Novel Strategies to Prevent Pulmonary Embolism and DVT: APEX Trial and Substudies

C. Michael Gibson, M.S., M.D.Professor of Medicine

Harvard Medical School

There WILL be off-label and/or investigational discussion in this presentation.

Conflict of Interest StatementPresent Research/Grant Funding

Angel Medical Corporation Bayer Corp.CSL BehringGoogleIkaria, Inc.Janssen PharmaceuticalsJohnson & Johnson Corporation Portola PharmaceuticalsStealth Peptides, Inc.St. Jude Medical

Consultant(all with moderate support)

Boston Clinical Research InstituteCardiovascular Research FoundationCSL BehringGilead Sciences, Inc.The Medicines CompanyNovo NordiskPfizerSt. Jude MedicalWeb MD

Consultant (with $0.00 monies received by Dr. Gibson)

Bayer CorporationJanssen PharmaceuticalsJohnson & Johnson CorporationOrtho McNeil

Spouse: Employee of Boston Clinical Research Institute, she has equity position

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There WILL be off-label and/or investigational discussion in this presentation.

Learning Objectives

• Describe the results of the landmark trials in extended duration anticoagulation.

• Describe the design and rationale of the APEX trial.

• Describe the risks and benefits of betrixaban based on clinical research.

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There WILL be off-label and/or investigational discussion in this presentation.

Previous Novel Oral Anticoagulant Trials of Extended Thromboprophylaxis in Acute Medically Ill Patients

5.7%

4.4%

Enoxaparin Rivaroxaban

3.1% 2.7%

Enoxaparin Apixaban

Inci

denc

e (%

) VTE

Even

ts

More M

ajor Bleeding

ADOPTEnoxaparin vs. Apixaban

MAGELLANEnoxaparin vs. Rivaroxaban

0.2% 0.5% 0.4%1.1%

p=0.44

p=0.04

p=0.02

p

Betrixaban

• Oral factor Xa inhibitor• Renal clearance of administered dose (5%)• Renal clearance of absorbed dose (17%)• 1 day half-life (19-25 h)• Not a substrate for major CYP450 enzymes• Rapid onset Cmax achieved at 3-4 hours

• Safety and efficacy of 80 mg daily dose of Betrixaban previously described in approximately 1,200 patients in phase I and II studies

Connolly S et al. Eur Heart J 2013;34(20):1498-505Turpie A et al. Thromb Haemost 2009;101:68-76Cohen AT et al. Am Heart J 2014; 167:335-41

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Gibson et. al. ISTH SSC 2016 – May 27, 2016There WILL be off-label and/or investigational discussion in this presentation.

EvaluationExtended

Prophylaxis35 – 42 days

APEX Study DesignR

1:

1

Subj

ects

enr

olle

d(N

=7,5

13)

Enoxaparin40 mg Placebo

Betrixaban80 mg

Follow-up safety visit

30 Days After Visit 3

(+5 days)Betrixaban80 mg

Primary Efficacy Endpoint: Composite of asymptomatic proximal DVT (detected on ultrasound), symptomatic DVT (proximal or distal), non-fatal PE, and VTE-related death through Visit 3Primary Safety Endpoint: ISTH Major bleeding through 7 days after drug discontinuationNet Clinical Benefit: Composite of primary efficacy and primary safety endpoints

Dose adjustments in severe renal insufficiency (CrCl < 30 mL/min): Betrixaban 40 mg PO qd and Enoxaparin 20 mg SC qd

Standard Prophylaxis10 ± 4 days

Ultrasound & Visit 3

Day 35(+7 days)

Loading dose160 mg

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Double blind, double dummy

Gibson et. al. ISTH SSC 2016 – May 27, 2016There WILL be off-label and/or investigational discussion in this presentation.

Study Design: Key Inclusion Criteria

• Age/Risk Factors:− ≥ 75 yo OR− 60 - 74 yo with D-dimer ≥ 2x ULN OR− 40 - 59 yo with D-dimer ≥ 2x ULN and a history of either VTE, or

cancer*

• Anticipated to be severely immobilized for at least 24 hours after randomization with anticipated length of hospitalization ≥ 3 days

• Hospitalized for one of the following acute presentation:− Acute on chronic heart failure decompensation− Acute on chronic respiratory failure− Acute infection without septic shock− Acute rheumatic disorders− Acute ischemic stroke (w/ immobilization)

*Pre-amendment 3, other risk factors were allowed including: previous history of superficial VT, obesity, varicose veins of lower extremities, hormone therapy, thrombophilia, concomitant use of erythropoiesis stimulating agents

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Gibson et. al. ISTH SSC 2016 – May 27, 2016

There WILL be off-label and/or investigational discussion in this presentation.

Study Design: Key Exclusion Criteria

• End stage renal disease with CrCl

CONSORT Diagram

Randomized(n=7,513)

n=3,759

n=2,842

n=3,754

n=3,720

n=1,956

Enoxaparin Betrixaban

Did not receive any dose of study drug

n=34 n=38

n=2,893

n=1,914

n=3,721No ultrasound AND no symptomatic event

n=546 n=609

n=3,174 n=3,112

Cohort 1

Cohort 2

Cohort 1

Cohort 2

Cohort 3:Overall

efficacy population

Cohort 3:Overall efficacy population

mITTpopulation

mITTpopulation

9

Cohen et al. N Engl J Med. 2016; 375(6):534-44. There WILL be off-label and/or investigational discussion in this presentation.

0

2

4

6

8

10

Enoxaparin(N=2,313)

Betrixaban(N=2,314)

Enoxaparin(N=3,391)

Betrixaban(N=3,407)

Enoxaparin(N=3,720)

Betrixaban(3,721)

mITT Efficacy Analysis Including All Patients Who Received Study Drug Including Those

with Missing Ultrasound As Included in US FDA LabelEv

ent r

ate

(%)

Cohort 1D-dimer ≥ 2 x ULN

Cohort 2D-dimer ≥ 2 x ULN

or age ≥ 75 y

Cohort 3Overall efficacy

population

7.18%

5.70%6.02%

4.70%

5.99%

4.43%

P = 0.018RRR = 21.6%

P = 0.003RRR = 25.4%

P = 0.038RRR = 20.9%

n=166 n=132 n=204 n=160 n=223 n=165

P-values reported using the Mantel-Haenszel test stratified for dosing criteria in Cohort 1 and dosing and entry criteria in Cohort 2 and mITT. mITT defined as patients who received at least one dose of study drug. Symptomatic events from Day 1 till Day 42 or the date of Visit 3, if Visit 3 occurred before Day 42; Asymptomatic DVT between Day 32 and 47.

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Gibson et. al. ISTH SSC 2016 – May 27, 2016There WILL be off-label and/or investigational discussion in this presentation.

Subgroup Analysis: Primary EfficacyOverall Efficacy Population (Cohort 3)

Age ≥ 75 years Age < 75 years

≥ 2 VTE risk factors< 2 VTE risk factors

No dosing modificationP-gp inhibitorSevere renal insufficiency

MaleFemale

Acute decompensated HFAcute infection Acute respiratory failure Acute ischemic stroke Acute rheumatic disorders

Composite of Asymptomatic Proximal DVT, Symptomatic

Proximal or Distal DVT, Nonfatal PE, or VTE-related Death

Reason for Hospital Admission

Dosing Criteria

Additional VTE Risk Factors

Gender

Age

OverallRR (95% CI)

0.76 (0.63, 0.92)

0.75 (0.60, 0.95) 0.77 (0.54, 1.09)

0.82 (0.62, 1.09) 0.70 (0.54, 0.92)

0.68 (0.51, 0.89) 0.84 (0.64, 1.10)

1.06 (0.67, 1.70) 0.88 (0.40, 1.94)

0.70 (0.56, 0.87)

0.85 (0.62, 1.16) 0.72 (0.50, 1.02)0.89 (0.53, 1.49) 0.58 (0.34, 1.02) 0.63 (0.22, 1.78)

Event Rate(Enoxaparin)

Event Rate(Betrixaban)

223 / 3174 165 / 3112

152 / 2136 115 / 213871 / 1038 50 / 974

102 / 1447121 / 1727

81 / 140684 / 1706

114 / 1253109 / 1921

77 / 125288 / 1860

180 / 251133 / 553

120 / 242633 / 540

10 / 110 12 / 146

83 / 148169 / 854

69 / 142849 / 883

29 / 375 24 / 35333 / 363 18 / 3539 / 101 5 / 94

Favors EnoxaparinFavors Betrixaban10.80.60.40.20.1 2 3 4 65

P-value for interaction is non-significant for all analyses.All analysis were stratified for dosing and entry criteria.

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Gibson et. al. ISTH SSC 2016 – May 27, 2016There WILL be off-label and/or investigational discussion in this presentation.

Prob

abilit

y of

Sym

ptom

atic

Eve

nt (%

)

Time (Days)

Enoxaparin

Betrixaban

1.44%

0.93%

Through Visit 3HR = 0.65 (0.42, 0.99)ARR = 0.51%NNT = 196

p=0.043

Through End of Trial*HR = 0.56 (0.38, 0.84)ARR = 0.80%NNT = 125

p=0.004

1.84%

1.04%

Parenteral Therapy

Visi

t 3

Symptomatic VTEAll Patients Randomized

Composite of Symptomatic Proximal or Distal DVT, Non-Fatal PE, or VTE-related Death

*End of Trial defined as final follow-up visit (30 + 5 days after Visit 3)

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Gibson et. al. ISTH SSC 2016 – May 27, 2016There WILL be off-label and/or investigational discussion in this presentation.

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Stroke Type Enoxaparin(N=3716)Betrixaban(N=3716)

Relative Risk (95% CI) p-value

All-cause stroke 0.97% (36) 0.54% (20) 0.56 (0.32, 0.96) 0.032

Ischemic 0.91% (34) 0.48% (18) 0.53 (0.30, 0.94) 0.026

Hemorrhagic 0.03% (1) 0.03% (1) 1.00 (0.06, 15.98) 1.00

Uncertain type 0.03% (1) 0.03% (1) 1.00 (0.06, 15.98) 1.00

TIA 0.13% (5) 0.11% (4) 0.80 (0.22, 2.98) 0.74

All-cause stroke or TIA 1.10% (41) 0.65% (24) 0.59 (0.35, 0.97) 0.034

Stroke or TIAModified Intent-to-Treat Population

Gibson et al. Circulation. 2017;135(7):648-55There WILL be off-label and/or investigational discussion in this presentation.

14Stroke or TIAModified Intent-to-Treat Population – Received 80 mg

Gibson et al. Circulation. 2017;135(7):648-55

Stroke Type Enoxaparin(N=2991)Betrixaban(N=2986)

Relative Risk(95% CI) p-value

All-cause stroke 30 (1.00%) 14 (0.47%) 0.47 (0.25, 0.88) 0.016

Ischemic 28 (0.94%) 13 (0.44%) 0.47 (0.24, 0.90) 0.019

Hemorrhagic 1 (0.03%) 0 (0.00%) – 0.32

Uncertain type 1 (0.03%) 1 (0.03%) 1.00 (0.06, 16.01) 1.00

TIA 5 (0.17%) 3 (0.10%) 0.60 (0.14, 2.51) 0.48

All-cause stroke or TIA 35 (1.17%) 17 (0.57%) 0.49 (0.27, 0.87) 0.012

There WILL be off-label and/or investigational discussion in this presentation.

15Time to Ischemic Stroke Among Subjects with CHF or Ischemic Stroke at Entry

Modified Intent-to-Treat Population

Gibson et al. Circulation. 2017;135(7):648-55There WILL be off-label and/or investigational discussion in this presentation.

Primary Safety Endpoint: ISTH Major BleedingSafety Population

Major bleeding events (ISTH) through 7 days after drug discontinuation

0.0

0.2

0.4

0.6

0.8

1.0

Enoxaparin (N=3,716) Betrixaban (N=3,716)

Even

t rat

e (%

)

n=21

0.57%0.67%

p = 0.55

n=25

Safety population defined as patients who received at least one dose of active study drug. Analysis by actual treatment. NNH not reported given p=NS.

16

Cohen et al. N Engl J Med. 2016; 375(6):534-44. There WILL be off-label and/or investigational discussion in this presentation.

Secondary Safety EndpointSafety Population

Major or clinically relevant non-major bleeding events (ISTH) through 7 days after drug discontinuation

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Enoxaparin (N=3,716) Betrixaban (N=3,716)

Even

t rat

e (%

)

n=59

1.59%

3.12%

p < 0.001

n=116

Safety population defined as patients who received at least one dose of active study drug. Analysis by actual treatment.

17

Cohen et al. N Engl J Med. 2016; 375(6):534-44. There WILL be off-label and/or investigational discussion in this presentation.

Fatal Bleeding and ICHSafety Population

n=9

Even

t rat

e (%

)

0

0.05

0.1

0.15

0.2

0.25

Enoxaparin(N=3,716)

0.03% 0.03%

0.19%

0.05%

n=7 n=2

p = 0.18

n=1 n=1Betrixaban(N=3,716)

Enoxaparin(N=3,716)

Betrixaban(N=3,716)

Fatal Bleeding ICHSafety population defined as patients who received at least one dose of active study drug. Analysis by actual treatment.

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Gibson et. al. ISTH SSC 2016 – May 27, 2016There WILL be off-label and/or investigational discussion in this presentation.

Unger et al of FDA suggests that net clinical outcome analyses include events that are clinically meaningful and are of similar clinical significance such as fatal or irreversible events.

Benefit = Non-hemorrhage CV death + Non-fatal PE + MI + ischemic stroke

Harm = Fatal Bleeding + ICH

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Gibson et. al. ISTH SSC 2016 – May 27, 2016There WILL be off-label and/or investigational discussion in this presentation.

Fatal or Irreversible OutcomesAll Patients Randomized

Non-hemorrhage cardiopulmonary death + Non-fatal PE + MI + ischemic stroke + Fatal bleeding + ICH

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*End of Trial defined as final follow-up visit (30 + 5 days after Visit 3) Gibson et al. J Am Heart Assoc. 2017;6(7)

Through Visit 3HR = 0.71 (95% CI: 0.55-0.90)ARR = 1.18%NNT = 85

Through End of Trial*HR = 0.70 (95% CI: 0.57-0.88)ARR = 1.53%NNT = 65

There WILL be off-label and/or investigational discussion in this presentation.

Fatal or Irreversible OutcomesAll Patients Randomized – Received 80 mg

Non-hemorrhage cardiopulmonary death + Non-fatal PE + MI + ischemic stroke + Fatal bleeding + ICH

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*End of Trial defined as final follow-up visit (30 + 5 days after Visit 3) Gibson et al. J Am Heart Assoc. 2017;6(7)

Through Visit 3HR = 0.62 (95% CI: 0.47-0.83)ARR = 1.47%NNT = 68

Through End of Trial*HR = 0.64 (95% CI: 0.50-0.83)ARR = 1.77%NNT = 56

There WILL be off-label and/or investigational discussion in this presentation.

RRR = 29.0% (8.0, 46.0)p

Comparison to Previous Novel Oral Anticoagulant Trials of Extended Thromboprophylaxis in Acute Medically Ill Patients

p

Summary

• In an mITT analysis that includes all patients treated with study drug performed by the FDA in the label and pre-specified in the protocol, Betrixaban reduced the composite endpoint of symptomatic and asymptomatic events as well as symptomatic events

• Betrixaban was not associated with a significant increase in major, ICH, or fatal bleeding but was associated with more CRNM bleeding

• Betrixaban reduced stroke

• Betrixaban reduced fatal or irreversible events

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Gibson et. al. ISTH SSC 2016 – May 27, 2016There WILL be off-label and/or investigational discussion in this presentation.