AGGRENOX TM Advisory Committee Meeting

Manfred Haehl, MD Senior Vice President, Medical & Drug Regulatory Affairs Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, Connecticut

AGGRENOX TM Proposed Indication To reduce the combined risk of death and non-fatal stroke in patients who have had transient ischemia of the brain or completed ischemic stroke

FDA Approved Aspirin Label (1998) “To reduce the combined risk of death and non- fatal stroke in patients who have had ischemic stroke or transient ischemia of the brain due to fibrin platelet emboli.” (dose 50–325 mg/d) “To reduce the combined risk of death and non- fatal stroke in patients who have had ischemic stroke or transient ischemia of the brain due to fibrin platelet emboli.” (dose 50–325 mg/d) Based on relative risk reduction of 13–18% (63 FR 56802) Based on relative risk reduction of 13–18% (63 FR 56802)

ESPS-2170/ /164923(4, 37)0.019 Eight Other Studies399/ /258418(5, 30)0.010 Combined569/ /423320(9, 29)<0.001 Nonfatal Stroke in Nine Randomized, Placebo-Controlled Trials 1 of Aspirin in TIA or Stroke Patients Odds Reduction AspirinPlacebo(95% CI)P-Value 2 1 AITIA (1977), AITIA (1978), AICLA (1983), DANISH (1983), SWEDISH (1987), SALT (1991), UK-TIA (1991), EAFT (1993). 2 Cochran Mantel-Haenszel test, stratified by study.

ESPS patients, TID dosing 75 mg dipyridamole instant/330 mg Aspirin 75 mg dipyridamole instant/330 mg Aspirin Placebo Placebo

ESPS patients, BID dosing AGGRENOX TM AGGRENOX TM ASA ASA ER-DP ER-DP Placebo Placebo

AGGRENOX TM

200 mg ER–Dipyridamole Granules + 25 mg Immediate Release ASA ASA Dipyridamole HP cellulose protective coating: water soluble polymers Tartaric acid: dipyridamole solubiliser Sustained release coating: water insoluble polymers Dipyridamole depot pellets

AGGRENOX TM ESPS-2 Findings Highly significant additive risk reduction for stroke Highly significant additive risk reduction for stroke Safety comparable to components Safety comparable to components Trend (N.S.) reduction in death consistent with previous ASA findings Trend (N.S.) reduction in death consistent with previous ASA findings Robust and reliable findings Robust and reliable findings

Characteristics of a Single Adequate and Well-Controlled Study for Effectiveness Claim Large multicenter study Large multicenter study Consistency across study subsets Consistency across study subsets Multiple studies in a single study Multiple studies in a single study Multiple endpoints involving different events Multiple endpoints involving different events Statistically very persuasive finding Statistically very persuasive finding

FDA Regulations for Fixed- Combination Prescription Drugs (21 CFR § ) Each component makes a contribution to the claimed effects Each component makes a contribution to the claimed effects The dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy The dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy

Participants and Guests J. Donald Easton, MD (Professor and Chairman of Neurology, Brown University – RI Hospital) J. Donald Easton, MD (Professor and Chairman of Neurology, Brown University – RI Hospital) David G. Sherman, MD (Professor and Chief of Neurology, The University of Texas Health Science Center) David G. Sherman, MD (Professor and Chief of Neurology, The University of Texas Health Science Center) Charles Hennekens, MD (Visiting Professor of Epidemiology and Public Health, University of Miami, School of Medicine, Miami, FL and Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Clinical Medicine, University of Oxford, UK) Charles Hennekens, MD (Visiting Professor of Epidemiology and Public Health, University of Miami, School of Medicine, Miami, FL and Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Clinical Medicine, University of Oxford, UK)

John Pathy, MD (Director and Emeritus Professor, Health Care Research Unit, University of Wales, Cardiff) John Pathy, MD (Director and Emeritus Professor, Health Care Research Unit, University of Wales, Cardiff) Hans Christoph Diener, MD (Professor and Chairman Department of Neurology, University of Essen, Germany) Hans Christoph Diener, MD (Professor and Chairman Department of Neurology, University of Essen, Germany) Participants and Guests

Agenda IntroductionManfred Haehl, MD Senior Vice President for Medical & Drug Regulatory Affairs Boehringer Ingelheim Pharmaceuticals Stroke ManagementGregory W. Albers, MD Associate Professor of Neurology Director of the Stanford Stroke Center Development RationaleThomas Müller, MD, PhD Head, Haemostasis Laboratory Blood Transfusion Center of the German Red Cross Oldenburg, Germany Clinical Findings EfficacyJames Street, PhD Sr. Biostatistician Boehringer Ingelheim Pharmaceuticals SafetyKenneth J. Rakowski, MD Head, Drug Surveillance and Information Boehringer Ingelheim Pharmaceuticals ConclusionsManfred Haehl, MD

FDA Guidance – Single Trial* *Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products. “Reliance on a single study will generally be limited to situations in which a trial has demonstrated a clinically meaningful effect on mortality, irreversible morbidity, or prevention of a disease with potentially serious outcome, such that confirmation of the result in a second trial would be ethically difficult or impossible.”

Clinical Trial of AGGRENOX TM ESPS-2 (1996) 6602 patients 6602 patients 200 mg ER-DP/25 mg ASA bid (AGGRENOX™ formulation) 200 mg ER-DP/25 mg ASA bid (AGGRENOX™ formulation) 37% RRR vs Placebo (Stroke) 37% RRR vs Placebo (Stroke) Tolerability comparable to components Tolerability comparable to components

AGGRENOX TM Capsule containing 200 mg Extended Release Dipyridamole (ER-DP) Granules + 25 mg Immediate Release Aspirin (ASA) Tablet

Aspirin C9H8O4C9H8O4C9H8O4C9H8O4OHO O CH 3 O

FDA Approved Aspirin Label (1980) “For reducing the risk of recurrent transient ischemic attacks (TIA) or stroke in men who have had transient ischemia of the brain due to fibrin platelet emboli.” (dose 1,300 mg/d) “For reducing the risk of recurrent transient ischemic attacks (TIA) or stroke in men who have had transient ischemia of the brain due to fibrin platelet emboli.” (dose 1,300 mg/d) “…inadequate evidence of efficacy in women” “…inadequate evidence of efficacy in women” “…no evidence of benefit in treatment of completed stroke” “…no evidence of benefit in treatment of completed stroke”