Andexanet alfa in Factor Xa

Inhibitor-Associated Acute Major Bleeding

Stuart J. Connolly, M.D., Truman J. Milling, Jr., M.D., John W. Eikelboom, M.D.,
C. Michael Gibson, M.D., John T. Curnutte, M.D., Ph.D., Michele D. Bronson,
Ph.D., Patrick Yue, M.D., Genmin Lu, Ph.D., Pamela B. Conley, Ph.D., Peter
Verhamme, M.D., Ph.D., Jeannot Schmidt, M.D., Saskia Middeldorp, M.D.,
Alexander T. Cohen, M.D., Jan Beyer-Westendorf, M.D., Pierre Albaladejo,
M.D., Jose Lopez-Sendon, M.D., Andrew Demchuk, M.D., Shelly Goodman,
B.S.N., Janet Leeds, Ph.D., Deborah M. Siegal, M.D., Elena Zotova, Ph.D.,
Brandi Meeks, M.Sc., Juliet Nakamya, Ph.D., Balakumar Swaminathan, M.Sc.,
Mark Crowther, M.D.
on behalf of the ANNEXA-4 investigators
Background

Factor Xa (FXa) inhibitors reduce thrombotic events, but can

precipitate major bleeding
>100,000 bleeding hospitalizations per year in the US
Fatality rate of 15-20%
Andexanet alfa was developed as a specific reversal agent for all
direct and indirect FXa inhibitors
It rapidly and safely reversed anti-FXa activity in healthy
volunteers
Truven Health Analytics, 12 months ending December 31, 2016 for Commercial,
Medicare, and Medicaid patients
Held C et al, Eur Heart J 2015; 36: 1264-72.
Piccini JP et al, Eur Heart J 2014; 35: 1873-80. 2
Insights from the ARISTOTLE Trial: Clinical Outcomes
and Management Associated with Major Bleeding in Patients
with Atrial Fibrillation Treated with Apixaban or Warfarin

Randomized trial of apixaban and warfarin in

18,200 patients
ICH
ISTH major bleeding occurred in 5% of
patients
30 day mortality after bleeding was 15% Non ICH
43% mortality after ICH

European Heart Journal (2015) 36, 1264-1272

doi:10.1093/eurheartj/ehu463 3
ARISTOTLE: Risk of Thrombotic Events (without
andexanet) after Bleeding
71% OAC interrupted
54% resumed
For ICH 91% interrupted
11% resumed
22- and 13-fold increase
in stroke/MI after ICH
and non-ICH bleeding,
respectively

European Heart Journal (2015) 36, 1264-1272

doi:10.1093/eurheartj/ehu463 4
ANNEXA-4 Study Design
Bleeding and Laboratory Assessment
Patient Screening Andexanet Safety
2-hour After end of
IV follow-up visit
Patient Within 18 Bolus IV Infusion infusion
with acute hours of
major last dose
bleeding of FXa
inhibitor
1 hr 4 hr 8 hr 12 hr
Assessments: Day 1 Day 3 Day 30

Efficacy Outcomes Safety Measurements

◆Change in anti-fXa activity ◆Thrombotic events
◆Clinical hemostatic efficacy ◆Antibodiesto FX, FXa, andexanet
through 12 hours ◆30-day mortality

5
 Baseline Characteristics
Includes all patients as of October 20, 2017
Safety Population Efficacy Population
N=227 N=137
Age (yr), mean ± SD 77(±11) 77 (±12)
Male 117 (52%) 70 (51%)
Time from presentation until Andexanet (hrs) 4.7 ± 2.8 5.0 ± 3.1
Estimated creatinine clearance < 30 mL/min 21 (9%) 13 (10%)
Indication for anticoagulation
Atrial fibrillation 178 (78%) 104 (76%)
Venous Thromboembolic Disease 52 (23%) 38 (28%)
Atrial fibrillation and VTE 8 (4%) 6 (4%)
Medical History
Myocardial infarction 32 (14%) 15 (11%)
Stroke 47 (21%) 32 (23%)
Heart Failure 52 (23%) 36 (26%)
Diabetes mellitus 67 (30%) 42 (31%) 6
 Site of Initial Bleeding
Safety Population Efficacy Population
N=227 N=137
Intracranial Bleeding 139 (61%) 78 (57%)
Glasgow Coma Scale, mean ± SD 13.9 ± 1.63 13.9 ± 1.70
Intracerebral site 74 (52%) 44 (54%)
Sub-dural site 45 (32%) 24 (30%)
Subarachnoid site 23 (16%) 13 (16%)

Gastrointestinal Bleeding 62 (27%) 43 (31%)

Other Bleeding site 26 (12%) 16 (12%)

7
 Anti-factor Xa Activity: Rivaroxaban n = 75
800
Anti-factor Xa Activity (ng/ml)

600

400

200

0
Baseline End of Bolus End of Infusion 4 Hr 8 Hr 12 Hr

Median 169.75 11.30 14.40 96.80 82.60 72.20

Percent Change -88% -87% -42% -49% -60%
(95% CI) (-92 to -82) (-89 to -82) (-46 to -33) (-53 to -45) (-65 to -53) 8
 Anti-factor Xa Activity: Apixaban n = 105

800
Anti-factor Xa Activity (ng/ml)

600

400

200

0
Baseline End of Bolus End of Infusion 4 Hr 8 Hr 12 Hr
Median 132.60 9.45 10.10 79.65 90.05 80.90
Percent change -91% -91% -36% -30% -35%
(95% CI) (-92 to -90) (-92 to -90) (-41 to -29) (-36 to -25) (-41 to -32) 9
 Effective Hemostasis at 12 Hours Post Andexanet

Number of Patients Percent of Patients who

95%
Number of Major who Achieved Achieved
Confidence
Bleeds Adjudicated Excellent or Good Excellent or Good
Interval
Hemostasis Hemostasis
132 109 83% 76% - 89%

10
 Clinical Hemostatic Efficacy
Subgroup No. of Patients Excellent or Good (95% CI)
Total Efficacy Patients 132 83 ( 76- 89 )
Drug
Rivaroxaban 54 83 ( 73- 93 )
Apixaban 68 82 ( 73- 91 )
Enoxaparin 10 80 ( 55-100 )
Sex
Male 67 81 ( 71- 90 )
Female 65 85 ( 76- 93 )
Site of bleeding
Gastrointestinal 43 86 ( 76- 96 )
Intracranial 74 81 ( 72- 90 )
Other 15 80 ( 60-100 )
Age
<65 yr 18 83 ( 66-100 )
65-75 yr 38 87 ( 76- 98 )
>75 yr 76 80 ( 71- 89 )
Andexanet dose
Low 117 81 ( 74- 88 )
High 15 93 ( 81-100 )
25 50 75 100 11
Safety Assessment

Thrombotic events occurred within 3 days of andexanet in

6 (2.6%) patients and by 30 days in 24 (11%)
Anticoagulation re-started in 129 patients (57%) by 30 days
Therapeutic anticoagulation was re-started in only 9 patients
before a thrombotic event occurred
27 deaths occurred by 30 days (12%), of which 11 were
cardiovascular

12
 Thrombotic Events
All events Events after re-start of anticoagulation
0.12 0.12 Data as of: 20OCT2017
11% # Unrefuted TE after restart of AC among those restarted AC: 7 / 129

0.10 0.10
Proportion with an Event

0.08 0.08
7%
0.06 0.06

0.04 0.04

0.02 0.02

0.00 0.00
0 3 6 9 12 15 18 21 24 27 30 0 3 6 9 12 15 18 21 24 27 30
Days of Follow-up Days Since Re-start of AC
No. at risk: 227 221 216 210 202 201 196 188 181 179 171 129 125 124 117 114 110 99 93 82 70 48
13
 Thrombosis/Mortality Rates in Bleeding Patients
in Recently Completed Studies
Hemostatic Efficacy Thrombotic Event Mortality
Reversal Agent Number
Study (95% CI) Rate (95% CI) (95% CI)
Anticoagulant
Total % ICH Total ICH Total ICH Total ICH
ANNEXA-4 * Andexanet 83% 81% 11% 12% 12% 12%
227 61
(2018) FXa Inhibitors (76-89) (72-90) (7-16) (7-19) (8-18) (7-20)
REVERSE-AD Idarucizumab 5% 6% 14% 16%
301 33 68% a NR b
(2017) Dabigatran (3-8) (2-13) (10-18) (10-25)
Sarode 4F-PCC 72% 42% 8% 6%
98 12 NR NR
(2013) Warfarin (64-81) (15-72) (3-15) (2-12)
Sarode Plasma 65% 58% 6% 5%
104 12 NR NR
(2013) Warfarin (56-75) (28-85) (3-13) (2-10)

Ezekwudo None 15% 15% 45% 45%

125 100 N/A N/A
(2017) VKA 60%/FXai 35% (9-23) (9-23) (36-54) (36-54)

4F-PCC = Four factor prothrombin complex concentrate; CI = Confidence interval; ICH = Intracranial hemorrhage; N/A = Not applicable; NR = Not reported
a 68% had investigator-determined, non-adjudicated time to hemostasis within 24 hours
b Time to hemostasis not calculated in ICH patients 14
Conclusions
Andexanet rapidly reverses anti-fXa activity

Effective hemostasis achieved in 83% of patients

Thrombotic events/mortality rates consistent with the high risk

profile of the patients

Andexanet reversal of FXa inhibitor-bleeding has similar efficacy

and safety as reported with other approved reversal agents

15
Biomarker Reversal vs. Hemostatic Efficacy of
Andexanet Compared to Approved Reversal Agents
% with Full Hemostatic Efficacy
Reversal
Study N Biomarker Biomarker
Agent
Reversal Excellent/Good Poor/None

ANNEXA-4 * 137 Andexanet Anti-fXa 88% a 83% 17%

DTT 98% b
REVERSE-AD 123 Idarucizumab 68% c 32%
ECT 89% b
98 4F-PCC INR 88% 72% 28%
Sarode 2013
104 Plasma INR 58% 65% 35%

4F-PCC = Four factor prothrombin complex concentrate; CI = Confidence interval; DTT = Diluted thrombin time; ECT = Ecarin clotting time;
INR = International normalized ratio
a Percentage of patients with a post-treatment nadir in anti-fXa activity of < 75 ng/mL
b Percentage of patients as documented in BLA 761025
c Percentage of patients with investigator-determined hemostasis at 24 hours (only indicated at study completion) 16
* Based on 228 patient data cut 20 Oct 2017
Recent Publications of the APEX Trial:
Betrixaban for VTE Prevention
in Hospital to Home for
Acute Medically Ill Patients
Previous VTE Prophylaxis Studies Failed Due to
Significant Increase in Major Bleeding and Limited Efficacy
EXCLAIM† MAGELLAN
(Failed Interim Futility) Enoxaparin vs. Rivaroxaban
Enoxaparin* vs. Extended Enoxaparin N=8,101
N=5,963
RRR=22.8%
ARR=1.31%
6 5.7%
P=0.02
4.4%
VTE Events

4.0%

3.3%
3.3% 2.5%
Event Rate (%)

2.4%

0
More Major Bleeding

0.3%
0.4%
0.8% 1.1%
P<0.05 P<0.001
3 Standard Enoxaparin (6-14d)* Standard Enoxaparin (6-14d)
Extended Enoxaparin (24-32d) Extended Rivaroxaban (31-39d)

†EXCLAIM efficacy analysis based on revised eligibility criteria and enrollment after DSMB stopped trial for futility.
* Patients in both study arms received open label enoxaparin for 6-14 days followed by placebo or extended duration enoxaparin.
Cohen AT et al. N Eng J Med. 2013;368(6):513-523; Hull RD et al. Ann Intern Med. 2010;153(1):8-18.
18
 mITT Analysis; Primary Efficacy and Safety Outcomes
(80 mg and 40 mg population)

VTE and VTE Death Major Bleeding

DAY 42 DAY 42

Enoxaparin/Placebo RRR=25% Enoxaparin/Placebo

RR=1.2
Betrixaban ARR=1.56% Betrixaban P=0.54
P=0.003 7%
7%
NNT=65
6% 6.0% 6%

223/3720 5%
4.4%
5%
4%
4%
165/3721
3%
3%
2%
2%

1%
1% 0.6% 0.7%
21/3716 25/3716
0%
0%

mITT=Modified intent-to-treat; RRR=relative risk reduction

BEVYXXA [Package Insert], Portola Pharmaceuticals, Inc.
19
 Reduction in VTE-Related Death
(mITT population)

New results published last month in The American Heart Journal

VTE-Related Death (80 mg)

HR = 0.46 (95% CI: 0.22 – 0.96)

p = 0.035
0.79%
ARR = 0.45%
VTE-related Death (%)

NNT = 223
Enoxaparin

Betrixaban 0.34%

Gibson et al. Symptomatic event reduction with extended-duration betrixaban

in acute medically ill hospitalized patients. Am Heart J. 2018; 198:84-90. 20
 Reduction in VTE-Related Rehospitalizations
VTE-Related Rehospitalizations (80 mg)
(miTT population)
1.50

1.25%
1.25
Probability of Rehospitalization (%)

0.94%
1.00

P=0.0015
NNT=127
0.75
P=0.0006
ENOXAPARIN NNT=143
0.50

0.46%
0.25
0.24%
BETRIXABAN
0.00
0 10 20 30 40 50 60 70 77
Time (days)
Chi G et al. Circulation. 2018; 137(1):91-94 21
 Time to Ischemic Stroke in Patients
With Ischemic Stroke or CHF as Index Event
Time to Ischemic Stroke
(Post hoc, 80 mg and 40 mg doses)
1.5
1.38%
Probability of Ischemic Stroke (%)

P=0.014

1.0

ENOXAPARIN 0.63%

0.5
HR
HR = 0.45
= 0.45 (0.24,(0.24,
0.87) 0.87)
ARR
ARR = 0.75%
= 0.75%
BETRIXABAN NNT = 134
NNT = 133
0.0

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75
Time (days)
“The results presented by the APEX investigators highlight the urgent need for more effective
secondary prevention therapies in these patients and provide the first evidence that a NOAC 22
may reduce stroke in this population.” - Editorial Gibson CM et al. Circulation. 2017;135(7):648-655
 Reduction of VTE in Patients with a History of VTE
Composite VTE
(miTT population)

20% 18.9%
RRR = 43%
P=0.006
NNT = 12
16%

12% 10.4%

8%

4%

55/291 32/307
0%

Standard Enoxaparin (6-10d)

Extended Betrixaban (36-42d)

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

Yee et al 2017 J Thromb Thrombolysis 23
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