ezekowitz explore
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 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
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
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
8
Baseline Characteristics of Patients
9
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
11
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
13
Type of G-I Adverse Events by Treatment
14
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
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
16*By number of patients contributed