Rivaroxaban (XARELTO )

CC-1

Cardiovascular

and

Renal

Drugs

Advisory

Committee

January

16,

2014

Paul

Burton,

MD,

PhD,

FACC

Vice

President,

Janssen

Research

&

Development,

L.L.C.

CC-3

Rivaroxaban

(XARELTO®)

is

Approved

for

6

Indications

in

the

US



Over

70,000

patients

participated

in

clinical

trials

leading

to

the

approval

of

Xarelto

for:

Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation

Treatment of Deep Vein Thrombosis

Treatment of Pulmonary Embolism

Reduction in the Risk of Recurrence of Deep Vein Thrombosis and 

of Pulmonary Embolism

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee 

Replacement Surgery



Global

use

of

XARELTO

at

the

currently

approved

doses

Regulatory

History

of

the

Rivaroxaban

ACS

sNDA

in

the

United

States

 June 2009 ATLAS ACS program granted “Fast Track” status  December 2011 sNDA submitted, and application granted 

“Priority Review”

 May 2012 Advisory Committee meeting

 June 2012 Complete Response Letter (CRL) issued  September 2012 Janssen submits response to CRL 1  March 2013 CRL 2 issued

 May 2013 Janssen submits an application for Dispute  Resolution

CC-5

Proposal

Under

Consideration

Today

–

Shortened

Duration

of

Therapy

in

ACS

Patients

Rivaroxaban

2.5

mg

BID is

indicated

to:

Reduce the risk of thrombotic cardiovascular events in patients 

with ACS (STEMI, NSTEMI or UA) in combination with ASA 

alone or with ASA plus a thienopyridine (clopidogrel or 

ticlopidine).

Rivaroxaban has been shown to reduce the risk of a combined 

endpoint of CV death, MI or stroke. The difference between 

Key

Recommendations

from

the

May

2012

Advisory

Committee

Meeting

 Follow up and retrieve missing vital status data to assess if  differential informative censoring had biased the study results  Conduct sensitivity analyses to assess the robustness of the 

study results

 Conduct additional analyses to assess the balance of  benefit and risk

CC-7

What

Has

Been

Done

Since

the

May

2012

Advisory

Committee

Meeting?



Vital

status

retrieved

for

an

additional

930

subjects

The

sponsor

performed

the

analyses

recommended

by

the

advisory

committee

as

well

as

those

raised

in

CRL1

and

CRL2



These

analyses

demonstrate

the

consistency

of

the

original

study

finding

and

the

robustness

of

the

Outcome

of

the

Dispute

Resolution

Process

 The Office of Drug Evaluation stated that 4 out of 5 topics identified in the  Complete Response had been addressed and did not represent a barrier to 

approval

Impact of missing data 

A lack of supporting data with other anticoagulants

A lack of internal consistency between the two rivaroxaban doses

Inability to confirm concomitant thienopyridine therapy during the study   Strength of evidence could represent a potential barrier to approval  Identified a pathway forward based on a shortened duration of therapy

“…a limitation in rivaroxaban’s use for one month following ACS would provide a better benefit-risk relation, because the efficacy is more evident in the early period after

administration, whereas the overall risk of bleeding would be smaller. If you would like to pursue this path, the Division will be glad to work with you.”

CC-9

Rationale

Supporting

a

90

Day

Duration

of

Rivaroxaban Therapy

in

ACS

Patients

(1

of

2)



Risk

of

recurrent

thrombotic

events

is

high

during

the

first

90

days



49%

of

cardiovascular

death,

MI,

and

stroke

events

occurred

within

the

first

90

days



Rivaroxaban (2.5

mg

BID)

substantially

reduced

Primary endpoint: CV death, MI or stroke; 0.78 (0.65, 0.93)

CV death: 0.65 (0.44, 0.97)



Few

TIMI

life

threatening

bleeding

events

in

the

first

Rationale

Supporting

a

90

Day

Duration

of

Rivaroxaban Therapy

in

ACS

Patients

(2

of

2)

 94% of stratum 2 subjects were receiving thienopyridine  Evidence of effectiveness is consistent across

Stratum 1 and 2

Subgroups

Both doses

Components of the composite endpoint

 Net clinical benefit (mITT, Stratum 2, 2.5 mg BID)

In a hypothetical population of 10,000 patients treated, 81 fewer cases of 

ischemic CVD/MI/stroke events and no excess fatal bleeding or ICH 

CC-11

EU

Approved

Rivaroxaban for

ACS

Based

on

a

Refined

Patient

Population



Rivaroxaban 2.5

mg

BID

indicated

for

cardiac

biomarker

positive

ACS

in

patients

with

no

prior

stroke/TIA

Overall study population 0.84 (0.72, 0.97) 0.66 (0.51, 0.86) Exclude prior stroke/TIA 0.81 (0.69, 0.94) 0.63 (0.48, 0.82) Biomarker positive and exclude 

Sponsor

Presentation

Paul Burton, MD, PhD

Vice President, Clinical Development, Janssen

 ATLAS ACS Program Overview and Results

C. Michael Gibson, MS, MD

Principal Investigator ATLAS ACS 2 TIMI 51 Trial Professor of Medicine, Harvard Medical School

Roderick A Little, PhD

Richard D. Remington Distinguished University Professor of Biostatistics, 

University of Michigan

 Evidence of Effectiveness

Jay P. Siegel, MD

Head of Scientific Strategy and Policy, Johnson & Johnson

 Balancing Benefit and Risk

Marvin A Konstam, MD

Chief Physician Executive, The CardioVascular Center at Tufts Medical Center 

CC-13

Additional

Experts

Available

for

Questions

Professor of Cardiology 

Edinburgh

 Christopher Hammett, MD Interventional Cardiologist, 

Royal Brisbane Hospital, Australia  Janet Wittes, PhD

President, Statistics Collaborative Washington DC 

C.

Michael

Gibson,

MS,

MD

Principal

Investigator

ATLAS

ACS

2

TIMI

51

Trial

Professor

of

Medicine,

Harvard

Medical

School

ATLAS

ACS

Program:

Rationale

CC-15

“Each

year,

an

estimated

 ≈

635

000

Americans

have

a

new

coronary

attack

and

 ≈

280

000

have

a

recurrent

attack”

“Approximately

every

34

seconds,

1

American

has

a

coronary

event,

and

approximately

every

1

minute,

an

American

will

die

of

one.”

Executive Summary: Heart Disease and Stroke Statistics 2013 Update: A Report From the American Heart Association

Despite

New

Therapies

ACS

Continues

to

Represent

an

Unmet

Medical

Need

0 0 180 360 540 720 20 15 10 5 Clopidogrel Prasugrel Endpoin t   (%) Days 900 2.5% 18.7% 20.3% 1.8%

The risk of CV death, MI or stroke is 

very high early after ACS

Within 3 years of an ACS event 

1/5 patients will have died, 

had another MI or a stroke

CV death/MI/Stroke

TIMI Major Bleeding TRILOGY Study: Prasugrel vs Clopidogrel in medically managed patients

CC-17

Persistent

Elevation

of

Thrombin

Generation

in

Post

‐

ACS

Patients

Merlini et al. Circ 1994;90:61‐68

0 0.2 0.4 0.6 0.8 1 1.2 1.4

Controls Stable Angina Unstable Angina MI

Admission 6 Months F   1.2   nmol/L

Anticoagulation

is

a Therapeutic

Strategy

for

ACS

Patients

with

a

Proven

Track

Record



Based

on

the

WARIS

(n=1,214)

and

WARIS

‐

II

(n=3,630)

studies

warfarin

is

indicated

for

chronic

use

in

ACS

patients

INDICATIONS AND USAGE COUMADIN is a vitamin K antagonist indicated for:

• Prophylaxis and treatment of venous thrombosis and its extension, 

pulmonary embolism (1)

• Prophylaxis and treatment of thromboembolic complications associated 

with atrial fibrillation and/or cardiac valve replacement

• Reduction in the risk of death, recurrent myocardial infarction, 

and thromboembolic events such as stroke or systemic embolization 

CC-19

Anticoagulation

is

a Therapeutic

Strategy

for

ACS

Patients

with

a

Proven

Track

Record



Anticoagulation

(e.g.

enoxaparin)

is

part

of

the

foundation

of

the

acute

management

of

ACS

patients

INDICATIONS AND USAGE

Lovenox is a low molecular weight heparin [LMWH] for:

• Prophylaxis of ischemic complications of unstable angina and non‐Q‐wave myocardial infarction [MI] (1.3)

• Treatment of acute ST‐segment elevation myocardial infarction [STEMI] 

managed medically or with subsequent percutaneous coronary 

RECORD:

Rivaroxaban

Significantly

Reduces

Thrombosis

Risk

Compared

to

Enoxaparin

Ev e n t   Ra te   (%) D V T/PE/Dea th RECORD 1 40 mg  QD 10 mg  QD 10 mg QD 40 mg  QD 10 mg  QD Enoxaparin Rivaroxaban RECORD 2 RECORD 3 0 5 10 15 20 25 30 9.3% 2.0% 18.9% 9.6% RRR = 70% 3.7% 1.1% RRR = 79% RRR = 49% 40 mg QD

CC-21 APTT (seconds) at 12 Hours

Probability of Death 30 50 70 90 110 130 150 6% 4% 2% 8% 0%

U Shaped Dose Response Curve: 

APTT After Thrombolytic Therapy for Acute MI

Slide by C. Michael Gibson, M.S., M.D. Granger, CB et al. Circulation 1996 vol. 93, no. 5, p.870‐878

Therapeutic Window

Dose

Ranging

and

Finding

Studies

with

Fondaparinux:

Lowest

Dose

Associated

with

Best

Efficacy

In

ACS

Patients

Death/MI/Recurrent Ischemia n=1138

Phase 3 OASIS 5 Study Death n=20,078 0% 10% 20% 30% 40% Incidence 0 10 20 30 Days 4.0 mg 8.0 mg 12.0 mg 2.5 mg Enoxaparin Fondaparinux

Simoons et al. J Am Coll Cardiol. 2004; The Fifth Organization to Assess Strategies in Acute 

0.00 0 Cumula tiv e   Haz ar d 30 60 90 120 150 180 Days 0.02 0.04 0.06 Fondaparinux 2.5 mg Enoxaparin HR (95% CI) 0.89 (0.80, 1.00) p=0.05

CC-23

U

Shaped

Dose

Response

Curve:

Warfarin

Dose

in

Atrial

Fibrillation

Abbreviation: INR = International Normalized Ratio.

Adapted from Fuster V et al. J Am Coll Cardiol. 2011;57(11):e101-e198. Modified with permission from Hylek EM, Singer DE. Ann Intern

Med. 1994;120:897-902. Data from Odén A, Fahlén M, Hart RG. Thromb Res. 2006;117:493-499.

1. Freeman WD, Aguilar MI. Expert Rev Neurother. 2008;8(2):271-290. 2. Aguilar MI et al. Mayo Clin Proc. 2007;82(1):82-92.

INR Odds Ratio Intracranial Bleeding Ischemic Stroke Therapeutic Window 5 6 8 1 2 3 4 7 0 5 20 15 10

ICH is the most lethal form of stroke. 30-day mortality rates with ICH estimated at 30% to 55%1,2

Lower

Dose

Edoxaban has

Greater

Mortality

Benefit

in

AF

Patients

 Edoxaban 30 mg reduces bleeding events and is associated with a lower  mortality than 60 mg

 Offset in mortality not completely explained by fatal bleeding deaths

Edoxaban  30 mg od  %/year (N=7034) Edoxaban  60 mg od  %/year (N=7035) Warfarin %/year (N=7036) Edoxaban  30 mg od vs warfarin HR, p‐value* Edoxaban  60 mg od vs warfarin HR, p‐value* Myocardial infarction 0.89 0.70 0.75 1.19 (0.95–1.49) 0.94 (0.74–1.19) Major bleeding 1.61 2.75 3.43 0.47  (0.41–0.55) 0.80  (0.71–0.91) Fatal 0.13 0.21 0.38 0.35  (0.21–0.57) 0.55  (0.36–0.84) Mortality 3.80 3.99 4.35 0.87  (0.79–0.96) p=0.006 0.92 (0.83–1.01) p=0.08

CC-25

Lower

Edoxaban

Doses

Reduce

Mortality

 Edoxaban 60 mg reduces the primary efficacy endpoint more than  Edoxaban 30 mg

 However, Edoxaban 30 mg reduces bleeding events and is associated with a  lower mortality than 60 mg

 Offset in mortality not completely explained by fatal bleeding deaths 60 mg Edoxaban (%/yr) 30 mg Edoxaban (%/yr) 60 mg ‐ 30 mg  Edoxaban (%/yr) Efficacy 1.18  1.61 ‐ 0.43  Minor Bleeding 4.12  3.52 + 0.60  Major Bleeding 2.75 1.61 + 1.14  Fatal Bleeding 0.21 0.13  + 0.08 Mortality 3.99 3.80 + 0.19

ATLAS

ACS

Program:

Efficacy

Results

CC-27

ATLAS

Phase

2

Study

 Collected >200 primary endpoint events (death, myocardial  infarction, stroke, or severe recurrent ischemia requiring 

revascularization)

 Suggested that rivaroxaban may reduce the risk of important  clinical events in ACS patients

 Lowest rivaroxaban twice daily doses seemed to have the  promise of efficacy with the best bleeding profile

ATLAS

Phase

2:

Higher

Rivaroxaban Total

Daily

Doses

Increased

the

Rate

of

Bleeding

Events

Days After Start of Treatment

Cumula tiv e   Ev e n t   Ra te   (%) 5 10 15 0 Placebo Rivaroxaban 5 mg Rivaroxaban 10 mg Rivaroxaban 15 mg Rivaroxaban 20 mg P < 0.0001

Clinical Significant Bleeding All Strata

CC-29 0

2 4 6

ATLAS

Phase

2:

Higher

Rivaroxaban

Doses

Did

Not

Result

in

Improved

Efficacy

Stratum 2: ASA + Thienopyridine 6 Month Treatment

Ev e n t   Ra te   (%) Dea th,   MI,   Str o ke Total Dose (mg) Placebo 5 10 15 20 3.7% 2.6% 3.0% 5.9% 3.1%

HR (95% CI)

All Doses _{0.69 (0.50, 0.96) p=0.03}

ATLAS

ACS

TIMI

46

Phase

2:

Rivaroxaban Showed

Promise

In

Reducing

Important

Clinical

Events

N =3,491 30 0 0 2 4 6 60 90 120 150 180 3.9% Death, MI, or Stroke (%) 5.5% Placebo Rivaroxaban

CC-31

ATLAS

Phase

2:

Low

Dose

(2.5

mg

and

5

mg)

BID

Rivaroxaban

Doses

Selected

for

Phase

3

Gibson CM, AHA 2008

TIMI Major Bleed p=0.03

Death, MI, Stroke HR=0.55 (0.27‐1.11) p=0.09 5 4 3 2 1 0 0 90 180 Placebo 3.8% Riva 2.0% Riva 1.2% Placebo 0.2% Days Cumula tiv e   Ev e n t   Ra te   (%)

Stratum 2: ASA + thienopyridine 6 month treatment BID dosing

The ATLAS ACS 2 TIMI 51 Trial (The second trial of Anti-Xa Therapy to Lower

cardiovascular events in Addition to standard therapy in Subjects with Acute

Coronary Syndrome, Thrombolysis In Myocardial Infarction 51 Trial)

Randomized, Double‐Blind, Placebo‐Controlled, Event Driven, Multicenter Phase III

766 Study Centers 44 Countries

ATLAS

ACS

2

TIMI

51:

CC-33

ATLAS

ACS

2

TIMI

51

Primary

Efficacy

and

Safety

Objectives

 To determine if rivaroxaban when added to a foundation of  standard antiplatelet therapy:

Is effective at reducing the risk of the primary composite of 

cardiovascular (CV) death, MI, or stroke compared with 

placebo in subjects with a recent ACS

If rivaroxaban is effective, what is the preferred dose?

 Assess the occurrence of TIMI major bleeding events not  associated with CABG surgery (primary safety endpoint)

 Assess the overall safety profile of rivaroxaban in subjects with  a recent ACS

ATLAS

ACS

2

TIMI

51

Study

Design

STRATUM 1

Primary Efficacy Endpoint: CV Death, MI or All Cause Stroke Target 983 Primary Efficacy Endpoint Events

Stratum 1: ASA Only

Stratum 2: ASA + Thienopyridine

YES NO

MD Decision to Treat with a Thienopyridine

Recent ACS Patients

Stabilized 1‐7 Days Post‐Index Event

N=up to 16000 STRATUM 2 Placebo RIVA 5mg BID RIVA 2.5mg BID Placebo RIVA 5mg BID RIVA 2.5mg BID

CC-35

Principal

Efficacy

Analyses†



mITT:

1,002

events

All randomized subjects

All data included up to the earlier of global treatment end 

date, and 30 days after early discontinuation of study drug



ITT:

1,101

events

All randomized subjects

All data included up to global treatment end date

† mITT and ITT analyses exclude 184 subjects from  three sites (091001, 091019 and 

The

Primary

Analysis

Population

for

ATLAS

is

The

mITT Population

CC-37

The

Pre

‐

Planned

Statistical

Testing

Strategy

on

the

mITT

Population

was

Agreed

with

the

FDA

Endpoint

Rivaroxaban

Group

vs

Placebo

Test

1:

Primary

Efficacy

Endpoint

All

Strata

All

Riva

vs

Placebo

Test

2:

Primary

Efficacy

Endpoint

Stratum

2

All

Riva

vs

Placebo

Test

3:

Primary

Efficacy

Endpoint

Stratum

2

2.5

mg

Riva

Stratum

2

5

mg

Riva

Test

1,

in

The

mITT Population

is

the

Correct

Test

to

Determine

if

ATLAS

Succeeded

or

Failed

Endpoint

Rivaroxaban

Group

vs

Placebo

Test

1:

Primary

Efficacy

Endpoint

All

Strata

CC-39

TEST

1:

Combined

Doses

vs

Placebo

0 30 90 180 270 360 450 540 630 720 810 Days from Randomization

2 ‐ Year Cumulative Event Rate:  8.9% vs 10.7%

Cumula tiv e   Ev e n t   Ra te   (%) 15 10 5 0 Placebo Rivaroxaban

HR (95% CI) mITT ITT

Test

1:

The

Effect

of

Rivaroxaban

is

Consistent

Across

All

Analysis

Populations

All Strata/Combined Doses

p‐value mITT 0.008 ITT 0.002 ITT‐Total 0.005 Safety‐TE 30 days 0.009 Per‐Protocol 0.006

mITT Per Investigator 0.013

0.5 1 2

CC-41

TEST

2:Combined

Doses

vs

Placebo

Placebo

2 ‐ Year Cumulative Event Rate:  8.8% vs 10.4%

Rivaroxaban 15 10 5 0 0 30 90 180 270 360 450 540 630 720 810 Days from Randomization

HR (95% CI) mITT ITT

Combined Doses 0.86 (0.75, 0.98) p=0.024 p=0.004 Cumula tiv e   Ev e n t   Ra te   (%)

TEST

3:

Each

Dose

vs

Placebo

HR (95% CI) mITT ITT

2.5 mg BID 0.85 (0.72, 0.99) p=0.039 p=0.011

5 mg BID 0.87 (0.74, 1.01) p=0.075 p=0.020

Placebo

Riva 2.5 mg BID

Riva 5 mg BID

2.5 mg, 2 ‐ Year Cumulative Event Rate:  10.3% vs 8.9% 5 mg, 2 ‐ Year Cumulative Event Rate:  10.3% vs 8.7%

Cumula tiv e   Ev e n t   Ra te   (%) 15 10 5 0 0 30 90 180 270 360 450 540 630 720 810 Days from Randomization

CC-43 Parameter 2.5 mg BID vs Placebo 5 mg BID vs Placebo HR (95% CI) mITT p‐value ITT p‐value HR (95% CI) mITT p‐value ITT  p‐value Primary 0.85  (0.72, 0.99) 0.039† 0.011 0.87  (0.74, 1.01) 0.075† 0.02 CV Death 0.62  (0.47, 0.82) <0.001 <0.001 0.95  (0.74, 1.21) 0.67 0.56 MI 0.92  (0.75, 1.12) 0.40 0.14 0.83  (0.68, 1.02) 0.08 0.03 Stroke 1.31  (0.84, 2.05) 0.24 0.23 1.39  (0.89, 2.16) 0.15 0.16

Effect

of

Rivaroxaban

on

Components

of

the

Primary

Efficacy

Endpoint

mITT/Stratum 2/Each Dose

† Tes ng the primary endpoint for each dose in the mITT population was pre‐defined 

in the statistical analysis plan and adjusted by multiplicity.  All other p‐values are 

Rivaroxaban

Substantially

Reduces

the

Risk

of

Cardiovascular

Death

mITT/Stratum 2/2.5 mg BID

0

0 30 90 180 270 360 450 540 630 720 810 2 ‐ Year Cumulative Event Rate:  2.5% vs 4.2%

Days from Randomization 6.0 5.0 4.0 3.0 2.0 1.0 Cumula tiv e   Ev e n t   Ra te   (%) Placebo Riva 2.5 mg BID

HR (95% CI) mITT ITT

CC-45

Weight [kg] (<60; ≥90 kg)

Race (White, Other) Age [years] (<55≥75)

Sex (Male; Female) Overall

CrCl [mL/min] (<30; >80)

Index Event (STEMI; NSTEMI; Unstable angina)

Prior MI (yes, no)

PCI for Index Event (yes, no)

Elevated Cardiac Biomarker (yes, no)

Congestive Heart Failure (yes, no)

Prior Ischemic Stroke/TIA (yes, no)

Hypertension (yes, no)

Diabetes (yes, no)

Primary

Efficacy

Endpoint

Results

are

Consistent

Across

Subgroups

mITT/Stratum 2/2.5 mg BID

0.4 0.67 1 1.5 2.5

Hazard Ratio and 95%CI

Favors Placebo

Favors Rivaroxaban

p=0.023

p=0.082 Interaction p‐value:

CC-47

Rivaroxaban Plus

Aspirin

and

Clopidogrel Reduces

in

Stent

Thrombosis

ex

vivo

Adapted from Becker et al., J. Thrombosis and Haemostasis, 2012, 10: 2470‐2480

Rivaroxaban + ASA + Clopidogrel N=6 N=7 N=7 0 2 4 6 8 10 12 Thrombus Mass (mg) * p<0.01 vs control # p<0.01 vs ASA + clopidogrel * #

Assessment

of

Stent

Thrombosis

in

ATLAS

 Cardiovascular events were assessed for stent thrombosis  using the Academic Research Consortium (ARC) criteria

 At the request of the FDA, a sample of angiographic films for  cases of definite or probable stent thrombosis underwent

Blinded angiographic core lab assessment at the Cardiac Research 

Foundation (Dr. G. W. Stone)

Complete, independent clinical re‐adjudication at Duke Clinical Research 

CC-49

Stent

Thrombosis:

Definite

or

Probable

HR (95% CI) 2.5 mg BID 0.61 (0.39, 0.93) p=0.022 5 mg BID 0.74 (0.49, 1.12) p=0.15 0 30 0 Placebo Riva 2.5 mg BID Riva 5 mg  BID Cumula tiv e   Ev e n t   Ra te   (%)

Relative Days From Randomization

90 180 270 360 450 540 630 720 810 870 0.5 1.0 1.5 2.0 2.5 3.0

CC-51

Ideal

World:

All

ACS

Patients

Get

a

Thienopyridine

Real

World:

They

Don’t

 251 “Get With The Guidelines” US Centers 

 26.8% of patients go home without clopidogrel after an ACS event

Somma KA et al., Circ Cardiovasc Qual Outcomes.

Overall n=72,352 STEMI n=23,386 NSTEMI n=48,966 0 50 75 100 25 Clopidogr e l   at   Dischar ge   (%) 73.2 % 85.6 % 67.0%

Each

Dose

vs

Placebo:

Primary

Endpoint

mITT/Stratum 1/Each Dose

HR (95% CI) 2.5 mg BID 0.74 (0.45, 1.22) p=0.234 5 mg BID 0.64 (0.38, 1.07) p=0.089 0 30 90 180 270 360 450 540 630 720 810 0 2 4 6 8 10 12 14 16 18 Cumula tiv e   Ev e n t   Ra te   (%) _Placebo Riva 2.5 mg BID Riva 5 mg BID

CC-53

Multiple

Studies

Within

Each

Study:

Consistent

Results

Across

Phase

2

and

3

Studies

0.25 0.5 1 2 4 Stratum 1: Stratum 2: Combined Strata: Favors Placebo Favors Rivaroxaban

Hazard Rate (95% CI)

mITT Population

Phase 2: 2.5 and 5 mg BID

Phase 2 Phase 3 Phase 2 + 3 Phase 2 Phase 3 Phase 2 + 3 Phase 2 + 3 0.084 0.084 0.016 0.157 0.024 0.013 0.002 p‐value†

†Nominal p‐ value not adjusted for 

Summary:

Efficacy



The

ATLAS

study

demonstrated

that

Rivaroxaban

2.5

mg

BID

when

added

to

antiplatelet

therapy

reduced

the

rate

of

the

primary

endpoint

(CV

Death/MI/

Stroke)



Result

driven

by

a

38%

reduction

in

CV

death



Consistent

benefit

in

both

Stratum

1

(ASA

alone)

and

in

Stratum

2

(ASA

plus

a

thienopyridine)



Benefit

consistent

across

subgroups

CC-55

ATLAS

ACS

Program:

Safety

Results

Non

‐

CABG

TIMI

Major

Bleeding:

Primary

Safety

Endpoint

TE/Stratum 2/Each Dose

HR (95% CI) 2.5 mg BID 3.35 (2.01, 5.60) p<0.001 5 mg BID 4.26 (2.58, 7.03) p<0.001 0 30 90 180 270 360 450 540 630 720 810 0 1 2 3 Placebo Riva 2.5 mg BID Riva 5 mg BID Cumula tiv e   Ev e n t   Ra te   (%)

CC-57

TIMI

Life

‐

Threatening

Bleeding

Events

TE/Stratum 2/2.5 mg Riva 2.5 mg BID N=4772 n (%) Placebo N=4773 n (%)

TIMI life‐threatening bleeding 40 (0.8) 18 (0.4)

Fatal 5 (0.1) 8 (0.2)

Symptomatic intracranial hemorrhage 13 (0.3) 5 (0.1) Hypotension requiring inotropic agents 3 (0.1) 2 (<0.1) Surgical intervention for ongoing bleeding 7 (0.1) 8 (0.2) Blood transfusion of ≥4 units over 48 h 19 (0.4) 5 (0.1)

Adverse

Event

Profile

of

Rivaroxaban

TE bleeding AE 948 (19.9) 616 (12.9)

Bleeding resulting in study drug D/C 179 (3.8) 91 (1.9) TE bleeding resulting in death 5 (0.1) 8 (0.2) AE resulting in study drug D/C 436 (9.1) 386 (8.1) Post baseline AEs occurring within

CC-59

Summary:

Safety

– 2.5

mg

BID



Rivaroxaban

increased

the

risk

of

bleeding

in

ACS

patients

The

rate

of

non

‐

bleeding

adverse

events

and

serious

adverse

events

were

similar

between

the

rivaroxaban

and

placebo

groups



Bleeding

events

leading

to

irreversible

harm

were

low

in

number

ICH and hemorrhagic stroke were more common in the 

rivaroxaban group compared to the placebo group

The rates of fatal ICH and fatal bleeding events were balanced 

Evaluation

of

Shorter

Duration

of

CC-61

Shorter

Duration

of

Rivaroxaban

Therapy

Makes

Good

Clinical

Sense

30 Days of therapy:

 A profound reduction in the risk of the primary efficacy endpoint  A reduction in the risk of all components of the primary endpoint  All of this achieved in the setting of >99% of patients have 

confirmed vital status, >97% of patients receiving a thienopyridine

mITT, 30 Days HR (95% CI) p‐value

TEST 1 (S1+S2, Combined doses) 0.66 (0.52, 0.84) <0.001 TEST 2 (S2, Combined doses) 0.73 (0.57, 0.94) 0.013 TEST 3 (S2, 2.5mg BID) 0.71 (0.53, 0.97) 0.028

CV death 0.81 (0.49, 1.31) NS MI 0.71 (0.48, 1.06) NS Stroke 0.67 (0.27, 1.63) NS

90 Days of therapy:

 Maintains profound benefit seen with 30 days of treatment  Stronger CV mortality reduction

 >98% of patients have confirmed vital status, >94% of patients  

receiving a thienopyridine

Shorter

Duration

of

Rivaroxaban

Therapy

Makes

Good

Clinical

Sense

mITT, 90 Days HR (95% CI) p‐value

TEST 1 (S1+S2, Combined doses) 0.78 (0.65, 0.93) 0.006 TEST 2 (S2, Combined doses) 0.82 (0.68, 0.99) 0.041 TEST 3 (S2, 2.5mg BID) 0.76 (0.61, 0.96) 0.020

CV death 0.65 (0.44, 0.97) 0.031 MI 0.79 (0.59, 1.05) NS Stroke 0.94 (0.46, 1.90) NS

CC-63

Effect of Rivaroxaban Therapy for 90 Days on the 

Risk of the Primary Endpoint

mITT/ Stratum 2 / 2.5 mg / 90 Days HR (95% CI) 2.5 mg BID 0.76 (0.61, 0.96) p=0.020 0 Placebo Riva 2.5 mg BID 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 15 30 45 60 75 90

Days from Randomization

Cumula tiv e   Ev e n t   Ra te   (%)

HR (95% CI) 2.5 mg BID 0.65 (0.44, 0.97) p=0.031 0 Placebo Riva 2.5 mg BID 0.0 0.25 0.50 0.75 1.00 1.25 1.50 1.75 15 30 45 60 75 90

Days from Randomization

Cumula tiv e   Ev e n t   Ra te   (%)

Effect of Rivaroxaban Therapy for 90 Days on the 

Risk of Cardiovascular Death

CC-65

HR (95% CI) Overall HR (95% CI) 90 Days

2.5 mg BID 0.61 (0.39, 0.93) 0.69 (0.41,1.14)

5 mg BID 0.74 (0.49, 1.12) 0.64 (0.38,1.07)

Stent

Thrombosis:

Definite

or

Probable

(Any

Stent

Placement

at

Baseline)

ITT Total/Stratum 2/Each Dose 0 30 0 Placebo Riva 2.5 mg BID Riva 5 mg  BID Cumula tiv e   Ev e n t   Ra te   (%)

Relative Days From Randomization

90 180 270 360 450 540 630 720 810 870 0.5 1.0 1.5 2.0 2.5 3.0

Effect

Of

Shorter

Duration

Rivaroxaban

Therapy

in

Patients

Only

Receiving

Aspirin

mITT/Stratum 1/Combined Dose HR (95% CI) Combined Doses 0.49 (0.28, 0.87) p=0.012 0 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 15 30 45 60 75 90 Cumula tiv e   Ev e n t   Ra te   (%) Rivaroxaban Placebo

CC-67

†All safety subjects who had at least 1 day of follow‐up after last dose of study drug administration. Rivaroxaban Combined N=9864 n/N (%) Placebo N=4910 n/N (%) From Last  Dose 1 to 2 days CV Death/MI/Stroke 133/9864 (1.3) 63/4910 (1.3) Cardiovascular Death 82/9864 (0.8) 46/4910 (0.9) MI 43/9864 (0.4) 11/4910 (0.2) Stroke 22/9864 (0.2) 10/4910 (0.2) 3 to 30  days CV Death/MI/Stroke 82/9643 (0.9) 39/4810 (0.8) Cardiovascular Death 57/9693 (0.6) 26/4827 (0.5) MI 32/9658 (0.3) 13/4817 (0.3) Stroke 11/9675 (0.1) 7/4820 (0.1)

Primary

Efficacy

Endpoints

After

Last

Dose

Off

Treatment/All

Strata/Combined

Doses

TIMI

Life

‐

Threatening

Bleeding

Over

the

1

90

Days

Non‐CABG TIMI major 21 (0.4) 7 (0.1) TIMI life‐threatening bleeding 15 (0.3) 10 (0.2)

Fatal 2 (<0.1) 5 (0.1)

Symptomatic intracranial hemorrhage 3 (0.1) 2 (< 0.1) Hypotension requiring inotropic agents 2 (< 0.1) 2 (<0.1) Surgical intervention for ongoing bleeding 4 (0.1) 5 ( 0.1) Blood transfusion of ≥4 units over 48 h 6 (0.1) 2 (<0.1)

CC-69

Rationale

Supporting

a

90

Day

Duration

of

Rivaroxaban Therapy

in

ACS

Patients

(1

of

2)



Risk

of

recurrent

thrombotic

events

is

high

during

the

first

90

days



49%

of

cardiovascular

death,

MI,

and

stroke

events

occurred

within

the

first

90

days



Rivaroxaban (2.5

mg

BID)

substantially

reduced

Primary endpoint: CV death, MI or stroke; 0.78 (0.65, 0.93)

CV death: 0.65 (0.44, 0.97)



Few

TIMI

life

threatening

bleeding

events

in

the

first

Rationale

Supporting

a

90

Day

Duration

of

Rivaroxaban Therapy

in

ACS

Patients

(2

of

2)

 94% of stratum 2 subjects were receiving thienopyridine  Evidence of effectiveness is consistent across

Stratum 1 and 2

Subgroups

Both doses

Components of the composite endpoint

 Net clinical benefit (mITT, Stratum 2, 2.5 mg BID)

In a hypothetical population of 10,000 patients treated, 81 fewer cases of 

ischemic CVD/MI/stroke events and no excess fatal bleeding or ICH 

CC-71

Analyses

Addressing

Issues

Raised

A

Lack

of

Supporting

Data

with

CC-73

In

ATLAS

ACS

2

TIMI

51

Patients

With

a

Prior

Stroke

or

TIA

Were

Specifically

Excluded

Placebo Better  Rivaroxaban  Better 0.88 (0.75‐1.03) 1.61 (0.63‐4.10) 0.22 ATLAS2‐TIMI 51 Rivaroxaban  5 mg BID 15 month 

‐

+

+

‐

‐

+

A

Lack

of

Internal

Consistency

Between

CC-75

All

Cause

Mortality

in

Subjects

Without

Non

‐

CABG

TIMI

Major

Bleeding

TE/Stratum 2/5 mg

Exclusion of 97 patients with non‐CABG TIMI major bleeding HR = 0.75 (0.56, 0.99) 0.0 0.5 1.0 1.5 2.0 2.5 3.0 84 events 1.8% 117 events 2.5%  All   Cause   Mort ality   (%) Rivaroxaban 5 mg BID (n=4631) Placebo  (n=4693)

What

Types

of

MI

Would

Rivaroxaban

be

Expected

to

Reduce?

Type

1:

Spontaneous

Type 2:

Secondary

Type 3:

SCD

due

to

Suspected

MI

Type

4A:

Peri

‐

PCI

Type

4B:

Stent

Thrombosis

Type

5:

Peri

‐

CABG

CC-77

18

Rivaroxaban

Reduces

the

Risk

of

Spontaneous

MI:

Both

Doses

Have

a

Similar

Effect

Incidence   of   Spon ta neous   MI   (%) 2 Year KM Estimates HR (95% CI) Placebo 5.7% Rivaroxaban 2.5 mg BID  4.7% 2.5 mg BID HR 0.84 (0.68‐1.02) p=0.08 12 24 6 18 Placebo 5.7% Rivaroxaban 5 mg BID  4.1% 5 mg BID HR 0.77 (0.62‐0.94) p=0.01 Cavender, JACC 2013 Time (Months) 1 3 2 5 4 6 1 3 2 5 4 6 0 0 0 6 12 24 Time (Months) 0

1 3 2 Incidence of Spontaneous MI (%) > 10 X ULN Placebo 2.4% Rivaroxaban 2.5 mg BID 1.8% 2.5 mg BID HR 0.75 (0.54‐1.04) p=0.08 Placebo 2.4% Rivaroxaban 5 mg BID 1.5% 5 mg BID HR 0.71 (0.51‐0.99) p=0.04

Rivaroxaban

Reduces

the

Risk

of

Large

MIs:

Both

Doses

Have

a

Similar

Effect

0 0 1 3 2 2 Year KM Estimates 12 24 6 18 Time (Months) 0 6 12 18 24 Time (Months) 0

CC-79

Inability

to

Confirm

Concomitant

The

Effect

of

Rivaroxaban

is

Present

in

Patients

Receiving

Active

Thienopyridine



A

sensitivity

analysis

was

performed,

censoring

patients

prior

to

the

initiation

of

a

PPI

(omeprazole

or

esomeprazole)

or

cessation

of

their

thienopyridine

therapy

 The effect of rivaroxaban is consistent with the overall study 

result in subjects receiving active thienopyridine therapy

 The overall study result: Stratum 2, mITT CV death, MI, stroke: HR=0.85 (0.73, 1.00)

 The 90 day study result: Stratum 2, mITT CV death, MI, stroke: HR=0.84 (0.68, 1.05)

CC-81

Roderick

A

Little,

PhD

Richard

D.

Remington

Distinguished

University

Professor

of

Biostatistics

University

of

Michigan

Key

Questions

Raised

by

the

Advisory

Committee

in

2012



Is

it

possible

to

collect

more

vital

status

data?

Does

including

the

new

vital

status

information

change

the

conclusion?



Is

there

evidence

of

bias

from

differential

informative

censoring?



Is

the

study

result

robust

to

a

variety

of

CC-83

Key

Questions

Raised

by

the

Advisory

Committee

in

2012



Is

it

possible

to

collect

more

vital

status

data?

Does

including

the

new

vital

status

information

change

the

conclusion?



Is

there

evidence

of

bias

from

differential

informative

censoring?



Is

the

study

result

robust

to

a

variety

of

Subjects

and

Person

‐

Years

Missing

Data

on

Vital

Status

Missing 

Vital Status mITT ITT

Subjects 698/15,526  (4.5%) 1338/15,526  (8.6%) Person‐ Years 38.2/16,470  (0.2%) 1,184/19,962  (5.9%)

CC-85

Subjects

and

Person

‐

Years

Missing

Data

on

Vital

Status

Missing 

Vital Status mITT

mITT  new VS ITT ITT new VS Subjects 698/15,526  (4.5%) 278/15,526 (1.8%) 1338/15,526  (8.6%) 495/15,526 (3.2%) Person‐ Years 38.2/16,470  (0.2%) 15/16,470  (0.09%) 1,184/19,962  (5.9%) 486/19,934 (2.4%)

Missing vital status at the time of the last AC, May 23rd ₂₀₁₂

Missing

Data

Have

Been

Substantially

Reduced

Sponsor was not allowed to contact 182 313

Sponsor was allowed to contact 516 1,025 Vital status confirmed* 469 930 Still missing vital status 229 408

* Includes 49 and 87 subjects in the mITT and ITT populations respectively 

whose vital status was known, but where subject consent was not obtained to 

CC-87

Why

did

the

Sponsor

Follow

up

on

Vital

Status

Rather

than

the

Primary

Outcome?

 The May 2012 Advisory Committee recommended following‐up 

of vital status data

 The sponsor discussed the approach with the FDA

 Vital status is the most objective clinical endpoint, not subject to 

recall and ascertainment bias 

 Following up vital status rather then the primary outcome 

substantially increases the proportion of subjects in which 

information can be obtained

 A very high proportion (87%) of all‐cause deaths reported in 

ATLAS are cardiovascular (CV) deaths and the reduction in the 

*Includes 87 subjects whose vital status was known, but where subject consent 

Follow

‐

Up:

Distribution

of

Cases

by

Treatment

Group

for

All

Randomized

Subjects/ITT

Number of subjects:  Rivaroxaban Placebo N=410 2.5 mg BID N=457 5 mg BID N=471

Vital status confirmed* 303 329 298

Alive 290 317 286

Died 13 12 12

Still missing vital status 154 142 112

Allowed to be contacted 52 (34%) 49 (35%) 41(36%) Not allowed to be contacted 102 (66%) 93 (65%) 71 (64%)

CC-89 Number of subjects: Rivaroxaban Placebo N=207 2.5 mg BID N=245 5 mg BID N=246

Vital status confirmed* 157 162 150

Alive 154 160 148

Died 3 2 2

Still missing vital status 88 84 57

Allowed to be contacted 23 (26%) 29 (35%) 16 (28%) Not allowed to be contacted 65 (74%) 55 (65%) 41 (72%)

Follow

‐

Up:

Distribution

of

Cases

by

Treatment

Group

for

All

Randomized

Subjects/mITT

*Includes 49 subjects whose vital status was known, but where subject consent 

Key

Questions

Raised

by

the

Advisory

Committee

in

2012



Is

it

possible

to

collect

more

vital

status

data?



Does

including

the

new

vital

status

information

change

the

conclusion?



Is

there

evidence

of

bias

from

differential

informative

censoring?



Is

the

study

result

robust

to

a

variety

of

CC-91

Implications

of

the

New

Vital

Status

Data

for

All

Cause

Mortality

mITT/Stratum 2/2.5 mg BID 0 30 90 180 270 360 450 540 630 720 810 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 Cumula tiv e   Ev e n t   Ra te   (%)

Days from Randomization

Riva 2.5 mg Placebo

HR (95% CI) mITT

Implications

of

the

New

Vital

Status

Data

for

All

Cause

Mortality

mITT/Stratum 2/2.5 mg BID 0 30 90 180 270 360 450 540 630 720 810 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 Cumula tiv e   Ev e n t   Ra te   (%)

Days from Randomization

Riva 2.5 mg Placebo

Riva 2.5 mg including new VS data Placebo including new VS data

HR (95% CI) mITT

2.5 mg BID 0.64 (0.49, 0.83) p<0.001

CC-93

All

‐

Cause

Mortality

Results

are

Unchanged

Following

Vital

Status

Ascertainment

All Strata 2.5 mg BID vs  Placebo HR (95% CI) 5 mg BID vs  Placebo HR  (95% CI) Originally reported mITT 0.68 (0.53, 0.87) 0.95 (0.76, 1.19)

All

‐

Cause

Mortality

Results

are

Unchanged

Following

Vital

Status

Ascertainment

All Strata 2.5 mg BID vs  Placebo HR (95% CI) 5 mg BID vs  Placebo HR  (95% CI) Originally reported mITT 0.68 (0.53, 0.87) 0.95 (0.76, 1.19)

Following VS 

ascertainment mITT 0.69 (0.54, 0.88) 0.95  (0.76, 1.19)

Originally reported ITT 0.72 (0.57, 0.90) 0.99 (0.80, 1.21)

Following VS 

CC-95

Key

Questions

Raised

by

the

Advisory

Committee

in

2012



Is

it

possible

to

collect

more

vital

status

data?

Does

including

the

new

vital

status

information

change

the

conclusion?



Is

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