Download Bleeding and Blood Transfusion Issues Among Patients with Acute

Does the Elinogrel Data
Support a Phase 3 Study?
Sunil V. Rao MD
The Duke Clinical Research Institute
Duke University Medical Center
Sunil V. Rao, MD
 Honoraria:
 Ikaria
My presentation will include off-label
discussions:
Bivalirudin for ACS, Fondaparinux for ACS
and Clopidogrel post-stent
Disclosures
Research funding
Cordis Corporation, Ikaria, sanofi-aventis
Consultant
Zoll, Terumo Medical, Daiichi Sankyo-Lilly
Speakers’ Bureau
The Medicines Co, Abbott Vascular, Boehringer
Ingelheim
Off-label uses of drugs or devices may be
discussed during this lecture
Elinogrel
What is Elinogrel?
How does it work?
What are the data?
Does it justify moving to a larger trial?
Background
• Antiplatelet therapy is essential to reduce adverse
events in patients with ischemic heart disease
• Recent clinical trials demonstrate that greater
platelet inhibition is associated with improved
ischemic outcomes, but increased major bleeding
• Reversible platelet inhibition may mitigate these
risks and further improve outcomes
• Elinogrel is a novel potent platelet inhibitor that
competitively and reversibly binds to the P2Y12
receptor and can be administered both
intravenously and orally
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Rao SV. ESC 2010
Properties of Elinogrel
• The only reversible and competitive P2Y12 receptor antagonist
• Direct-acting: no metabolic activation required
• Available for intravenous and oral administration, enabling acute
and chronic use
• Immediate and near maximal platelet inhibition achieved with
IV
• Duration of action
‐ Half-life: 12 hours
• No major CYP metabolism – low potential for drug-drug
interactions (including PPIs)
• Balanced clearance: 50% renal; 50% hepatic (10% metabolized
to pharmacologically inactive metabolite)
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Rao SV. ESC 2010
ADP in Platelet Thrombosis
Genetic and pharmacological targeting has shown that continued P2Y12
signaling by the < 1 mM ADP generated by platelets during thrombosis at arterial
rates of shear is required to maintain stable thrombi
ADP
P2Y12
Thrombin
GP IIb-IIIa
Fibrinogen,
vWf
Collagen
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Fibrinogen
Local change in ADP concentration*  local change
in elinogrel anti-platelet effect
*BJ Folie and LV McIntire, Biophys J.,56, 1121-1141 (1989).
G.V. Born and MA Kratzer, J.Physiol., 354, 419-429 (1984)
8
Local change in ADP concentration  local change
in elinogrel anti-platelet effect
Thrombosis
(Efficacy)
Blood Flow/Shear
High
Low
ADP concentration*
Low
High
Antiplatelet Effect clopidogrel/prasugrel
+++
+++
Antiplatelet effect –
elinogrel
+++
+
*BJ Folie and LV McIntire, Biophys J.,56, 1121-1141 (1989).
G.V. Born and MA Kratzer, J.Physiol., 354, 419-429 (1984)
9
Hemostasis
(Bleeding)
Effects of elinogrel vs thienopyridines on thrombosis
and bleeding in the mouse
Hemostasis
clopidogrel
elinogrel elinogrel
clopidogrel
prasugrel
(blood loss following
tail transection)
I
H I M H I MH
IM
Blood Volume Loss (uL)
700
H I
MH
†
†
prasugrel
IM H
M
†
•
600
500
Thrombosis
(FeCl3 injury to
400
mesenteric arteries
300
‡
200
‡
‡
*
*
‡ P<0.0001 vs Prasugrel eq. dose
* P<0.005 vs clopidogrel eq. dose
. P<0.005vs P2Y
12 KO
† P<0.0005 vs P2Y12 KO
100
P
R
T0
V
.C
tl
60
12
P
8
R
7.
T0
5
60
1
P
28
R
T0
20
60
12
8
60
C
lo
p.
1.
5
C
lo
p.
15
C
lo
p.
50
P
ra
s.
1
P
ra
s.
3
P
ra
s.
1
P
2Y 0
12
K
O
BLQ<10
0
At each dose level, elinogrel consistently caused less effect on hemostasis.
Doses (mg/kg) selected to yield equivalent inhibition of
High dose clopidogrel and prasugrel
effect
hemostasis
more
than P2Y12-/thrombosis
(p<0.001
vs vehicle
control)
mice
10
Inclusion & Exclusion Criteria
INCLUSION
• Nonurgent PCI with ≥ 1 coronary lesion amenable to PCI
EXCLUSION
• Bleeding risk
‐ Anemia/thrombocytopenia, recent trauma or bleeding, CVA or TIA within prior 5
years
• Concomitant therapies
‐ Clopidogrel loading dose within 7 days prior to PCI, thrombolytics, oral
anticoagulants, fondaparinux
• General
‐ Age > 75 yrs, weight < 55 kg, CrCL < 45 cc/min, allergy to study drugs
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Leonardi S, Rao SV, Harrington RA, et. al. AHJ 2010
Treatment Schema
ACUTE PHASE
CHRONIC PHASE
Peri-PCI
ARM 1:
clopidogrel
Post-PCI
300-600mg
Loading Dose
PCI
75 mg QD
n=200
ARM 2:
elinogrel
80 mg IV
Bolus+ 50mg PO
PCI
50 mg BID
n=200
ARM 3:
elinogrel
120
mgIVIV
80mg
Bolus ++ 100mg
100mg PO
PO
Bolus
PCI
100 mg BID
n=200
80mg
120
mgIVIV
ARM 4:
n=200
150 mg BID
PCI
Bolus + 150mg PO
elinogrel
• April 8, 2009 (116 pts enrolled): The DSMC recommended
discontinuation of the 50 mg BID dose and increasing IV bolus dose to
120 mg as per protocol
• April 16, 2009: Chronic phase extended from 60 days to 120 days of
treatment
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Rao SV. ESC 2010
Endpoints
Safety – 24-hr or d/c &
120-day
Clinical efficacy
• TIMI bleeding: major, minor,
• 24-hr or d/c death, MI,
stroke, uTVR, GP
IIb/IIIa bailout, stent
thrombosis
bleeding requiring medical
attention
• Clinically relevant bleeding:
major, minor, nuisance
• 120-day death, MI,
Biological efficacy - periprocedural
• 120-day death, MI,
stroke, uTVR
• Any Troponin* elevation at
24 hrs or d/c
• Troponin* elevation > 2 X
ULN at 24 hrs or d/c
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Rao SV. ESC 2010
*Core lab troponin I
stroke, uTVR, stent
thrombosis
INNOVATE-PCI Enrollment
US and Canada
424
Europe
228
Canada
132
United States
292
Germany
Poland
126
74
Austria
28
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Rao SV. ESC 2010
Baseline Characteristics
Clopidogrel
(N=208)
Pooled elinogrel
100 mg
(N=201)
Pooled elinogrel
150 mg
(N=207)
61
61
61
Male (%)
77%
77%
78%
BMI (kg/m2)
29.0
28.6
29.4
Diabetes mellitus
36%
30%
40%
Prior MI
37%
36%
33%
ASA
96%
95%
93%
On maintenance clopidogrel
46%
46%
45%
Femoral access
70.7%
74.0%
75.0%
Vascular closure device
33.2%
29.5%
28.9%
Median age (yrs)
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Rao SV. ESC 2010
Pharmacodynamic Effect of Elinogrel vs. Clopidogrel
PD Sub-study
5 uM ADP - Peak
Peri-PCI
70
Extent of platelet aggregation (%)
C (N=17)
E100 (N=12)
E150 (N=17)
60
50
40
*
pre-2nd
oral
dose
*
pre-3rd
oral dose
or
discharge
*
30
clopidogrel
20
120mg IV + 150mg oral
120mg IV + 100mg oral
10
0
0 0.5 2
6
8
20
TIME AFTER DOSING (hrs)
74% of pts represented above were on maintenance clopidogrel
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* p<0.025 for both elinogrel vs. clopidogrel comparisons
Median, quartiles
Pharmacodynamic Effect of Elinogrel vs. Clopidogrel
PD Sub-study
5 uM ADP - Peak
Day 30
60
Extent of platelet aggregation (%)
C (N=17)
E100 (N=12)
E150 (N=17)
50
40
30
clopidogrel
100mg oral
predose
20
150mg oral
10
0
0
2
6
TIME AFTER DOSING (hrs)
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Rao SV. ESC 2010
Median, quartiles
Bleeding at 24 hrs or d/c – TIMI Scale
Event Rate (%)
Rates and 95% confidence intervals
14
13
12
11
10
9
8
7
6
5
4
3
2
1
0
Pooled Clopidogrel (n=208)
Pooled Elinogrel 80mg IV (n=122)
Pooled Elinogrel 120mg IV (n=312)
TIMI Major
* Mainly at access site
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TIMI Minor
Bleeding Requiring
Medical Attention *
Rao SV. ESC 2010
Bleeding at 24h-120d – TIMI Scale
Rates and 95% confidence intervals
11
Pooled Clopidogrel (n=208)
Event Rate (%)
10
9
Pooled Elinogrel 100mg po (n=201)
8
Pooled Elinogrel 150mg po (n=207)
7
6
5
4
3
2
1
0
TIMI Major
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Rao SV. ESC 2010
TIMI Minor
Bleeding Requiring
Medical Attention
Efficacy at 24 hrs or Discharge
Clinical and Biological Endpoints
Rates and 95% confidence intervals
35
Event Rate (%)
30
Pooled Clopidogrel (n=208)
Pooled Elinogrel 80mg IV (n=118)
25
Pooled Elinogrel 120mg IV (n=312)
20
15
10
5
0
D/MI/S/uTVR/2b3a/ST
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Any Tn Elevation
Any Tn > 2 X ULN
Efficacy at 24h-120 Days
Event Rate (%)
Rates and 95% confidence intervals
8
Pooled Clopidogrel (n=208)
7
Pooled Elinogrel 100mg (n=200)
Pooled Elinogrel 150mg (n=204)
6
5
4
3
2
1
0
Death/MI/Stroke/uTVR
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Death/MI/Stroke/uTVR/ST
Adverse Events
Clopidogrel
N=208
Pooled elinogrel
100 mg
N=201
Pooled elinogrel
150 mg
N=207
Any SAE
11.1%
14.9%
12.6%
Drug d/c due to AE or SAE
7.2%
7.5%
10.1%
Dyspnea*
4.3%
15.4%
12.1%
Bradycardia
0.5%
1.0%
0.5%
Syncope
0.5%
1.5%
0.5%
ALT/AST > 3x^
1.0%
4.0%
4.8%
ALT/AST > 5x
0.5%
2.0%
3.4%
* Dyspnea was generally mild, transient, and infrequently led to discontinuation
^ Most cases occurred within first 60 days and were asymptomatic; All cases resolved, even when
treatment was continued; No Hy’s Law cases.
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Conclusions
• IV and oral elinogrel result in greater and more
rapid antiplatelet effect than clopidogrel during
both the acute and chronic phase of therapy
• No excess TIMI major or minor bleeding at both
the 24-hr and 120-day timepoints
• Dose-dependent trend of increase in less severe
bleeds (Bleeding Requiring Medical Attention),
mostly occurring at the vascular access site in the
peri-procedural period
• No significant differences in efficacy at 24 hrs or
120 days (trial not powered for efficacy)
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Conclusions (2)
• Adverse events similar between elinogrel and
clopidogrel
‐ Dyspnea more frequent in the elinogrel arms
• Mild, transient, infrequently led to discontinuation
‐ Excess in transaminase elevation cases in the elinogrel arms
• Occurred early and were generally asymptomatic
• All resolved even when treatment was continued
• No Hy’s Law cases
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What is a phase 2 trial?
PHASE II TRIALS: Controlled clinical studies
conducted to evaluate the effectiveness of the drug
for a particular indication or indications in patients
with the disease or condition under study and to
determine the common short-term side effects and
risks.
A unicorn?
Phase 2 trials are NOT phase 3 trials
Not usually powered for clinical endpoints
Unusual to see statistically significant
differences in clinical outcomes
An overwhelmingly positive Phase 2 trial is a
unicorn…
We all wish they existed, but they don’t!
So…is a phase 3 trial justified?
Yes!
Attractive IV to oral transition
The drug inhibits platelets
PK/PD data
Bleeding
Only way to determine efficacy, safety, and liver
outcomes is with an adequately powered pahse
3 trial
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