1. Anticoag: Update on Pipeline Agents for TSOAC Reversal
Sandy Bartlett, PhD, PharmD, BCPS, BCCCP
Associate Professor | Department of Pharmacy Practice

2. Conflict of Interest
I have no actual or potential conflicts of interest in relation to this program to disclose.

3. Learning Objectives
Identify molecular entities that are currently in development for reversal of target-specific oral anticoagulant (TSOAC) agents
Discuss FDA approaches to speed drug approval of these agents
Compare drug design strategies and evaluate current data related to these potential agents

4. Target Specific Oral Anticoagulants (TSOACs)
BACKGROUND

5. TSOACs & Their Targets IXa VIIa Xa X TF IIa Va II Clot XIIIa I Ia
Apixaban
Edoxaban
Rivaroxaban
IXa
Intrinsic Pathway
VIIa
Extrinsic Pathway Xa X TF
IIa Va II
Dabigatran
Clot
XIIIa I Ia
Adapted by S Bartlett from Sabir I et al., Nat Rev Cardiol, Drug Discovery, 2014;11:290–303.

6. Reversal Agents & Their Targets
Apixaban
Edoxaban
Rivaroxaban
IIa Xa
Clot
Dabigatran

7. TSOACs Awaiting Reversal Agents
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
Adapted by S Bartlett from Perzborn E et al., Nature Reviews Drug Discovery, 2011;10:61–75.

8. 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:

9. 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.

10. 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:

11. 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
Age (75 years or older) 2
Diabetes
Stroke or TIA
Vascular disease (MI, PAD)
Age (65 – 74 years)
Sex (Female)
Olesen JG, Lip GY, Lindhardsen J, Lane DA et al.,Thromb Haemost, 2011;106: ; Banerjee A, Lane DA, Torp-Pedersen C, Lip GY, Thromb Haemost, 2012;107:584 – 589.

12. Risk of Stroke vs Risk of Fall
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.

13. 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
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 - 6
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.

14. 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 ) 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.

15. Learning Objectives
Identify molecular entities that are currently in development for reversal of target-specific oral anticoagulant (TSOAC) agents
Discuss FDA approaches to speed drug approval of these agents
Compare drug design strategies and evaluate current data related to these potential agents

16. Pipeline Reversal Agents
PER977
Ciraparantag
Aripizine
Andexanet alfa

17. Learning Objectives
Identify molecular entities that are currently in development for reversal of target-specific oral anticoagulant (TSOAC) agents
Discuss FDA approaches to speed drug approval of these agents
Compare drug design strategies and evaluate current data related to these potential agents

18. Expedited Programs for Serious conditions
US Department of Health & Human Services
Food & Drug Administration
Center for Drug Evaluation and Research
Expedited Programs for Serious conditions

19. 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

20. https://www. google. com/url

21. Pipeline Agents for TSOAC Reversal
Andexanet alfa
Breakthrough Therapy
Designation

22. 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:

23. 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:

24. 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:

25. 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:

26. Decoy Mechanism for NOACs
Ligand
Andexanet
KD (nM)
Factor Xa
Affinity
Apixaban
0.58
0.100
5.8-fold 
Rivaroxaban
1.53
0.400
3.8-fold 
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: ; 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:

27. 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:

28. 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 post-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:

29. 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 post-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:

30. PER 977 ~ Apipazine ~ ciraparantag
Pipeline Agents for TSOAC Reversal
PER 977 ~ Apipazine ~ ciraparantag
Fast Track Designation

31. Potential Universal Reversal Agent
Aripazine
Small molecule inhibitor
Targets
UFH
LMWH & Fondaparinux
Factor Xa inhibitors
Rivaroxaban, Apixaban, Edoxaban
Thrombin inhibitors
Dabigatran
National Center for Biotechnology Information. PubChem Substance Database; SID= , (accessed 30 Mar 2016).
Potential Universal Reversal Agent

32. Aripazine Forms H-bonds with NOACs
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).

33. 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:

34. 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:

35. Comparison Summary For Pipeline Agents
Molecular Entity
Design Strategy
Reversal 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
Thrombin Inhibitor
UFH = unfractionated heparin
LMWH = low molecular weight heparin
Factor Xa inhibitors = apixaban, edoxaban & rivaroxaban
Thrombin inhibitor = dabigatran