EXPLORE-Xa

A Phase 2, Randomized, Parallel Group, DoseFinding,

Multicenter, Multinational Study of the Safety, Tolerability and
Pilot Efficacy of Three Blinded Doses of the Oral Factor Xa
Inhibitor Betrixaban Compared With OpenLabel Dose-
Adjusted Warfarin in Patients With Non-Valvular Atrial
Fibrillation (EXPLORE-Xa)
Steering Committee
Stuart J. Connolly, MD, FRCPC (Chairman) Michael D. Ezekowitz, MD, PhD
Population Health Research Institute Lankenau Institute for Medical Research
McMaster University Thomas Jefferson Medical College
Hamilton, Ontario, Canada Wynnewood, Pennsylvania, United States
Rafael Diaz, MD Stefan H. Hohnloser, MD, FESC, FACC
Dept. of Cardiology and Clinical Research Dept. of Clinical Electrophysiology
Instituto Cardiovascular de Rosario Johann Wolfgang Goethe University
Rosario, Argentina Frankfurt, Germany
Paul Dorian, MD
Dept. of Medicine
University of Toronto
Toronto, Ontario, Canada

Study Sponsored by Portola Pharmaceuticals, Inc. and Merck

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 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.
 Patient Disposition and Follow-Up
N=561
Patients Screened

N=53
N=508 Patients Not Randomized
Patients Randomized

N=127 N=127 N=127 N=127

Betrixaban 40 mg Betrixaban 60 mg Betrixaban 80 mg Open-Label Warfarin

N=116 N=115 N=116 N=119

Completed Completed Completed Completed

Minimum follow-up 3 months; Maximum 12 months;

Median 4.9 months 7
 Baseline Characteristics of Patients
All Betrixaban Warfarin Total
N=381 N=127 N=508
Median Age (years) 74 74 74
Age 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 - - 2.2
Baseline 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% 8
No Vitamin K Antagonist Experience 12.6% 14.2% 13.0%
 Major Bleeding or Clinically Relevant
Non-Major Bleeding
0.15
Cumulative Hazard Rates
0.10

Betrix Low
Betrix Med *P=0.035 W
Betrix High
Warfarin
0.05

80
60
40
0.0

0 50 100 150 200

Days of Follow-up

Overall TTR = 64% 9

Bleeds, strokes and deaths

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 D-Dimer (Change from Baseline)

Change from Baseline

0.15 p=0.003*
D-Dimer (ug/mL FEU)

0.10

0.05

-0.00

-0.05

-0.10

-0.15

B 40mg B 60mg B 80mg W

*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 0.5 0.8

elevations 3xULN

-No Hys law cases

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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* Coutu, Benoit Canada
Cossu, Sergio USA Hotchkiss, David USA
Vicari, Ralph M. USA O'Hara, Gilles Canada
Teixeira, Jose USA Chodnicki, Dennis USA
O'Dea, Daniel USA Boucher, Pierre Jr. Canada
Weiss, Robert USA Burstein, Jason Canada
Henderson, David USA Gill, Santosh USA
Fialkow, Jonathan USA Horacek, Thomas Germany
Pesant, Yves Canada
Aycock, G. Ramon USA
Promisloff, Steven USA
Dorian, Paul Canada
Gogia, Harinder USA
Hartmann, Franz Germany
Bakbak, Asaad Canada
Labovtiz, Arthur USA
Goldstein, Mark USA
Morillo, Carlos Canada
Blonder, Ronald USA
Butter, Christian Germany
Kouz, Simon Canada
Rebane, Thomas Canada
Ezekowitz, Michael USA
Herzog, William USA
Teitelbaum, Ivor Canada DSMC members
Bose, Sabyasachi Canada Dr. Alexander Graham G. Turpie (Chairman)
Constance, Christian Canada Prof. Robin Roberts
Bertolet, MD, Barry USA Dr. Jonathan Halperin
Dr. Ken Bauer

*By number of patients contributed 15