Mark Blostein, MD Director, Anticoagulation Clinic and Coagulation Laboratories Jewish General Hospital McGill University Montreal, Canada

Transcription

1 Mark Blostein, MD Director, Anticoagulation Clinic and Coagulation Laboratories Jewish General Hospital McGill University Montreal, Canada

2 OBJECTIVES 1. Understand how Warfarin can be reversed 2. Understand how NOACs can be reversed 3. Update the latest data on the available reversal agents 4. Know the indications for reversing all anticoagulants

3 Disclosures for: Mark Blostein Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Bayer, Glaxo Smith- Kline No relevant conflicts of interest to declare Boehringer-Ingelheim, CSL-Behring No relevant conflicts of interest to declare No relevant conflicts of interest to declare Honouraria received from these sources deposited in university-based research accounts Bayer, Boehringer-Ingelheim, Alexion, Amgen, Baxter, Octapharma

4 Warfarin, INR and Mortality Mortality / 1000 Patienten years % major bleeds/pts-y ( emergencies/y [G]) 0 Target INR: Optimal INR: 2,2-2, Hemorrhage Thromboembolism Mortality in matched non OAT pts INR Analysis of INR-values patients: death Indications: AF 58% Another > /y non-hemorrhagic induced urgent interventions [G] VTE 25% Stroke/TIA 22% Heart valves 18% Myocardial Infarction 3% Odén, A, BMJ 2002; 325: Palareti, G, Lancet 1996; 348: Go, AS, JAMA 2003;290:

5 Treatment option for reversal of OAT Withhold VKA: Half lifes: 11 h Acenocoumarol (Sintrom) 40 h Warfarin (Coumadin) 31 h Fluindione (Previscan) 140 h Phenprocoumon Will take >>24 h to reach INR < 1.5 Application of vitamin K: oral: slow decrease of INR, start within h i.v. : slow decrease of INR, start within 6-8 h s.c.:???role Factor replacement: immediate increase in factor activities Ansell, J, Chest 2004;126:204S-233S Baglin, TP, Br J Haematoll 2006;132: Aguilar, MI, Nayo Clin Proc 2007;83:82-92 Schulman,S, Transfus Me Rev 2007; 21:37-48

6 Oral Vitamin K Lowers the International Normalized Ratio More Rapidly Than Subcutaneous Vitamin K in the Treatment of Warfarin-Associated Coagulopathy ARandomized,ControlledTrial Mark A. Crowther, MD, MSc; James D. Douketis, MD; Terri Schnurr, RN; Luigi Steidl, MD; Valentina Mera, MD; Carolina Ultori, MD; Achille Venco, MD; and Walter Ageno, MD Background: Excessive anticoagulation due to warfarin use is Measurements: The primary outcome measure was the INR international normalized ratio. 20 August 2002 Annals of Internal Medicine Volume 137 Number 4

7 Annals of Internal Medicine Article Oral Vitamin K Versus Placebo to Correct Excessive Anticoagulation in Patients Receiving Warfarin ARandomizedTrial Mark A. Crowther, MD, MSc; Walter Ageno, MD; David Garcia, MD; Luqi Wang, PhD; Dan M. Witt, PharmD; Nathan P. Clark, PharmD; Mark D. Blostein, MD; Susan R. Kahn, MD, MSc; Sara K. Vesely, PhD; Sam Schulman, MD; Michael J. Kovacs, MD; Marc A. Rodger, MD, MSc; Phillip Wells, MD, MSc; David Anderson, MD, MSc; Jeffery Ginsberg, MD; Rita Selby, MD, MSc; Sergio Siragusa, MD; Mauro Silingardi, MD; Mary Beth Dowd, PharmD; and Clive Kearon, MD, PhD In a double blind randomized trial of 763 non-bleeding patients, oral vitamin K did not reduce bleeding when INRs were between 4 and 10

8 What are prothrombin complex concentrates (PCCs)? Concentrated product of the vitamin dependent coagulation factors Prothrombin Factor VII Factor IX Factor X Protein C Protein S Heparin Two commercial products in Canada: Octaplex (Octapharma) and Beriplex (CSL Behring)

9 Benefits of prothrombin complex concetnrate (PCC) over fresh frozen plasma (FFP) for reversal of warfarin PCC vs Plasma FFP Blood group specific Slow process to acheive target INR Takes time to thaw Large volumes needed Varying content of coagulation factors Unpredictable effect Not virus inactivated Risk of TRALI PCC Not blood group specific Fast application: 10 mins Room temperated Small volume Standardised content of coagulation factors (1:1:1:1 ratio of FII, FVII, FIX, FX) Predictable effect Virus inactivated No risk of TRALI

10 Clinical studies: LEX-203 Efficacy and Safety of OCTAPLEX in Patients Under Oral Anticoagulant Therapy and Undergoing Surgery or Invasive Procedures A Prospective, Non-Randomised, Non-Controlled, Open-Label, Multi-Centre Phase III Study (N = 60)

11 Clinical studies: LEX-203 Correction of INR.

12 Dosing recommendations The dose will depend on the INR before treatment and the targeted INR. In the following table approximate doses (ml / kg body weight of the reconstituted product) required for normalisation of INR ( 1.2 within 1 hour) at different initial INR levels are given. Initial INR >3.5 Approximate dose* (ml octaplex / kg body weight) >1.9 One vial of octaplex is 20 ml and contains 500 IU FIX For example: Recommended dose of octaplex for a 70 kg patient with starting INR of 2.5: 1.3 ml x 70 kg = 91 ml octaplex 91 ml octaplex / 20 ml per vial = 4.55 vials octaplex (2275 IU octaplex)

13

14

15 ORIGINAL RESEARCH The effectiveness and safety of fixed low-dose prothrombin complex concentrates in patients requiring urgent reversal of warfarin Cindy Varga, Sultan Al-Touri, Stella Papadoukakis, Stephen Caplan, Susan Kahn, and Mark Blostein WTransfusion, 53:1451, 2013

16 Retrospective chart review of 103 patients who received PCCs for bleeding or need for an urgent procedure while patient on coumadin Received 1000 U (~16.7 U/kg) regardless of size and INR INR checked 30 minutes after infusion with the option of administering more if needed as judged by the treating physician Assessed clinical efficacy, INR response and toxicity within 30 days

17 Message 1: INR response not great (~50%<1.5) to PCC but clinical response excellent INR Response Clinical Response INR < patients (48.5%) Excellent: 44 patients Moderate: 0 patients No response: 6 patients Total Patients 103 INR : 45 patients (43.7%) INR : 7 patients (6.8%) Excellent: 36 patients Moderate: 5 patients No response: 3 patient Unknown: 1 patient* Excellent: 5 patients Moderate: 1 patient No response: 1 patient INR : 1 patients (0.97%) Excellent: 1 patient Moderate: 0 patients No response: 0 patients Transfusion, 53:1451, 2013

18 Message 2: Intracranial Haemorrhage (ICH) do poorly despite PCCs Clinical Presentation No. (N = 103) Clinical Response No. (%) Deaths due to bleeding (no.) No. pts > 1 dose Thrombosis Excellent Moderate None ICH (63.6) 0 (0.0) 8 (36.4) Extracranial Bleed (87.0) 5 (9.3) 2 (3.7) Gastrointestinal (82.4) 5 (14.7) 1 (2.9) Traumatic 8* 6 (75.0) 0 (0.0) 1 (12.5) Genito-urinary 7 7 (100.0) Mucosal bleed 2 2 (100.0) Epistaxis 1 1 (100.0) Hemothorax 1 1 (100.0) Hemoptysis 1 1 (100.0) Procedure (96.3) 1 (3.7) Transfusion, 53:1451, 2013

19 Message 3: Toxicity low Ø Of 103 patients, 5 thrombotic events within 30 days Ø All patient had other comordities Thrombosis Deep Venous Thrombosis Non STelevation myocardial infarction Non STelevation myocardial infarction Bilateral Deep Venous Thrombosis Days post PCC Dose ( IU) Pre INR Post INR Management/ Clinical Outcome IU Bridged to warfarin IU Treated conservatively. Good cardiac outcome IU Treated conservatively. Good cardiac outcome IU Bridged to warfarin Non STelevation myocardial infarction IU Treated conservatively. Good cardiac outcome. Transfusion, 53:1451, 2013

20 New changes in NAC recommendations /29/2011 DOSING, ADMINISTRATION & MONITORING: The following recommendation is based on review of literature and the desire to prevent thrombotic complications. The working group is aware that it is less than the manufacturer s recommended dose in many individuals. This is in part due to the fact the package insert recommendations will correct factor levels to normal despite the fact that normal hemostasis does not require 100% factor levels. The working group would also like to highlight that 50% of patients in the audit responded to the previously recommended standardized dose of 1000 IU (40 ml octaplex ). For adult patients: Dosing of prothrombin complex concentrate should be based on the INR as per the table below. If the INR is unknown and major bleeding is present, 80 ml should be administered. INR <3.0 INR INR >5.0 Dose of Prothrombin Complex 40 ml (1000 IU) 80 ml (2000 IU) 120 ml (3000 IU) Administration: Vitamin K: Must be administered intravenously. May be administered by direct IV push, syringe pump or minibag. The manufacturer s recommended maximal rates of infusion are: octaplex = 3mL/min Beriplex P/N = 8 ml/min. Vitamin K (10 mg IV) co-administration is strongly recommended if a

21 Efficacy and Safety of a 4-Factor Prothrombin Complex Concentrate in Patients on Vitamin K Antagonists Presenting With Major Bleeding: A Randomized, Plasma-Controlled, Phase IIIb Study Ravi Sarode, Truman J. Milling, Jr, Majed A. Refaai, Antoinette Mangione, Astrid Schneider, Billie L. Durn and Joshua N. Goldstein Randomized open label- 4 Factor PCC vs FFP 200 patients, ~100 per arm Non-surgical Table 2. Dose of Study Treatment per Baseline INR

22 Primary endpoint analysis Table 7. Rapid INR Reduction (Intention-to-Treat Efficacy Population) P P Table 5. Hemostatic Efficacy (Intention-to-Treat Efficacy Population) P P P

23 Toxicity Table 8. Summary of AEs (Intention-to-Treat Safety Population) d t c l s h 4 i h p b r t t d r b p l u r r s r a a c

24

25 What about the NOACs [DOACs, TSOACs]

26 Managing Bleeding Complications in Patients Treated with noacs */**Recommendation based only on limited non-clinical data PCC = prothrombin complex concentrates (non-activated or activated) Siegal and Crowther. Eur Heart J 2012; 34: b

27 Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate: A Randomized, Placebo-Controlled, Crossover Study in Healthy Subjects Elise S. Eerenberg, Pieter W. Kamphuisen, Meertien K. Sijpkens, Joost C. Meijers, Harry R. Buller and Marcel Levi Circulation 124:1573, 2011 Rivaroxaban Dabigatran Octaplex reverses Rivaroxaban, not dabigatran?

28 Antidotes in development: Molecule Idarucizumab Andexanet Alfa PER977 Developed by Boehringer Ingelheim Portola Pharmaceuticals Inc. Perosphere Inc. Molecule type Humanized Antibody Fab Recombinant human FXa variant Small synthetic molecule Target(s) Dabigatran FXa inhibitors UFH, LMWH, FXa inhibitors, anti-thrombin Binding qualities (affinity) Noncompetitive (350x for dabigatran) Competitive (equal) Route of administration Intravenous (5 min infusion) Intravenous (bolus + infusion) Intravenous Noncovalent hydrogen bonding (affinity unknown) PK/PD Effect Safety Terminal t½: Elimination: Start: Sustained: In volunteers: Clinical settings: 4.5-9h Renal <5min 12-14h up to 8g 5g (Phase 3) min unknown <10min during infusion up to 800mg Variable Dosing Off Target Effects None known Competes with Fxa binding to TFPI inducing procoagulant effect Schiele et al. Blood 2013;121: ; Lu et al. Nat Med 2013;9: ; Ansell et al. N Engl J Med, 2014, 371: ; Bahkru et al. AHA Nov 2013; unknown unknown ~10min 12-24h up to 300mg unknown Binds calcium chelators Lauw et al. Can. J. Cardiol 2014;30:381-84e; Portola Pharmaceuticals. Presentatation at Jan 2015 Investigator s Meeting; Crowther et al. Weitz et al. J Thromb Thrombolysis DOI /s ; TFPI= tissue factor pathway inhibitor

29 Idarucizumab is a true, specific antidote to dabigatran DEVELOPMENT Monoclonal mouse antibody developed with high dabigatran binding affinity Monoclonal antibody then humanized and directly expressed as a Fab fragment in hamster cells Fully humanized antibody fragment (Fab) PROPERTIES Potent binding affinity ~350 times higher than binding of dabigatran to thrombin No procoagulant or anticoagulant effects expected Short half life Intravenous administration, immediate onset of action EXPECTED LOW RISK OF ADVERSE REACTIONS No Fc receptor binding No endogenous targets References: Glund S et al. Presented at AHA, Dallas, TX, USA, November 2013; Schiele F et al. Blood. 2013;121:

30 o Monoclonal antibody was then humanized and directly expressed as a Fab fragment in mammalian cells (hater) o Fully humanized antibody fragment (Fab) o Monoclonal mouse antibody developed with high dabigatran binding affinity (350x) Dabigatran Antidote (adabi-fab): Mouse antibody Humanized Fab Dabigatran 500 daltons Thrombin ~36000 daltons Idarucizumab ~47800 daltons 29

31 Idarucizumab demonstrated immediate, complete, and sustained reversal of dabigatran in elderly subjects dtt (s) End of idarucizumab injection (5 min infusion) years, dabigatran 220 mg BID + idarucizumab 5 g years, dabigatran 220 mg BID + idarucizumab 5 g dtt = dilute thrombin time Dabigatran dosed over 3 days and morning of 4 th day (day of infusion) Minutes Dabigatran Antidote Time after end of infusion (h) Glund S et al. Blood :344 30

32 Re-administration of dabigatran 24 hours after idarucizumab restores anticoagulation End of idarucizumab injection (5 min infusion) years, dabigatran 220 mg + Idarucizumab 5 g dtt = dilute thrombin time dtt (s) (s) Restart dabigatran Peak Dabigatran dosed over 3 days and morning of 4 th day (day of infusion) Dabigatran anticoagulation restored to levels similar to baseline regardless of prior use of antidote Trough Time 0 0after 0end 0 of infusion 0 (h) Dabigatran Antidote Similar results after administration of 2.5 g idarucizumab (data not shown). A partial return of anticoagulant effect of dabigatran was observed starting ~0.5h after infusion of 1g idarucizumab (data not shown) Glund S et al. Blood :344 31

33 A Phase III Case Series Clinical Study of the Reversal of the Anticoagulant Effects of Dabigatran by Intravenous Administration of 5.0g Idarucizumab (BI ) in Patients Treated With Dabigatran Etexilate Who Have Uncontrolled Bleeding or Require Emergency Surgery or Procedures TRIAL RECRUITMENT NOW OPEN

34 STUDY OBJECTIVE To assess whether idarucizumab can remove the activity of dabigatran from a bleeding or pre-procedure patient s circulation, allowing normal thrombin activity STUDY DESIGN Prospective, open-label, single treatment group, 3 month follow-up study SETTING ~500 sites in 39 countries SAMPLE SIZE patients Based on practical considerations and FDA regulatory feedback Estimate data on 5 10% of patients for BLA filing.

35 PATIENT ELIGIBILITY INCLUSION CRITERIA* Group A: Bleeding patients 1. Overt bleeding judged by physician to require a reversal agent 2. Currently taking dabigatran etexilate years of age 4. Written informed consent Group B: Patients requiring emergency surgery or procedure 1. Condition requiring emergency surgery or procedure where adequate haemostasis is required (emergency = next 8 hours) 2. Currently taking dabigatran etexilate years of age 4. Written Informed consent. Others please consult with the clinical trial investigator to discuss additional inclusion criteria <insert local site coordinator> MAIN EXCLUSION CRITERIA* Group A: Bleeding Patients 1. Minor bleeds (epistaxis, haematuria) that can be managed with standard supportive care 2. No clinical signs of bleeding 3. Contraindications to study medication including known hypersensitivity to drug or excipients (i.e. hereditary fructose intolerance) Group B: Patients requiring emergency surgery or procedure 1. Surgery or procedure which is elective or with low risk of uncontrolled or unmanageable bleeding 2. Contraindications to study medication including known hypersensitivity to drug or excipients (i.e. hereditary fructose intolerance) Others please consult with the clinical trial investigator to discuss additional exclusion criteria <insert local site coordinator> Symbol * Please consult with the clinical trial investigator to discuss additional inclusion and exclusion criteria.

36 The new england journal of medicine Original Article Idarucizumab for Dabigatran Reversal Charles V. Pollack, Jr., M.D., Paul A. Reilly, Ph.D., John Eikelboom, M.B., B.S., Stephan Glund, Ph.D., Peter Verhamme, M.D., Richard A. Bernstein, M.D., Ph.D., Robert Dubiel, Pharm.D., Menno V. Huisman, M.D., Ph.D., Elaine M. Hylek, M.D., Pieter W. Kamphuisen, M.D., Ph.D., Jörg Kreuzer, M.D., Jerrold H. Levy, M.D., Frank W. Sellke, M.D., Joachim Stangier, Ph.D., Thorsten Steiner, M.D., M.M.E., Bushi Wang, Ph.D., Chak-Wah Kam, M.D., and Jeffrey I. Weitz, M.D. NEJM 373: , 2015

37 Primary Endpoint in Group A: Reversal of Dabigatran Anticoagulation with Idarucizumab based on dtt [Dilute Thrombin ime {Hemoclot}] Diluted thrombin time (dtt) dtt (s) Idarucizumab 2x 2.5 g Assay upper limit of normal 20 Baseline Between vials min 1h 2h 4h 12h 24h Time post idarucizumab Pollack et al. NEJM 2015 Idarucizumab is an investigational product currently in development. Its safety and efficacy have not been established and is not approved for use in any country. Boehringer Ingelheim (Canada) Ltd. cannot recommend the use of products outside the approved Canadian product monograph.

38 Primary endpoint in Group B: Reversal of Dabigatran Anticoagulation with Idarucizumab based on dtt and ECT Ecarin clotting time (ECT) dtt (s) Idarucizumab 2x 2.5 g ECT (s) Assay upper limit of normal Idarucizumab 2x 2.5 g 20 Baseline Between vials min 1h 2h 4h 12h 24h Time post idarucizumab 25 Baseline Between vials min 1h 2h 4h 12h 24h Time post idarucizumab

39 RE-VERSE AD : Results Median maximum reversal within 4 hours was 100% for both dtt and ECT (95% CI, ), evident after first vial of idarucizumab dtt normalized in 98% and 93% of Group A and B patients, respectively* ECT normalized in 89% and 88% of Group A and B patients, respectively* Sustained reversal of dabigatran effect over 12 hours was observed in at least 90% of patients Similar results with aptt and TT

40 Original Article Idarucizumab for Dabigatran Reversal Full Cohort Analysis Charles V. Pollack, Jr., M.D., Paul A. Reilly, Ph.D., Joanne van Ryn, Ph.D., John W. Eikelboom, M.B., B.S., Stephan Glund, Ph.D., Richard A. Bernstein, M.D., Ph.D., Robert Dubiel, Pharm.D., Menno V. Huisman, M.D., Ph.D., Elaine M. Hylek, M.D., Chak-Wah Kam, M.D., Pieter W. Kamphuisen, M.D., Ph.D., Jörg Kreuzer, M.D., Jerrold H. Levy, M.D., Gordon Royle, M.D., Frank W. Sellke, M.D., Joachim Stangier, Ph.D., Thorsten Steiner, M.D., Peter Verhamme, M.D., Bushi Wang, Ph.D., Laura Young, M.D., and Jeffrey I. Weitz, M.D. N Engl J Med Volume 377(5): August 3, 2017

41 Study Overview Idarucizumab was 100% effective in reversing the anticoagulant effect of dabigatran among 300 patients with uncontrolled bleeding (median time to bleeding cessation, 2.5 hours) and among 200 patients who required an urgent procedure (median time to procedure initiation, 1.6 hours).

42 Key Measurements before and after the Administration of Idarucizumab. Pollack CV Jr et al. N Engl J Med 2017;377:

43 160 Case at JGH (88 y.o. female: Hemothorax from Rib fracture. On dabigatran 110 mg po bid) Idarucizumab Thrombin Time Time (hours)

44 Andexanet alpha A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa Genmin Lu 1, Francis R DeGuzman 2, Stanley J Hollenbach 2, Mark J Karbarz 1, Keith Abe 2, Gail Lee 2, Peng Luan 1, Athiwat Hutchaleelaha 3, Mayuko Inagaki 3, Pamela B Conley 1, David R Phillips 1 & Uma Sinha 1 a b MK MW (kda) pd-fxa r-antidote PrePro LC RKR AP HC (Ser419) PrePro ANSFL Deletion RKRRKR HC (S419A) fx r-antidote HC (, ) LC LC 4 Figure 1 Design of r-antidote and protein expression in CHO cells. (a) Schematic illustration of the domain structure of full-length human fx and Nature Medicine 19:446, 2013

45 Andexanet alpha a 100 Betrixaban 100 Rivaroxaban 100 Apixaban b In vitro Rate (mod min 1 ) [I] = 0 nm [I] = 2.5 nm [I] = 5.0 nm [I] = 7.5 nm Rate (mod min 1 ) [I] = 0 nm [I] = 2.5 nm [I] = 5.0 nm [I] = 7.5 nm Rate (mod min 1 ) [I] = 0 nm [I] = 2.5 nm [I] = 5.0 nm [I] = 7.5 nm PT (s) r-antidote (nm) r-antidote (nm) r-antidote (nm) c In vivo Blood loss (g) Nature Medicine 19:446, P < 0.05 P < P < Vehicle Riva Riva + r-antidote Vehicle + r-antidote Figure 4 Mitigation of blood loss caused by rivaroxaban-induced a i b a c a i i p r a t a a v

46 Original Article Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity Deborah M. Siegal, M.D., John T. Curnutte, M.D., Ph.D., Stuart J. Connolly, M.D., Genmin Lu, Ph.D., Pamela B. Conley, Ph.D., Brian L. Wiens, Ph.D., Vandana S. Mathur, M.D., Janice Castillo, B.S., Michele D. Bronson, Ph.D., Janet M. Leeds, Ph.D., Florie A. Mar, Ph.D., Alex Gold, M.D., and Mark A. Crowther, M.D. N Engl J Med Volume 373(25): December 17, 2015

47 Time Courses of Anti Factor Xa Activity before and after Administration of Andexanet. Siegal DM et al. N Engl J Med 2015;373:

48 Conclusions Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects.

49 DOI: /NEJMoa

50 ANNEXA-4 Study Design Patient with acute major bleed, meeting inclusion criteria Patient Screening If last dose of fxa inhibitor was within 18 hours Assessment s: Andexanet Treatment IV Bolus Bleeding and Laboratory Assessment 2-hour IV Infusion Day 1 After end of infusion 1 hr 4 hr 8 hr 12 hr Safety follow-up visit Day 3 Day 30 Efficacy Measurements Change in anti-fxa activity Clinical hemostatic efficacy through 12 hours Safety Measurements Thrombotic events Antibodies to FX, FXa, andexanet 30-day mortality

51 ANNEXA-4: Design and Analysis Plan Criteria for Major Acute Bleeding Life-threatening bleeding with hemodynamic compromise Bleeding with hemoglobin drop of >2 gm/dl, or falling below 8 gm/dl Critical organ bleeding, such as intra-cranial, intra-spinal, etc. Analysis Populations Safety population included all patients receiving andexanet Efficacy population excluded patients with baseline anti-fxa activity <75 ng/ml (<0.5 IU/ml for enoxaparin) Preliminary analysis Includes all patients with complete data on June 17, 2016 ANNEXA-4 study is ongoing

52 Assessment of Clinical Hemostatic Efficacy All cases assessed by independent committee Specific efficacy criteria for each type of bleed Independent Core Lab interpreted brain CT and MRI Cases rated as excellent/good vs. poor/none Based on method developed for assessment of PCC in warfarin bleeding, where efficacy reported was 71%* *Sarode et al, Circulation 2013; 128,

53 Anti-factor Xa Activity: Rivaroxaban n= 26

54 Clinical Hemostatic Efficacy

55 Conclusions Andexanet bolus plus 2 hour infusion rapidly reversed anti-fxa activity Effective hemostasis observed in 79% of patients Thrombotic events occurred at rates consistent with the high risk profile of the patients

56 Perosphere: PER977 (Aripazine) Universal inhibitor: low molecular weight heparin, unfractionated heparin, rivaroxaban, apixaban, dabigatran, edoxaban Mechanism of action: Small molecule (~500 daltons), highly positively charged Binds to negatively charged molecules (heparin) Binds to neutrally charged molecules by hydrogen bonding (ratio of inhibitor 6:1 PER977:inhibitor) Bahkru et al. AHA Nov 2013;

57 Perosphere: PER977 (Aripazine) in Healthy Volunteers taking Edoxaban Dose-rise finding with PER977 in healthy volunteers Reversal with edoxaban in volunteers with doses up to 300 mg Whole blood clotting time to determine reversibility Ansell JE. et al. N Engl J Med 2014; 371: Ansell JE et al. European Heart Journal. 2015; 35 (Abstract Suppl): Abstract Presented as a Rapid Fire Oral Presentation at the 2014 European Society of Cardiology Congress Barcelona Spain, September 2, Laulicht B et al. PER977 Reverses UFH and LMWH, Fondaparinux, and NOACs. Presented at ACCP Austin, TX, October