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 DoseAdjusted Warfarin in Patients With Non-Valvular Atrial
Fibrillation (EXPLORE-Xa)
Steering Committee
Stuart J. Connolly, MD, FRCPC (Chairman)
Population Health Research Institute
McMaster University
Hamilton, Ontario, Canada
Michael D. Ezekowitz, MD, PhD
Lankenau Institute for Medical Research
Thomas Jefferson Medical College
Wynnewood, Pennsylvania, United States
Rafael Diaz, MD
Dept. of Cardiology and Clinical Research
Instituto Cardiovascular de Rosario
Rosario, Argentina
Stefan H. Hohnloser, MD, FESC, FACC
Dept. of Clinical Electrophysiology
Johann Wolfgang Goethe University
Frankfurt, Germany
Paul Dorian, MD
Dept. of Medicine
University of Toronto
Toronto, Ontario, Canada
Study Sponsored by Portola Pharmaceuticals, Inc. and Merck
1
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
3
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=508
Patients Randomized
N=53
Patients Not Randomized
N=127
Betrixaban 40 mg
N=127
Betrixaban 60 mg
N=127
Betrixaban 80 mg
N=127
Open-Label Warfarin
N=116
Completed
N=115
Completed
N=116
Completed
N=119
Completed
•Minimum follow-up 3 months; Maximum 12 months;
•Median 4.9 months
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Baseline Characteristics of Patients
Median Age (years)
Age ≥75 years
Male
White
Weight > 90 kg
Country
US
Canada
Germany
Baseline CHADS2 score
0-1
2
3-6
Mean CHADS2 score
Baseline GFR (Cockcroft-Gault)
< 40 mL/min
40-70 mL/min
> 70 mL/min
Concurrent Aspirin Use < 162 mg
No Vitamin K Antagonist Experience
All Betrixaban
N=381
74
47.2%
65.4%
97.4%
45.1%
Warfarin
N=127
74
47.2%
70.1%
99.2%
48.8%
Total
N=508
74
47.2%
66.5%
97.8%
46.1%
72.4%
24.9%
2.6%
73.2%
25.2%
1.6%
72.6%
25.0%
2.3%
28.1%
39.9%
32.0%
-
29.1%
33.1%
37.8%
-
28.3%
38.2%
33.5%
2.2
9.2%
38.6%
52.2%
38.6%
12.6%
4.7%
37.8%
57.5%
38.6%
14.2%
8.1%
38.4%
53.5%
38.6%
13.0%
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0.10
Betrix Low
Betrix Med
W
*P=0.035
0.05
Betrix High
Warfarin
80
60
40
0.0
Cumulative Hazard Rates
0.15
Major Bleeding or Clinically Relevant
Non-Major Bleeding
0
50
100
150
200
Days of Follow-up
Overall TTR = 64%
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Bleeds, strokes and deaths
8
Major+CRNM
Strokes
Deaths
7
7
# of Patients
6
5
5
5
4
3
2
1
1
1
1
1
B60
B80
1
0
B40
W
10
D-Dimer (Change from Baseline)
Change from Baseline
D-Dimer (ug/mL FEU)
0.15
p=0.003*
0.10
0.05
-0.00
-0.05
-0.10
-0.15
B 40mg
*vs. warfarin (Kruskal-Wallis test)
B 60mg
B 80mg
W
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
-No Hy’s law cases
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Type of G-I Adverse Events by Treatment
Percentage of patients
Vomiting
Abdominal Pain
W
Dyspepsia
B80
Nausea
B60
B40
Constipation
Diarrhoea
0
2
4
6
8
10
12
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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*
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Cossu, Sergio
Vicari, Ralph M.
Teixeira, Jose
O'Dea, Daniel
Weiss, Robert
Henderson, David
Fialkow, Jonathan
Pesant, Yves
Promisloff, Steven
Gogia, Harinder
Bakbak, Asaad
Goldstein, Mark
Blonder, Ronald
Kouz, Simon
Ezekowitz, Michael
Herzog, William
Teitelbaum, Ivor
Bose, Sabyasachi
Constance, Christian
Bertolet, MD, Barry
USA
USA
USA
USA
USA
USA
USA
Canada
USA
USA
Canada
USA
USA
Canada
USA
USA
Canada
Canada
Canada
USA
*By number of patients contributed
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Coutu, Benoit
Hotchkiss, David
O'Hara, Gilles
Chodnicki, Dennis
Boucher, Pierre Jr.
Burstein, Jason
Gill, Santosh
Horacek, Thomas
Aycock, G. Ramon
Dorian, Paul
Hartmann, Franz
Labovtiz, Arthur
Morillo, Carlos
Butter, Christian
Rebane, Thomas
Canada
USA
Canada
USA
Canada
Canada
USA
Germany
USA
Canada
Germany
USA
Canada
Germany
Canada
 DSMC members
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Dr. Alexander Graham G. Turpie (Chairman)
Prof. Robin Roberts
Dr. Jonathan Halperin
Dr. Ken Bauer
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