Transcript 13-Bartlett-Spring-MPA-Presentation-Slide-Deck-for

Sandy Bartlett, PhD, PharmD, BCPS, BCCCP
Associate Professor | Department of Pharmacy Practice
Conflict of Interest
 I have no actual or potential conflicts of interest in relation
to this program to disclose.
Slide 2
Learning Objectives
 Identify molecular entities
development for reversal
anticoagulant (TSOAC) agents
that are currently in
of target-specific oral
 Discuss FDA approaches to speed drug approval of these
agents
 Compare drug design strategies and evaluate current data
related to these potential agents
Slide 3
Target Specific Oral Anticoagulants
(TSOACs)
BACKGROUND
Slide 4
TSOACs & Their Targets
Intrinsic
Pathway
Apixaban
Edoxaban
Rivaroxaban
IXa
Extrinsic
Pathway
VIIa
TF
Xa
X
Va
II
IIa
I
X
Dabigatran
Ia
XIIIa
Clot
Adapted by S Bartlett from Sabir I et al., Nat Rev Cardiol, Drug Discovery, 2014;11:290–303.
Reversal Agents & Their Targets
Apixaban
Edoxaban
Rivaroxaban
Xa
IIa
Clot
Dabigatran
TSOACs Awaiting Reversal Agents
FDA Approvals
DVT/PE
Treatment
TSOACs
NVAF Stroke
Prevention
Rivaroxaban
11/ 2011
11/2012
07/2011
Apixaban
12/2012
08/2014
03/2014
Edoxaban
01/2015
01/2015
Adapted by S Bartlett from Perzborn E et al., Nature Reviews Drug Discovery, 2011;10:61–75.
Knee/Hip VTE
Prevention
Slide 7
No TSOAC Reversal Agent Consequences
 Issues
 Providers may be wary about
prescribing NOACs
 Patients concern with taking NOACs
 Situations that may benefit from antidote availability
 Major bleeding complications
 Trauma injuries
 Urgent / emergent surgery
Majeed A and Schulman S. Bleeding and Antidotes in New Oral Anticoagulants, Best Pract Res Clin Haematol, 2013;26:191-202.
Slide 8
Adult Fall Risk
 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 height
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.
Slide 9
Intracranial Hemorrhage with TSOACs
 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 disability
Chatterjee S, Sardar P, Biondi-Zoccau G, Kumbhani J, New Oral Anticoagulants and the Risk of Intracranial Hemorrhage, JAMA Neurol, 2013;7:1486-1490.
Slide 10
Anticoagulation Benefit in AF
 Secondary stroke prevention
 CHA2DS2-VASc scores  2 are considered
“high risk”
 Studies support benefit > risk for
anticoagulation
CHA2DS2-VASc Criteria
Pts
Congestive heart failure
1
Hypertension
1
Age (75 years or older)
2
Diabetes
1
Stroke or TIA
2
Vascular disease (MI, PAD)
1
Age (65 – 74 years)
1
Sex (Female)
1
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.
Slide 11
Risk of Stroke vs Risk of Fall
14
Stroke Rate (% / yr)
12.2
12
11.2
10.8
9.7
10
8
7.2
6
4.8
4
3.2
2.2
2
0.6
0
1
2
3
4
5
6
7
8
9
CHA2DS2-VASc Score
 Mortality from ground level fall for patients  65 is 6.7%
 Risk vs benefit stratification
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.
Slide 12
ICH and TSOACs
 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
 68% had an unfavorable outcome
 Modified Rankin Scale 3 - 6
0
No symptoms
1
No significant disability despite symptoms
2
Slight disability
3
Moderate disability
4
Moderately severe disability
5
Severe disability
6
Dead
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.
Slide 13
Does Reversal Agent Change ICH Outcome?
 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 = 0.76
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.
Slide 14
Learning Objectives
 Identify molecular entities
development for reversal
anticoagulant (TSOAC) agents
that are currently in
of target-specific oral
 Discuss FDA approaches to speed drug approval of these
agents
 Compare drug design strategies and evaluate current data
related to these potential agents
Slide 15
Pipeline Reversal Agents
Andexanet alfa
PER977
Ciraparantag
Aripizine
Slide 16
Learning Objectives
 Identify molecular entities
development for reversal
anticoagulant (TSOAC) agents
that are currently in
of target-specific oral
 Discuss FDA approaches to speed drug approval of these
agents
 Compare drug design strategies and evaluate current data
related to these potential agents
Slide 17
US Department of Health & Human Services
Food & Drug Administration
Center for Drug Evaluation and Research
EXPEDITED PROGRAMS FOR
SERIOUS CONDITIONS
Slide 18
FDA Expedited Review Programs
 Speed drug approval process for selected
new drugs
 Life-threatening or serious conditions with no
satisfactory therapy
 Make therapy available ASAP
 Benefits justify risks
 Utilize Phase 2 studies for efficacy
 Accept greater risks and adverse events
 Patients & providers
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf
Slide 19
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%2Fno
vellaclinical.com%2Fblog_post%2Fpathway-better-care-understanding-fdas-expedited-approval-programs%2F&psig=AFQjCNFY9e3L00OJot2Ywc9YhDRKAjw_Q&ust=1459094182171166
Slide 20
Pipeline Agents for TSOAC Reversal
ANDEXANET ALFA
Slide 21
Andexanet alfa
 Modified recombinant Factor X
protein expressed in CHO cells
 Targets
 Factor Xa inhibitors
 Rivaroxaban, Apixaban, Edoxaban
 Heparin, LMWH & Fondaparinux
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.
Slide 22
Andexanet Protein Design
 Modifications to Factor X
 Removal of the activation peptide
 Replace with RKR to form the linker that connects the light
chain to the heavy chain
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.
Slide 23
Andexanet Protein Design
 Modifications to Factor X to prevent procoagulant activity
 Mutation of Ser  Ala in active site
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.
Slide 24
Andexanet Protein Design
 Modifications to Factor X to prevent anticoagulant activity
 Removal of ɣ-carboxyglutamic acid membrane binding
domain
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.
Slide 25
Decoy Mechanism for NOACs
Andexanet
Factor Xa
KD (nM)
KD (nM)
Affinity
Apixaban
0.58
0.100
5.8-fold 
Rivaroxaban
1.53
0.400
3.8-fold 
Ligand
 Decoy binds NOACs and reverses Factor Xa inhibition
 Restores ability to generate thrombin for hemostasis
Yeh 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.
Slide 26
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
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.
Slide 27
ANNEXA-A Trial Demonstrates Reversal
 Anti-Xa level decreased
by 92  3% over placebo
(p<0.001)
 Participants had  80%
reversal of anti-Xa activity
 Reversal maintained for 2
hr post-infusion
 Baseline at 5 hr postinfusion
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.
Slide 28
ANNEXA-R Trial Demonstrates Reversal
 Anti-Xa level decreased
by 97 2% over placebo
(p<0.001)
 Participants had  80%
reversal of anti-Xa activity
 Reversal maintained for 2
hr post-infusion
 Baseline at 5 hr postinfusion
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.
Slide 29
Pipeline Agents for TSOAC Reversal
PER 977 ~ APIPAZINE ~ CIRAPARANTAG
Slide 30
Aripazine
 Small molecule inhibitor
 Targets
 UFH
 LMWH & Fondaparinux
 Factor Xa inhibitors
 Rivaroxaban, Apixaban,
Edoxaban
National Center for Biotechnology Information. PubChem Substance
Database; SID=249807675,
https://pubchem.ncbi.nlm.nih.gov/substance/249807675 (accessed 30 Mar
2016).
 Thrombin inhibitors
 Dabigatran
Slide 31
Aripazine Forms H-bonds with NOACs
NOAC
H-Bond Site
Apixiban
Edoxaban
Rivaroxaban
Dabigatran
Laulicht 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).
Slide 32
Apirazine to Reverse Edoxaban
 Phase 2, prospective, double-blind, placebo-controlled trial
 Healthy persons (n=80)
 Intervention
 Subjects received escalating doses of aripazine (5 – 300 mg) IV
 Alone
 After 60 mg PO edoxaban
 Primary end point
 Whole blood clotting time (WBCT) used to determine
 Anticoagulant effect of edoxaban
 Reversal of edoxaban by aripazine
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.
Slide 33
Successful Reversal of Edoxban
 WBCT decreased to within 10% above baseline in  10 min
 Remained at ± 10% of baseline for 24h after 1 dose of antidote
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.
Slide 34
Comparison Summary For Pipeline Agents
Molecular
Entity
Andexanet alfa
Aripazine
Design Strategy
Reversal Target
Modified Factor Xa protein acts as a
decoy target for NOACs
UFH
LMWH
fondaparinux
Factor Xa inhibitors
Small molecule designed for noncovalent 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 & rivaroxaban
Thrombin inhibitor = dabigatran
Slide 35