EXPLORE-Xa

1. 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 Study Sponsored by Portola Pharmaceuticals, Inc. and Merck

2. Disclosures • Michael D. Ezekowitz, MD, PhD • Consultant for Portola and Merck • Received grant support from Portola • Has a sibling employed by Merck

3. 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

4. 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

5. 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.

6. 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.

7. 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 Patient Disposition and Follow-Up • Minimum follow-up 3 months; Maximum 12 months; • Median 4.9 months

8. All Betrixaban Warfarin Total N=381 N=127 N=508 Median Age (years) 74 74 74 47.2% Age ≥75 years 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% - - 2.2 Mean CHADS2 score Baseline 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% Baseline Characteristics of Patients

9. Major Bleeding or Clinically Relevant Non-Major Bleeding Betrix Low Betrix Med Betrix High 0.15 0.10 W *P=0.035 Cumulative Hazard Rates 0.05 Warfarin 80 60 0.0 40 0 50 100 150 200 Days of Follow-up Overall TTR = 64% 9

10. Bleeds, strokes and deaths

11. D-Dimer (Change from Baseline) p=0.003* *vs. warfarin (Kruskal-Wallis test)

12. ALT Elevations (in % of Patients) -No Hy’s law cases

13. Type of G-I Adverse Events by Treatment

14. 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

15. 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