AGGRENOXAGGRENOXTM TM AdvisoryAdvisoryCommittee MeetingCommittee Meeting

Manfred Haehl, MDManfred Haehl, MD

Senior Vice President, Medical & DrugSenior Vice President, Medical & DrugRegulatory AffairsRegulatory AffairsBoehringer Ingelheim Pharmaceuticals, Inc.Boehringer Ingelheim Pharmaceuticals, Inc.Ridgefield, ConnecticutRidgefield, Connecticut

AGGRENOXAGGRENOXTM TM Proposed IndicationProposed Indication

To reduce the combined risk of death To reduce the combined risk of death and non-fatal stroke in patients who and non-fatal stroke in patients who have had transient ischemia of the brainhave had transient ischemia of the brainor completed ischemic strokeor completed ischemic stroke

FDA Approved Aspirin FDA Approved Aspirin Label (1998)Label (1998)

““To reduce the combined risk of death and non-To reduce the combined risk of death and non-fatal stroke in patients who have had ischemicfatal stroke in patients who have had ischemicstroke or transient ischemia of the brain due to stroke or transient ischemia of the brain due to fibrin platelet emboli.” (dose 50–325 mg/d)fibrin platelet emboli.” (dose 50–325 mg/d)

Based on relative risk reduction of 13–18%Based on relative risk reduction of 13–18%(63 FR 56802)(63 FR 56802)

ESPS-2ESPS-2 170/1649170/1649 213/1649213/1649 2323 (4, 37)(4, 37) 0.0190.019

Eight Other StudiesEight Other Studies 399/3406399/3406 372/2584372/2584 1818 (5, 30)(5, 30) 0.0100.010

CombinedCombined 569/5055569/5055 585/4233585/4233 2020 (9, 29)(9, 29) <0.001<0.001

Nonfatal Stroke in Nine Randomized, Nonfatal Stroke in Nine Randomized, Placebo-Controlled TrialsPlacebo-Controlled Trials11 of Aspirin of Aspirinin TIA or Stroke Patientsin TIA or Stroke Patients

Odds ReductionOdds ReductionAspirinAspirin PlaceboPlacebo (95% CI)(95% CI) PP-Value-Value22

11AITIA (1977), AITIA (1978), AICLA (1983), DANISH (1983), SWEDISH (1987),AITIA (1977), AITIA (1978), AICLA (1983), DANISH (1983), SWEDISH (1987),SALT (1991), UK-TIA (1991), EAFT (1993).SALT (1991), UK-TIA (1991), EAFT (1993).22Cochran Mantel-Haenszel test, stratified by study.Cochran Mantel-Haenszel test, stratified by study.

ESPS-1ESPS-1

2500 patients, TID dosing2500 patients, TID dosing

75 mg dipyridamole instant/330 mg Aspirin75 mg dipyridamole instant/330 mg Aspirin

PlaceboPlacebo

ESPS-2ESPS-2

6602 patients, BID dosing6602 patients, BID dosing

AGGRENOXAGGRENOXTMTM

ASAASA

ER-DPER-DP

PlaceboPlacebo

AGGRENOXAGGRENOXTMTM

200 mg ER–Dipyridamole Granules200 mg ER–Dipyridamole Granules

++

25 mg Immediate Release ASA25 mg Immediate Release ASA

ASA

Dipyridamole

HP celluloseprotectivecoating:water solublepolymers

Tartaric acid:dipyridamole

solubiliser

Sustained release coating:water insoluble polymers

Dipyridamole depot pellets

AGGRENOXAGGRENOXTM TM ESPS-2 FindingsESPS-2 Findings

Highly significant additive risk reduction for strokeHighly significant additive risk reduction for stroke

Safety comparable to componentsSafety comparable to components

Trend (N.S.) reduction in death consistent with Trend (N.S.) reduction in death consistent with previous ASA findingsprevious ASA findings

Robust and reliable findingsRobust and reliable findings

Characteristics of a Single Characteristics of a Single Adequate and Well-Controlled Adequate and Well-Controlled Study for Effectiveness ClaimStudy for Effectiveness Claim

Large multicenter studyLarge multicenter study

Consistency across study subsetsConsistency across study subsets

Multiple studies in a single studyMultiple studies in a single study

Multiple endpoints involving different eventsMultiple endpoints involving different events

Statistically very persuasive findingStatistically very persuasive finding

FDA Regulations for Fixed-Combination FDA Regulations for Fixed-Combination Prescription Drugs Prescription Drugs (21 CFR § 300.50)(21 CFR § 300.50)

Each component makes a contributionEach component makes a contributionto the claimed effects to the claimed effects

The dosage of each component (amount, The dosage of each component (amount, frequency, duration) is such that the combination frequency, duration) is such that the combination is safe and effective for a significant patient is safe and effective for a significant patient population requiring such concurrent therapy population requiring such concurrent therapy

Participants and GuestsParticipants and Guests

J. Donald Easton, MD (Professor and ChairmanJ. Donald Easton, MD (Professor and Chairmanof Neurology, Brown University – RI Hospital)of Neurology, Brown University – RI Hospital)

David G. Sherman, MD (Professor and Chief David G. Sherman, MD (Professor and Chief of Neurology, The University of Texas Health of Neurology, The University of Texas Health Science Center)Science Center)

Charles Hennekens, MD (Visiting Professor Charles Hennekens, MD (Visiting Professor of Epidemiology and Public Health, University of Epidemiology and Public Health, University of Miami, School of Medicine, Miami, FL and of Miami, School of Medicine, Miami, FL and Clinical Trial Service Unit and Epidemiological Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Clinical Studies Unit, Nuffield Department of Clinical Medicine, University of Oxford, UK) Medicine, University of Oxford, UK)

John Pathy, MD (Director and Emeritus Professor, John Pathy, MD (Director and Emeritus Professor, Health Care Research Unit, University of Health Care Research Unit, University of Wales, Cardiff)Wales, Cardiff)

Hans Christoph Diener, MD (Professor and Hans Christoph Diener, MD (Professor and Chairman Department of Neurology, University Chairman Department of Neurology, University of Essen, Germany)of Essen, Germany)

Participants and GuestsParticipants and Guests

AgendaAgendaIntroductionIntroduction Manfred Haehl, MDManfred Haehl, MD

Senior Vice President for Medical & Drug Regulatory AffairsSenior Vice President for Medical & Drug Regulatory AffairsBoehringer Ingelheim PharmaceuticalsBoehringer Ingelheim Pharmaceuticals

Stroke ManagementStroke Management Gregory W. Albers, MDGregory W. Albers, MDAssociate Professor of NeurologyAssociate Professor of NeurologyDirector of the Stanford Stroke CenterDirector of the Stanford Stroke Center

Development RationaleDevelopment Rationale Thomas Müller, MD, PhDThomas Müller, MD, PhDHead, Haemostasis LaboratoryHead, Haemostasis LaboratoryBlood Transfusion Center of the German Red CrossBlood Transfusion Center of the German Red CrossOldenburg, Germany Oldenburg, Germany

Clinical FindingsClinical Findings

EfficacyEfficacy James Street, PhDJames Street, PhDSr. BiostatisticianSr. BiostatisticianBoehringer Ingelheim Pharmaceuticals Boehringer Ingelheim Pharmaceuticals

SafetySafety Kenneth J. Rakowski, MDKenneth J. Rakowski, MDHead, Drug Surveillance and InformationHead, Drug Surveillance and InformationBoehringer Ingelheim PharmaceuticalsBoehringer Ingelheim Pharmaceuticals

ConclusionsConclusions Manfred Haehl, MDManfred Haehl, MD