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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
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
4
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
8
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
10
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
12
-No Hy’s law cases -No Hy’s law cases
Type of G-I Adverse Events by Treatment
13
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
14
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