Sandy Bartlett, PhD, PharmD, BCPS Associate Professor | Department - - PowerPoint PPT Presentation

Sandy Bartlett, PhD, PharmD, BCPS Associate Professor | Department of Pharmacy Practice

Conflict of Interest

• I have no actual or potential conflict of interest in relation

to this program to disclose.

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Learning Objectives

• Identify three molecular entities that are currently in

development for reversal of NOACs

• Compare the drug design strategy for each of these new

pipeline reversal agents that are currently in clinical trials

• Evaluate how these potential new agents may be

incorporated into a treatment strategy for significant bleeding related to NOAC use based on patient specific information

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BACKGROUND New Oral Anticoagulants (NOACs)

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Dabigatran (Boehringer Ingelheim)

• FDA approvals
• NVAF
• October 2010
• DVT/PE Treatment
• April 2014

Slide 5

Structure adapted by S Bartlett from Blommel ML and Blommel AL, AJHP, 2011;68:1506-19.

Rivaroxaban (Janssen)

• FDA approvals
• NVAF
• November 2011
• DVT/PE
• November 2012
• Knee/Hip VTE
• July 2011

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

Apixaban (Bristol-Myers Squibb)

• FDA approvals
• NVAF
• December 2012
• DVT/PE Treatment
• August 2014
• Knee/Hip VTE Prevention
• March 2014

Slide 7

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

Edoxaban (Daiichi Sankyo)

• FDA approvals
• NVAF
• January 2015
• DVT/PE Treatment
• January 2015

Slide 8

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

NOAC Targets

Adapted by S Bartlett from Sabir I et al., Nat Rev Cardiol, Drug Discovery, 2014;11:290–303.

Apixa xaban ban Edoxa xaban ban Rivaroxa xaban ban Dabig igatr tran an

IIa IIa Va II II IXa

Intri trinsic sic Pathway

Clot XIIIa IIa I Ia Ia VII IIa

Extrinsic rinsic Pathway

Xa Xa X X TF TF

No Specific NOAC Antidote Available

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Majeed A and Schulman S. Bleeding and Antidotes in New Oral Anticoagulants, Best Pract Res Clin Haematol, 2013;26:191-202.

• Patient taking NOACs may still

experience

• Major bleeding complications
• Similar or lower bleeding rates than

with warfarin

• Trauma injuries
• Require urgent / emergent surgery

Learning Objectives

• Identify three molecular entities that are currently in

development for reversal of new oral anticoagulant (NOAC) agent(s)

• Compare the drug design strategy for each of these new

pipeline reversal agents that are currently in clinical trials

• Evaluate how these potential new agents may be

incorporated into a treatment strategy for significant bleeding related to NOAC use based on patient specific information

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Pipeline Reversal Agents

• Idarucizumab (Boehringer Ingelheim)
• Andexanet alfa (Portola Pharmaceuticals)
• Aripazine (Perosphere)

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Learning Objectives

• Identify three molecular entities that are currently in

development for reversal of new oral anticoagulant (NOAC) agent(s)

• Compare the drug design strategy for each of these new

pipeline reversal agents that are currently in clinical trials

• Evaluate how these potential new agents may be

incorporated into a treatment strategy for significant bleeding related to NOAC use based on patient specific information

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IDARUCIZUMAB Pipeline Agents for NOAC Reversal

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Idarucizumab

• Humanized mAb fragment

against dabigatran

• Target
• Dabigatran

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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. http://www.rcsb.org/pdb/explore/explore.do?structureId=4YGV

Tight Binding Affinity for Dabigatran

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Pollack Jr CV, Reilly PA, Bernstein R, Dubiel R et al., Design and Rationale for RE-VERSE AD: A Phase 3 Study of Idarucizumab, a Specific Reversal Agent for Dabigatran, Thromb Haemost, 2015;114:198-205.

Ligand – Target Binding KD (nM) Dabigatran - Thrombin 0.7 Dabigatran - Idarucizumab 0.002

• Binding affinity is 350-fold higher for idarucizumab over

thrombin

Dabigatran Binding to Idarucizumab

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Schiele F, van Ryn J, Canada K, Newsome C et al., A Specific Antidote for Dabigatran: Functional and Structural Characterization, Blood, 2013;121:3554- 3526.

RE-VERSE AD Interim Results

• REVERSal Effects of Idarucizumab in Patients on Active

Dabigatran

• Phase 3 multicenter, prospective cohort study
• Group A: Uncontrollable or life-threatening bleeding (n=51)
• Group B: Urgent surgery or intervention (n=39)
• Intervention
• Patient received idarucizumab 5 g IV
• Two 50 mL bolus infusions  15 minutes apart

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Pollack Jr CV, Reilly PA, Eikelboom J, Glund S et al., Idarucizumab for Dabigatran Reversal, N Engl J Med, 2015;373:511-520.

RE-VERSE AD Interim Results

• Primary end point
• Maximal reversal of dabigatran based on laboratory assessment

within 4 h after idarucizumab administration

• Dilute thrombin time or ecarin clotting time
• Results
• Median maximum reversal = 100%
• 68/90 patients (75%) had an elevated dilute thrombin time at baseline
• 81/90 patients (90%) had an elevated ecarin clotting time at baseline

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Pollack Jr CV, Reilly PA, Eikelboom J, Glund S et al., Idarucizumab for Dabigatran Reversal, N Engl J Med, 2015;373:511-520.

Successful Reversal in Bleeding Patients

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Pollack Jr CV, Reilly PA, Eikelboom J, Glund S et al., Idarucizumab for Dabigatran Reversal, N Engl J Med, 2015;373:511-520.

Successful Reversal for Urgent Procedures

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Pollack Jr CV, Reilly PA, Eikelboom J, Glund S et al., Idarucizumab for Dabigatran Reversal, N Engl J Med, 2015;373:511-520.

ANDEXANET ALFA Pipeline Agents for NOAC Reversal

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Andexanet alfa

• Modified recombinant Factor X

protein expressed in CHO cells

• Targets
• Factor Xa inhibitors
• Rivaroxaban, Apixaban, Edoxaban
• LMWH & Fondaparinux

Slide 23

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. http://www.portola.com/clinical- development/andexanet-alfa-prt4445-fxa- inhibitor-antidote/

• Modifications to Factor Xa

Andexanet Protein Design

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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 and replace with RKR to

form the linker that connects the light chain to the heavy chain

• Modifications to Factor Xa to prevent procoagulant activity

Andexanet Protein Design

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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.

• Mutation of Ser  Ala in active site

• Modifications to Factor Xa to prevent anticoagulant activity

Andexanet Protein Design

Slide 26

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

domain

Decoy Mechanism for NOACs

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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.

• Decoy binds NOACs and reverses Factor Xa inhibition and

restores ability to generate thrombin for hemostasis

Ligand

Andexanet

KD (nM)

Factor Xa

KD (nM)

Affinity

Apixaban 0.58 0.100 5.8-fold  Rivaroxaban 1.53 0.400 3.8-fold 

Andexanet Reverses Rivaroxaban in Rabbit Liver Laceration Model

• 75 mg andexanet IV reduces blood loss by > 85% in

rivaroxaban treated rabbits (1 mg/kg)

Slide 28

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.

Andexanet Infusion Achieved Sustained Reversal of Apixaban Anticoagulation

• Phase 2 placebo controlled trial in healthy volunteers
• 5 mg PO Apixaban BID x 5 days

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Adapted from Crowther M, Lu G, Conley P, Hollenbach S et al., Sustained Reversal of Apixaban Anticoagulation with Andexanet alfa Using a Bolus Plus Infusion Regimen in a Phase 2 Placebo Controlled Trial, Eur Heart J, 2014;35:137 (Abstract). http://www.sec.gov/Archives/edgar/data/1269021/000156459014000472/ptla-10k_20131231.htm

ARIPAZINE (PER977) Pipeline Agents for NOAC Reversal

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Aripazine

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National Center for Biotechnology Information. PubChem Substance Database; SID=249807675, https://pubchem.ncbi.nlm.nih.gov/substance/249807675 (accessed Aug. 31, 2015).

• Small molecule inhibitor
• Targets
• UFH
• LMWH & Fondaparinux
• Factor Xa inhibitors
• Rivaroxaban, Apixaban,

Edoxaban

• Thrombin inhibitors
• Dabigatran

Aripazine Forms H-bonds with NOACs

Slide 32

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).

NOAC H-Bond Site Apixiban Edoxaban Rivaroxaban Dabigatran

Aripazine Reverses Rivaroxaban in Rat Tail Transection Model

• 12.5 mg IV aripazine reduces blood loss to control in treated

rats

• rivaroxaban, apixaban or dabigatran

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Laulicht B, Bakhru S, Lee C, Baker C et al., Small Molecule Antidote for Anticoagulants, Circulation, 2012;126:A11395 (Abstract).

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

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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.

Apirazine to Reverse Edoxaban

• Primary end point
• Whole blood clotting time (WBCT) used to determine
• Anticoagulant effect of edoxaban
• Reversal of edoxaban by aripazine

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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.

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

Slide 36

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.

Comparison Summary For Pipeline Agents

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Pipeline Entity Design Strategy Reversal Target

Idarucizumab Humanized mAb against dabigatran; designed similar in structure to dabigatran-binding pockets of thrombin dabigatran Andexanet alfa Modified Factor Xa protein to be a decoy target for NOACs 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 & rivaroxaban Thrombin inhibitor = dabigatran

Learning Objectives

• Identify three molecular entities that are currently in

development for reversal of new oral anticoagulant (NOAC) agent(s)

• Compare the drug design strategy for each of these new

pipeline reversal agents that are currently in clinical trials

• Evaluate how these potential new agents may be

incorporated into a treatment strategy for significant bleeding related to NOAC use based on patient specific information

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PATIENT CASE Pipeline Agents for NOAC Reversal

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Patient Case

• CC: BB is a 39 y/o female who presents to the ED at a

Critical Access Hospital with fatigue, dyspnea, lightheadedness, abdominal pain, low back pain and vaginal bleeding

• HPI: Two week history of vaginal bleeding
• PMH: Recent bilateral pulmonary emboli currently being

treated with a NOAC. Changed from warfarin to NOAC ~ 6 weeks ago due to distance to anticoagulation clinic. NKDA.

Slide 40

Adapted by S Bartlett from Nannapaneni N, Singh R, McKay P and Al-Hajeili M, Case Rep Hematol, 2014;2014:548272.

Patient Case

• Physical Exam:
• VS: BP 122/70, HR 79 bpm, RR 18 bpm with O2 sat of 99% on

RA; temp 36°C

• Pelvic exam: fresh blood with clots in vaginal vault and

bleeding from closed cervical os

• Medication Reconcillation
• Patient doesn’t recall name of medication but thinks it is

something that ends with “ban”. Last dose 2 hrs PTA.

• Patient’s pharmacy is currently closed, no access to clinic

records and no family available.

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Adapted by S Bartlett from Nannapaneni N, Singh R, McKay P and Al-Hajeili M, Case Rep Hematol, 2014;2014:548272.

Patient Case

• Pertinent Labs:

Slide 42

Adapted by S Bartlett from Nannapaneni N, Singh R, McKay P and Al-Hajeili M, Case Rep Hematol, 2014;2014:548272.

Result Hospital Day

• 45

Hgb (g/dL) 6.8 10.8

Patient Case

• 1. Based on patient review do you recommend reversal of

anticoagulation?  Yes  No

• 2. Which agent(s) would be most appropriate?

(Assume all pipeline agents are FDA approved)

• A. Idarucizumab
• B. Andexanet alfa
• C. Aripazine

Slide 43

Adapted by S Bartlett from Nannapaneni N, Singh R, McKay P and Al-Hajeili M, Case Rep Hematol, 2014;2014:548272.

POST-LECTURE QUESTIONS Pipeline Agents for NOAC Reversal

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Post-Lecture Test Questions

• 1. Which of the following is a potential reversal agent for

dabigatran?

• A. trastuzumab
• B. idarucizumab
• C. andexanet alfa
• D. aripiprazole

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Post-Lecture Test Questions

• 2. Which of the following molecular entities is designed as

a factor Xa decoy?

• A. prothrombin complex concentrate (PCC)
• B. aripazine
• C. andexanet alfa
• D. idarucizumab

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Post-Lecture Test Questions

• 3. Which of the following pipeline reversal agents could

potentially be used as a “universal” reversal agent for low molecular weight heparins, factor Xa inhibitors and direct thrombin inhibitors?

• A. idarucizumab
• B. andexanet alfa
• C. aripazine
• D. protamine

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