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. Slide 2

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 Slide 3

New Oral Anticoagulants (NOACs) BACKGROUND Slide 4

Dabigatran (Boehringer Ingelheim)  FDA approvals  NVAF  October 2010  DVT/PE Treatment  April 2014 Structure adapted by S Bartlett from Blommel ML and Blommel AL, AJHP, 2011;68:1506-19. Slide 5

Rivaroxaban (Janssen)  FDA approvals  NVAF  November 2011  DVT/PE  November 2012  Knee/Hip VTE  July 2011 Slide 6 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 Apixa xaban ban Intri trinsic sic Extrinsic rinsic Edoxa xaban ban IXa VII IIa Pathway Pathway Rivaroxa xaban ban TF TF X Xa Xa X Va IIa IIa Dabig igatr tran an II II I Ia Ia XIIIa IIa Clot Adapted by S Bartlett from Sabir I et al., Nat Rev Cardiol, Drug Discovery, 2014;11:290 – 303.

No Specific NOAC Antidote Available  Patient taking NOACs may still experience  Major bleeding complications  Similar or lower bleeding rates than with warfarin  Trauma injuries  Require 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 10

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 Slide 11

Pipeline Reversal Agents  Idarucizumab (Boehringer Ingelheim)  Andexanet alfa (Portola Pharmaceuticals)  Aripazine (Perosphere) Slide 12

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 Slide 13

Pipeline Agents for NOAC Reversal IDARUCIZUMAB Slide 14

Idarucizumab  Humanized mAb fragment against dabigatran  Target  Dabigatran http://www.rcsb.org/pdb/explore/explore.do?structureId=4YGV 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 15

Tight Binding Affinity for Dabigatran Ligand – Target Binding K D (nM) Dabigatran - Thrombin 0.7 Dabigatran - Idarucizumab 0.002  Binding affinity is 350-fold higher for idarucizumab over thrombin 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 Slide 16 Agent for Dabigatran, Thromb Haemost, 2015;114:198-205.

Dabigatran Binding to Idarucizumab Schiele F, van Ryn J, Canada K, Newsome C et al., A Specific Antidote for Dabigatran: Functional and Structural Characterization, Blood, 2013;121:3554- Slide 17 3526.

RE-VERSE AD  Interim Results  REVER Sal E ffects of Idarucizumab in Patients on A ctive D abigatran  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 Pollack Jr CV, Reilly PA, Eikelboom J, Glund S et al., Idarucizumab for Dabigatran Reversal, N Engl J Med, 2015;373:511-520. Slide 18

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 Pollack Jr CV, Reilly PA, Eikelboom J, Glund S et al., Idarucizumab for Dabigatran Reversal, N Engl J Med, 2015;373:511-520. Slide 19

Successful Reversal in Bleeding Patients Pollack Jr CV, Reilly PA, Eikelboom J, Glund S et al., Idarucizumab for Dabigatran Reversal, N Engl J Med, 2015;373:511-520. Slide 20

Successful Reversal for Urgent Procedures Pollack Jr CV, Reilly PA, Eikelboom J, Glund S et al., Idarucizumab for Dabigatran Reversal, N Engl J Med, 2015;373:511-520. Slide 21

Pipeline Agents for NOAC Reversal ANDEXANET ALFA Slide 22

Andexanet alfa  Modified recombinant Factor X protein expressed in CHO cells  Targets  Factor Xa inhibitors  Rivaroxaban, Apixaban, Edoxaban http://www.portola.com/clinical- development/andexanet-alfa-prt4445-fxa- inhibitor-antidote/  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 23

Andexanet Protein Design  Modifications to Factor Xa  Removal of the activation peptide and 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 Slide 24 Inhibitors of Coagulation Factor Xa, Nat Med, 2013;19:446-451.

Andexanet Protein Design  Modifications to Factor Xa 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 Slide 25 Inhibitors of Coagulation Factor Xa, Nat Med, 2013;19:446-451.

Andexanet Protein Design  Modifications to Factor Xa 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 Slide 26 Inhibitors of Coagulation Factor Xa, Nat Med, 2013;19:446-451.

Decoy Mechanism for NOACs Andexanet Factor Xa Ligand Affinity  K D (nM) K D (nM) 5.8-fold  Apixaban 0.58 0.100 3.8-fold  Rivaroxaban 1.53 0.400  Decoy binds NOACs and reverses Factor Xa inhibition and 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 Slide 27 Med, 2013;19:446-451.

Andexanet Reverses Rivaroxaban in Rabbit Liver Laceration Model  75 mg andexanet IV reduces blood loss by > 85% in rivaroxaban treated rabbits (1 mg/kg) Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ et al., A Specific Antidote for Reversal of Anticoagulation by Direct and Indirect Inhibitors of Coagulation Slide 28 Factor Xa, Nat Med, 2013;19:446-451.

Andexanet Infusion Achieved Sustained Reversal of Apixaban Anticoagulation http://www.sec.gov/Archives/edgar/data/1269021/000156459014000472/ptla-10k_20131231.htm  Phase 2 placebo controlled trial in healthy volunteers  5 mg PO Apixaban BID x 5 days 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). Slide 29

Pipeline Agents for NOAC Reversal ARIPAZINE (PER977) Slide 30

Aripazine  Small molecule inhibitor  Targets  UFH  LMWH & Fondaparinux National Center for Biotechnology Information. PubChem Substance  Factor Xa inhibitors Database; SID=249807675, https://pubchem.ncbi.nlm.nih.gov/substance/249807675 (accessed Aug. 31, 2015).  Rivaroxaban, Apixaban, Edoxaban  Thrombin inhibitors  Dabigatran Slide 31