CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE Protocol CV185057 A Safety and Efficacy Trial Evaluating the Use of Apixaban for the Extended Treatment of Deep Vein Thrombosis and Pulmonary Embolism Background Design The information in this presentation is for an unapproved investigational product. Use of this presentation is restricted to apixaban investigator related activities. 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE Agenda Background Clinical need CV185057 design Discussion 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

Current Treatment Standard Initial DVT/PE treatment Heparin (LMWH) + vitamin K antagonist (e.g. warfarin) Typically 6 to 12 months for unprovoked events (e.g., cancer, idiopathic event, prothrombotic state)1. Usually 3 months for provoked events (e.g. prolonged immobility)1 but may be longer--6 mo--when there is persistent thrombosis risk2. 1Buller HR, et al. ACCP Guidelines2004. Chest 2004;126:Suppl 3:401S-428S. 2Schulman S. New Concepts. Thromb Haemost 2006; 96: 258-266. 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE Intrinsic Current Standard Low Molecular Weight Heparin XII XI Extrinsic IX VII VIII X Enoxaparin V II I Fibrin Clot 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE Current Standard Vitamin K Antagonist XII XI Factor Half-lives IX 24 hrs 6 hrs VII VIII X 36 hrs Warfarin V II 60 hrs I Fibrin Clot 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE Study Rationale Risk for recurrent VTE persists after treatment ends ~3%/year over 10 years1. Uncertainty whether to extend treatment in this setting because bleeding risk with a vitamin K antagonist offsets potential benefit1. Clinical need for an anticoagulant in this setting that is effective and has an acceptable safety risk. 1Schulman S. New Concepts. Thromb Haemost 2006; 96: 258-266. 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

The Clinical Need …current therapies are effective but have limitations… Low Molecular Weight Heparins (LMWHs) [e.g., Enoxaparin] Injectable Difficult for chronic use Vitamin K Antagonists (VKAs) [e.g., Warfarin] Slow onset and offset of action Significant food and drug-drug interactions High variability in response Narrow therapeutic window Blood monitoring (INR) and dose adjustments required Second generation bisphosphonate OD Fosamax has been available in the US since 1995 and in EU since 1996. The OW Fosamax is also available in all countries except Japan and is the major driver of revenue. The once weekly formulation of Fosamax was developed to alleviate one of the agent’s major side effects: upper GI events such as reflux. 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE New Paradigm: Factor Xa Inhibition XII XI IX VII VIII X Apixaban V II I Fibrin Clot 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

Apixaban is being developed jointly by Pfizer and Bristol Myers Squibb 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

Apixaban: A FXa inhibitor Apixaban is an orally administered, highly potent (Ki=0.08 nM) reversible, direct inhibitor of FXa The direct mechanism of action does not require the presence of antithrombin III Apixaban has a small volume of distribution, good oral absorption, multiple (renal and non-renal) pathways of elimination He K et al. Blood 2006; 108(11): 910 Luettgen JM et al. Blood 2006; 108(11): 4130 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

Apixaban: A FXa inhibitor Mean half-life ~12 hours No food effect Effective in preclinical animal models of venous and arterial thrombosis No organ specific toxicity in animal models of up to 12 months exposure duration He K et al. Blood 2006; 108(11): 910 Luettgen JM et al. Blood 2006; 108(11): 4130 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE CV185057: A SAFETY AND EFFICACY TRIAL EVALUATING THE USE OF APIXABAN FOR THE EXTENDED TREATMENT OF DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

CV185057 Research Hypothesis Apixaban is superior to placebo for extended treatment of subjects who have: An objectively documented index event of symptomatic proximal DVT or symptomatic PE; Completed approximately 6 to 12 months of standard anticoagulant therapy for the treatment of the index event; and No objectively documented symptomatic recurrence of VTE after the index event. 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE CV185057 Study Details Phase 3 Randomized Double blinded Placebo controlled Three parallel treatment groups Stratified by DVT or PE Study Duration: 12 months of treatment 30-day post-treatment follow-up. 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE CV185057 Primary Objective To determine if at least one of the two apixaban doses is superior to placebo in the combined endpoint of: Symptomatic, recurrent VTE (nonfatal DVT or nonfatal PE); or All-cause death 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE CV185057 Primary Outcomes Primary Efficacy: Incidence of an adjudicated composite of recurrent symptomatic VTE (nonfatal DVT and/or nonfatal PE) or all-cause death. Primary Safety: Incidence of adjudicated major bleeding during the treatment period. All suspected thromboembolic events, deaths, episodes of bleeding will be adjudicated. 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

CV185057 Basis for Dose Selection Phase 2 DVT prevention and treatment data Decision based upon empiric experience 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

DVT Prevention: A Proof of Concept Model DVT prevention permitted assessment of a proposed anticoagulant as a “Proof of Concept”, since untreated, >60% of patients undergoing knee replacement will develop venographically apparent DVT Such a study also provided a safety assessment, as the surgical wound is a sensitive predictor of bleeding The combination of high event rates for both VTE and total bleeding permitted an accurate dose ranging study The short term exposure (< 14 days) was appropriate early in phase 2, but limits the inferences that can be made to chronic exposure The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004: 126 (3 Suppl) 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

CV185010 Phase 2 Prevention of VTE in Knee Replacement Surgery Randomized, parallel-arm, double-blind (apixaban and enoxaparin) and open-label (warfarin) Treatments (~150/arm; total N=1238): Apixaban 2.5, 5, and 10 mg bid; 5, 10, and 20 mg qd Enoxaparin 30 mg sc q12h Warfarin titrated to INR 1.8-3.0 Treatment duration: 12+/-2 days (first dose 12-24 hrs post-op) Efficacy endpoint: symptomatic & asymptomatic (by venogram) venous thromboembolism and all-cause death Safety endpoints: Bleeding (major and minor) Lassen M et al. J Thromb Haemost 2007; 5(12): 2368-2375. 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

Venous Thromboembolism/Death CV185010 Results % Venous Thromboembolism/Death Total Bleeding Lowest dose of apix still maintained a 30% RRR compared to enox, the gold standard Event rate with warfarin was similar in previous studies (EXULT-A 27%, EXULT-B 31%) Not a “fair” trial vs warfarin There does appear to be at least a trend of dose response in bleeding (89% of major bleeding at the wound site) No other safety (e.g. LFT) issues raised Daily Dose: 5 10 20 5 10 20 QD BID QD BID QD BID Enox Warf (mg) QD BID QD BID QD BID Enox Warf Lassen M et al. J Thromb Haemost 2007; 5(12): 2368-2375. 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

CV185010: Exposure - Response Modeling & Simulation Total # of subjects = 855 (>90% of apixaban-treated subjects had PK samples) Total # of PK observations = 4694 Feng Y et al. International Society of Thrombosis and Haemostasis; July 2007; Geneva, Switzerland. Poster P-M-663. 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE CV185010 Observed and Fitted Rates for Composite of VTE or Death BID dosing chose for pivotal DVT prevention studies: Potential for superior efficacy vs active comparator BID event rate ~4% lower than QD event rate Bleeding rate potentially lower versus active comparator Feng Y et al. International Society of Thrombosis and Haemostasis; July 2007; Geneva, Switzerland. Poster P-M-663. 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

CV185010 Summary/Implications All doses of apixaban had lower VTE/death rates than either comparator (enoxaparin, warfarin) For any given apixaban daily dose, bid administration had fewer VTE events than qd Bleeding rates showed a dose response trend, and were acceptable The above results supported the “Proof of Concept” of apixaban as an effective anticoagulant with an acceptable safety profile in short term exposure Lassen M et al. J Thromb Haemost 2007; 5(12): 2368-2375. 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

BOTTICELLI (Study CV 185017) 3-month Phase 2 study in DVT treatment N= 520 pts Randomized parallel-arm dose-ranging study with independent, blinded efficacy & safety outcome assessments CUS/PLS CUS/PLS 12 weeks Apixaban 5mg bid 3 D a y s Symptomatic proximal or extensive calf-vein thrombosis without PE 12 weeks Apixaban 10mg bid R 12 weeks Apixaban 20mg od LMWH/Fondaparinux and VKA Buller H et al. A Dose Finding Study of the Oral Direct Factor Xa Inhibitor Apixaban in the Treatment of Patients With Acute Symptomatic Deep Vein Thrombosis. Late Breaking Clinical Trial: 21st Congress of the International Society on Thrombosis and Haemostasis (ISTH). 8 June 2007 Blinded Apixaban / OL Comparator 12 weeks of treatment followed by a 30 day observational period CUS: compression ultrasound PLS: perfusion lung scan 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

BOTTICELLI (Study CV 185017) Results Buller H et al. A Dose Finding Study of the Oral Direct Factor Xa Inhibitor Apixaban in the Treatment of Patients With Acute Symptomatic Deep Vein Thrombosis. Late Breaking Clinical Trial: 21st Congress of the International Society on Thrombosis and Haemostasis (ISTH). 8 June 2007 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

BOTTICELLI (Study CV 185017) Incidence of Symptomatic VTE LMWH/VKA Buller H et al. Late Breaking Clinical Trial: 21st Congress of the International Society on Thrombosis and Haemostasis (ISTH). 8 June 2007. Lagerstedt CI et al. Lancet, 1985; 515-518. Hull R et al. NEJM, 1979; 301:855-858 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

BOTTICELLI Study (CV185017) Conclusions/Implications Rates of symptomatic VTE events were comparable across all apixaban dosing regimens studied and to LMWH/VKA Rates of adjudicated major or clinically relevant non-major bleeding were comparable across all apixaban dosing regimens studied and similar to LMWH/VKA Chronic exposure to apixaban was not associated with any appreciable liver function test abnormality or other significant laboratory abnormality Buller H et al. A Dose Finding Study of the Oral Direct Factor Xa Inhibitor Apixaban in the Treatment of Patients With Acute Symptomatic Deep Vein Thrombosis. Late Breaking Clinical Trial: 21st Congress of the International Society on Thrombosis and Haemostasis (ISTH). 8 June 2007 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

Previous Extended VTE Treatment Studies STUDY POPULATION COMPARISON DUR %VTE* %MB DEATHS* (DRUG/COMPARATOR) % PE CV Bleed Ca Other PREVENT DVT or PE rx 6.5 mos Warfarin 1.5-2.0 Placebo 2.4 yr (mean) 2.6 7.2 0.9 0.4 0.7 1.4 2 --- 1 4 5 THRIVE III DVT or PE rx 6 mos Ximelagatran 36 BID 18 mo 2.8 12.6 1.1 1.3 3 VAN GOGH Extension DVT or PE rx 6 mos Idraparinux 6 mo 3.7 1.9 1.5 0.6 ELATE DVT or PE rx ≥3 mo for unprovoked Warfarin INR 2.0-3.0 Warfarin INR 1.5-1.9 2.1 yr (mean) 7 8 DB: Double-Blind DTI: Direct Thrombin Inhibitor DUR: Duration MB: Major Bleeding PE: Pulmonary embolism rx: Previous treatment duration VTE: Venous thromboembolism (symptomatic, nonfatal DVT or nonfatal PE) ---: Not reported *: Annual rate (except VAN GOGH Extension [6 mo] and Thrive III [18 mo] PREVENT. NEJM 2003; 348: 1425-1434. THRIVE III. NEJM 2003: 349:1713-1721. VAN GOGH Ext. Blood 2006; 108:172A. ELATE. NEJM 2003; 349:631-639. 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

Uniqueness of Apixaban Development Program All phase 3 studies are double-blind, randomized trials for all indications: VTE prevention, VTE treatment, and Atrial fibrillation These studies individually and overall should provide unbiased data of the highest scientific quality 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE CV185057 12-Month Double-Blind Placebo-Controlled Extended Treatment Study Placebo BID n~810 DVT/PE subjects who have completed 6-12 mos of standard anti-coagulant rx End of Treatment 30-Day Follow-up n~810 Apixaban 2.5 mg BID R Apixaban 5 mg BID n~810 Day 1 12 Mo 30 Days N based on power 90% to detect superiority of apixaban to placebo (~60% RRR) using two-sided alpha=0.025 for comparing each apixaban arm to placebo. Study ends after all subjects have completed 12 months of treatment. …2,430 subjects planned… 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

CV185057 Apixaban Dose Selection Clinical uncertainty regarding which dose provides the best balance of efficacy and safety Therefore, two doses selected 5 mg bid: same dose for initial DVT/PE treatment (CV185056) 2.5 mg bid: same dose for pivotal VTE prevention studies 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

Rationale for Placebo Control Previous extended treatment studies have suggested a potential benefit. However, none of the studies has included a placebo-controlled trial of an approved drug. There is no approved alternative therapy available currently for such patients. Therefore, placebo is an appropriate comparator for this study. 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

CV185057 Key Inclusion Criteria Subjects must have an objectively documented index event of symptomatic proximal DVT or symptomatic PE. Subjects must have completed approximately 6 to 12 months of standard anticoagulant therapy for the treatment of the index event; and no objectively documented symptomatic recurrence of VTE after the index event. In order to ensure entry of appropriate study subjects, the index DVT or PE will be adjudicated. 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

CV185057 Key Exclusion Criteria Subjects will be excluded if they are intended for long-term treatment with a vitamin K antagonist, such as: Mechanical valve Atrial fibrillation or atrial flutter with moderate to high risk of systemic thromboembolism Multiple episodes of unprovoked DVT or PE Documented anti-phospholipid antibodies, anti-thrombin III deficiency, protein C deficiency, protein S deficiency, homozygous factor V Leiden, or homozygous prothrombin. 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

CV185057 Key Exclusion Criteria Subjects whose index DVT or index PE was due solely to a transient (reversible) risk factor (i.e. provoked event, e.g. secondary to surgery). Subjects with cancer who will be treated indefinitely with anticoagulation therapy are ineligible for this study. 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE CV185057 Subject Safety Regular assessments and clinical laboratory monitoring will be performed during the study. Subjects will not be charged for these services. 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

CV185057 Committees Internationally recognized experts Steering Committee Responsible for ensuring that the study design, execution and management are of the highest quality. Independent Data Monitoring Committee Responsible for ongoing review of the safety of all investigational treatments and to ensure the study has acquired adequate information to address the primary objectives Independent Central Adjudication Committee Will adjudicate the index events Will adjudicate all suspected venous or arterial thromboembolic events, all deaths, and all episodes of suspected bleeding 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE

CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE Discussion 07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE