Background Design

07 May 2008 CONFIDENTIAL--DO NOT REPRODUCE OR DISTRIBUTE 1

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.


Agenda

• Background

• Clinical need

• CV185057 design

• Discussion


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.


Fibrin Clot

Current Standard Low Molecular Weight Heparin

XII

VIIVIII

IX

XI

II

V

X

I

Enoxaparin

Intrinsic

Extrinsic


Fibrin Clot

Current Standard

Vitamin K AntagonistXII

VIIVIII

IX

XI

II

V

X

I

6 hrs

60 hrs

24 hrs

36 hrs

Warfarin

Factor Half-lives


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.


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

The Clinical Need …current therapies are effective but have limitations…


Fibrin Clot

New Paradigm: Factor Xa InhibitionXII

VIIVIII

IX

XI

II

V

X

I

Apixaban


Apixaban is being developed jointly by Pfizer and Bristol Myers Squibb


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


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


CV185057: A SAFETY AND EFFICACY TRIAL EVALUATING THE USE OF APIXABAN FOR THE EXTENDED TREATMENT OF DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM


CV185057Research 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.


• 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.

CV185057Study Details


• 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

CV185057Primary Objective


• 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.

CV185057Primary Outcomes


CV185057Basis for Dose Selection

• Phase 2 DVT prevention and treatment data

• Decision based upon empiric experience


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)


CV185010Phase 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.


0

5

10

15

20

25

30

35

40Venous Thromboembolism/Death Total Bleeding

Daily Dose: 5 10 20 5 10 20 QD BID QD BID QD BID QD BID QD BID QD BID Enox Warf Enox Warf

%

(mg)

CV185010Results



CV185010: Exposure - Response Modeling & Simulation

AUCss (ng*hr/mL)C

linic

al O

utco

me

(%Su

bjec

ts w

ith E

vent

)0 5000 10000 15000

05

1015

2025

30

Safety

BID

QD

AUCss (ng*hr/mL)

Clin

ical

Out

com

e (%

Subj

ects

with

out E

vent

)

0 5000 10000 15000

7075

8085

9095

100

Efficacy

BID

QD

• 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.


CV185010Observed and Fitted Rates for Composite of VTE or Death

CV185010: Observed and Fitted VTE/Death Rates

0

2

4

6

8

10

12

14

5 10 20

Total Apixaban Daily Dose (mg)

VT

E/D

eath

Rat

e (%

)

Observed QD

Observed BID

Fitted QD

Fitted BID

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.


CV185010Summary/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



LMWH/Fondaparinux and VKA LMWH/Fondaparinux and VKA

CUS/PLS

12 weeks Apixaban 5mg bid12 weeks Apixaban 5mg bid

CUS/PLS

Symptomatic proximal or extensive calf-vein

thrombosis without PE

•Blinded Apixaban / OL Comparator •12 weeks of treatment followed by a 30 day observational period

Randomized parallel-arm dose-ranging study Randomized parallel-arm dose-ranging study with independent, blinded efficacy & safety outcome with independent, blinded efficacy & safety outcome assessmentsassessments

12 weeks Apixaban 20mg od12 weeks Apixaban 20mg od

12 weeks Apixaban 10mg bid12 weeks Apixaban 10mg bid

CUS: compression ultrasound PLS: perfusion lung scan

BOTTICELLI (Study CV 185017)3-month Phase 2 study in DVT treatment N= 520 pts

R

3300

DDaayyss

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


BOTTICELLI (Study CV 185017) Results

Apixaban Apixaban Apixaban LMWH

5 mg BID 10 mg BID 20 mg BID and VKA

n=117 n=125 n=116 n=118

Fatal PE 0 0 1 0Non-fatal PE 0 0 0 1Symptomatic DVT 3 4 1 2Total Symptomatic VTE 3 4 2 3Major bleeding (%, n) 0.8 (1) 0.0 (0) 0.8 (1) 0.0 (0)MB + CSNMB (%, 95 CI) 8.6 [4.4,14.9] 4.5 [1.7,9.6] 7.3 [3.4,13.3] 7.9 [3.9, 14.1]ALT ≥ 3x ULN (%, n) 0.8 (1) 0.0 (0) 2.5 (3) 1.6 (2)



BOTTICELLI (Study CV 185017) Incidence of Symptomatic VTE

LMWH/VKA

2.6 3.2 1.7 2.54.8

25.728.6

52.6

0

10

20

30

40

50

60

Apixaban5 mg BID

Apixaban10 mg BID

Apixaban20 mg QD

LMWH /VKA

Cochrane2001

Hull 1979

Lagerstedt1985

Barritt 1960

Inc

ide

nc

e (

%)

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


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



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

0

2

---

---

0

1

---

---

4

5

THRIVE III DVT or PE rx 6 mos

Ximelagatran 36 BID

Placebo

18 mo 2.8

12.6

1.1

1.3

1.1

1.4

0

3

1

1

0

0

2

3

3

0

VAN GOGH Extension

DVT or PE rx 6 mos

Idraparinux

Placebo

6 mo 1

3.7

1.9

0

1.5

0.6

2

1

---

---

3

0

2

2

2

1

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)

0.7

1.9

0.9

1.1

0.9

1.9

2

1

---

---

---

---

1

7

5

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.


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


CV18505712-Month Double-Blind Placebo-Controlled Extended Treatment Study

•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…

DVT/PE subjects who have completed 6-12 mos of standard anti-coagulant rx

R

En

d o

f T

reat

men

t

30-D

ay F

oll

ow

-upPlacebo BID

Apixaban 2.5 mg BID

Apixaban 5 mg BID

Day 1 12 Mo

n~810

n~810

n~810

30 Days


CV185057Apixaban 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


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.


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.


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.


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.


CV185057Subject Safety

• Regular assessments and clinical laboratory monitoring will be performed during the study.

• Subjects will not be charged for these services.


CV185057Committees 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


Discussion

Documents

Background Design