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New Reversal Agents for the
New Oral Anticoagulants
Jack Ansell, MD
Hofstra North Shore/LIJ School of Medicine
Nov 4, 2016
Disclosures
CONSULTANT: Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Daiichi, Janssen
SPEAKER: BMS/Pfizer; Boehringer Ingelheim; Daiichi
SCIENTIFIC ADVISORY BOARDS: Instrumentation Laboratories, Perosphere
EQUITY: Perosphere
Emerging Therapies
Factor Xa Inhibitors and
Direct Thrombin Inhibitors
XII
XI
New Oral Xa
Inhibitors
IX
VII
VIII
Unfractionated
Heparin
X
Low
Molecular
Weight
Heparin
V
Rivaroxaban
Apixaban
Edoxaban
Betrixaban
Warfarin
II
I
Fibrin Clot
New Oral IIa
Inhibitors
Dabigatran etexilate
PK and other attributes of
warfarin vs DOACs
Features
Warfarin
DOACs
Onset
Slow
Rapid
Dosing
Variable
Fixed
Food effect
Drug interactions
(some variability)
Yes
No
Many
Few
(but can be managed)
(difficult to manage)
Monitoring
Yes
Half-life
Long
Antidote
Yes
No
(but some questions)
Short
(with normal renal fx)
Yes
(eventually)
What might reversal agents do?
• Improve outcomes from major or life-threatening
bleeding.
• Allow for emergent surgery when drug is onboard.
• Reassure physicians leading to greater use of AC
• Reassure patients leading to peace of mind (?
improved adherence).
• Effectively treat overdose.
• Improve management of brief interruptions of
therapy for invasive procedure.
Reversal Agents in Development
Company
Agent
Target
Phase
BoehringerIngelheim
Idarucizumab:
Fully humanized
Fab
Dabigatran only
III
Approved
Portola
Pharmaceuticals,
Inc.
Andexanet alfa:
Recombinant,
modified human
Factor Xa
Factor Xa Inhibitors
(Riva; Apix; Edox &
LMWH)
III
All NOACs
(Dabi; Riva; Apix; Edox)
UFH, LMWH,
fondaparinux
II
Ciraparantag:
Perosphere Inc.
(PER977; Aripazine)
Di-arginine
piperazine
Idarucizumab: Dabigatran Reversal Agent Under
Development
• Humanized antibody fragment specific for dabigatran
(Boehringer Ingelheim Pharma GmbH & Co, Biberach, Germany)
– Affinity for dabigatran 350 x the affinity for thrombin
– In vitro human plasma studies
• Fab had no effect on thrombin generation or coagulation studies
– Dose-ranging animal studies
• IV administration produced a rapid, dose-dependent decrease in
blood loss that was maintained for 6 hrs after the largest dose.
• Ex vivo coagulation assays (aPTT, TT, ECT) were reversed.
– Phase I human studies completed
1. Van Ryn J, et al. Circulation. 2012;126: A9928.
2. Schiele F, et al. Blood 2013;
Idarucizumab for Reversal of Dabigatran
Pollack et al. N Engl J Med 2015;373:511-520
REVERSE-AD:
Idarucizumab
for
Reversal
of
Dabigatran
Multicenter, ongoing, open-label, single-arm phase III study
Group A:
Uncontrolled
bleeding +
dabigatran-treated
Group B:
Emergency surgery
or procedure +
dabigatran-treated
5 g idarucizumab
(two separate
infusions of 2.5 g)
0–15 minutes
Reverses up to the
99th percentile of
dabigatran levels
measured in RE-LY
N=300
90 days follow-up
0–24 hours
Hospital
arrival
Pre-1st vial
Pre-2nd vial
~20 min 1 h 2 h 4 h
12 h
24 h
30 d
90 d
Blood
samples
Pollack et al. N Engl J Med 2015;373:511-520
Idarucizumab for Reversal of Dabigatran
Select patient characteristics
Group A
Group B
Pollack et al. N Engl J Med 2015;373:511-520
Idarucizumab produced sustained
reversal of dabigatran
Bleeding
Patients
Surgical
Patients
Pollack et al. N Engl J Med 2015;373:511-520
Secondaryproduced
Endpoints:
Clinical Outcomes
Idarucizumab
“potentially”
good outcomes
Group A
51 Patients
Group B
39 Patients
Assessable in 38
patients
Surgery performed
in 36 patients
Median local investigatordetermined time to bleeding
cessation 11.4 hours*
Intraoperative hemostasis:
• 33 normal
• 2 mildly abnormal
• 1 moderately abnormal
*Assessment of bleeding cessation may be difficult wotj internal bleeding
into confined space such as intramuscular or intracranial bleeding.
Pollack et al. N Engl J Med 2015;373:511-520
RE-VERSE AD: Updated Interim Analysis(ACC 4/16)
123 Patients
• Group A 66 Patients
• Median time to bleeding cessation was 9.8 hours (investigatorreported among assessed patients)
• Group B 57 Patients
• Mean time to surgery was 1.7 hours following administration of
idarucizumab.
• Normal hemostasis) during surgery reported in 92% percent of
patients (48/52).
• Thrombotic events occurred in five patients between 2-24 days after
idarucizumab administration. None of these patients were receiving
antithrombotic therapy at the time of their event.
• 26 deaths, which appear to have been related to reason for emergency
admission to the hospital and/or to co-morbidities
12
Pollack et al. ACC abstract April 2016
Praxbind prescribing information
Andexanet: Factor Xa Inhibitor Reversal Agent Under
Development
• Andexanet (PRT064445; aka PRT4445; Portola, South San Francisco)
–
–
–
–
Recombinant protein (r-Antidote) (Chinese hamster ovary cells)
Binds to both direct- and indirect-acting Factor Xa inhibitors
Catalytically inactive
Ex vivo studies
• Reverses Factor Xa inhibition in dose-dependent manner
• Corrects prolongation of clotting times
– Restores hemostasis in animal models of blood loss associated
with Factor Xa inhibitors
– Phase I study
• 32 healthy volunteers, “Generally safe and well-tolerated”
• Reversed anticoagulation within 5 min and was sustained for 3 hrs
– Phase III study ongoing with apixaban and rivaroxaban
1.Lu G, et al. Nat Med. 2013; 2. Portola Pharmaceuticals. Portola initiates phase 2 study of PRT4445, universal antidote for factor Xa
inhibitor anticoagulants. December 10, 2012. 3. Clinicaltrials.gov database.
http://www.clinicaltrials.gov/ct2/show/NCT01758432?term=PRT064445&rank=1
Siegal et al. N Eng J Med. pub Nov 11, 2015 online; 10.1056/NEJMoa1510991
Andexanet reversal of Xa Inhibitors in healthy volunteers
Time course of anti-factor Xa activity before and after administration of a bolus or bolus +
infusion of andexanet alfa in healthy elderly volunteers treated with apixaban or rivaroxaban
Siegal DM et al. N Engl J Med 2015; 373:2413-2424
NEJM published August 30, 2016’ DOI: 10.1056/NEJMoa1607887
Anti–Factor
Xa Activity
and Percent
Change from Baseline in Patients
Andexanet
effect
on
anti-Xa
assay
Receiving Rivaroxaban and Apixaban (Efficacy Population).
in patients with bleeding
Connolly SJ et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1607887
Subgroup
Hemostatic Efficacy.
Andexanet effect
onAnalysis
majorof bleeding
Andexanet achieved hemostatic efficacy at 12 hrs in 79% of patients (37/47)
Connolly SJ et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1607887
Ciraparantag (PER977): Factor Xa & Direct Thrombin
Inhibitor Reversal Agent Under Development
 Synthetic, small molecule that non-covalently binds oral direct Xa and IIa
inhibitors, unfractionated heparin, LMWH, and fondaparinux
 Reduces blood loss and bleeding time, reversing the anticoagulant activity of
dabigatran, rivaroxaban, apixaban and edoxaban in rat tail transection and liver
laceration assays
 Does not bind to a range of cardiovascular, antiepileptic and anesthetic drugs
 Stable as a ready-to-use solution for 2 years, refrigerated
Laulicht B et al. Circulation. 2012;126:A11395. Laulicht B et al. Small molecule antidote for anticoagulants.
Available at: www.perosphere.com/pdf/PER977_AHA-presentation.pdf. Accessed 1/3/14.
Ciraparantag (PER977) reverses edoxaban
In a phase I/II study PER977 restored normal clotting after single IV doses
of 25, 100 and 300 mg vs placebo 3 hours following a single oral dose of
edoxaban 60 mg
Change from baseline
whole blood clotting time (WBCT)
50%
PER977 Administered
60 mg edoxaban
Placebo reversal
25 mg PER977
aripazine reversal
100 mg PER977
aripazine reversal
PER977 reversal
300 mg aripazine
40%
30%
* p < 0.05 vs placebo
20%
*
*
*** * *
*
* *
10%
*
*
0%
0
-10%
3
6
9
12
15
18
21
24
27
Hours post edoxaban administration
Ansell et al. N Engl J Med 2014;371:2141-2142
Ciraparantag (PER977) reverses steady-state edoxaban,
allows for re-anticoagulation and re-reversal
Reversal of steady-state
edoxaban dosing
Re-anticoagulation with edoxaban
and re-reversal with PER 977
Ciraparantag (PER977) reverses enoxaparin
45%
1.5mg/kg s.c. enoxaparin
Change from baseline WBCT
ciraparantag
40%
Saline placebo
35%
100mg i.v. ciraparantag
200mg i.v. ciraparantag
30%
300mg i.v. ciraparantag
25%
20%
15%
10%
5%
0%
0
4
8
12
16
20
24
28
-5%
-10%
Hours post enoxaparin administration
Ansell et al. Thromb Res 2016 (in press)
Bleeding on DOAC
If drug unknown
check TT and PT*
Check creatinine
IIa
Inhibitor
Xa
Inhibitor
Check PTT or TT
to estimate effect**
Minor
Bleed
Hold dose until
bleeding controlled
Local measures
Check PT to
estimate effect***
Major
Bleed
Hold dose
Local measures
Transfusion as needed
(RBC or Plt)
Activated charcoal if
last dose < 2hr
Idarucizumab
(aPCC a possible altern)
Consider hemodialysis
Minor
Bleed
Hold dose until
bleeding controlled
Local measures
Major
Bleed
Hold dose
Local measures
Transfusion as needed
(RBC or Plt)
Activated charcoal if
last dose < 2hr
Consider PCC
Future: andexanet or
ciraparantag
* Normal TT suggests Xa inhibitor or IIa inhibitor at negligible concentration;
** Normal TT= negligble IIa inhibitor present; normal PTT does not exlcude significant IIa present, but suggests low concentration;
***Only rivaroxaban somewhat responsive to PT and only with some reagents; apixaban not responsive. Chromogenic anti-Xa assay is quantitative, but not readily available.
Thank you!