1. No category

Cardiovascular and Renal Drugs
Advisory Committee
Edoxaban
NDA 206316
Statistical Considerations, ENGAGE AF Trial
John Lawrence, PhD
Senior Statistical Reviewer, FDA/CDER/OB/Division of Biometrics I
Jim Hung, PhD
Division Director, FDA/CDER/OB/Division of Biometrics I
1
1. Summary
• Confirmed applicant’s analysis and agree with their results
• All doses studied should be approved.
- 60 mg for most people.
- 30 mg for people who need a lower dose adjustment
(e.g. eCrCL<50 mL/min)
2
2. 60 mg Dose appeared Effective in
eCrCL>80 mL/min Subgroup
• In the subgroup with eCrCL>80 mL/min, the estimated hazard
ratio for the primary endpoint (60 mg edoxaban vs. warfarin)
was 1.41 with a wide confidence interval.
• Because the noninferiority margin was 1.38, this is similar to a
superiority trial where the drug is superior overall, but in one
subgroup the point estimate is slightly above 1.
3
3. Event Rate in Smaller Subgroups
In the subgroup eCrCL>80 mL/min, warfarin performed very well.
Number of events nearly the same in both arms in subgroup 80-106
4
4. 30 mg Dose was Effective
• Low dose regimen (30 mg or 15 mg) was shown effective in the
overall population (median eCrCL=70 mL/min)
• A typical patient with eCrCL>80 (median eCrCL=100 mL/min)
taking 60 mg should have higher exposure than a typical patient
in the low dose arm.
• All cause mortality, low dose (30/15) vs. warfarin:
HR 0.87; 95% CI (0.79, 0.96); p-value = 0.006
• Primary endpoint, 30 mg no dose adj. vs. warfarin no dose adj.:
HR 1.02 with 95% CI (0.82, 1.28)
median eCrCL = 78 mL/min
5
5. Possible consequence of approving unstudied
higher dose
• Even if a higher dose is safe and more effective for people
with eCrCL>80 mL/min, there may be dosing errors (people
confusing eGFR for eCrCL, etc.)
6
Cardiovascular and Renal Drugs
Advisory Committee
Edoxaban (Savaysa™)
NDA 206316
October 30, 2014
Clinical Review Team
Melanie Blank, MD
Tzu-Yun McDowell, PhD
Martin Rose, MD
1
How to Approach
the Observed Decreased Efficacy of Edoxaban
in Subjects with Normal Renal Function
2
ENGAGE AF Results
• Trial met its non-inferiority success criteria for both edoxaban
dose regimens on efficacy
• Both dose regimens were superior on International Society of
Thrombosis and Hemostasis (ISTH) major bleeding compared
to warfarin
• The low dose regimen was inferior on ischemic stroke
• Main review issue: inferior efficacy relative to warfarin in the
normal renal function subgroup for both dose regimens on
ischemic stroke
3
Outline
• Historical perspective on nonvalvular atrial fibrillation (NVAF),
and the impact of anticoagulants on stroke rates
• Show how anticoagulant exposure determines the balance
between thromboembolic events and bleeding
• Discuss how we should be thinking about ischemic stroke
separately from hemorrhagic stroke
• Review approved non-vitamin K dependent oral anticoagulant
(NOAC) trial results on ischemic and hemorrhagic stroke
• Describe the deficiencies of the phase 2 dose-finding study
which led to doses for ENGAGE that were on the low side
• Describe interaction between efficacy results and renal function,
with decreased efficacy in the normal renal function subgroup
• Discuss possible regulatory responses
4
Warfarin and stroke in nonvalvular
atrial fibrillation (NVAF)
• The annual rate of stroke in NVAF without any treatment would be
~ 5%/year based on data from historical placebo-controlled trials
• With NVAF affecting ~ 0.4% of the population, there would be
~63,000 strokes per year in the U.S. without treatment
• Warfarin reduces stroke rate by 62% in NVAF; theoretically if every
NVAF patient were on warfarin ~39,000 strokes/year would be
prevented (leaving ~ 24,000 strokes/year)
• The trade-off for this reduction is an increase in intracranial
bleeding and hemorrhagic stroke
– Hemorrhagic stroke used to account for 2% of stroke. For warfarin
treated patients, hemorrhagic stroke is now 1/3 of all strokes
5
Ischemic vs. hemorrhagic stroke rate;
trade-off by treatment
Ischemic
Stroke
%/year
Hemorrhagic
Stroke
%/year
Placebo
~5
~0.1
Warfarin
~1.0
0.4 - 0.5
~4
~0.2
0.8 – 1.0
0.1 – 0.3
Aspirin
Approved NOACs
6
Odds ratio of ischemic stroke/intracranial
bleeding by INR in patients treated with warfarin
Intracranial Bleed
○
Ischemic Stroke
From the
ACC/AHA/ESC
practice
guidelines
International Normalized Ratio
7
Exposure-response relationships for dabigatran
----------------+-----------------------------------------------------------------------110 BID ------------------+-------------------------------------------------150 BID
8
Hemorrhagic and ischemic stroke
should be examined separately
• Hemorrhagic strokes and ischemic strokes (for the most part)
have different pathophysiologies and different dose response
curves, and for these reasons should be examined separately
• Combining hemorrhagic and ischemic strokes into one
composite endpoint obscures different effects on the individual
components and can lead to misleading results, another reason
to examine them separately
E30/15mg vs.
Warfarin
Stroke/SEE
HR (95% CI)
Hem. Stroke
HR (95% CI)
Isch. Stroke
HR (95% CI)
1.07 (0.86, 1.34)
0.23 (0.13, 0.38)
1.54 (1.25, 1.90)
9
Exposure-response curve for edoxaban
Probability of Ischemic
stroke/SEE per year (%)
Edoxaban low dose regimen exposure range
(95%CI)
First ischemic stroke/SEE: event rate for
edoxaban low dose: 1.49 %/yr
First ischemic stroke/SEE: event rate for
edoxaban high dose: 0.93%/yr
(mITT, on treatment)
●
●
10
NOACs and performance on ischemic stroke
Drug
NOAC arm
event rate in
%/yr
Warfarin arm
event rate in
%/yr
HR relative to
warfarin
Dabigatran 150 mg
BID
0.90
1.10
0.76 (0.59, 0.98)
Dabigatran 110 mg
BID
1.30
1.10
1.13 (0.89,1.42)
11
NOACs and performance on ischemic stroke
Drug
NOAC arm
event rate in
%/yr
Warfarin arm
event rate in
%/yr
HR relative to
warfarin
Dabigatran 150 mg
BID
0.90
1.10
0.76 (0.59, 0.98)
Dabigatran 110 mg
BID
1.30
1.10
1.13 (0.89, 1.42)
Apixaban 5 mg
BID
0.83
0.82
1.02 (0.81, 1.29)
12
NOACs and performance on ischemic stroke
Drug
NOAC arm
event rate in
%/yr
Warfarin arm
event rates
in %/yr
HR relative to warfarin
Dabigatran 150 mg
BID
0.90
1.10
0.76 (0.59, 0.98)
Dabigatran 110 mg
BID
1.30
1.10
1.13 (0.89,1.42)
Apixaban 5 mg
BID
0.83
0.82
1.02 (0.81,1.29)
Rivaroxaban 20 mg
QD
1.3
1.4
0.94 (0.75, 1.17)
13
NOACs and performance on ischemic stroke
Drug
Drug
Dabigatran 150 mg
Dabigatran
150 mg
BID
BID
Dabigatran
110 mg
Dabigatran
110 mg
BID
BID
Apixaban
5 mg
Rivaroxaban
20 mg
BID
QD
Rivaroxaban 20 mg
Apixaban
QD 5 mg BID
Edoxaban
60 mg
mg QD
Edoxaban
60/30
QD
Edoxaban
30 mg
mg
Edoxaban
30/15
QD
Events
NOAC
arm
ExD in
event rate
(%/yr)
%/yr
Events
Warfarin armHR relative to
HR relative to
Warfarin
event rate in warfarin
warfarin
(% /yr)%/yr
0.90
12 (0.1)
45 (0.4)
1.10
0.76 (0.59,0.98)
0.26 (0.14,0.49)
1.30
14 (0.1)
45 (0.4)
1.10
1.13 (0.89,1.42)
0.31 (0.17,0.56)
0.83
29 (0.26)
0.82
1.02 (0.81,1.29)
50 (0.44)
0.59 (0.37, 0.93)
1.30
40
(0.24)
78 (0.47)1.40 0.51 (0.35,0.94
0.75)(0.75, 1.17)
40 (0.26)
0.87
76 (0.49)
0.53 (0.36, 0.78)
0.93
0.94 (0.75, 1.19)
18 (0.11)
1.43
76 (0.49)
0.23 (0.14, 0.39)
0.93
1.54 (1.25, 1.9)
14
NOACs and performance on hemorrhagic stroke
Drug
NOAC arm
event rate in
%/yr
Warfarin
arm event
rate in
%/yr
Dabigatran 150 mg
BID
0.10
0.40
0.26 (0.14, 0.49)
Dabigatran 110 mg
BID
0.10
0.40
0.31 (0.17, 0.56)
Rivaroxaban 20 mg
QD
0.26
0.44
0.59 (0.37, 0.93)
Apixaban 5 mg
BID
0.24
0.47
0.51 (0.35, 0.75)
Edoxaban 60/30 mg
QD
0.26
0.49
0.53 (0.36, 0.78)
Edoxaban 30/15 mg
QD
0.11
0.49
0.23 (0.14, 0.39)
HR relative to
warfarin
15
PRT-018 phase 2 design
Screening
Randomization
Edoxaban 30 mg QD
Edoxaban 30 mg BID
Edoxaban 60 mg QD
Follow-up
Assessment
Edoxaban 60 mg BID
Warfarin QD
<30 days
Day 1
3-month randomized
treatment phase
30 days after
last dose
16
PRT-018 results:
Doses selected to match warfarin bleeding rates
30 mg qd
(N=235)
60 mg qd
(N=234)
30 mg bid
(N=244)
60 mg bid
(N=180)
Warfarin
(N=250)
All bleeding n(%)
13 (5.5)
17 (7.3)
31 (12.7)
33 (18.3)
20 (8.0)
Diff. vs. warfarin
-2.5%
-0.7%
4.7%
10.3%*
7 (3.0)
9 (3.8)
19 (7.8)
19 (10.6)
-0.2%
0.6%
4.6%
7.4%*
1 (0.4)
1 (0.4)
3 (1.2)
2 (1.1)
Major or CR* nonmajor bleeding n(%)
Diff. vs. warfarin
STROKE/SEE
8 (3.2)
4 (1.6)
* Nominal p=0.002
*CR= clinically relevant
17
Warfarin arm: control of INR was suboptimal
Number (%) of Subjects in the Warfarin Group
INR
RANGE
<2.0
≥2.0 to ≤ 3.0
(target)
> 3.0
Baseline
(N=243)
Day 28
(N=229)
226 (93.0) 106 (46.3)
16 (6.6)
98 (42.8)
1 (0.4)
25 (10.9)
Day 42
(N=228)
93 (40.8)
Day 85
(N=215)
87 (40.5)
115 (50.4) 108 (50.2)
20 (8.8)
20 (9.3)
18
Dose finding study resulted in
doses that were too low
• PRT-018 was a small study, sized for bleeding
• Main deficiency:
– The warfarin arm was under-dosed which led to lower
bleeding rate
• Comparisons of bleeding rates in the edoxaban arms to
a poorly controlled warfarin arm were erroneous
• In conclusion, the edoxaban doses were selected on the
basis of a poorly conducted study and nearly guaranteed
that doses would be too low
19
ENGAGE AF
Major Review Issues
20
Stroke/SEE by renal function
subgroups (mITT/on treatment period)
30-50 mL/min*
Moderate renal impairment
0.88
E60/30 DA
1.19
E30/15 DA
>50-<80 mL/min
Mild renal impairment
0.51
E60/30 DA
0.82
E30/15 DA
≥80 mL/min
Normal renal function
E60/30 DA
1.41
1.61
E30/15 DA
0.5
1.5
0.75
1
Hazard Ratio (95% CI)
2
Edoxaban
n/N (% pt-yr)
Warfarin
n/N (% pt-yr)
43/1287 (1.73)
49/1297 (1.98)
58/1274 (2.33)
49/1297 (1.98)
69/2985 (1.04)
135/3030 (2.01)
115/3034 (1.66)
135/3030 (2.01)
66/2612 (1.07)
47/2595 (0.76)
76/2611 (1.22)
47/2595 (0.76)
*Dose Adjusted
21
Ischemic stroke/SEE by renal function
subgroups (mITT/on treatment period)
30-50 mL/min*
Moderate renal impairment
1.04
E60/30 DA
1.87
E30/15DA
>50-<80 mL/min
Mild renal impairment
1.10
≥80 mL/min
Normal renal function
32/1287 (1.28)
31/1297 (1.25)
58/1274 (2.33)
31/1297 (1.25)
54/2985 (0.82)
90/3030 (1.34)
104/3034 (1.51)
90/3030 (1.34)
55/2612 (0.89)
35/2595 (0.57)
69/2611 (1.11)
35/2595 (0.57)
1.58
E60/30 DA
1.97
E30/15DA
0.5
Warfarin
n/N (% pt-yr)
0.60
E60/30 DA
E30/15DA
Edoxaban
n/N (% pt-yr)
1.5
1
Hazard Ratio (95% CI)
2
2.5
3
*Dose Adjusted
22
Effect of CrCl on risk of
ischemic stroke/SEE
Probability of Ischemic Stroke/SEE within 1 year (%)
(Edoxaban 60 mg vs. Warfarin)
Edoxaban 60 mg
CrCl level
Model predicted
HR (95% CI)
50 ml/min
0.55 (0.36-0.86)
65 ml/min
0.71 (0.52-0.99)
80 ml/min
0.92 (0.70-1.22)
95 ml/min
1.19 (0.84-1.67)
110 ml/min
1.53 (0.96-2.44)
125 ml/min
1.98 (1.07-3.67)
Warfarin
CrCL (ml/min)
Cox model controlled for age, hx of stroke, CHADS2 score, CRCL, CRCL*treatment among
patients without dose adjustment in mITT set
23
Ischemic stroke (%/yr)
Ischemic stroke by CrCL decile in ENGAGE
2.8
2.6
2.4
2.2
2
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
Edoxaban 30 mg
Edoxaban 60 mg
Warfarin
CrCL
>50 - <80
≥80
HR
(mITT)
0.62
1.58
CRCL Decile (mL/min)
24
ISTH Major bleeding by renal
function subgroups
30-50 mL/min*
Moderate renal impairment
0.75
E60/30 DA
0.38
E30/15DA
>50-<80 mL/min
Mild renal impairment
Edoxaban
n/N (% pt-yr)
Warfarin
n/N (% pt-yr)
96/1287 (3.81)
128/1297 (5.09)
50/1274 (1.95)
128/1297 (5.09)
206/2985 (3.10)
235/3030 (3.45)
134/3034 (1.90)
235/3030 (3.45)
108/2612 (1.73)
154/2595 (2.48)
69/2611 (1.08)
154/2595 (2.48)
0.90
E60/30 DA
0.55
E30/15DA
≥80 mL/min
Normal renal function
E60/30 DA
0.70
0.44
E30/15DA
0.3
0.5
0.7
Hazard Ratio (95% CI)
1
*Dose Adjusted
25
Effect of creatinine clearance on
pre-dose (trough) edoxaban plasma
concentration (day 29)
Edoxaban Ctrough (ng/mL)
60
50
E60/30
48.6
E30/15
43.1
High dose group/ dose
adjusted to 30 mg
40
30
20
Subjects with
no dose adjustment
29.1
28.2
24.8
21.3
14.6
10
0
30-50
1/1/1900
>50-<80
1/2/1900
≥ 80
1/3/1900
CrCl (ml/min)
26
Warfarin TTR (INR 2-3) was similar
among renal function subgroups in ENGAGE AF
CrCl
(mL/min)
% TTR
(average)
%Time
above TR
(average)
%Time
below TR
(average)
30 – 50
65.0
12.3
22.7
>50 - <80
65.3
12.1
22.6
≥80
64.7
12.1
23.1
27
Warfarin Stroke/SEE event
rates in the normal renal function
subgroup in pivotal NOAC trials
Warfarin stroke/SEE rate (%/yr)
Trial
RE-LY; dabi vs. warfarin
(ITT, overall study period)
ROCKET AF; riva vs. warfarin
(per-protocol, on-treatment)
ARISTOTLE; apix vs. warfarin
(ITT, overall study period)
ENGAGE AF; edox vs. warfarin
(mITT, on-treatment)
ENGAGE AF; edox vs. warfarin
(ITT, overall study period)
Decrease in
event rate
from B to A
Normal Renal
Function
A
Mild renal
impairment
B
1.03
1.87
45%
1.42
2.41
41%
1.12
1.69
34%
0.76
2.01
62%
0.98
2.19
55%
28
Strokes/SEE rates and
outcomes in NOAC trials by renal function
subgroup
Drug, Trial
Dabigatran 150 mg; RE-LY
(ITT, overall study period)
Rivaroxaban; ROCKET AF
(per-protocol, On-treatment)
Apixaban; ARISTOTLE
(ITT, overall study period)
Edoxaban 60/30; ENGAGE
AF (mITT, On-treatment)
CrCL in
mL/min
First stroke/SEE Rates
(%/yr)
HR rel. to
Warfarin
NOAC
Warfarin
>50 - <80
1.21
1.87
0.65
≥80
0.73
1.03
0.71
>50 - <80
1.75
2.41
0.73
≥80
1.27
1.42
0.89
>50 - <80
1.24
1.69
0.73
≥80
0.99
1.12
0.88
>50 - <80
1.04
2.01
0.51
≥80
1.07
0.76
1.41
29
First ischemic stroke rates and
outcomes in NOAC trials by renal function subgroup
Drug, Trial
Dabigatran 150; RE-LY
(ITT, overall study period)
Rivaroxaban; ROCKET AF
(per-protocol, on-treatment)
Apixaban; ARISTOTLE
(per-protocol, on-treatment)
Edoxaban 60/30; ENGAGE AF
(mITT, on-treatment)
Edoxaban 60/30; ENGAGE AF
(ITT, overall study period)
CrCL in
mL/min
First stroke/SEE
Rates (%/yr)
Hazard Ratio
NOAC
Warfarin
NOAC vs. Warfarin
>50 - <80
0.94
1.22
0.77
≥80
0.61
0.72
0.84
>50 - <80
1.39
1.70
0.82
≥80
0.94
0.87
1.07
>50 - <80
0.77
0.89
0.87
≥80
0.69
0.51
1.35
>50 - <80
0.77
1.23
0.62
≥80
>50 - <80
≥80
0.84
1.21
1.02
0.53
1.49
0.73
1.58
0.81
1.40
30
Summary
1. The dose chosen for ENGAGE AF was too low because
it was based on a dose-finding trial in which the warfarin
arm was under-dosed
2. There are several reasons to believe that the poorer
performance in the normal renal subgroup is not a
chance finding:
A. Increased ischemic stroke in the normal renal function
subgroup
B. Decreased major bleeding in the normal renal function
subgroup
C. Consistent finding of decreased efficacy in normal renal
function in both high and low dose edoxaban regimens
D. Exposures were lower (low trough edoxaban levels) in the
normal renal function subgroup
31
Summary (cont.)
3. The warfarin arm performance in ENGAGE AF was in line with
other trials
4. Hemorrhagic stroke and ischemic stroke should be analyzed
and considered separately.
5. We should start considering exposure targeting to maximize
the benefit-risk profile of NOACs
32
Regulatory options
• Approval for high-dose edoxaban with applicant’s
proposed dosing instructions; not an option in the
opinion of the clinical reviewers
• Don’t approve during this review cycle and hope that the
applicant does a trial in which they titrate dose to optimal
exposure, which might usher in a new era of more
refined NOAC management
• Approve with labeling that would limit use to patients with
mild and moderate renal impairment
• Exposure match the normal renal function to exposures
observed in the mild renal impairment subgroup, which
had the best results for edoxaban
33
Back-ups
34
Ischemic stroke by CrCL decile in RE-LY
2.4
2.2
Ischemic stroke (%/yr)
2
1.8
Dabigatran 110 mg
Dabigatran 150 mg
Warfarin
CrCL
HR
1.4
>50 - <80
0.77
1.2
≥80
0.84
1.6
1
0.8
0.6
0.4
0.2
0
CRCL Decile (mL/min)
ITT, overall study period
35
Ischemic stroke by CrCL decile in ARISTOTLE
2
Apixaban
Warfarin
1.8
Ischemic stroke (%/yr)
1.6
1.4
1.2
1
0.8
CrCL
HR
>50 - <80
0.87
≥80
1.35
0.6
0.4
0.2
0
CRCL Decile (mL/min)
36
Edoxaban Dosing Considerations Based
on Renal Function
Justin C. Earp, PhD
Office Clinical Pharmacology,
Division of Pharmacometrics
October 30, 2014
1
Outline
• Subgroup Finding & Motivation
• Exposure - Response Relationships
– Stroke Events
– Bleeding Events
• Exposure - Response by Renal Function
Category
• Exposure Matching for Dose Recommendation
2
Patients with Normal Renal
Function and 60 mg Edoxaban had a Higher
Risk for Stroke/SEE Relative to Warfarin
Renal Function Category
Hazard Ratio (95% CI)
Hazard Ratio (95% CI)
Stroke/SEE
Major Bleeds
Edoxaban Better
Applicant: CSR U-301, Tables 14.2.5.2, 14.5.3.24, Edoxaban 60 mg
Warfarin Better
3
Renal Clearance is the
Major Edoxaban Elimination Pathway
• Patients with moderate renal
impairment received a 50%
dose reduction in the Phase 3
ENGAGE AF study
Normal
Mild
• AUC increased 32%, 74%, and
72% for mild, moderate, and
severe impairment
High Dose Arm
Moderate
• 60% of systemic edoxaban
cleared by the kidneys
50% Dose Reduction
Edoxaban Ctrough (ng/mL)
Applicant: CSR U-120, Table 11.2, Edoxaban 60 mg
4
Patients with Lower Exposures
in the High Dose Edoxaban Appeared to do
Better on Major Bleeds and Worse on Stroke/SEE
Relative to Warfarin
Mild
Moderate
Hazard Ratio
Major Bleeds
Normal
Mild
Mild
Normal
Moderate
Stroke/SEE
Normal
Edoxaban PK
Moderate
50% Dose Reduction
Ctrough (ng/mL)
Applicant: CSR U-301, Tables 14.2.5.2, 14.5.3.24, Edoxaban 60 mg
Hazard Ratio
5
Dose Response Is Evident
For Stroke & Major Bleeding Events
mITT population,
on-treatment events
Applicant: CSR U-301, Tables 14.2.5.2, 14.5.3.24, Edoxaban 60 mg
6
Exposure - Response
Efficacy & Safety Analyses
Exposure - response relationships are shown for:
– Stroke/SEE, Ischemic stroke
– Major bleeds, Life-threatening/fatal bleeds
Significant Predictors for
Stroke/SEE & Ischemic Stroke:
Significant Predictors for
Major & LTB/Fatal Bleeding Events:
– Edoxaban log(Ctrough)
– Edoxaban Ctrough or log(Ctrough)
– Age
– Age
– Prior Stroke / TIA
– Concomitant Aspirin Use
– Weight
– CHADS2
– CHADS2
Data: Only Edoxaban Patients, On-treatment Strokes/Bleeds, mITT population
7
Edoxaban Exhibits
Concentration Dependent Relationships
for Stroke/SEE & Major Bleeds
Analysis shown for “typical” patient population: Age: 72 years old, Renal Function: (70.4 mL/min),
28.3% with prior stroke, 29.2% with baseline aspirin use.
Note: y-axis scales on the right are 4-fold higher than the scale on the left
8
Edoxaban Exhibits
Concentration Dependent Relationships
for Ischemic Stroke & Life-Threatening/Fatal Bleeds
Analysis shown for “typical” patient population: Age: 72 years old, Renal Function: (70.4 mL/min),
28.3% with prior stroke, 29.2% with baseline aspirin use.
9
Projected Ischemic
Stroke and Life-Threatening Bleeding
Rates Agree with Observed Data
10
Projected Ischemic
Stroke and Life-Threatening Bleeding
Rates Agree with Observed Data
11
This Benefit - Risk
Relationship Is not Novel
Dabigatran: RE-LY Trial
• Warfarin also has a similar relationship based on INR
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/
12
EXPOSURE RESPONSE BY
RENAL IMPAIRMENT CATEGORY
13
The Probability of an
Ischemic Stroke Increases with
Decreasing Renal Function
Analysis shown for “typical” patient with normal renal function: 64 years old, CrCL of 100 mL/min,
24.8% with prior stroke, 29.2% with baseline aspirin use, body weight of 95.3 kg
14
The Probability of an
Ischemic Stroke Increases with
Decreasing Renal Function
Analysis shown for “typical” patient with normal renal function: 64 years old, CrCL of 100 mL/min,
24.8% with prior stroke, 29.2% with baseline aspirin use, body weight of 95.3 kg
15
The Probability of an
Ischemic Stroke Increases with
Decreasing Renal Function
Analysis shown for “typical” patient with normal renal function: 64 years old, CrCL of 100 mL/min,
24.8% with prior stroke, 29.2% with baseline aspirin use, body weight of 95.3 kg
16
The Probability of an
Ischemic Stroke Increases with
Decreasing Renal Function
Analysis shown for a “typical” patient with either normal or mild renal function.
Mild Renal Function: 74years old, CrCL of 64.2 mL/min, 30.4% with prior stroke, 29.1% with baseline aspirin
use, body weight of 78 kg
17
The Probability of an
Ischemic Stroke Increases with
Decreasing Renal Function
Analysis shown for a “typical” patient with either normal or mild renal function.
Mild Renal Function: 74years old, CrCL of 64.2 mL/min, 30.4% with prior stroke, 29.1% with baseline aspirin
use, body weight of 78 kg
18
The Probability of an
Ischemic Stroke Increases with
Decreasing Renal Function
Analysis shown for a “typical” patient with either normal or mild renal function.
Mild Renal Function: 74years old, CrCL of 64.2 mL/min, 30.4% with prior stroke, 29.1% with baseline aspirin
use, body weight of 78 kg
19
Similar Observations with
Regards to Exposure - LFT/Fatal Bleed
Relationship
warfarin – mild impairment
warfarin – normal
Analysis shown for “typical” patient with normal and mild renal function
20
DOSES THAT MATCH EDOXABAN
EXPOSURES IN PATIENTS WITH MILD
RENAL IMPAIRMENT
21
Edoxaban Ctrough (ng/mL)
Exposure Matching
Requires a Dose that is Higher than 75 mg
Mild
Normal
22
Projected Lower Stroke/SEE
Rate with Higher Doses Approaching the
Rate of Warfarin: Normal Renal Function
Proposed dose adjustment
is aimed at moving the hazard
ratio estimate towards
non-inferiority
Analysis shown based on observed demographics and event rates for patients with normal
renal function from ENGAGE AF
23
Fewer Ischemic Strokes with
Less Increase in Life-Threatening/Fatal
Bleeds at Higher Doses: Normal Renal Function
Analysis shown based on observed demographics and event rates for patients with normal
renal function from ENGAGE AF
24
Excess of Events in Edoxaban
Arm Compared to Warfarin for
Normal Renal Function Patients:
# Events / 10,000 Patients / Year
Edoxaban Dose
Ischemic Stroke
LT / Fatal Bleed
30 mg
60
-35
60 mg
22
14
8
-23
-17
-14
75 mg
90 mg
Positive numbers indicate that edoxaban has more
events than warfarin
25
Summary
• Edoxaban exposure is a critical determinant for both
efficacy and safety
• Analyses suggest that further increases in efficacy are
attainable in patient subgroups with lower exposures
• Exposure matching is one viable approach for dosing in
patients with normal renal function
– Decrease ischemic stroke rate and move the relative risk
towards non-inferiority
– Life-threatening/fatal bleeding risk is projected to remain less
than that of warfarin
26
Back-ups
27
‘Typical’ Patient Definitions
Descriptor
Overall
Population
Normal
Renal
Function
Mild
Renal
Function
Moderate
Renal
Function
Edoxaban Ctrough:
High Dose (ng/mL)
30
27
36
26
Age (yr)
72
64
74
79
Weight (kg)
82
96
78
68
Prior Stroke
History (%)
28
25
31
30
CHADS2 Score
22
15
24
30
Concomitant
Aspirin Use (%)
29
29
29
28
28
Pharmacodynamics
Edoxaban
Apixaban
Rivaroxaban
Potency
Free fXa (nM)
Prothrombinase
(nM)
0.561
2.98 (noncomp. /mixed)
0.08
1.7 (noncompetitive)
0.4
2.1
(competitive)
Anticoagulant assay
None
Rotachrom®
heparin
HepTest®
Concentration
dependent ↑ in
anti-fXa activity,
PT, aPTT
Concentration
dependent ↑ in antifXa activity, mPT
Concentration
dependent ↑ in
anti-fXa activity,
PT
(not recommended for
monitoring)
Response
Trough EDX concentration
is a Predictor of Bleeds
● 30 mg QD ● 60 mg QD
● 30 mg BID ● 60 mg BID
------ Warfarin
N=230-250/arm
30
Source: Study PRT018 datasets PKPD2, SUPPAB, DM
30
Edoxaban conc. (ng/mL)
BID vs. QD – Trough concentration critical
50
60 mg QD
30 mg BID
5
0
20
Projected time-course for 30 mg BID using
superposition
40
Time (h)
60
80
31
Edoxaban NDA 206316
Charge to the Committee
Martin Rose, MD, JD
Cross-Discipline Team Leader
Division of Cardiovascular and Renal Products
October 30, 2014
1
ENGAGE AF-TIMI 48
• A large and well-conducted non-inferiority trial
with a well-treated warfarin control arm
• Included high and low exposure edoxaban arms
and a large population PK subset
• Overall analysis of ENGAGE AF was favorable
for the edoxaban high exposure regimen for
both efficacy and safety
• If not for the substantial heterogeneity in the
renal function subgroup outcomes data and
related exposure data, there probably would not
have been an AC meeting
2
Opinions Expressed Today
• Applicant: Approve with dosing based on the
high exposure regimen used in ENGAGE AF.
• Statistical reviewer: Approve with dosing based
on the high exposure regimen used in ENGAGE
AF, and a 15 mg tablet should be available for
those with severe renal impairment.
• Clinical reviewer: Approve for use in patients
with renal impairment only with a dose of 60 mg
once daily for those with mild renal impairment.
The applicant should establish the benefits and
risks of a higher dose for those with normal renal
function in a postmarketing clinical trial.
3
Opinions Expressed Today
• Pharmacometrics reviewer: Approve with a 60 mg
once daily dose for those with mild renal impairment
and a higher once daily dose based on exposure
matching for those with normal renal function. This
dose would be higher than any once daily dose used
in Phase 2 or Phase 3 studies.
4
Opinions Expressed Today
• All recommendations favoring approval contemplate
use of a dose less than 60 mg daily in patients with
moderate renal impairment
• No FDA speaker has argued for non-approval
– But it is a plausible option because 4 other drugs are
approved for the proposed indication, provided that one
believes that • Edoxaban 60 mg once daily is not an acceptable dose
in patients with normal renal function,
• Recommending a dose greater than 60 mg is not
acceptable without more clinical data and
• Approval only for patients with mild or moderate renal
impairment is not acceptable
5
Questions
The questions before you today include one voting
question and several discussion questions. They
are focused on –
• The renal function subgroup findings
• The various proposals made by the Sponsor and
the FDA speakers relating to dosing of edoxaban
and the appropriate indicated populations and
• Whether to approve edoxaban for its proposed
indication
THANK YOU
6