EXPLORE-Xa

A Phase 2, Randomized, Parallel Group, Dose‑Finding, Multicenter, Multinational Study of the Safety, Tolerability and Pilot Efficacy of Three Blinded Doses of the Oral Factor Xa Inhibitor Betrixaban Compared With Open‑Label Dose-Adjusted Warfarin in Patients With Non-Valvular Atrial Fibrillation (EXPLORE-Xa)

Steering Committee

Stuart J. Connolly, MD, FRCPC (Chairman) Michael D. Ezekowitz, MD, PhDPopulation Health Research Institute Lankenau Institute for Medical ResearchMcMaster University Thomas Jefferson Medical CollegeHamilton, Ontario, Canada Wynnewood, Pennsylvania, United States

Rafael Diaz, MD Stefan H. Hohnloser, MD, FESC, FACCDept. of Cardiology and Clinical Research Dept. of Clinical ElectrophysiologyInstituto Cardiovascular de Rosario Johann Wolfgang Goethe UniversityRosario, Argentina Frankfurt, Germany

Paul Dorian, MDDept. of MedicineUniversity of Toronto Toronto, Ontario, Canada

Study Sponsored by Portola Pharmaceuticals, Inc. and MerckStudy Sponsored by Portola Pharmaceuticals, Inc. and Merck1

Disclosures

Michael D. Ezekowitz, MD, PhD Consultant for Portola and Merck Received grant support from Portola Has a sibling employed by Merck

Characteristics of Betrixaban

Orally-active and selective fXa inhibitor Oral bioavailability 34%, Ki 117 pM

Peak to trough concentration profile 2.5 : 1

~20 hour effective half-life

No dose adjustment expected for renal impairment Excreted mostly unchanged through bile with minimal renal

excretion (<5%)

Antidote in development No major drug interactions expected

Not substrate for CYP450 system Substrate for efflux proteins including P-glycoprotein

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Study Objectives

Primary Objective Safety and tolerability of oral betrixaban at doses of 40, 60 and

80 mg once a day compared with dose-adjusted warfarin in patients with non-valvular atrial fibrillation or atrial flutter

Primary Endpoint• Time to major and clinically relevant non-major bleeding

Secondary Endpoints• Time to any bleeding, death, stroke, MI or systemic embolism

Secondary Objective Pharmacokinetics (PK) and pharmacodynamics (PD) of

betrixaban

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Main Inclusion Criteria

Male or female, age ≥ 18 years.

AF at the time of enrollment or documented within the last year.

At least one risk factor for stroke.

Main Exclusion Criteria

Need for renal dialysis within one year.

AF due to reversible causes, mechanical prosthetic valve.

SBP > 160 mmHg on repeated measurements.

Active infective endocarditis.

Scheduled major surgery, pulmonary vein ablation.

Recent ischemic stroke, systemic embolic event or acute coronary syndrome within 30 days.

N=561Patients Screened

N=508Patients Randomized

N=53Patients Not Randomized

N=127Betrixaban 40 mg

N=127Betrixaban 60 mg

N=127Betrixaban 80 mg

N=127Open-Label Warfarin

N=116Completed

N=115Completed

N=116Completed

N=119Completed

Patient Disposition and Follow-Up

•Minimum follow-up 3 months; Maximum 12 months;

•Median 4.9 months7

Baseline Characteristics of Patients

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All Betrixaban Warfarin TotalN=381 N=127 N=508

Median Age (years) 74 74 74Age ≥75 years 47.2% 47.2% 47.2%Male 65.4% 70.1% 66.5%White 97.4% 99.2% 97.8%Weight > 90 kg 45.1% 48.8% 46.1%Country US 72.4% 73.2% 72.6% Canada 24.9% 25.2% 25.0% Germany 2.6% 1.6% 2.3%Baseline CHADS2 score 0-1 28.1% 29.1% 28.3% 2 39.9% 33.1% 38.2% 3-6 32.0% 37.8% 33.5%Mean CHADS2 score - - 2.2Baseline GFR (Cockcroft-Gault) < 40 mL/min 9.2% 4.7% 8.1% 40-70 mL/min 38.6% 37.8% 38.4% > 70 mL/min 52.2% 57.5% 53.5%Concurrent Aspirin Use < 162 mg 38.6% 38.6% 38.6%No Vitamin K Antagonist Experience 12.6% 14.2% 13.0%

Major Bleeding or Clinically Relevant Non-Major Bleeding

9Overall TTR = 64%Overall TTR = 64%

Days of Follow-up

Cum

ulat

ive

Haz

ard

Rat

es

0.0

0.0

50

.10

0.1

5

0 50 100 150 200

Warfarin

WBetrix Med

60

Betrix High

80

Betrix Low

40

*P=0.035

Bleeds, strokes and deaths

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Change from Baseline

B 40mg B 60mg B 80mg W

-0.15

-0.10

-0.05

-0.00

0.05

0.10

0.15

D-D

imer

(ug

/mL

FE

U)

D-Dimer (Change from Baseline)

p=0.003*p=0.003*

*vs. warfarin (Kruskal-Wallis test)*vs. warfarin (Kruskal-Wallis test) 11

ALT Elevations (in % of Patients)

Betrixaban Warfarin

>2x ULN 2.4 2.4

>3x ULN 1.8 0.8

>5x ULN 0.5 0.8

>10x ULN 0.3 0.0

Consecutive elevations ≥ 3xULN

0.5 0.8

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-No Hy’s law cases -No Hy’s law cases

Type of G-I Adverse Events by Treatment

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Conclusions

Bleeding was significantly less for betrixaban 40 mg vs.warfarin

Bleeding at 60 and 80 mg was comparable to warfarin The number of strokes were within the range expected

for warfarin (0-1 per group) All 3 doses were well tolerated D-dimer shows activity across dose spectrum with a

trend toward a dose response Compared to well-treated experienced warfarin patients

there was a dose dependent effect on the primary endpoint of major and clinically relevant non-major bleeding

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Study Investigators and DSMC Study Investigators* Cossu, Sergio USA   Vicari, Ralph M. USA   Teixeira, Jose USA   O'Dea, Daniel USA   Weiss, Robert USA   Henderson, David USA   Fialkow, Jonathan USA   Pesant, Yves Canada   Promisloff, Steven USA   Gogia, Harinder USA   Bakbak, Asaad Canada   Goldstein, Mark USA   Blonder, Ronald USA   Kouz, Simon Canada   Ezekowitz, Michael USA   Herzog, William USA   Teitelbaum, Ivor Canada   Bose, Sabyasachi Canada   Constance, Christian Canada Bertolet, MD, Barry USA  

Coutu, Benoit Canada   Hotchkiss, David USA   O'Hara, Gilles Canada   Chodnicki, Dennis USA   Boucher, Pierre Jr. Canada   Burstein, Jason Canada   Gill, Santosh USA   Horacek, Thomas Germany   Aycock, G. Ramon USA   Dorian, Paul Canada   Hartmann, Franz Germany Labovtiz, Arthur USA Morillo, Carlos Canada   Butter, Christian Germany   Rebane, Thomas Canada

DSMC members Dr. Alexander Graham G. Turpie (Chairman) Prof. Robin Roberts Dr. Jonathan Halperin Dr. Ken Bauer

15*By number of patients contributed