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, PhDPopulation Health Research Institute Lankenau Institute for Medical ResearchMcMaster University Thomas Jefferson Medical CollegeHamilton, Ontario, Canada Wynnewood, Pennsylvania, United States

Rafael Diaz, MD Stefan H. Hohnloser, MD, FESC, FACCDept. of Cardiology and Clinical Research Dept. of Clinical ElectrophysiologyInstituto Cardiovascular de Rosario Johann Wolfgang Goethe UniversityRosario, Argentina Frankfurt, Germany

Paul Dorian, MDDept. of MedicineUniversity of Toronto Toronto, Ontario, Canada

Study Sponsored by Portola Pharmaceuticals, Inc. and MerckStudy Sponsored by Portola Pharmaceuticals, Inc. and Merck1

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

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

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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

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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.

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.

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.

N=561Patients Screened

N=508Patients Randomized

N=53Patients Not Randomized

N=0Did Not Receive Study Medication

N=508Received Study Medication

N=127Betrixaban 40 mg

N=127Betrixaban 60 mg

N=127Betrixaban 80 mg

N=127Open-Label Warfarin

N=11Prematurely Withdrawn

Patient Request / Withdrew Consent = 4

Adverse Event = 5Death = 1

Investigator Decision = 1

N=12Prematurely Withdrawn

Patient Request / Withdrew Consent = 2

Adverse Event = 6Endpoint = 1

Investigator Decision = 2Other Reason = 1

N=11Prematurely Withdrawn

Patient Request / Withdrew Consent = 4

Adverse Event = 3Endpoint = 1

Other Reason = 3

N=8Prematurely Withdrawn

Patient Request / Withdrew Consent = 1

Adverse Event = 1Endpoint = 2

Death = 1Other Reason = 3

N=116Completed

N=115Completed

N=116Completed

N=119Completed

Patient Disposition and Follow-Up

•Minimum follow-up 3 months; Maximum 12 months; Median 147 days

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Baseline Characteristics of Patients

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All Betrixaban Warfarin TotalN=381 N=127 N=508

Median Age (years) 74 74 74Age 75 years 180 (47.2%) 60 (47.2%) 240 (47.2%)Male 249 (65.4%) 89 (70.1%) 338 (66.5%)White 371 (97.4%) 126 (99.2%) 497 (97.8%)Weight > 90 kg 172 (45.1%) 62 (48.8%) 234 (46.1%)Country US 276 (72.4%) 93 (73.2%) 369 (72.6%) Canada 95 (24.9%) 32 (25.2%) 127 (25.0%) Germany 10 (2.6%) 2 (1.6%) 12 (2.3%)

Baseline CHADS2 Score* 0-1 107 (28.1%) 37 (29.1%) 144 (28.3%) 2 152 (39.9%) 42 (33.1%) 194 (38.2%) 3-6 122 (32.0%) 48 (37.8%) 170 (33.5%)

Mean CHADS2 Score - - 2.2Baseline GFR (Cockcroft-Gault) < 40 mL/min 35 (9.2%) 6 (4.7%) 41 (8.1%) 40-70 mL/min 147 (38.6%) 48 (37.8%) 195 (38.4%) > 70 mL/min 199 (52.2%) 73 (57.5%) 272 (53.5%)Concurrent Aspirin Use < 162 mg 147 (38.6%) 49 (38.6%) 196 (38.6%)No Vitamin K Antagonist Experience 48 (12.6%) 18 (14.2%) 66 (13.0%)

≥≥

Major Bleeding or Clinically Relevant Non-Major Bleeding

Days of Follow-up

Cu

mu

lativ

e H

aza

rd R

ate

s

0.0

0.0

50

.10

0.1

5

0 50 100 150 200

Betrix LowBetrix MedBetrix HighWarfarin

# at Risk 30 60 90 120 150 180 210BLowBMedBHigWarf

127 124 121 109 77 56 32 18127 125 119 116 76 57 33 21127 123 120 111 71 50 30 18127 127 126 107 72 54 24 13

Time to Major Bleeding or Clinically Relevant Non-Major Bleeding

3 months minimum f/u3 months minimum f/u

10* Overall TTR = 64%* Overall TTR = 64%

Bleeds at 12 weeks, strokes and deaths

+ Cardiovascular death (Reported as MI. Not adjudicated as MI per CEC) after 29 days on treatment

++ Cardiovascular death (CHF) after 108 days on treatment

+ ++

Strokes after 35 days and 54 days on treatment for B60 and B80 respectively

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Change from Baseline

B 40mg B 60mg B 80mg W

-0.15

-0.10

-0.05

-0.00

0.05

0.10

0.15

D-D

imer

(u

g/m

L F

EU

)

D-Dimer (Change from Baseline)

p=0.003*p=0.003* p=0.062*p=0.062*

p=0.166*p=0.166*

*vs. warfarin (Kruskal-Wallis test)*vs. warfarin (Kruskal-Wallis test) 12

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

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Type of G-I Adverse Events by Treatment

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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

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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