Transcript EXPLORE-Xa
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 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. 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 7 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% 8 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% 9 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 12 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 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 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 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 Dr. Alexander Graham G. Turpie (Chairman) Prof. Robin Roberts Dr. Jonathan Halperin Dr. Ken Bauer 15