BCPS BCCCP Associate Professor Department of Pharmacy Practice Anticoag Update on Pipeline Agents for TSOAC Reversal Conflict of Interest I have no actual or potential conflicts of interest in relation to this program to disclose ID: 675976
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Slide1
Sandy Bartlett, PhD,
PharmD, BCPS, BCCCPAssociate Professor | Department of Pharmacy Practice
Anticoag
: Update on Pipeline Agents for TSOAC
ReversalSlide2
Conflict of Interest
I have no actual or potential conflicts of interest in relation to this program to disclose.Slide 2Slide3
Learning Objectives
Identify molecular entities that are currently in development for reversal of target-specific oral anticoagulant (TSOAC) agentsDiscuss FDA approaches to speed drug approval of these agents
Compare drug design strategies and evaluate current data related to these potential agentsSlide 3Slide4
BACKGROUND
Target Specific Oral Anticoagulants (TSOACs)Slide 4Slide5
Apixaban
Edoxaban
Rivaroxaban
TSOACs & Their Targets
Adapted by S Bartlett from Sabir I et al.,
Nat Rev
Cardiol
, Drug Discovery,
2014;11:290–303.
Dabigatran
IIa
V
a
II
IXa
Intrinsic Pathway
Clot
XIIIa
I
Ia
VIIa
Extrinsic Pathway
Xa
X
X
TFSlide6
Reversal Agents & Their Targets
Dabigatran
IIa
Xa
Clot
Apixaban
Edoxaban
RivaroxabanSlide7
TSOACs
Awaiting Reversal AgentsSlide 7
Adapted by S Bartlett from Perzborn E et al., Nature Reviews Drug Discovery, 2011;10:61–75.
TSOACs
FDA Approvals
NVAF Stroke
Prevention
DVT/PE
Treatment
Knee/Hip VTE Prevention
Rivaroxaban
11/ 2011
11/2012
07/2011
Apixaban
12/2012
08/2014
03/2014
Edoxaban
01/2015
01/2015
Slide8
No TSOAC Reversal Agent Consequences
Slide 8
Majeed A and Schulman S. Bleeding and Antidotes in New Oral Anticoagulants, Best Pract Res Clin Haematol, 2013;26:191-202.
Issues
Providers may be wary about prescribing NOACs
P
atients concern with taking NOACs
Situations that may benefit from antidote availability
Major bleeding complications
Trauma injuries
U
rgent / emergent surgerySlide9
Adult Fall Risk
Slide 9
Stanek S, Gupta V, Jamil T, Clancy C et al., Warfarin is Associated with Increased Intracranial Hemorrhage and Mortality in Patients with Ground Level Falls: A Retrospective Cohort Study, Int J Neurol Neurother, 2015;2:023.
1 of 3 adults
65 fall each year
Falls are the leading cause of injury related death among adults
65
Adults
65 are ~2X more likely to sustain an ICH
Adults
65 are ~
5X
more likely to
die after a fall from standing heightSlide10
Intracranial Hemorrhage with TSOACs
Slide 10
Chatterjee S, Sardar P, Biondi-Zoccau G, Kumbhani J, New Oral Anticoagulants and the Risk of Intracranial Hemorrhage, JAMA Neurol, 2013;7:1486-1490.
ICH is the most feared complication associated with TSOACs
Good News
Rate of ICH is about half that of warfarin
Bad News
Mortality from TSOAC-associated ICH is 45 – 67%
Most survivors with permanent disabilitySlide11
Anticoagulation Benefit in AF
Slide 11
Olesen JG, Lip GY, Lindhardsen J, Lane DA et al.,Thromb Haemost, 2011;106:739 - 749; Banerjee A, Lane DA, Torp-Pedersen C, Lip GY, Thromb Haemost
,
2012;107:584 – 589.
S
econdary stroke prevention
CHA
2
DS
2
-VASc scores 2 are considered “high risk”
S
tudies support benefit > risk for anticoagulation
CHA
2
DS
2
-VASc
Criteria
Pts
C
ongestive
heart failure
1
H
ypertension
1
A
ge
(
75 years or older
)
2
D
iabetes
1
S
troke
or TIA
2
V
ascular
disease (MI, PAD)1
A
ge (65 – 74 years
)1
Sex (Female)
1Slide12
Risk of Stroke vs Risk of Fall
Slide 12
Stanek S, Gupta V, Jamil T, Clancy C et al., Warfarin is Associated with Increased Intracranial Hemorrhage and Mortality in Patients with Ground Level Falls: A Retrospective Cohort Study, Int J Neurol Neurother, 2015;2:023.
Mortality from ground level fall for patients
65 is 6.7%
Risk vs benefit stratificationSlide13
ICH and TSOACs
Slide 13
Purrucker JC, Haas K, Rizos T, Khan S et al., Early Clinical and Radiological Course, Management, and Outcome of Intracerebral Hemorrhage Related to New Oral Anticoagulants, JAMA Neurol, 2016;73:169 – 177.
Small study of patients with non-traumatic ICH on TSOACs
Mean age 79.1 11.6 years
Outcomes
Mortality
16% of patients died during acute in-patient stay
28% had died at 3 months
Modified Rankin Scale
0
No symptoms
1
No
significant disability despite symptoms
2
Slight disability
3
Moderate disability
4
Moderately severe disability
5
Severe
disability
6
Dead
68% had an unfavorable outcome
Modified Rankin Scale 3 - 6Slide14
Does Reversal Agent Change ICH Outcome?
Slide 14
Purrucker JC, Haas K, Rizos T, Khan S et al., Early Clinical and Radiological Course, Management, and Outcome of Intracerebral Hemorrhage Related to New Oral Anticoagulants, JAMA Neurol, 2016;73:169 – 177.
57% of patients received 4-factor prothrombin complex concentrate
No effect on frequency of hematoma expansion
43% (+ PCC) vs 29% (- PCC) p = 0.53
No
effect on unfavorable outcome
OR 1.20 (95% CI 0.37-3.87) p = 0.76Slide15
Learning Objectives
Identify molecular entities that are currently in development for reversal of target-specific oral anticoagulant (TSOAC) agentsDiscuss FDA approaches to speed drug approval of these agents
Compare drug design strategies and evaluate current data related to these potential agentsSlide 15Slide16
Pipeline Reversal Agents
Slide 16
PER977
Ciraparantag
A
ripizine
Andexanet
alfaSlide17
Learning Objectives
Identify molecular entities that are currently in development for reversal of target-specific oral anticoagulant (TSOAC) agentsDiscuss FDA approaches to speed drug approval of these agents
Compare drug design strategies and evaluate current data related to these potential agentsSlide 17Slide18
Expedited Programs for Serious conditions
US Department of Health & Human ServicesFood & Drug AdministrationCenter for Drug Evaluation and Research
Slide 18Slide19
FDA Expedited Review Programs
Speed drug approval process for selected new drugs
Life-threatening or serious conditions with no satisfactory therapyMake therapy available ASAPBenefits justify risksUtilize Phase 2 studies for efficacyAccept greater risks and adverse eventsPatients & providersSlide 19
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdfSlide20
Slide 20
https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjngdDK297LAhXGbj4KHfKoCygQjRwIBw&url=http%3A%2F%2Fnovellaclinical.com%2Fblog_post%2Fpathway-better-care-understanding-fdas-expedited-approval-programs%2F&psig=AFQjCNFY-9e3L00OJot2Ywc9YhDRKAjw_Q&ust=1459094182171166Slide21
Andexanet
alfaPipeline Agents for TSOAC Reversal
Slide 21
Breakthrough Therapy
DesignationSlide22
Andexanet alfa
Modified recombinant Factor X protein expressed in CHO cellsSlide 22
Schiele F, van Ryn J, Litzenburger T, Ritter M et al., Structure-guided Residence Time Optimization of a Dabigatran Reversal Agent, MAbs, 2015;7:871-880.
Targets
Factor
Xa
inhibitors
Rivaroxaban
,
Apixaban
,
Edoxaban
Heparin, LMWH &
FondaparinuxSlide23
Modifications to Factor X
Andexanet Protein DesignSlide 23
Adapted by S Bartlett from Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ et al., A Specific Antidote for Reversal of Anticoagulation by Direct and Indirect Inhibitors of Coagulation Factor Xa, Nat Med,
2013;19:446-451.
Removal of the activation peptide
Replace with RKR to form the linker that connects the light chain to the heavy chainSlide24
Modifications to Factor X to prevent procoagulant
activityAndexanet Protein DesignSlide
24Adapted by S Bartlett from Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ et al., A Specific Antidote for Reversal of Anticoagulation by Direct and Indirect Inhibitors of Coagulation Factor Xa
,
Nat Med,
2013;19:446-451.
Mutation of
Ser
Ala
in active siteSlide25
Modifications to Factor X to prevent anticoagulant activity
Andexanet Protein DesignSlide 25
Adapted by S Bartlett from Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ et al., A Specific Antidote for Reversal of Anticoagulation by Direct and Indirect Inhibitors of Coagulation Factor Xa,
Nat Med,
2013;19:446-451.
Removal of
ɣ-
carboxyglutamic
acid
membrane binding domainSlide26
Decoy Mechanism for NOACs
Slide 26Yeh CH, Fredenburgh
JC, Weitz JL. The Real Decoy: An Antidote for Factor Xa-directed Anticoagulants, Circ Res, 2013;113:954-957; Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ et al., A Specific Antidote for Reversal of Anticoagulation by Direct and Indirect Inhibitors of Coagulation Factor
Xa
,
Nat Med,
2013;19:446-451.
Decoy binds NOACs and reverses Factor
Xa
inhibition
R
estores ability to generate thrombin for hemostasis
Ligand
Andexanet
K
D
(
nM
)
Factor
Xa
K
D
(
nM
)
Affinity
Apixaban
0.58
0.100
5.8-fold
Rivaroxaban
1.53
0.400
3.8-fold
Slide27
ANNEXA Clinical Trials
Phase 2 randomized, double-blind, placebo-controlled studies in healthy older volunteers (50-75 years old) 5 mg
apixaban PO BID x 3.5 days (ANNEXA-A)20 mg rivaroxaban PO daily x 4days (
ANNEXA-
R
)
Part 1:
andexanet
bolus IV
Part 2:
andexanet
bolus
IV followed by continuous infusion
Slide
27
Siegal
DM,
Curnutte
JT, Connolly SJ, Lu G et al.,
Andexanet
A
lfa for the Reversal of Factor Xa
Inhibitor Activity, New Engl J Med,
2015;373:2413-2424.Slide28
ANNEXA-
A Trial Demonstrates ReversalSlide 28
Siegal DM, Curnutte JT, Connolly SJ, Lu G et al., Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity, New Engl J Med, 2015;373:2413-2424.
Reversal maintained for 2
hr
post-infusion
Anti-
Xa
level decreased by 92
3
% over placebo (p<0.001)
Participants had
80% reversal
of anti-
Xa
activity
Baseline at 5
hr
post-infusionSlide29
ANNEXA-
R Trial Demonstrates ReversalSlide 29
Siegal DM, Curnutte JT, Connolly SJ, Lu G et al., Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity, New Engl J Med, 2015;373:2413-2424.
Reversal maintained for 2
hr
post-infusion
Anti-
Xa
level decreased by 97
2
% over placebo (p<0.001)
Participants had
80% reversal of anti-
Xa
activity
Baseline at 5
hr
post-infusionSlide30
PER 977 ~
Apipazine ~ ciraparantag
Pipeline Agents for TSOAC ReversalSlide 30
Fast Track DesignationSlide31
Aripazine
Slide 31
National Center for Biotechnology Information. PubChem Substance Database; SID=249807675, https://pubchem.ncbi.nlm.nih.gov/substance/249807675 (accessed 30 Mar 2016).Small molecule inhibitor
Targets
UFH
LMWH &
Fondaparinux
Factor
Xa
inhibitors
Rivaroxaban
,
Apixaban
,
Edoxaban
Thrombin inhibitors
Dabigatran
Potential Universal Reversal AgentSlide32
Aripazine Forms H-bonds with NOACs
Slide 32Laulicht B,
Bakhru S, Jiang X, Chen L et al., Antidote for New Oral Anticoagulants: Mechanism of Action and Binding Specificity of PER977, J Thromb Haemost, 2013;11 (Suppl 2):1-84 (Abstract 47.1).
NOAC
H-Bond Site
Apixiban
Edoxaban
Rivaroxaban
DabigatranSlide33
Apirazine to Reverse Edoxaban
Phase 2, prospective, double-blind, placebo-controlled trialHealthy persons (n=80)InterventionSubjects received escalating doses of aripazine (5 – 300 mg) IVAloneAfter 60 mg PO
edoxabanPrimary end pointWhole blood clotting time (WBCT) used to determineAnticoagulant effect of edoxabanReversal of edoxaban by aripazine
Slide
33
Ansell JE,
Bakhru
SH,
Laulicht
BE, Steiner SS et al., Use of PER977 to Reverse the Anticoagulant Effect of
Edoxaban
,
N
Engl
J Med,
2014;371:2141-2142. Slide34
Successful Reversal of Edoxban
WBCT decreased to within 10% above baseline in 10 minSlide 34
Ansell JE, Bakhru SH, Laulicht BE, Steiner SS et al., Use of PER977 to Reverse the Anticoagulant Effect of Edoxaban, N Engl J Med,
2014;371:2141-2142.
Remained at
± 10% of baseline for 24h after 1 dose of antidoteSlide35
Comparison Summary For Pipeline Agents
Slide 35
Molecular EntityDesign StrategyReversal Target
Andexanet
alfa
Modified
Factor
Xa
protein acts as a decoy target for NOACs
UFH
LMWH
fondaparinux
Factor
Xa
inhibitors
Aripazine
Small molecule designed for non-covalent
interaction with anticoagulant; has potential to be “universal” antidote
UFH
LMWH
fondaparinux
Factor
Xa
inhibitors
Thrombin Inhibitor
UFH = unfractionated heparin
LMWH = low molecular weight
heparin
Factor
Xa
inhibitors =
apixaban
,
edoxaban
&
rivaroxabanThrombin inhibitor =
dabigatran