™ Pervasis Therapeutics vascular disease Phase II endothelial Cambridge, MA (617) 621-3407 cell-therapy VM-202 ViroMed peripheral arterial disease Phase I (modified Seoul, Korea (see also ischemic disorders) www.viromed.co.kr hepatocyte growth factor gene therapy)

M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 17 P ULMONARY V ASCULAR D ISEASE Product Name Sponsor Indication Development Status Aironite ™ Aires Pharmaceuticals pulmonary arterial hypertension Phase I nitrite inhalation Woburn, MA (781) 937-0110 (Orphan Drug) aviptadil Biogen Idec pulmonary arterial hypertension Phase II (vasoactive Cambridge, MA (617) 679-2000 intestinal polypeptide) (Orphan Drug) beraprost United Therapeutics pulmonary arterial hypertension Phase II modified release Silver Spring, MD (301) 608-9292 Gleevec ® Novartis Pharmaceuticals pulmonary hypertension Phase II/III imatinib East Hanover, NJ (888) 669-6682 INOmax ® Ikaria pulmonary hypertension Phase I nitric oxide Clinton, NJ (see also heart failure) (908) 238-6600 inhalation macitentan Actelion pulmonary hypertension Phase III Pharmaceuticals US (650) 624-6900 South San Francisco, CA nitric oxide MaxCyte pulmonary arterial hypertension Phase II synthase Gaithersburg, MD (301) 944-1700 gene therapy Northern Therapeutics (514) 842-0071 Montreal, QC PF-489791 Pfizer pulmonary hypertension Phase I New York, NY (860) 732-5156 PRX-08066 EPIX Pharmaceuticals pulmonary hypertension Phase II Lexington, MA (781) 761-7600 PulmoLAR ® PR Pharmaceuticals pulmonary arterial hypertension Phase I 2-methoxyestradiol Fort Collins, CO (970) 484-5560 Remodulin ® United Therapeutics pulmonary arterial hypertension Phase III treprostinil Silver Spring, MD (oral) (301) 608-9292 (see also peripheral vascular disease) riociguat Bayer HealthCare pulmonary hypertension Phase II Pharmaceuticals (888) 842-2937 Wayne, NJ sapropterin BioMarin Pharmaceutical pulmonary hypertension Phase I Novato, CA (see also hypertension, (415) 506-6700 peripheral vascular disease) tadalafil Eli Lilly pulmonary arterial hypertension application submitted Indianapolis, IN (see also hypertension) (800) 545-5979 Thelin ™ Encysive Pharmaceuticals pulmonary arterial hypertension application submitted sitaxsentan Houston, TX (see also acute coronary syndrome, (713) 796-8822 (Orphan Drug) heart failure) Viveta ™ Lung RX pulmonary arterial hypertension application submitted treprostinil Silver Spring, MD (inhalation) www.lungrx.com

18 M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 S TROKE Product Name Sponsor Indication Development Status 813893 GlaxoSmithKline prevention of stroke in patients Phase I (factor Xa Rsch. Triangle Park, NC with atrial fibrillation (888) 825-5249 inhibitor) apixaban Bristol-Myers Squibb prevention of stroke in patients Phase III (factor XA Princeton, NJ with atrial fibrillation (212) 546-4000 inhibitor) Pfizer (see also acute coronary syndrome, (860) 732-5156 New York, NY thrombosis) arundic acid Merck stroke Phase II Whitehouse Station, NJ (800) 672-6372 betrixaban Portola Pharmaceuticals prevention of stroke in patients Phase II South San Francisco, CA with atrial fibrillation (650) 246-7000 (see also thrombosis) BVI-007 BioVascular thrombotic stroke in patients Phase I San Diego, CA who have had a previous (858) 455-5000 cardiovascular event (see also heart attack) clazosentan Actelion vasospasm as a consequence of Phase II Pharmaceuticals US subarachnoid hemorrhage (650) 624-6900 South San Francisco, CA crobenetine Boehringer Ingelheim stroke Phase I Pharmaceuticals (800) 243-0127 Ridgefield, CT desmoteplase Lundbeck Research USA ischemic stroke Phase III Paramus, NJ (201) 261-1331 DU176b Daiichi Sankyo prevention of stroke Phase III Parsippany, NJ (see also thrombosis ) (973) 359-2600 MC-1 Medicure stroke Phase I completed Winnipeg, Canada (888) 435-2220 MK-0724 Merck stroke Phase II Whitehouse Station, NJ (800) 672-6372 NA 1 Arbor Vita stroke Phase I Sunnyvale, CA (408) 585-3900 Nectiv ® Pfizer stroke Phase II traxoprodil New York, NY (860) 732-5156 NEU2000 Amkor Pharma stroke Phase I Seattle, WA (see also heart attack) (206) 332-5587 PL2100 PLx Pharma stroke Phase I (aspirin/ Houston, TX (see also heart attack) (713) 842-1249 phosphatidyl- choline) rivaroxaban Bayer HealthCare prevention of stroke Phase III Pharmaceuticals (see also acute coronary syndrome, (888) 842-2937 West Haven, CT thrombosis) Johnson & Johnson Pharmaceutical Research & Development Raritan, NJ

M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 19 S TROKE Product Name Sponsor Indication Development Status S-0139 GlaxoSmithKline stroke Phase II Rsch. Triangle Park, NC (888) 825-5249 Shionogi (973) 966-6900 Florham Park, NJ SUN N8075 Asubio Pharmaceuticals acute ischemic stroke Phase I Rochelle Park, NJ (201) 368-5020 TNKase ® Genentech stroke Phase II tenecteplase South San Francisco, CA (see also thrombosis) (800) 626-3553 TS-011 Taisho stroke Phase I Pharmaceutical R&D Morristown, NJ V10153 Vernalis Pharmaceuticals stroke Phase II completed Morristown, NJ (see also heart attack) (973) 867-5555 zonampanel Astellas Pharma US acute ischemic stroke Phase II Deerfield, IL (800) 727-7003

T HROMBOSIS Product Name Sponsor Indication Development Status APD-791 Arena Pharmaceuticals arterial thrombosis Phase I completed San Diego, CA (858) 453-7200 apixaban Bristol-Myers Squibb prevention and treatment of Phase III (factor XA Princeton, NJ deep vein thrombosis (DVT) (212) 546-4000 inhibitor) Pfizer (see also acute coronary syndrome, (860) 732-5156 New York, NY stroke) ARC1779 Archemix thrombosis associated with acute Phase II Cambridge, MA coronary syndrome (617) 621-7700 ATI-5923 ARYx Therapeutics prevention of thromboembolism Phase II/III Fremont, CA in patients requiring chronic (510) 585-2200 anticoagulation treatment AVE5026 sanofi-aventis prevention of venous Phase II Bridgewater, NJ thromboembolism (800) 633-1610 AZD0837 AstraZeneca thrombosis Phase II Wilmington, DE (800) 236-9933 AZD6482 AstraZeneca thrombosis Phase I Wilmington, DE (800) 236-9933 betrixaban Portola Pharmaceuticals prevention of thromboembolism Phase II South San Francisco, CA (see also stroke) (650) 246-7000 BIBT986 Boehringer Ingelheim thrombosis Phase I Pharmaceuticals (800) 243-0127 Ridgefield, CT certoparin Novartis Pharmaceuticals thromboembolism Phase III East Hanover, NJ (888) 669-6682 diaplasinin Wyeth Pharmaceuticals thrombosis Phase I (PAI-749) Collegeville, PA (800) 934-5556

20 M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 T HROMBOSIS Product Name Sponsor Indication Development Status DU176b Daiichi Sankyo prevention of embolism Phase III Parsippany, NJ (see also stroke) (973) 359-2600 DX9065a Daiichi Sankyo thrombosis Phase I Parsippany, NJ (see also acute coronary syndrome, (973) 359-2600 coronary artery disease) Elaprin ® Emisphere Technologies deep vein thrombosis (DVT) Phase III oral heparin Tarrytown, NY (914) 347-2220 eribaxaban Pfizer venous thrombosis Phase II New York, NY (860) 732-5156 idrabiotaparinux sanofi-aventis long-term treatment of DVT and Phase III Bridgewater, NJ pulmonary embolism (800) 633-1610 (see also arrhythmia) idraparinux sanofi-aventis long-term treatment of DVT and Phase III Bridgewater, NJ pulmonary embolism (800) 633-1610 (see also arrhythmia) LMWH Emisphere Technologies thrombosis Phase I (low molecular Cedar Knolls, NJ (973) 532-8000 weight heparin oral) LY517717 Eli Lilly thrombosis Phase I Indianapolis, IN (800) 545-5979 MER-102 Merrion Pharmaceuticals thrombosis Phase I Wilmington, NC (910) 799-1847 MPC-0920 Myriad Pharmaceuticals thrombosis Phase I Salt Lake City, UT (801) 584-3600 NU-172 Nuvelo thrombosis Phase I San Carlos, CA (650) 517-8000 ORG-27306 Schering-Plough thrombosis Phase I Kenilworth, NJ (908) 298-4000 PCI-27483 Pharmacyclics treatment of thrombotic Phase I Sunnyvale, CA complications of cancer (408) 774-0330 PM103 CyDex Pharmaceuticals thrombosis Phase I Lenexa, KS (913) 685-8850 Prism Pharmaceuticals (610) 265-7710 King of Prussia, PA Plavix ™ Bristol-Myers Squibb prevention of thromboembolism in clinical trials clopidogrel Princeton, NJ complications associated with (212) 546-4000 sanofi-aventis atrial fibrillation (800) 633-1610 Bridgewater, NJ PSI-697/ Wyeth Pharmaceuticals thrombosis Phase I WAY-197697 Collegeville, PA (see also atherosclerosis) (800) 934-5556 R1663 Roche thrombosis Phase I Nutley, NJ (973) 235-5000 RB006/RB007 Regado Biosciences thrombosis Phase II Durham, NC (919) 287-9428

M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 21 T HROMBOSIS Product Name Sponsor Indication Development Status Rendix ™ Boehringer Ingelheim thromboembolism Phase III dabigatran Pharmaceuticals (prevention and treatment) (203) 798-9988 etexilate Ridgefield, CT rivaroxaban Bayer HealthCare prevention of DVT, application submitted Pharmaceuticals pulmonary embolism and (888) 842-2937 Wayne, NJ thromboembolism in patients Johnson & Johnson undergoing hip or knee Pharmaceutical Research replacement surgery & Development (see also acute coronary syndrome, Raritan, NJ stroke) saratin BioVascular thrombosis Phase I/II San Diego, CA (858) 455-5000 SPP200 Speedel Pharmaceuticals thrombosis Phase II (PEG-hirudin) (Novartis) (see also peripheral vascular disease) (732) 537-2290 Bridgewater, NJ TAK-442 Takeda Pharmaceuticals thromboembolism Phase II North America (see also acute coronary syndrome) (877) 582-5332 Deerfield, IL TAL-0500018 Talecris Therapeutics thrombosis Phase I Rsch. Triangle Park, NC (see also peripheral vascular disease) (919) 316-6300 ticagrelor AstraZeneca arterial thrombosis Phase III Wilmington, DE (see also acute coronary syndrome) (800) 236-9933 tiplasinin Wyeth Pharmaceuticals thrombosis Phase I Collegeville, PA (800) 934-5556 TNKase ® Genentech catheter thrombosis Phase III tenecteplase South San Francisco, CA (see also stroke) (800) 626-3553 TTP-889 TransTech Pharma thrombosis Phase II High Point, NC (336) 841-0300 YM-150 Astellas Pharma US DVT, thromboembolism Phase II Deerfield, IL (800) 727-7003

O THER Product Name Sponsor Indication Development Status 2190914 Amira Pharmaceuticals cardiovascular disorders Phase I (AM103) San Diego, CA (858) 228-4650 GlaxoSmithKline (888) 825-5249 Rsch. Triangle Park, NC AM803 Amira Pharmaceuticals cardiovascular disorders Phase I San Diego, CA (858) 228-4650 GlaxoSmithKline (888) 825-5249 Rsch. Triangle Park, NC Aranesp ® Amgen anemia in heart failure Phase III darbepoetin alfa Thousand Oaks, CA (805) 447-1000

22 M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 O THER Product Name Sponsor Indication Development Status ART-123 Artisan Pharma disseminated intravascular Phase II (recombinant Waltham, MA coagulation (781) 419-1919 human thrombomodulin alpha) Certican ® Abbott Laboratories prevention of rejection episodes application submitted everolimus Abbott Park, IL following heart transplantation (847) 937-6100 Crestor ® Abbott Laboratories cardiovascular outcomes in patients Phase III rosuvastatin Abbott Park, IL with elevated C-reactive protein (847) 937-6100 AstraZeneca (800) 236-9933 Wilmington, DE DB-772d Daiichi Sankyo cardiovascular disorders Phase I Parsippany, NJ (973) 359-2600 defibrotide Sigma-Tau Pharmaceuticals venous-occlusive disorders Phase III Gaithersburg, MD (800) 447-0169 droxidopa Chelsea Therapeutics orthostatic hypotension Phase III Charlotte, NC (704) 341-1516 ------intradialytic hypotension Phase II (704) 341-1516 Evista ® Eli Lilly cardiovascular disorders Phase III raloxifene HCl Indianapolis, IN (see also lipid disorders) (800) 545-5979 fluasterone Aeson Therapeutics cardiovascular disorders Phase II (DHEA) Tucson, AZ (520) 748-4462 Fx 1006A FoldRx Pharmaceuticals familial amyloid cardiomyopathy Phase II Cambridge, MA (617) 252-5500 Hemospan ™ Sangart hypovolemia Phase II human San Diego, CA (858) 450-2400 hemoglobin INO-1001 Inotek Pharmaceuticals cardiac reperfusion injury Phase II Beverly, MA (978) 232-9660 iroxanadine Cytrx cardiovascular disorders Phase II Los Angeles, CA (310) 826-5648 ISIS 353512 Isis Pharmaceuticals cardiovascular disorders Phase I Carlsbad, CA (760) 931-9200 ivabradine Servier left ventricular dysfunction Phase III Cedex, France www.servier.com Lantus ® sanofi-aventis reduction in cardiovascular Phase III insulin glargine Bridgewater, NJ morbidity and mortality (800) 633-1610 lixivaptan Biogen Idec hyponatremia Phase III Cambridge, MA (617) 679-2000 Cardiokine Philadelphia, PA LY458202 Cardiome Pharma cardiogenic shock Phase I Vancouver, BC (800) 330-9928

M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 23 O THER Product Name Sponsor Indication Development Status MK-0448 Merck cardiovascular disease Phase I Whitehouse Station, NJ (800) 672-6372 MK-1809 Merck cardiovascular disorders Phase I Whitehouse Station, NJ (800) 672-6372 MTR-104 Meditor Pharmaceuticals hypotension Phase II Fort Lauderdale, FL (904) 501-5882 mycophenolate Novartis Pharmaceuticals heart transplant rejection in clinical trials East Hanover, NJ (888) 669-6682 PA32540 POZEN cardiovascular disorders Phase I (aspirin/ Chapel Hill, NC (919) 913-1030 omeprazole) polidocanol BioForm varicose veins Phase III (intravenous) San Mateo, CA (650) 286-4000 Chemische Fabrik KREUSSLER Wiesbaden, Germany polidocanol BTG International varicose veins Phase II/III (microfoam West Conshohocken, PA (610) 278-1660 formulation) PolyHeme ® Northfield Laboratories hypovolemia application submitted human Evanston, IL (847) 864-3500 hemoglobin Rapamune ® Wyeth Pharmaceuticals heart transplant rejection Phase II sirolimus Collegeville, PA (800) 934-5556 renin inhibitor Actelion cardiovascular disorders Phase I Pharmaceuticals US (650) 624-6900 South San Francisco, CA (800) 672-6372 Merck Whitehouse Station, NJ RVX-208 Resverlogix cardiovascular disorders Phase I/II Calgary, AB (403) 254-9252 Samska ™ Otsuka America hyponatremia application submitted tolvaptan Pharmaceutical (see also heart failure) (800) 562-3974 Rockville, MD SLx-2101 Surface Logix cardiovascular disorders Phase I Brighton, MA (617) 746-8500 tissue repair Aastrom Biosciences cardiomyopathy Phase II stem cell therapy Ann Arbor, MI (see also ischemic disorders) (734) 930-5555 TP10 Celldex Therapeutics reperfusion injury Phase II Phillipsburg, NJ (908) 454-7120 Vascana ™ MediQuest Therapeutics Raynaud’s disease application submitted nitroglycerin Bothell, WA (425) 398-9580 topical xemilofiban VDDI Pharmaceuticals cardiovascular disorders Phase III Brentwood, TN (615) 467-3080

24 M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 O THER Product Name Sponsor Indication Development Status

Zenapax ® PDL BioPharma heart transplant rejection Phase III daclizumab Incline Village, NV (775) 832-8500 zoniporide Pfizer cardiovascular disorders Phase II New York, NY (860) 732-5156

The content of this report has been obtained through industry sources and the Adis “R&D Insight” database based on the latest information. Report current as of January 30, 2009 . The information in this report may not be comprehensive. For more specific information about a particular product, contact the individual company directly or go to www.clinicaltrials.gov. The entire series of Medicines in Development is available on PhRMA’s web site. A publication of PhRMA’s Communications & Public Affairs Department. (202) 835-3460 www.phrma.org | www.innovation.org | www.pparx.org | www.buysafedrugs.info | www.sharingmiracles.com Provided as a Public Service by PhRMA. Founded in 1958 as the Pharmaceutical Manufacturers Association. Copyright © 2009 by the Pharmaceutical Research and Manufacturers of America. Permission to reprint is awarded if proper credit is given.

M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 25 G LOSSARY

adjunctive therapy —Auxiliary the patient or by using synthetic substances, including cholesterol) treatment that is secondary to the tubing. in the blood. Hyperlipidemia is main treatment. cardiac —Of or relating to the heart. a risk factor for accelerated angina pectoris —Chest pain, atherosclerosis and premature cardiovascular —Of or relating to heart attacks. usually caused by “myocardial the heart and blood vessels. ischemia,” a low supply of oxygen hypertension (high blood to the heart muscle resulting from coronary artery disease —Caused pressure) —Persistent elevation of hardening, narrowing, and by atherosclerosis of the arteries blood pressure above the normal sometimes spasm of the coronary that supply the heart. range while the heart is in systolic arteries. critical limb ischemia —CLI is a (contracting) or diastolic (relaxed) application submitted —An severe obstruction of the arteries mode. Uncontrolled, chronic application for marketing has been that seriously decreases blood flow hypertension strains the heart, submitted by the company to the to the extremities (arms, hands, damages arteries and creates a Food and Drug Admin istra tion legs, feet) and has progressed to greater risk of heart attack, stroke (FDA). the point of severe pain and even and kidney problems. skin ulcers of sores. The pain, hypertriglyceridemia —An elevated arrhythmia —Abnormal heart called “rest pain,” caused by CLI rhythm, usually detected by an triglyceride concentration in the can wake up a person at night. CLI blood. electrocardiogram. Arrhythmias can is a very severe condition of be caused by several factors, such peripheral arterial disease and hyponatremia —Reduced sodium as coronary artery disease, heart needs comprehensive treatment by concentration in the blood. valve problems or hyperthyroidism. a vascular surgeon or specialist. hypotension —A sudden fall in atherosclerosis —A common deep vein thrombosis —Blood blood pressure that occurs when a disease in which deposits of clotting within the deep-lying person assumes a standing position. plaque containing calcium and veins, often in the legs or pelvic It may be caused by hypovolemia fatty substances, such as veins. resulting from the excessive use of cholesterol, are formed within the diuretics, vasodi lators, or other inner layers of the arteries. It is a dyslipidemia —A condition marked types of drugs, dehydration, or condition that progresses over by abnormal concentrations of prolonged bed rest. The disorder decades, chiefly affecting the lipids or lipoproteins in the blood. may be associated with Addison’s arteries of the heart, brain and heart attack ( myocardial disease, atherosclerosis (build-up extremities. Its complications infarction) —A part of the heart of fatty deposits in the arteries), include heart attacks and strokes. muscle (myocardium) dies as a diabetes, and certain neurological atrial fibrillation and atrial flutter — result of blood and oxygen disorders. Symptoms, which Very fast electrical discharge deprivation. generally occur after sudden patterns that make the heart’s atria heart failure —The end result of standing, include dizziness, light - contract extremely rapidly, which many different types of heart headedness, blurred vision, and the causes the ventricles to contract disease. The heart cannot pump temporary loss of consciousness. faster and less efficiently than blood out normally. This results hypovolemia —A deficiency in the normal. As a result, inadequate in congestion (water and salt amount of blood in the body. amounts of blood are pumped out retention) in the lungs, swelling imaging agent —A substance used of the heart, blood pressure falls, in the extremities, and reduced to enhance x-ray images of organs and heart failure may occur. blood flow to body tissues. and spaces in the body. bypass graft —A vein or artery graft hypercholesterolemia —The intermittent claudication —The that bypasses blockage in an artery. presence of an abnormally large most prominent symptom of bypass surgery —A surgical amount of cholesterol in the cells peripheral arterial disease (PAD). procedure to bypass the blockage and plasma of the circulating blood. It occurs in one-third to one-half or narrowing of an artery. Blockages hyperlipidemia —A group of of PAD patients. Claudication can be bypassed using sections of metabolic disorders characterized refers to the pain that occurs in normal artery or vein taken from by high levels of lipids (fatty PAD patients when they exercise,

26 M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 G LOSSARY particularly during walking, which likely. Plaques in the coronary electrical impulses arising within is relieved only by rest. Leg pain arteries, which supply blood to the the upper chambers of the heart occurs in one leg in 40 percent of heart muscle, are the cause of taking over control of the heart patients and in both legs in 60 coronary heart disease . beat from the heart’s pacemaker percent of patients. preeclampsia —The development (sinoatrial node). ischemia —Insufficient supply of of hypertension with proteinuria or systolic —A period of muscular blood to an organ or tissue, which edema, or both, due to pregnancy or contraction of a chamber of the can cause organ damage such as an the influence of a recent pregnancy. heart that alternates with a resting ischemic stroke . pulmonary hypertension —High period (diastolic). lipids —A group of fatty substances blood pressure in the arteries thromboembolism —Blockage of a that includes triglycerides (the supplying the lungs due to blood vessel by a fragment that principal forms of fat in body fat), increased resistance to blood flow has broken off and been carried phospholipids (important through the lungs. from a thrombus (blood clot) constituents of cell membranes), Raynaud’s disease —A circulatory elsewhere in the circulation. and sterols (such as cholesterol). disorder caused by insufficient thrombosis —The formation of a peripheral vascular disease —The blood supply to the hands and feet, blood clot within the heart or a obstruction of blood supply to the resulting in cyanosis, numbness, blood vessel. extremities, particularly the legs, pain, and, in extreme cases, vascular dementia —A common caused by atherosclerosis. gangrene. form of dementia in older people Phase 0 —First-in-human trials reperfusion injury —Refers to that is due to cerebrovascular conducted in accordance with myocardial, vascular, or electro- disease, usually with stepwise FDA’s 2006 guidance on physiological dysfunction that is deterioration from a series of small exploratory Investigational New induced by the restoration of blood strokes and a patchy distribution Drug (IND) studies designed to flow to previously ischemic tissue. of neurologic deficits affecting speed up development of promising restenosis —A condition where an some functions and not others. drugs by establishing very early artery plugs up again following Risk factors include high blood on whether the agent behaves in treatment to open it up. pressure and advanced age. human subjects as was anticipated Symptoms include confusion, from preclinical studies. stroke —A blood clot obstructing a problems with recent memory, major blood vessel of the brain or Phase I —Safety testing and wandering or getting lost in familiar by bleeding into a major brain places, incontinence, emotional pharmacological profiling in blood vessel. Stroke can result in humans. problems such as laughing or crying death or serious brain damage, inappropriately, and difficulty Phase II —Effectiveness testing in such as paralysis or loss of following instructions. The damage humans. speech. is typically so slight that the change Phase III —Extensive clinical trials supraventricular arrhythmia — is noticeable only as a series of in humans. Irregular heart beats ( arrhythmias ) small steps. However, over time, plaque —An area of atherosclerosis that occur in the area above the as more small blood vessels in the (hardening of the arteries). The ventricles, usually in the upper brain are blocked, there is notice - atheromatous plaques give no chambers of the heart, called the able gradual mental decline. indication of their presence until atria. The irregular beats can be Vascular dementia commonly they become so large that they either too slow (bradycardia) or begins between the ages of 60 reduce blood flow in a vessel or too fast (tachycardia). and 75 and affects men more until some disturbance of the supraventricular tachycardia —An often than women. It is also known plaque surface develops, causing abnormally fast but regular heart as multi-infarct dementia. thrombosis (blood clot) at the site. rate that occurs in intermittent vasospasm —A sudden constriction When this occurs in a small- or episodes lasting for several hours of a blood vessel that reduces the medium-sized vessel, blockage is or days. It is caused by abnormal blood flow.

M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 27 S ELECTED F ACTS A BOUT H EART D ISEASE AND S TROKE IN THE U NITED S TATES

Cardiovascular Diseases (CVD) 1 • More than 80.7 million American adults (37.9 million men; 42.7 million women) have one or more types of CVD . Of that total, 38.2 million are estimated to be age 60 and older. • The average annual rates of first major cardiovascular events rise from 3 per 1,000 men at ages 35-44 to 74 per 1,000 at ages 85-94. For women, comparable rates occur 10 years later in life, and the gap narrows with advancing age. • CVD accounted for 36.3 percent of all 2,397,615 deaths, or 1 of every 2.8 deaths, in 2004. CVD total mention deaths accounted for about 57 percent of all deaths in 2004. Nearly 2,400 Americans die of CVD each day, an average of one death every 37 seconds. CVD claims about as many lives each year as cancer, chronic lower respiratory diseases, accidents, and diabetes mellitus combined. • More than 148,000 Americans killed by CVD in 2004 were under age 65. • The estimated direct and indirect costs of CVD for 2008 are $448.5 billion. Arrhythmias • Millions of Americans have arrhythmias (disorders of heart rhythm), which are very common in older adults. 2 • Arrhythmias were responsible for 835,000 hospital discharges and for 37,633 deaths in 2005. 3 • About 2.2 million Americans have atrial fibrillation (AF). 2 • In 2006, $3.1 billion ($7,783 per discharge) was paid to Medicare beneficiaries for cardiac dysrhythmias .3

Arterial Disease s 2 • Atherosclerosis of the coronary arteries is the leading cause of illness and death in the United States. In men, the risk increases after age 45; in women, the risk increases after age 55.

Coronary Heart Disease (CHD) 1 (Heart Attack, Angina Pectoris, or both) • In 2005, 16 million American adults (age 20 and older) suffered from coronary heart disease (8.7 million men; 7.3 million women). Annually, more than 1 million people are diagnosed with CHD (710,000 males; 490,000 females). Nearly half a million Americans die each year from CHD, which caused one of every five deaths in 2004. About 82 percent of the people who die of CHD are age 65 or older. • CHD comprises more than half of all cardiovascular events in men and women under age 75. The lifetime risk of developing CHD after age 40 is 49 percent for men and 32 percent for women. • In 2005, of the 9.1 million Americans who had angina pectoris , 4.6 million were women and 4.4 million were men. Each year, some 500,000 people are diagnosed with stable angina . • In 2005, 920,000 new or recurrent myocardial infarctions (MIs or heart attack ) occurred, and in 2004 nearly 157,000 people died. In addition, some 190,000 silent first heart attacks occur annually. The average age of a person having a first heart attack is 64.5 for men and 70.4 for women. • Within one year following a first MI , at age 40 and older, 18 percent of men and 23 percent of women will die; within five years for that same age group, 33 percent of men and 43 percent of women will die. • The estimated direct and indirect costs of CHD for 2008 are $156.4 billion.

Heart Failure (HF) 1 • Of the 5.3 million adults living with heart failure (HF) , 2.7 million are women and 2.7 million are men. At age 40, the lifetime risk of developing HF for both men and women is 1 in 5. High blood pressure precedes 75 percent of HF cases.

28 M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 S ELECTED F ACTS A BOUT H EART D ISEASE AND S TROKE IN THE U NITED S TATES

Heart Failure (HF) 1 (continued) • In 2004, 57,120 people died from HF . Eighty percent of men and 70 percent of women under age 65 who have HF will die within eight years. • In people diagnosed with HF , sudden cardiac death occurs up to nine times the rate of the general population. • Hospital discharges for HF rose from 400,000 in 1979 to nearly 1.1 million in 2005, an increase of 171 percent. • The estimated direct and indirect costs of HF for 2008 are $34.8 billion.

Hypertensio n1 (High Blood Pressure—HBP) • In 2005, 73 million people (39 million females and 34 million males) had high blood pressure (HBP) . Nearly one in three adults has HBP. Of those with HBP age 18 and older, 71.8 percent were aware of their condition, 61.4 percent were under current treatment, 35.1 percent had it under control, and 64.9 percent did not have it controlled. • A higher percentage of men than women have HBP until age 45. From ages 45-54, the percentage of men and women is similar. After that, a much higher percentage of women have HBP than men do. • The prevalence of HBP in African Americans is among the highest in the world, and it is increasing. Compared with whites, blacks develop HBP earlier in life and their average blood pressures are much higher. As a result, blacks have a 1.3 times greater rate of nonfatal stroke , a 1.8 times greater rate of fatal stroke , a 1.5 times greater rate of heart disease death, and a 4.2 times greater rate of end-stage kidney disease. • In 2004, HBP was responsible for 54,707 deaths—23,099 males and 31,608 females. That year, the death rates for HBP were 15.7 for white males, 51 for black males, 14.5 for white females, and 40.9 for black females. • The estimated direct and indirect costs of HBP for 2008 are $69.4 billion.

Lipid Disorder s1 • Among adolescents ages 12-19, the mean total blood cholesterol level is 161.7 mg/dL. About 10 percent of adolescents in that age group have total cholesterol levels exceeding 200 mg/dL. • The 2005 estimated prevalence of total cholesterol in adults age 20 and older at or above 200 mg/dL was 106.7 million (50.8 million men; 55.9 million women). Overall in 2005, 35.6 percent of adults age 18 and older had been told that they had high blood cholesterol.

Peripheral Vascular Diseas e1 • Peripheral arterial disease (PAD) affects about 8 million Americans and is associated with significant morbidity and mortality. PAD affects between 12 percent to 20 percent of Americans age 65 and older. • In the general population, only about 10 percent of people with PAD have the classic symptoms of intermittent claudication , which is present in less than 1 percent of people under age 50 and about 5 percent or more in those over age 80.

Risk Factor s1 • The 2005 estimated prevalence of physician-diagnosed diabetes among adults age 20 and older was 15.1 million. The prevalence of undiagnosed diabetes was 6 million. About 154,369 people age 20 or younger have diabetes. The incidence of diabetes doubled over the past 30 years, most dramatically during the 1990s. • At least 65 percent of people with diabetes mellitus die of some form of heart disease or stroke . Heart disease death rates among adults with diabetes are two to four times higher than the rates for adults without diabetes. People who have diabetes are about two to six times more likely to have a stroke. • More than 9 million children and adolescents ages 6-19 are considered overweight. The prevalence of overweight in children ages 6-11 increased from 4 percent between 1971-74 to 17.5 percent between 2001-04. The prevalence of overweight in adolescents ages 12-19 increased from 6.1 percent to 17 percent during the same time periods.

M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 29 S ELECTED F ACTS A BOUT H EART D ISEASE AND S TROKE IN THE U NITED S TATES

Risk Factor s1 (continued) • In 2005, an estimated 142 million U.S. adults (age 20 and older) were overweight , and 67.3 million were obese . • About 80 percent of people who use tobacco start doing so before age 18. The most common age of initiation is 14-15. Each day, about 4,000 people ages 12-17 begin smoking cigarettes in the United States, and an estimated 1,140 people in that age group become daily smokers. • In 2005, the estimated prevalence for smoking among people age 18 and older was 46.6 million. That’s 23.9 percent of men and 18.1 percent of women who are smokers, putting them at increased risk of heart attack and stroke . Since 1965, smoking in the United States has declined by 50 percent among people in that age group. • From 1997-2001, an estimated 438,000 Americans died each year of smoking-related illnesses , and 34.7 percent of these deaths were related to cardiovascular disease . • Cigarette smoking results in a two- to three-fold risk of dying from coronary heart disease (CHD) , and it approximately doubles a person’s risk for stroke . Cigarette smokers are two to four times more likely to develop CHD than nonsmokers and are more than 10 times as likely as nonsmokers to develop peripheral vascular disease .

Strok e1 • On average, someone in this country has a stroke every 40 seconds. In 2005, 5.8 million Americans (3.4 million females; 2.3 million males) suffered a stroke, and each year about 780,000 people experience a new or recurrent stroke. • African Americans have almost twice the risk of first-ever stroke compared with whites. In 2004, death rates for stroke were 48.1 for white males, 74.9 for black males, 47.2 for white females, and 65.5 for black females. • Of all strokes, 87 percent are ischemic ; strokes due to intracerebral hemorrhage and subarachnoid hemorrhage make up the remainder. Among people ages 45-64, up to 12 percent of ischemic strokes and 38 percent of hemorrhagic strokes result in death within 30 days. • On average, every three to four minutes someone dies of a stroke , which accounted for about one of every 16 deaths in 2004. That year, 150,074 people died of stroke—91,274 females and 58,800 males. Stroke ranks as the third leading cause of death behind diseases of the heart and cancer. • The estimated direct and indirect costs of stroke for 2008 are $65.5 billion. Sources: 1. Heart Disease and Stroke Statistics—2008 Update (At-A-Glance Version), American Heart Association, www.americanheart.org 2. National Heart, Lung and Blood Institute, www.nhlbi.nih.gov 3. Heart Disease and Stroke Statistics—2009 Update, American Heart Association, www.americanheart.org

30 M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 T HE D RUG D ISCOVERY , D EVELOPMENT AND A PPROVAL P ROCESS It takes 10-15 years on average for an experimental drug to travel from the lab to U.S. patients. Only five in 5,000 compounds that enter preclinical testing make it to human testing. One of these five tested in people is approved.

Clinical Trials Discovery/ Phase Phase Phase Phase Preclinical Testing I II III FDA IV

Years 6.5 1.5 2 3.5 1.5

20 to 100 100 to 500 1,000 to 5,000 Test Laboratory and healthy patient patient A D A F

Population animal studies volunteers volunteers volunteers t Review Additional D a F

t process/ post- A a L

Assess safety, Determine Evaluate Confirm effectiveness, B approval marketing D / N A

Purpose biological I safety effectiveness, monitor adverse testing

D e l N

activity and i and look for reactions from required

F e l

formulations dosage side effects long-term use i by FDA F Success 5,000 5 1 Rate compounds evaluated enter trials approved

T HE D RUG D EVELOPMENT AND A PPROVAL P ROCESS

he U.S. system of new drug approvals is perhaps Clinical Trials, Phase I. These tests involve about 20 Tthe most rigorous in the world. to 100 normal, healthy volunteers. The tests study a It takes 10-15 years, on average, for an experimental drug’s safety profile, including the safe dosage range. drug to travel from lab to U.S. patients, according to The studies also determine how a drug is absorbed, the Tufts Center for the Study of Drug Development, distributed, metabolized, and excreted as well as the based on drugs approved from 1994 through 1998. duration of its action. Only five in 5,000 compounds that enter preclinical Clinical Trials, Phase II. In this phase, controlled testing make it to human testing. And only one of those trials of approximately 100 to 500 volunteer patients five is approved for sale. (people with the disease) assess a drug’s effectiveness. On average, it costs a company $1.3 billion to get Clinical Trials, Phase III. This phase usually involves one new medicine from the laboratory to U.S. patients, 1,000 to 5,000 patients in clinics and hospitals. according to a 2007 study by the Tufts Center for the Physicians monitor patients closely to confirm efficacy Study of Drug Development. and identify adverse events. Once a new compound has been identified in the New Drug Application (NDA)/Biologic License laboratory, medicines are developed as follows: Application (BLA). Following the completion of all Preclinical Testing. A pharmaceutical company con - three phases of clinical trials, a company analyzes all ducts laboratory and animal studies to show biological of the data and files an NDA or BLA with FDA if the activity of the compound against the targeted disease, data successfully demonstrate both safety and effec - and the compound is evaluated for safety. tiveness. The applications contain all of the scientific information that the company has gathered. Investigational New Drug Application (IND). After Applications typically run 100,000 pages or more. completing preclinical testing, a company files an IND The average review time for the 26 new therapeutics with the U.S. Food and Drug Administration (FDA) to approved by the FDA in 2007 was 11.1 months. begin to test the drug in people. The IND becomes effective if FDA does not disapprove it within 30 days. Approval. Once FDA approves an NDA or BLA, the The IND shows results of previous experiments; how, new medicine becomes available for physicians to where and by whom the new studies will be conducted; prescribe. A company must continue to submit periodic the chemical structure of the compound; how it is reports to FDA, including any cases of adverse reactions thought to work in the body; any toxic effects found and appropriate quality-control records. For some in the animal studies; and how the compound is man - medicines, FDA requires additional trials (Phase IV) to ufactured. All clinical trials must be reviewed and evaluate long-term effects. approved by the Institutional Review Board (IRB) Discovering and developing safe and effective new where the trials will be conducted. Progress reports medicines is a long, difficult, and expensive process. on clinical trials must be submitted at least annually Pharmaceutical companies invested an estimated to FDA and the IRB. $58.8 billion in research and development in 2007.

M EDICINES IN D EVELOPMENT FOR Heart Disease and Stroke 2009 31 Medicines in Development for Heart Disease and Stroke is presented by PhRMA in cooperation with the following organizations:

American Association of Cardiovascular and Pulmonary Rehabilitation American College of Cardiology American Nurses Association American Society of Hypertension Children’s Cardiomyopathy Foundation The Children’s Heart Foundation Interamerican College of Physicians and Surgeons National Alliance for Hispanic Health National Hypertension Association National Medical Association Pulmonary Hypertension Association WomenHeart: The National Coalition for Women with Heart Disease Women’s Heart Foundation

Being listed in this report in no way implies that the above-mentioned organizations endorse or recommend the use of any of the products in development contained in this publication. For further information, patients should consult their physicians or health care providers.

New Medicines. New Hope .®

Pharmaceutical Research and Manufacturers of America 950 F Street, NW Washington, DC 20004

www.phrma.org | www.innovation.org | www.pparx.org | www.buysafedrugs.info | www.sharingmiracles.com 2/09