Presentation on theme: "EXPLORE-Xa A Phase 2, Randomized, Parallel Group, Dose Finding, Multicenter, Multinational Study of the Safety, Tolerability and Pilot Efficacy of Three."— Presentation transcript:
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 InstituteLankenau Institute for Medical Research McMaster UniversityThomas Jefferson Medical College Hamilton, Ontario, CanadaWynnewood, Pennsylvania, United States Rafael Diaz, MDStefan H. Hohnloser, MD, FESC, FACC Dept. of Cardiology and Clinical ResearchDept. of Clinical Electrophysiology Instituto Cardiovascular de RosarioJohann Wolfgang Goethe University Rosario, ArgentinaFrankfurt, 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 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.
ALT Elevations (in % of Patients) BetrixabanWarfarin >2x ULN2.4 >3x ULN >5x ULN >10x ULN Consecutive elevations 3xULN No Hys 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