Issues in Emerging Health Technologies

Antidote Treatments for the Reversal of Direct

Oral Issue 138  June 2015

situations such as life-threatening major bleeding or Summary non-elective major surgery.4 Currently, there are three

 There are three intravenous antidotes currently specific reversal drugs for DOACs under clinical under development for the reversal of direct oral development (see Table 1). anticoagulants. Idarucizumab (aDabi-Fab/BI 655075/Boehringer  Idarucizumab is a humanized, monoclonal, Ingelheim, Germany) is a humanized, monoclonal, antibody fragment that reverses the direct antibody fragment that specifically binds with high thrombin inhibitor dabigatran. is affinity to dabigatran, an oral direct thrombin inhibitor a modified recombinant factor Xa molecule that (DTI), also developed by Boehringer Ingelheim. It acts reverses oral direct (e.g., , edoxaban, by competitively displacing dabigatran from thrombin ) and injectable indirect (e.g., 5 enoxaparin, fondaparinux) factor Xa inhibitors. to reverse anticoagulation and restore fibrin formation. Dabigatran has an affinity for idarucizumab that is 350 Aripazine is a small, synthetic molecule with 8 potentially universal reversal times greater than its affinity for thrombin. The dose 9 activity. currently studied in the phase 3 trial is 5 g. Based on  Clinical evidence to support the use of individual pre-marketing information obtained from the antidotes is currently limited to phase 1 and manufacturer, idarucizumab will be available as a phase 2 trials in healthy volunteers. All three single package consisting of two 50 mL vials (2 x antidotes were well tolerated during these studies 2.5 g); no reconstitution will be required. The complete and no pro-coagulant activity was observed. dose of 5 g will be administered intravenously as two Phase 3 trials are underway for idarucizumab consecutive infusions over 5 to 10 minutes each, or as and andexanet alfa. bolus injections (Ernie Hampel, Executive Director,  Preliminary data shows promising results but Market Access and Healthcare Affairs, Boehringer assessment of long-term safety and efficacy Ingelheim Canada Ltd., Burlington, ON: personal requires more research. Additional research is communication, 2015 Mar 9). also needed to determine impact on clinical practice. Clear guidance should be available at Andexanet alfa (PRT064445 or PRT4445*/Portola the time these reversal drugs are commercialized Pharmaceuticals Inc., US) is a modified recombinant to promote their appropriate use. factor Xa (FXa) molecule intended for intravenous (IV) administration. It was developed as an antidote to reverse anticoagulant activity of oral direct (e.g., The Technology apixaban, edoxaban, and rivaroxaban) and injectable indirect (e.g., enoxaparin and fondaparinux) FXa In the past decade, the use of direct oral anticoagulants inhibitors. Andexanet alfa acts as a decoy to target and (DOACs; apixaban, dabigatran, edoxaban, rivaroxaban) sequester with high specificity both oral and injectable has been approved for a number of conditions such as FXa inhibitors in the blood.10 It lacks a membrane- the prevention of stroke in patients with non-valvular binding gamma-carboxyglutamic acid domain, atrial fibrillation (AF); the prevention of venous rendering it catalytically inactive, but it retains a high thromboembolism (VTE) after hip or knee replacement binding affinity to FXa inhibitors.6 Two doses are surgery; and the treatment of VTE, as well as the currently being studied in phase 3 trials: 400 mg IV prevention of VTE recurrence. [Note: apixaban, bolus followed by continuous infusion at 4 mg per dabigatran, and rivaroxaban are currently available in 11,12 1-3 minute for 120 minutes (reversal of apixaban) and Canada.] Unlike warfarin and other vitamin K 800 mg IV bolus followed by continuous infusion at antagonists, there are no specific antidotes available to 8 mg per minute for 120 minutes (reversal of reverse the anticoagulant effect of DOACs. Although rivaroxaban).11,13 the latter have short half-lives, which suggests reversal drugs may not be needed in non-urgent situations, the Aripazine (PER977/ciraparantag/Perosphere Inc., US) lack of such antidotes is a concern in emergency is a small, synthetic molecule designed with broad reversal activity and administered as a single IV bolus

1 dose. It binds to oral FXa inhibitors and DTIs, as well development program for aripazine is currently at the as to injectable unfractionated heparin (UFH) and low- phase 2 stage, it is not possible to comment on the dose molecular-weight heparin (LMWH) via non-covalent that will be studied in the phase 3 trial and which is bonding and charge-charge interactions to neutralize therefore more likely to be approved for clinical use. anticoagulation and bleeding.7,14 As the clinical

5-7 TABLE 1: ANTIDOTES UNDER DEVELOPMENT FOR DIRECT ORAL ANTICOAGULANTS

Antidote Target Structure Route Storage Idarucizumab Oral DTI Humanized IV Refrigerated (BI 655075) monoclonal antibody fragment Andexanet alfa Oral FXa inhibitors; Modified IV Refrigerated (PRT064445 or injectable LMWH recombinant FXa PRT4445*) and fondaparinux protein Aripazine Oral FXa inhibitors Synthetic small IV Room temperature (PER977) and DTI; molecule injectable UFH, LMWH, and fondaparinux

DTI = direct thrombin inhibitor; FXa = factor Xa; IV = intravenous; LMWH = low-molecular-weight heparin; UFH = unfractionated heparin.

reversal of the anticoagulant effect. At this time, it is Regulatory Status anticipated that the targeted population for these drugs will be patients in emergency situations such as those Currently, idarucizumab, andexanet alfa, and aripazine with major bleeding or who require non-elective major are not approved for use in Canada, the US, the United 4,9,24 15-17 surgery. Although the definition for major bleeding Kingdom, or European Union (EU) countries. may vary across clinical trials, the International Society Andexanet alfa and idarucizumab were granted on Thrombosis and Haemostasis (ISTH) developed a breakthrough therapy designation by the US Food and classification commonly used in research and that Drug Administration (FDA) in November 2013 and 18-20 provides a good description of these serious adverse June 2014, respectively. On February 26, 2015, the events (AEs). Overall, major bleeds are those that result FDA also granted orphan drug designation to andexanet in death, are life-threatening, cause chronic sequelae, or alfa for reversing the anticoagulant effect of direct or consume major health care resources. Types of major indirect FXa inhibitors in patients experiencing a bleeding events defined by ISTH’s classification serious, uncontrolled bleeding event or who require 10 include fatal bleedings and bleedings occurring in urgent or emergency surgery. On March 3, 2015, critical anatomical sites such as the brain, spine, eyes, Boehringer Ingelheim, the manufacturer of abdominal cavity, joints, or pericardium, or in muscle if idarucizumab, announced that submission for approval compartment syndrome is present. Other types of major was filed in the US, the EU, and Canada for use in 21 bleeding events under ISTH’s definition include a fall patients requiring an antidote to dabigatran. On April in hemoglobin levels of at least 2 g/dL or the need for 24, 2015, the FDA granted priority review/accelerated 25 22 transfusing at least two red cell packs. Of interest, approval status to idarucizumab. Of note, final results other potential conditions where reversal of DOACs from phase 3 clinical studies for both idarucizumab and 9,18,23 may be considered have been identified in a recent andexanet alfa are pending. Aripazine was granted review. These include clinical conditions at high risk of fast-track status in the US on April 15, 2015; phase 3 14 bleeding such as major head injury in patients treated trials are planned. with DOACs, DOAC overdose in patients with coagulation or platelet disorders or in patients also Patient Group taking antithrombotic drugs at the same time.26 Of note, Pending confirmation of their efficacy and safety, these these conditions are not specifically included in antidote treatments will fulfill an unmet need in currently ongoing phase 3 clinical trials. patients using a DOAC and who need immediate

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or require emergency surgery or procedures (see Table Current Practice 2). A dose of 5 g idarucizumab will be administered intravenously to reverse the effect of dabigatran. The In patients experiencing a DOAC-induced major trial will measure plasma-diluted thrombin time and bleeding event, current consensus-based guidelines ecarin clotting time as primary outcome measures. recommend withdrawing the anticoagulant and Time to cessation of bleeding will be a secondary administering oral charcoal (if within two hours of outcome. Results from the trial are anticipated in July DOAC ingestion). The use of prothrombin complex 2017.9 concentrate (PCC, Octaplex) at a dose of 25 U/kg (which may be repeated once or twice), activated Andexanet alfa prothrombin complex concentrate (aPCC, FEIBA) at a Two phase 2 trials evaluated the safety and efficacy of dose of 50 IE/kg (max 200 IE/kg/day) or recombinant andexanet alfa in healthy volunteers receiving apixaban factor VIIa (rFVIIa, NiaStase) may be considered.26-30 or rivaroxaban, which are two DOACs available in Overall, there appears to be relatively limited available Canada. Patients in one study by Crowther et al.34 data supporting the efficacy of these non-specific drugs received apixaban 5 mg twice daily orally for six days in the reversal of DOAC-induced bleeding events.29,31 before 420 mg of andexanet alfa was administered as an Also, given that thrombosis is a potential AE from IV bolus dose. This treatment was followed by a anticoagulant reversal therapy, these pro-coagulant continuous IV infusion of andexanet alfa for either 45 drugs must be administered with caution. minutes or two hours, at a rate of 4 mg per minute. At two minutes following the IV bolus dose, plasma Hemodialysis may also be considered to reverse the concentrations of unbound apixaban had decreased and anticoagulant effect but only in the case of dabigatran- 26-30 the mean anti-FXa activity was reduced by more than associated bleeding. Despite edoxaban being 90%, with the level of reversal sustained throughout the relatively low-protein-bound and slightly cleared by infusion periods for both regimens (P < 0.0001). hemodialysis (6% to 20%), a small open-label Thrombin generation remained within the normal range pharmacokinetic study of 10 patients with end-stage for two hours following cessation of infusion.34 In the renal disease indicates that hemodialysis is not effective 30,32,33 other placebo-controlled study, healthy patients were at removing edoxaban from the bloodstream. given rivaroxaban 20 mg per day orally for six days and were then randomly assigned to four different dosing The Evidence cohorts of andexanet alfa (210 mg IV bolus, 420 mg IV Current evidence for the reversal of a DOAC bolus, 600 mg IV bolus, or 720 mg IV bolus followed anticoagulant effect with antidote treatments is mostly by a one-hour IV infusion administered at a rate of limited to in vitro studies, animal models, and trials 4 mg per minute). Results showed a dose-dependent with healthy volunteers. reduction in anti-FXa activity by 20%, 53%, 70%, and 81%, respectively; anti-FXa activity returned to levels Idarucizumab seen with placebo approximately two hours after In an early phase trial, Van Ryn et al. evaluated the treatment cessation. Similarly, the plasma concentration reversal of dabigatran’s anticoagulant effect with of unbound rivaroxaban decreased by 32%, 51%, 75%, 5 and 70%, respectively, relative to pre-andexanet alfa idarucizumab in 35 healthy volunteers. They each 35,36 received 1 g, 2 g, or 4 g of idarucizumab or placebo. values. Findings from the two first-dose cohorts of The treatment was administered as a five-minute IV another small phase 2 trial were recently reported in infusion after four days of dabigatran 220 mg twice abstract form; in this study patients received edoxaban, daily orally. Blood was collected from an incision a DOAC not currently available in Canada. This study wound to explore restoration of wound site fibrin evaluated andexanet alfa for the reversal of the formation by measuring fibrinopeptide A (FPA). There anticoagulant effect of edoxaban, administered at a was a significant, dose-dependent return of fibrin dose of 60 mg daily for six days prior to andexanet alfa. formation with increasing doses of idarucizumab; Both dose cohorts (andexanet alfa 600 mg bolus [n = 9] reversal allowed participants to reach 24%, 45%, and and 800 mg bolus followed by 8 mg per minute 63% of control FPA values 30 minutes after 1 g, 2 g, infusion for one hour [n = 9]) resulted in an immediate and 4 g of idarucizumab was administered, respectively decrease in anti-FXa activity of 52% and 73%, (P < 0.05).5 A global phase 3 case series study known respectively, compared with the pre-andexanet alfa as RE-VERSE AD is currently enrolling patients administration level. This decrease remained constant treated with dabigatran who have uncontrolled bleeding during the infusion and returned to placebo levels approximately two hours following cessation of

3 andexanet alfa. The antidote was well tolerated and is ongoing and will investigate IV bolus followed by a there were no serious or severe AEs and no thrombotic two-hour continuous infusion to demonstrate sustained events.37 reversal.11,40 Part 1 of two phase 3 clinical trials — ANNEXA-A and Aripazine ANNEXA-R — was recently completed. They In a double-blind, placebo-controlled, phase 1/2 trial evaluated reversal of apixaban and rivaroxaban with involving 80 healthy volunteers, single IV doses andexanet alfa in older healthy volunteers (ages 50 to (administered over the course of two to five minutes) of 75 years);12,20,24 final results of these trials are pending aripazine (5 mg to 300 mg) or placebo were (see Table 2). Primary outcomes were measured by administered three hours after a 60 mg dose of anti-FXa activity. Secondary outcomes include edoxaban was given orally.7,16,41 The degree of reversal unbound FXa inhibitor plasma levels and thrombin in anticoagulation was measured by whole-blood generation.38,39 Of note, preliminary results from part 1 clotting time. At doses of 100 mg to 300 mg, aripazine of the ANNEXA-R trial — which compared the reduced whole-blood clotting time to within 10% above administration of an 800 mg IV bolus of andexanet alfa baseline value in 10 minutes; this effect was sustained to placebo in 39 patients pre-treated with rivaroxaban for 24 hours. In comparison, the time to reach that level 20 mg for four days — were presented at the 2015 in patients receiving placebo was approximately 12 to American College of Cardiology (ACC) Scientific 15 hours. Aripazine restored normal clot formation and Sessions on March 16, 2015.40 Andexanet alfa fibrin integrity within the clot, as shown by scanning produced a statistically significant and rapid reduction electron micrographs. There was also no evidence of in anti-FXa activity from baseline (primary outcome); pro-coagulant activity.7,16,41 A phase 2 clinical trial that mean per cent change anti-FXa from baseline to nadir evaluates re-anticoagulation in patients with edoxaban was 92% (P < 0.0001 versus placebo). Normalization following reversal of anticoagulant effect by aripazine of coagulation parameters was achieved within two is near completion. This study aims to identify a dose minutes of completing the IV bolus infusion; the effect regimen for aripazine that reverses the effects of lasted one to two hours with the IV bolus dose.11 Part 2 edoxaban for up to 21 hours (see Table 2).42

9,12,24,38,39,42 TABLE 2: ONGOING PHASE 2 AND 3 CLINICAL TRIALS WITH ANTIDOTES FOR DIRECT ORAL ANTICOAGULANTS

Key Study Title Study Design and Primary Outcomes Descriptors Intervention Idarucizumab A phase 3 case series Phase 3, single-group, open- Maximum reversal of anticoagulant clinical study of the reversal label, case series study effect of dabigatran based on central NCT02104947 of the anticoagulant effects laboratory determination of dTT or of dabigatran by IV Idarucizumab 5 g IV ECT, at any time point from the end of N = 300 administration of 5 g the first infusion up to 4 hours after the idarucizumab in patients last infusion treated with dabigatran etexilate who have uncontrolled bleeding, or require emergency surgery or procedures. (RE-VERSE AD; A Study of the RE-VERSal Effects of Idarucizumab on Active Dabigatran)

Andexanet alfa A study in older patients to Phase 3, randomized, Reversal of apixaban anticoagulation evaluate the safety and double-blind, placebo- effect as measured by anti-factor Xa NCT02207725 ability of andexanet alfa to controlled study activity reverse the anticoagulation N = 64 effect of apixaban. Andexanet alfa 400 mg IV (ANNEXA-A; Andexanet bolus followed by continuous alfa: A Novel Antidote to the infusion at 4 mg/minute for Anticoagulant Effects of FXa 120 minutes Inhibitors — Apixaban)

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Key Study Title Study Design and Primary Outcomes Descriptors Intervention Andexanet alfa A study in older patients to Phase 3, randomized, Reversal of rivaroxaban evaluate the safety and double-blind, placebo- anticoagulation effect as measured by NCT02220725 ability of andexanet alfa to controlled study anti-factor Xa activity reverse the anticoagulation N = 79 effect of rivaroxaban. Andexanet alfa 800 mg IV (ANNEXA-R; Andexanet bolus followed by continuous alfa: A Novel Antidote to the infusion at 8 mg/minute for Anticoagulant Effects of FXa 120 minutes Inhibitors — Rivaroxaban) Aripazine A phase 2, randomized, Phase 2, randomized, Whole-blood clotting time as a sequential group evaluation sequential group, single-blind measure of edoxaban anticoagulation NCT02207257 of ascending reversal doses study reversal by aripazine of PER977 administered to N = 50 patients with steady state Aripazine 25 mg, 50 mg, edoxaban dosing and re- 100 mg, 300 mg, and anticoagulation with 600 mg IV edoxaban following PER977 reversal. dTT = diluted thrombin time; ECT = ecarin clotting time; FXa = factor Xa; g = gram; IV = intravenous; mg = milligram; mg/minute = milligram per minute; N = estimated enrolment.

prevention or VTE treatment. Rebound anticoagulation Harms may also be a concern, especially for antidotes with a short half-life and a single IV bolus administration. Idarucizumab was well tolerated during a phase 1 trial Although no antibodies toward the antidotes have been with 145 healthy volunteers receiving dabigatran. Only detected in the studies conducted, another safety minor drug-related AEs were reported including 43 concern relates to immunogenicity, given that headache, migraine, warmth, and flushing. Similarly, idarucizumab is a monoclonal antibody and andexanet in patients who received andexanet alfa and alfa is an endogenous FXa variant. More research is rivaroxaban in a phase 2 randomized controlled trial needed to elucidate their long-term safety. (n = 18), the investigational antidote was well tolerated with no serious or severe AEs observed. Reported AEs included mild infusion-related reactions (n = 3; 33%), Administration and Cost post-procedural hematoma (n = 2; 22%), headache The manufacturers’ prices for idarucizumab, andexanet (n = 2; 22%), and postural dizziness (n = 2; 22%).35 alfa, and aripazine are currently unavailable, as these Preliminary findings from part 1 of the phase 3 drugs have not yet been approved for sale in Canada. ANNEXA-R trial included no serious or severe AEs Given that these antidotes are biologics in nature, with with andexanet alfa in any patient, including thrombotic the exception of aripazine, they are expected to be events. No antibodies to FX or FXa were reported.11 relatively costly. As the antidotes will most likely be Lastly, in a phase 1/2 clinical trial of 80 healthy administered intravenously in a hospital setting, volunteers, the use of aripazine in reversing edoxaban- additional costs could potentially be encountered for induced anticoagulation was well tolerated, with no their administration and subsequent monitoring of evidence of clinically significant or dose-limiting AEs. coagulation status. Reported AEs with aripazine were transient, mild, perioral, and facial flushing; dysgeusia; and moderate headache. One patient developed moderate muscle Concurrent Developments cramping with elevation in creatinine phosphokinase There are ongoing studies evaluating the use of levels; these AEs were considered to be unrelated to 7 andexanet alfa and aripazine to reverse supratherapeutic aripazine. anticoagulation states induced by non-oral All three antidotes have yet to exhibit thrombotic anticoagulants including UFH and LMWH. Current and/or pro-coagulant properties in clinical studies. This recommendations to reverse UFH involve administering is critical considering that numerous patients requiring protamine sulfate but no drug is effective for the these antidotes will be using DOACs for stroke

5 complete reversal of LMWH. Protamine sulfate can intend to also pursue regulatory approval for the only partially reverse 60% to 75% of enoxaparin.28 reversal of these drugs. Off-label use for reversal of DOACs may also be possible as the studied populations Early results from phase 2 trials demonstrate that are narrowly defined. Once these antidotes become andexanet alfa is able to safely and rapidly reverse the available, it is possible that they will contribute to a anticoagulant effects of enoxaparin in healthy larger adoption of DOACs, though clinical experience volunteers by reducing anti-FXa activity and restoring with the latter remains limited and their comparative thrombin generation.44,45 Given andexanet alfa’s design cost-effectiveness versus vitamin K antagonists is and mechanism of action, reversal of pentasaccharide unclear. antithrombin III-dependent inhibitors such as fondaparinux is possible, as well.11 More research is required to determine the safety and efficacy of Implementation Issues andexanet alfa when used in that context. Availability and timely administration may be a barrier Aripazine is designed with broad reversal activity. to the optimal usage of these antidotes. Given that Based on dynamic light-scattering data, it is a idarucizumab and andexanet alfa are injectable potentially universal antidote for parenteral heparin biologics that require refrigeration, they will likely be anticoagulants including UFH, LMWH, fondaparinux, used exclusively in hospital settings because of storage as well as all DOACs.46 Results are pending from a and distribution issues.50 Unlike the biologics, aripazine phase 1/2 clinical trial completed in healthy volunteers is a small molecule that is stable at room temperature evaluating the safety and pharmacodynamic effects of with the current formulation; this feature may result in aripazine following a single dose of enoxaparin.47 the potential for out-of-hospital use.51 Another trial evaluating aripazine following It is anticipated that these antidotes will be more costly administration of UFH is anticipated to be completed in than the antidote traditionally used for warfarin- March 2016.48 induced bleeding, i.e., vitamin K. However, compared with the cost of current non-specific reversal drugs for Rate of Technology Diffusion DOACs (i.e., PCC, aPCC, and rFVIIa), the use of these antidotes may be more favourable from a budget Considering the anticipated growth in the use of impact perspective. DOACs, the advent of these antidotes is of profound interest. Thus far, virtually all phase 2 or phase 3 Despite the promising results from existing clinical studies are limited by small sample size, with healthy data, currently available evidence to establish the safety volunteers enrolled as patients in several of these and efficacy of these antidotes remains limited. For studies and for short study duration. Portola example, whether the measurements of various Pharmaceuticals Inc. recently announced the initiation surrogate markers (i.e., PT, aPTT, ecarin clotting time, of an open-label, single-group, phase 4 (ANNEXA-4) diluted thrombin time, or anti-FXa) can be extrapolated clinical trial evaluating andexanet alfa’s ability to to mortality or morbidity benefits remains to be decrease anti-FXa activity and restore hemostasis. It demonstrated.4 Also, all ongoing phase 2 (aripazine) will be conducted in over 50 sites located in North and phase 3 trials (andexanet alfa and idarucizumab) America and Europe. Participants will be patients enrolled a small number of patients. In the case of receiving apixaban, rivaroxaban, or enoxaparin, who idarucizumab, the phase 3 trial is the study with the present with a major bleeding event.11,17,49 There are largest sample size (N = 300) and is recruiting patients also plans to add edoxaban to the study by mid-2015.11 who have either bleeding or require emergency surgery. However, it is an open-label case series a design in In the future, additional data will be necessary to — compare the pharmacoeconomics and cost-effectiveness which findings are typically not as robust as those from of the antidotes for DOACs, especially for those with randomized controlled trials. In the case of andexanet potential overlapping indications. For example, both alfa, data on patients who are bleeding will have to andexanet alfa and aripazine can reverse the effects of await the release of the findings from the ANNEXA-4 apixaban, but andexanet alfa may require a continuous study. IV infusion whereas aripazine is administered as a It is essential that clear guidance be provided to single IV bolus.7,34 The broad activity of both andexanet practitioners at the time these reversal drugs are alfa and aripazine also creates a potential for off-label commercialized in Canada to promote their optimal use in the reversal of non-oral anticoagulants including use. Areas of uncertainty for which guidance will be UFH, LMWH, and fondaparinux, unless manufacturers

6 needed for antidotes for DOACs include but are not 5. Van Ryn J, Schmoll M, Pillu H, Gheyle L, Brys J, limited to: Moschetti V, et al. Effect of dabigatran on the ability to generate fibrin at a wound site and its  Indications: type of bleeding, type of emergency reversal by idarucizumab, the antidote to procedures, overdose without bleeding. dabigatran, in healthy volunteers: an exploratory  Dosing: standard dose for all patients, or marker of blood loss [abstract]. Circulation. situational dosing (e.g., based on type of 2014;130. (Presented at American Heart procedure); duration of effect; risk of rebound Association's 2014 Scientific Sessions and anticoagulation; IV bolus versus continuous Resuscitation Science Symposium; Nov 15-18; infusion. Chicago, Illinois).  Appropriate use: optimal use (based on clinical 6. Shah N, Rattu M. Reversal agents for and economic factors), off-label use, use of anticoagulants: focus on andexanet alfa. Am Med Stud Res J. 2014;1(1):16-28. laboratory tests. 7. Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Given that the use of these reversal drugs is directly Grosso M, Brown K, et al. Use of PER977 to linked to the use of DOACs, clear guidance on the use reverse the anticoagulant effect of edoxaban. N of the latter may also reduce the need to reverse their Engl J Med [Internet]. 2014 [cited 2015 Feb anticoagulant effect. Development of such guidance is 3];371(22):2141-2. Available from: http://www.nejm.org/doi/pdf/10.1056/NEJMc1411 of interest to a number of organizations including 800 Canadian health technology assessment agencies that 8. Schiele F, Van Ryn J, Canada K, Newsome C, recently produced guidance for some of the approved Sepulveda E, Park J, et al. A specific antidote for 52,53 indications of DOACs. Also, ongoing clinical dabigatran: functional and structural trials and future research on reversal drugs will help characterization. Blood. 2013 May 2;121(18):3554- determine which patients are the most appropriate 62. candidates to benefit from these antidotes and how to 9. ClinicalTrials.gov [Internet]. Bethesda (MD): use these antidotes optimally. National Library of Medicine (US); 2000 -. Identifier NCT02104947, Reversal of dabigatran anticoagulant effect with idarucizumab; 2015 Jan References [cited 2015 Feb 3]. Available from: 1. PrPRADAXA® dabigatran etexilate capsules, 75 https://clinicaltrials.gov/ct2/show/NCT02104947 mg, 110 mg and 150 mg dabigatran etexilate, (as 10. Portola Pharmaceuticals, Inc. receives FDA orphan dabigatran etexilate mesilate) anticoagulant drug designation for andexanet alfa, its [product monograph] [Internet]. Burlington (ON): breakthrough-designated factor Xa inhibitor Boehringer Ingelheim Canada Ltd; 2015 Jan 7. antidote [Internet]. Centennial (CO): Biospace; BICL CCDS # 0266-13. [cited 2015 Feb 24]. 2015 Feb 26. [cited 2015 Mar 23]. Available from: Available from: http://www.boehringer- http://www.biospace.com/News/portola- ingelheim.ca/content/dam/internet/opu/ca_EN/docu pharmaceuticals-inc-receives-fda- ments/humanhealth/product_monograph/PradaxaP orphan/366327/source=MoreNews MEN.pdf 11. Crowther M, Gold AM, Levy GG, Lu G, Leeds J, 2. PrXARELTO® rivaroxaban tablet, 10 mg, 15 mg Wiens BL, et al. ANNEXA™-R: a phase 3 and 20 mg anticoagulant [product monograph] randomized, double-blind, placebo-controlled trial, [Internet]. Toronto: Inc.; 2015 Feb 20. demonstrating reversal of rivaroxaban-induced Submission Control No. 172618. [cited 2015 Feb anticoagulation in older subjects by andexanet alfa 24]. Available from: (PRT064445), a universal antidote for factor Xa http://www.bayer.ca/files/XARELTO-PM-ENG- (fXa) inhibitors [presentation slides].2015. 20FEB2015-178227.pdf?# (Presented at American College of Cardiology 64th 3. PrELIQUIS® apixaban tablets, 2.5 mg and 5 mg Annual Scientific Session & Expo; Mar 14-16, anticoagulant [product monograph] [Internet]. 2015; San Diego, California). Montreal: Bristol-Myers Squibb Canada; 2015 Feb 12. Portola Pharmaceuticals initiates phase 3 study of 20. Submission Control No. 178226. [cited 2015 andexanet alfa, potential first-in-class factor Xa Feb 24]. Available from: inhibitor reversal agent, under accelerated approval http://www.bmscanada.ca/static/products/en/pm_pd pathway: FDA-designated breakthrough therapy is f/ELIQUIS_EN_PM.pdf Portola's second drug to enter phase 3 development 4. Mo Y, Yam FK. Recent advances in the [Internet]. In: Newsroom: news Release. South San development of specific antidotes for target-specific Francisco (CA): Portola Pharmaceuticals; 2014 Mar oral anticoagulants. Pharmacotherapy. 2015 Feb 3. 19 [cited 2015 Feb 12]. Available from: http://investors.portola.com/phoenix.zhtml?c=1981 36&p=irol- newsroomArticle&ID=1910011&highlight. 7

13. Portola Pharmaceuticals, Inc. announces phase 3 21. BI files Pradaxa antidote in US, EU and Canada ANNEXA-R study of andexanet alfa and factor Xa [Internet]. London: PharmaTimes; 2015 Mar 3. inhibitor Xarelto® (rivaroxaban) met primary [cited 2015 Mar 23]. Available from: endpoint with high statistical significance http://www.pharmatimes.com/Article/15-03- [Internet]. In: Biospace: news. Centennial (CO): 03/BI_files_Pradaxa_antidote_in_US_EU_and_Ca BioSpace; 2015 Jan 9 [cited 2015 Feb 3]. Available nada.aspx#ixzz3UHHQtkTU from: http://www.biospace.com/News/portola- 22. FDA grants priority review to Boehringer's drug to pharmaceuticals-inc-announces-phase- reverse blood thinning [Internet]. In: Medscape 3/360540/source=MoreNews. multispecialty: news & perspective. New York: 14. New Drugs Online report for ciraparantag. 2015 WebMD; 2015 Apr 24 [cited 2015 May 14]. [cited 2015 May 20]. In: New Drugs Online Available from: [Internet]. London: UK Medicines Information, http://www.medscape.com/viewarticle/843617 Free National Health Service (NHS). Available from: registration required. http://www.ukmi.nhs.uk/applications/ndo/record_vi 23. Andexanet alfa: FXa inhibitor antidote [Internet]. ew_open.asp?newDrugID=6443. In: Portola Pharmaceuticals: clinical development. 15. New Drugs Online report for idarucizumab. 2014 San Francisco: Portola Pharmaceuticals Inc; 2015 [cited 2015 Feb 4]. In: New Drugs Online [cited 2015 Feb 4]. Available from: [Internet]. London: UK Medicines Information, http://www.portola.com/clinical- National Health Service (NHS). Available from: development/andexanet-alfa-prt4445-fxa-inhibitor- http://www.ukmi.nhs.uk/applications/ndo/record_vi antidote/. ew_open.asp?newDrugID=6275. 24. Portola Pharmaceuticals begins enrollment in phase 16. Media kit [Internet]. Danbury (CT): Perosphere; 3 study of FDA-designated breakthrough therapy 2014 Nov. [cited 2015 May 20]. Available from: andexanet alfa and factor Xa inhibitor http://perosphere.com/content/media/documents/E XARELTO(R): second phase 3 study of andexanet MediaKit.pdf alfa, potential first-in-class factor Xa inhibitor 17. New Drugs Online Report for andexanet alfa. 2015 reversal agent, to be conducted under accelerated [cited 2015 Feb 4]. In: New Drugs Online approval pathway [Internet]. In: Newsroom: news [Internet]. London: UK Medicines Information, Release. South San Francisco (CA): Portola National Health Service (NHS). Available from: Pharmaceuticals; 2014 May 12 [cited 2015 Feb 12]. http://www.ukmi.nhs.uk/applications/ndo/record_vi Available from: ew_open.asp?newDrugID=6169. http://investors.portola.com/phoenix.zhtml?c=1981 36&p=irol-newsroomArticle&ID=1929823. 18. Aggarwal SR. A survey of breakthrough therapy designations. Nat Biotechnol. 2014;32(4):323-30. 25. Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and 19. Boehringer Ingelheim's investigational antidote for Standardization Committee of the International Pradaxa® (dabigatran etexilate mesylate) receives Society on Thrombosis and Haemostasis. FDA breakthrough therapy designation [Internet]. Definition of major bleeding in clinical In: News & events: press release archive. investigations of antihemostatic medicinal products Ridgefield (CT): Boehringer Ingelheim; 2014 Jun in non-surgical patients. J Thromb Haemost 26 [cited 2015 Mar 23]. Available from: [Internet]. 2005 Apr [cited 2015 Mar 26];3(4):692- http://us.boehringer- 4. Available from: ingelheim.com/news_events/press_releases/press_r http://onlinelibrary.wiley.com/doi/10.1111/j.1538- elease_archive/2014/06-26-14-boehringer- 7836.2005.01204.x/pdf ingelheim-investigational-antidote-pradaxa- dabigatran-etexilate-mesylate-fda-breakthrough- 26. Masotti L, Landini G, Panigada G. The practical therapy-designation.html. management of bleedings during treatment with direct oral anticoagulants: the emergency reversal 20. Portola Pharmaceuticals receives breakthrough therapy. Ital J Med [Internet]. 2013 [cited 2015 Feb therapy designation from FDA for andexanet alfa 3];7(Suppl 8):48-58. Available from: (PRT4445*), investigational factor Xa inhibitor http://www.italjmed.org/index.php/ijm/article/view/ antidote [Internet]. In: Investor relations: new itjm.2013.s8.48/446 releases. South San Francisco (CA): Portola Pharmaceuticals; 2013 Nov 25 [cited 2015 Mar 23]. 27. Siegal DM. Managing target-specific oral Available from: anticoagulant associated bleeding including an http://investors.portola.com/phoenix.zhtml?c=1981 update on pharmacological reversal agents. J 36&p=irol-newsArticle&ID=1879666. Thromb Thrombolysis. 2015 Jan 14.

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28. Maddali S, Biring T, Bluhm J, Kopecky S, Krueger 36. Portola Pharmaceuticals announces new phase 2 K, Larson T, et al. Antithrombotic therapy results confirming immediate, dose-dependent and supplement [Internet]. Bloomington (MN): Institute well-tolerated reversal of anticoagulation activity of for Clinical Systems Improvement (ICSI); 2013 Xareto(R) (rivaroxaban) with andexanet alfa Feb. [cited 2015 Feb 4]. (Health Care Guideline). (PRT4445*), investigational factor Xa inhibitor Available from: reversal agent [Internet]. In: Newsroom: news https://www.icsi.org/_asset/bjr47w/Antithrombo.pd Release. South San Francisco (CA): Portola f Pharmaceuticals; 2013 Dec 9 [cited 2015 Feb 12]. 29. Heidbuchel H, Verhamme P, Alings M, Antz M, Available from: Hacke W, Oldgren J, et al. European Heart Rhythm http://investors.portola.com/phoenix.zhtml?c=1981 Association practical guide on the use of new oral 36&p=irol-newsArticle&ID=1883157. anticoagulants in patients with non-valvular atrial 37. Crowther M, Levy GG, Lu G, Leeds J, Lin J, fibrillation. Europace. 2013;15:625-51. Pratikhya P, et al. A phase 2 randomized, double- 30. The changing landscape in oral anticoagulation - blind, placebo-controlled trial demonstrating the last pieces of the puzzle: summary of reversal of edoxaban-induced anticoagulation in presentations from the Symposium, healthy subjects by andexanet alfa (PRT064445), a ESC Annual Congress 2013, Amsterdam, the universal antidote for factor XA (FXA) inhibitors Netherlands. Cardiology [Internet]. 2013 [cited [abstract]. Blood. 2014;124(21). (Presented at 56th 2015 May 14];October:52-71. Available from: Annual Meeting of the American Society of http://emjreviews.com/wp-content/uploads/The- Hematology; Dec 6-9, 2014; San Francisco, Changing-Landscape-in-Oral-Anticoagulation- California). %E2%80%93-The-Last-Pieces-of-the-Puzzle.pdf 38. ClinicalTrials.gov [Internet]. Bethesda (MD): 31. Anticoagulation monitoring and reversal strategies National Library of Medicine (US); 2000 -. for dabigatran, rivaroxaban, and apixaban: a review Identifier NCT02207725, A study in older subject of clinical effectiveness [Internet]. Ottawa: to evaluate the safety and ability of andexanet alfa CADTH; 2012 Apr. [cited 2015 Mar 26]. Available to reverse the anticoagulation effect of apixaban; from: 2014 Jul [cited 2015 Feb 3]. Available from: http://www.cadth.ca/media/pdf/TR0002_New_Oral https://clinicaltrials.gov/ct2/show/NCT02207725 _Anticoagulants.pdf 39. ClinicalTrials.gov [Internet]. Bethesda (MD): 32. Bounameaux H, Camm AJ. Edoxaban: an update National Library of Medicine (US); 2000 -. on the new oral direct factor Xa inhibitor. Drugs Identifier NCT02220725, A study in older subject [Internet]. 2014 [cited 2015 May 14];74(11):1209- to evaluate the safety and ability of andexanet alfa 31. Available from: to reverse the anticoagulation effect of rivaroxaban; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC410 2014 Aug [cited 2015 Feb 11]. Available from: 7274/ https://clinicaltrials.gov/ct2/show/NCT02220725 33. Parasrampuria DA, Marbury T, Matsushima N, 40. Gold AM, Crowther M, Levy G, Lu G, Leeds J, Chen S, Wickremasingha PK, He L, et al. Barron L, et al. ANNEXA™-R: a phase 3 Pharmacokinetics, safety, and tolerability of randomized, double-blind, placebo-controlled trial, edoxaban in end-stage renal disease subjects demonstrating reversal of rivaroxaban-induced undergoing haemodialysis. Thromb Haemost. 2015 anticoagulation in older subjects by andexanet alfa Mar 30;113(4):719-27. (PRT064445), a universal antidote for factor Xa (fXa) inhibitors [abstract]. J Am Coll Cardiol 34. Crowther M, Lu G, Conley P, Hollenbach S, [Internet]. 2015 Mar [cited 2015 Mar 23];65(10_S). Castillo J, Lawrence J, et al. Sustained reversal of Presentation number: 912-08. 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42. ClinicalTrials.gov [Internet]. Bethesda (MD): 48. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US); 2000 -. National Library of Medicine (US); 2000 -. Identifier NCT02207257, Study of PER977 Identifier NCT02206087, Evaluation of the safety, administered to subjects with steady state edoxaban tolerability, pharmacokinetics, and dosing and re-anticoagulation with edoxaban; 2014 pharmacodynamic effects of PER977 following Aug [cited 2015 Feb 11]. Available from: heparin; 2014 Dec [cited 2015 Feb 3]. Available https://clinicaltrials.gov/ct2/show/NCT02207257 from: 43. Glund S, Stangier J, Schmohl M, De Smet M, https://clinicaltrials.gov/ct2/show/study/NCT02206 Gansser D, Lang B, et al. Abstract 17765: a specific 087 antidote for dabigatran: immediate, complete and 49. Portola Pharmaceuticals, Inc. initiates phase 4 study sustained reversal of dabigatran induced to support accelerated approval of andexanet alfa -- anticoagulation in healthy male volunteers. its breakthrough-designated factor Xa inhibitor Circulation [Internet]. 2013 Nov 26 [cited 2015 Feb antidote [Internet]. In: Biospace: news. Centennial 9];128(22 Suppl). Available from: (CO): BioSpace; 2015 Jan 12 [cited 2015 Feb 3]. http://circ.ahajournals.org/cgi/content/meeting_abst Available from: ract/128/22_MeetingAbstracts/A17765 http://www.biospace.com/News/portola- 44. Crowther M, Levy G, Lu G, Conley PB, Castillo J, pharmaceuticals-inc-initiates-phase- Hollenbach S, et al. Reversal of enoxaparin- 4/360674/source=MoreNews. induced anticoagulation in healthy subjects by 50. Dolgin E. Antidotes edge closer to reversing effects andexanet alfa (PRT064445), an antidote for direct of new blood thinners. Nat Med. 2013 and indirect fXa inhibitors-a phase 2 randomized, Mar;19(3):251. double-blind, placebo-controlled trial [abstract]. J 51. Emerging treatment options for the reversal of oral Thromb Haemost [Internet]. 2014 [cited 2015 Feb anticoagulant therapy: the experts address questions 3];12:7. Available from: about reversal of oral anticoagulants [Internet]. http://onlinelibrary.wiley.com/doi/10.1111/jth.1258 Bathesda (MD): American Society of Health- 8/pdf (Presented at 60th Annual Meeting of the System Pharmacists (ASHP); 2013 Apr. [cited 2015 Scientific and Standardization Committee of the Feb 11]. (ASHP Advantage e-Newletter). Available International Society on Thrombosis and from: Haemostasis, SSC 2014; Jun 23-26, 2014; http://www.ashpadvantage.com/reversal/docs/rever Milwauke, Wisconsin). sal_e-newsletter_04-2013.pdf 45. Crowther M, Lu G, Conley PB, Castillo J, 52. Anticoagulant therapy for adult patients: atrial Hollenbach S, Leeds J, et al. Reversal of fibrillation [Internet]. Quebec: INESSS; 2014 Mar. enoxaparin-induced anticoagulation in healthy [cited 2015 May 27]. Available from: subjects by andexanet alfa (PRT064445), an https://www.inesss.qc.ca/fileadmin/doc/INESSS/Ra antidote for direct and indirect fXa inhibitors – a pports/Medicaments/INESSS_Anticoagulant_Thera phase 2 randomized, double-blind, placebo py_Adult.pdf controlled trial [powerpoint slides]. San Francisco: 53. Recommendations for antithrombotic agents for the Portola Pharmaceuticals; 2015. prevention of stroke and systemic embolism in 46. Laulicht B, Bakhru S, Jiang X, Chen L, Pan D, patients with atrial fibrillation [Internet]. Ottawa: Grosso M, et al. Antidote for new oral CADTH; 2013 Mar. [cited 2015 May 27]. (CADTH anticoagulants: mechanism of action and binding Therapeutic review; vol. 1, no.1c). Available from: specificity of PER977 [abstract]. J Thromb https://www.cadth.ca/media/pdf/TR0003_Antithro Haemost. 2013;11:75. (Presented at 24th Congress mboticAgents-AF_RecsReport-e.pdf of the International Society on Thrombosis and Haemostasis; Jun 29-Jul 4, 2013; Amsterdam, The Netherlands). 47. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US); 2000 -. Identifier NCT02206100, PK and PD of single, escalating doses of PER977 following enoxaparin; 2014 Oct [cited 2015 Feb 3]. Available from: https://clinicaltrials.gov/ct2/show/study/NCT02206 100

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Cite as: Chu S, Boucher M, Spry C. Antidote treatments for the reversal of direct oral anticoagulants [Issues in emerging health technologies, Issue 138]. Ottawa: CADTH; 2015.

CADTH would like to acknowledge the contribution of William Geerts, MD, FRCPC, Thromboembolism Consultant,

University of Toronto, and Marc Carrier, MD, MSc, FRCPC, Associate Professor, Senior Scientist, University of Ottawa and Ottawa Hospital Research Institute for their review of the draft version of this bulletin.

****************** Issues in Emerging Health Technologies is a series of concise bulletins describing drug and non-drug technologies that are not yet used (or widely diffused) in Canada. The contents are based on information from early experience with the technology; however, further evidence may become available in the future. These summaries are not intended to replace professional medical advice. They are compiled as an information service for those involved in planning and providing health care in Canada.

While CADTH has taken care in the preparation of this publication to ensure that its contents are accurate, complete, and up to date as of January 2015, CADTH does not make any guarantee to that effect. CADTH is not responsible for any errors or omissions or injury, loss or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the information in this publication or in any of the source documentation.

This document and the information provided in this document are prepared and intended for use in the context of the Canadian health care system. Other health care systems are different; the issues, information related to the subject matter of this document may be different in other jurisdictions and, if used outside of Canada, it is at the user’s risk. This disclaimer and any questions or matters of any nature arising from or relating to the content or use (or misuse) of this document will be governed by and interpreted in accordance with the laws of the Province of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusive jurisdiction of the courts of the Province of Ontario, Canada.

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ISSN: 1488-6324 (online)

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