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 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 • Flat diurnal peak/trough profile • ~20 h PD or “effective” half-life • No dose adjustment expected for renal impairment • Excreted mostly unchanged through bile with minimal renal excretion (<5%) • No major drug interactions expected • Not substrate for CYP450 system • Substrate for efflux proteins including P-glycoprotein • Antidote in development

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. Inclusion Criteria • Male or female, age ≥ 18 years. • AF at the time of enrollment (randomization) or documented within the last year. • At least one risk factor for stroke.

6. Exclusion Criteria • Weight less than 40 kg (88 lbs). • Need for either hemodialysis or peritoneal dialysis within one year. • AF due to reversible causes. • Mechanical prosthetic valve. • Conditions other than AF that require chronic anticoagulation. • 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. Exclusion Criteria (continued) • Severe co-morbid condition with life expectancy of ≤ 1 year. • Platelet count < 100,000/mm3. • Serum alanine aminotransferase (ALT) or aspirate aminotransferase (AST) > 2.5 times ULN. • A history (including family history) of “Long QT Syndrome”. • Aspirin > 162 mg daily. • Use of verapamil (pending the availability of a drug interaction study with betrixaban). • Use of an investigational drug or device within the past 30 days. • Inability to comply with INR monitoring. • Unable to give written informed consent.

8. Patient Disposition and Follow-Up • Minimum follow-up 3 months; Maximum 12 months; Median 147 days

9. ≥ Baseline Characteristics of Patients

10. Major Bleeding or Clinically Relevant Non-Major Bleeding 3 months minimum f/u * Overall TTR = 64%

11. Bleeds at 12 weeks, strokes and deaths + ++ Strokes after 35 days and 54 days on treatment for B60 and B80 respectively + Cardiovascular death (Reported as MI. Not adjudicated as MI per CEC) after 29 days on treatment ++ Cardiovascular death (CHF) after 108 days on treatment

12. D-Dimer (Change from Baseline) p=0.166* p=0.003* p=0.062* *vs. warfarin (Kruskal-Wallis test)

13. ALT Elevations (in % of Patients)

14. Type of G-I Adverse Events by Treatment

15. Conclusions • In the diverse patient population studied there was a dose and concentration dependent effect on the primary endpoint of major and clinically relevant non-major bleeding • Bleeding at 60 and 80 mg comparable to that on 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 • Larger studies will have to determine the full efficacy and safety of betrixaban

16. 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 16 *By number of patients contributed