Steering Committee

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)

• 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, 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

• Michael D. Ezekowitz, MD, PhD

• Consultant for Portola and Merck
• Received grant support from Portola
• Has a sibling employed by Merck

Orally-active and selective fXa inhibitor

• 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

Primary Objective

• 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

Male or female, age ≥ 18 years.

• 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.

Need for renal dialysis within one year.

• 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.

Bleeding was significantly less for betrixaban 40 mg vs.warfarin

• 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

Study Investigators*

• 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