Reversal agents in development for the new oral anticoagulants.

C L I N I C A L F O C U S : T H RO M B O S I S A N D C A R D I O VA S C U L A R M E D I C I N E

Reversal Agents in Development for the New Oral Anticoagulants

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DOI: 10.3810/pgm.2014.11.2829

James Costin, MD 1 Jack Ansell, MD 2 Bryan Laulicht, PhD 1 Sasha Bakhru, PhD 1 Solomon Steiner, PhD 1 Perosphere Inc., Danbury, CT; Hofstra North Shore/Long Island Jewish School of Medicine, NY 1 2

Abstract: The new oral anticoagulants have many advantages over vitamin K antagonists, but they are still associated with a troublesome incidence of major bleeding. Additionally, the absence of a reversal agent for the new oral anticoagulants is a barrier to their more widespread use. Currently, there are 3 potential reversal agents in development: idarucizumab is a humanized murine monoclonal antibody fragment directed specifically at dabigatran; andexanet alfa is a recombinant modified decoy factor Xa that binds to factor Xa inhibitors; and PER977 is a small molecule that binds to factor Xa and IIa inhibitors and to heparin-based anticoagulants through charge interaction. These agents have undergone phase I clinical testing, appear to be well tolerated in healthy volunteers, and are effective in neutralizing their respective targets. All 3 are currently undergoing or entering into a phase II or III clinical study. This article reviews the available data for idarucizumab, andexanet alfa, and PER977. Keywords: anticoagulation; reversal; atrial fibrillation; stroke; gastrointestinal bleed; PER977; new oral anticoagulants

Introduction

Correspondence: James Costin, MD, Perosphere, Inc., 20 Kenosia Ave, Danbury, CT 06810. Tel: 215-450-8698 Fax: 215-619-0106 E-mail: [email protected]

Until the introduction of the first new oral anticoagulant (NOAC) in 2009, the vitamin K antagonists, most commonly warfarin, were the only anticoagulants appropriate for long-term outpatient therapy. Although very effective, vitamin K antagonists consistently top the list of drugs associated with emergency room visits and hospitalizations because of bleeding-related adverse events.1–2 Warfarin is also indicated for stroke prevention in patients with nonvalvular atrial fibrillation (AF), although only approximately 50% to 60% of potential candidates for anticoagulation are prescribed therapy.3–4 Warfarin is generally underused because of a fear of bleeding, and its effect on quality of life because of the need for frequent monitoring, dose adjustments, drug interactions, and impact on diet.3–5 With the introduction of the NOACs, it was widely assumed that the undertreatment of AF would decrease because of the simplified dosing and there would be wider therapeutic windows, minimal drug or food interactions, and no need for routine monitoring. Despite these benefits, the undertreatment of patients with AF remains, in addition to the troubling incidence of bleeding and associated hospitalizations.6 There are many reports of bleeding in patients taking dabigatran, especially in the elderly and those with impaired renal function.7–8 In a recent report of rivaroxaban use in Germany,9 43% of 1776 patients reported bleeding events and of those events 6.1% were classified as major bleeding according to International Society on Thrombosis and Haemostasis (ISTH) criteria. In a time-to-first-event analysis, rates of major bleeding were 3.1% for patients

© Postgraduate Medicine, Volume 126, Issue 7, November 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 19 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.


Costin et al

with AF and 4.1% for those with venous thromboembolism. Lack of a reversal agent for NOACs is acknowledged as a barrier to their more widespread use. To date, no established reversal agents for bleeding associated with the NOACs exist. The lack of a reversal agent is problematic not only in emergent situations, such as major bleeding, trauma, or emergency surgery, but also for elective procedures in patients at high risk for thrombosis because anticoagulation must be stopped several days before and can only be restarted after the procedure. The prescribing information for dabigatran recommends stopping therapy within 1 to 5 days (depending on renal function) before invasive or surgical procedures and a longer time period is recommended for those undergoing major surgery or spinal procedures; the prescribing information also notes that discontinuation increases the risk of thrombotic events.10 Lastly, when evaluating response to a reversal agent, most incorrectly assume that restoration of in vitro coagulation parameters is synonymous with cessation of bleeding. The relationship between reversal of coagulation and cessation is not direct; reversal of anticoagulation does not necessarily mean cessation of bleeding. The tests typically used for monitoring anticoagulants or measuring their effect (prothrombin time and activated partial thromboplastin time) are of limited usefulness for monitoring the NOACs because of variability of results, lack of sensitivity or excess sensitivity, and reagent dependence.11 Management of bleeding associated with any anticoagulant must first be seen as achieving clinical hemostasis or cessation of bleeding, and secondarily as restoration of coagulation parameters to baseline normal values.

Current Guidelines for Management of NOAC-Associated Bleeding

Numerous hemostatic agents are available for the treatment of bleeding conditions (Table 1); however, labeled indications are generally limited to the management of hemophilias. The prothrombin complex concentrates (PCCs) are indicated for the treatment of major bleeding in patients on warfarin. Several of these factor concentrates have also been recommended for use in the management of bleeding attributed to NOAC therapy (Table 2).12 However, there is a fundamental difference between administering replacement therapies, as in the case of the PCCs to reverse the anticoagulation induced by warfarin, compared with using these agents to reverse bleeding induced by the NOACs. By their nature, the PCCs are procoagulant, limiting their use in the management of bleeding in patients treated with anticoagulants who have an underlying risk for thrombosis; only one 4-factor PCC is 20

approved for bleeding reversals from warfarin.13 There are no prospective clinical trials of PCCs in patients with bleeding, and there is very limited evidence that PCCs can induce a clinically significant reversal of anticoagulation and control bleeding that is associated with NOAC therapy.14

Specific Anticoagulant Reversal Agents in Development

An ideal anticoagulant reversal agent would have a rapid onset and sustained effect that correlates well with clinical hemostasis and correction of coagulation biomarkers. Preliminary clinical data regarding the safety and efficacy of several reversal agents are available. However, clinical outcome data such as time to onset and duration of bleeding reversal, resulting morbidity, duration of hospitalization, prothrombotic events, and death are not yet available. Prospective clinical trials in patients with active bleeding, in surgical settings, and undergoing elective procedures are needed. Available published data regarding 3 anticoagulant reversal agents under development in the United States are discussed in this article. Because of the limitations of early phase clinical data, differing indications, and breadth of use, it is not possible to compare the clinical attributes of the agents. At this timepoint in their clinical development, the trials and data presented do not clearly define the definition of reversal, doses, or duration of treatment, duration of effect or time to re-institution and effectiveness of re-anticoagulation. Further clinical study of each of the agents is needed to define their roles in therapy. The 3 reversal agents in the more advanced stages of development in the United States are (1) directed specifically at dabigatran (idarucizumab; BI 655075); (2) a modified coagulation factor Xa that acts as a decoy and binds to Xa inhibitors (andexanet alfa; PRT064445 or PRT4445); and (3) a compound that binds specifically to factor Xa and IIa NOACs and heparin-based anticoagulants through charge interaction (PER977; Table 3).

Idarucizumab

The dabigatran-specific reversal agent, idarucizumab, is a fully humanized mouse monoclonal antibody fragment (Fab) that reverses dabigatran anticoagulation in preclinical and clinical studies. The binding pattern of the Fab fragment to dabigatran shows structural similarity to the binding of dabigatran to thrombin, but the Fab fragment has an affinity for dabigatran that is 350 times stronger than its affinity for thrombin, and does not bind to thrombin substrates. It also shows no activity in routine coagulation tests or platelet

© Postgraduate Medicine, Volume 126, Issue 7, November 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

Reversal Agents for the NOACs


Table 1. Hemostatic Agents31-38 Agent

Mechanism

Indication

Aminocaproic acid (AMICAR)

Inhibition of fibrinolysis by plasminogen activators and via antiplasmin activity

Enhance hemostasis when fibrinolysis contributes to bleeding.

Tranexamic acid (Lysteda, Ctklokaprin)

Competitive inhibitor of plasminogen activation; at much higher concentrations, a noncompetitive inhibitor of plasmin, implying interference with the fibrinolytic process

Hereditary angioneurotic edema; short-term use for hyphema and in patients with established coagulopathies undergoing minor surgery; menorrhagia

3-factor prothrombin complex clotting factors II, IX, X (Bebulin, Profilnine)

Mixture of vitamin K–dependent clotting factors found in normal plasma that temporarily increases plasma levels of factor IX and can temporarily correct the coagulation defect of patients with factor IX deficiency

Prevention and control of bleeding in patients with factor IX deficiency due to hemophilia B

4-factor prothrombin complex clotting factors II,VII, IX, X, and proteins C and S (Beriplex, Kcentra)

Product containing vitamin K–dependent coagulation factors and the antithrombotic proteins C and S

Blood coagulation factor replacement product indicated for the urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonists (ie, warfarin) therapy in adult patients with acute major bleeding or need for urgent surgery/invasive procedure

Non-activated clotting factors II, IX, X; activated factor VII, factor VIII; Inhibitor bypassing activity; prothrombin complex factors; factor VII antigen; trace kinin generating system factors (Feiba)

Sterile, freeze-dried human plasma fraction with factor VIII inhibitor bypassing activity which, in vitro, shortens the activated partial thromboplastin time of plasma containing factor VIII inhibitor

Control of spontaneous bleeding episodes or to cover surgical interventions in patients with hemophilia A and B with inhibitors

Recombinant factor VIIa (NovoSeven)

Recombinant human coagulation factor VIIa intended for promoting hemostasis via activation of the extrinsic coagulation cascade pathway

Treatment of bleeding episodes and peri-operative management in adults and children with inhibitors; congenital factor VII deficiency and Glanzmann thromboasthenia with refractoriness to platelet transfusions, with or without antibodies to platelets and treatment of bleeding episodes and peri-operative management in adults with acquired hemophilia

Adapted from references 31–38.

aggregation studies. In a rat model of anticoagulation with dabigatran, the Fab fragment completely reversed prolongation of the thrombin time within 1 minute of an intravenous injection, and was sustained for 25 minutes despite continued infusion of further dabigatran.15 Investigators recently reported the results of a phase I trial of idarucizumab in healthy volunteers,16 which tested the safety, tolerability, pharmacokinetics, and pharmacodynamics of the Fab fragment in 145 healthy volunteers. Subjects received single doses of idarucizumab that were progressively increased (1, 2, 4, and 8 g) after receiving dabigatran, 200 mg, twice daily for 3 days. The onset of reversal was detected immediately after a 5-minute infusion using thrombin time, dilute thrombin time, and other coagulation assays. The effect was sustained in all subjects who received the 8-g dose. When lower doses were administered, the return of anticoagulation was seen in some patients. The drug was

well tolerated with minor drug-related effects including headache, migraine, warmth, and flushing. Idarucizumab is currently undergoing a multinational phase III prospective cohort study (RE-VERSE AD; A Study of the RE-VERSal Effects of Idarucizumab on Active Dabigatran), evaluating 5 g of idarucizumab in patients with dabigatran-associated bleeding.17

Andexanet Alfa

Andexanet alfa is a recombinant, modified version of human coagulation factor Xa produced in Chinese hamster ovary cells.18 It is similar to native factor Xa, but lacks the γ-carboxyglutamic acid domains required for efficient incorporation into the thrombinase complex. Andexanet alfa also has a mutation of the serine residue in the protease catalytic triad making it catalytically inactive. Nevertheless, it retains the ability to bind to the factor Xa inhibitors rivaroxaban,


Costin et al


Table 2. Current Strategies For Management of Coagulopathy or Bleeding With NOACs Reversal Agent

Apixaban

Rivaroxaban

Dabigatran Etexilate

Prothrombin complex concentrate

No published studies to date

• Prevented hematoma expansion and reversed tail bleeding time in vivo • No effect on reversal of dabigatran activity in healthy volunteers

Recombinant factor VII


Factor VIII inhibitor bypassing activity


Monoclonal antibodies


• Partially reversed PT prolongation • Reversed inhibition of thrombin formation • Shortened bleeding time in vivo • Reversed rivaroxaban activity in vivo; however, bleeding not reversed • Reversed PT prolongation and normalized endogenous thrombin potential in healthy volunteers • Partial reversal of thrombin generation in vitro • Reduced clotting times, aPTT, and bleeding time in vivo • Reversed PT prolongation and shortened bleeding time in vivo • Reduced clot initiation time to one-third of baseline in vitro • Partial neutralization of activity in vivo • No published studies to date

• Ineffective in vitro and in vivo • Reduced clot initiation times to baseline in vitro


Clone 22 completely inhibited dabigatran activity in vitro and in vivo

Modified from Bauer KA. Reversal of antithrombotic agents. Am J Hematol. 2012;87(Suppl 1):S119–126. Abbreviations: aPTT, activated partial thromboplastin time; NOAC, new oral anticoagulants; PT, prothrombin time.

apixaban, and edoxaban. Andexanet alfa has the ability to reverse apixaban, rivaroxaban, and edoxaban in vitro, but has no activity against dabigatran or unfractionated heparin (UFH). Because low-molecular-weight heparins (LMWH) have approximately 80% to 90% anti–factor Xa activity, andexanet alfa may be able to reverse the majority of LMWH activity. Andexanet alfa participates in the tissue factor pathway inhibitor (TFPI) pathway and has been shown to reduce TFPI activity in phase II studies.19 Because of the biologic nature of andexanet alfa combined with its homology to native factor Xa, antibody production to andexanet alfa, factor Xa, is being monitored as a biomarker in clinical trials. Phase II data indicate that a 420- to 720-mg bolus of andexanet alfa is required to neutralize a factor Xa inhibitor, and continued infusion is needed to sustain reversal of

anti–factor Xa.20 In phase II trials, a 420-mg bolus injection administered after apixaban produced an initial reversal to baseline state within 12 minutes (0.2 hours) as measured by anti–factor Xa. After the initial bolus and a 2-hour infusion (480 mg) of andexanet alfa, the anti–factor Xa level immediately started to return to an anticoagulated state. Within approximately 3 hours, the anticoagulant levels were the same as placebo, which was elevated at approximately 50% of baseline. The reversal of anticoagulation was more pronounced with either a 600-mg bolus injection alone, or a 720-mg bolus injection followed by an infusion of 240 mg after rivaroxaban: anti–factor Xa levels decreased to baseline immediately after the bolus and while the infusion was still ongoing. Immediately after stopping the infusion of andexanet alfa, the anti–factor Xa activity was at placebo anticoagu-

Table 3. Reversal Agent Targets Anticoagulant

Pharmacologic Class

Idarucizumab

Andexanet alfa

PER977

Apixaban Dabigatran Edoxaban Rivaroxaban UFH LMWH Fondaparinux Warfarin

Xa IIa Xa Xa Heparin Heparin ATIII-FXa VKA

N/A X N/A N/A N/A N/A N/A N/A

X N/A X X N/A N/A Unknown N/A

X X X X X X X N/A

Adapted from references 15, 18–20, 23, and 24. Abbreviations: ATIII-FXa, -antithrombin III factor Xa; LMWH, low-molecular-weight heparin; N/A-no activity; UFH, unfractionated heparin; VKA, vitamin K antagonist; X, active reversal agent.

22


Reversal Agents for the NOACs

lated levels within an hour. Reported adverse events included mild infusion-related reactions, hematomas, headache, and postural dizziness.21 Andexanet alfa is currently entering into phase III randomized, double-blind, placebo-controlled trials to assess the reversal of anticoagulation in healthy volunteers administered rivaroxaban22 or apixaban.23


PER977

PER977 is a small (512Da) synthetic, water-soluble new molecular entity that directly binds with UFH, LMWH, and the NOACs.24 Binding between PER977 and the heparins and NOACs has been documented by dynamic light scattering, isothermal titration calorimetry, and affinity chromatography. The noncovalent binding of PER977 to heparins and NOACs prevents them from binding to their endogenous targets, thus reversing anticoagulation. This reversal effect is due to direct binding to the anticoagulant molecule with no binding to blood coagulation factors or to other proteins in the blood. In in vivo animal studies, a single intravenous dose of PER977 reversed anticoagulation associated with the NOACs (dabigatran, rivaroxaban, apixaban, and edoxaban), UFH, enoxaparin, and fondaparinux in an external (rat tail transection) bleeding model. In an internal (rat liver laceration) bleeding model, PER977 controlled bleeding and corrected abnormal coagulation assays associated with edoxaban. There was no plasma protein binding in human plasma ex vivo indicating no binding to clotting factors or albumin. In a phase I/II clinical trial of 80 healthy volunteers, PER977 was well tolerated with no evidence of clinically significant or dose-limiting adverse events.25,26 There was a clear dose–response relationship with graded reversal of edoxaban-induced anticoagulation with escalating doses of PER977, and the compound showed no procoagulant signals. Single intravenous doses of PER977 (100–300 mg) that completely reversed anticoagulation associated with a single dose of edoxaban (60 mg) in healthy volunteers within 10 minutes and maintained reversal over 24 hours with no rebound and no need for infusions or repeat administration.27 Phase I/II trials are currently underway to evaluate the safety and efficacy of PER977 in reversing anticoagulation of edoxaban, LMWH, and UFH.28,29,30 Phase III studies are scheduled to begin in early 2015. The reversal agents under development are distinctly different in several aspects; PER977 is a small molecule designed to bind to multiple NOACs (both factor Xa and factor IIa), heparin, and LMWH. Initial clinical data indicate it is effective as a reversal agent after a single bolus dose

that requires no accompanying infusion. Andexanet alfa and idarucizumab are large biologic molecules, the former a recombinant protein and the latter a humanized mouse monoclonal antibody fragment, which each have more limited targets than PER977. However, andexanet alfa requires a continuous infusion to maintain anticoagulation reversal. All 3 agents (PER977, andexanet alfa, and idarucizumab) appear to be well tolerated in phase I clinical trials. Immunogenicity for the 2 proteins does not appear to be a problem, but longer-term studies are needed. Additional studies are also needed to assess the nonspecific binding of PER977 to other medications.

Conclusions

There is a need for a reversal agent for the NOACs and LMWH, and an improved, easier to use reversal agent for UFH would be clinically beneficial. Moreover, the availability of a reversal agent for NOACs may provide welcomed reassurance regarding risks of hemorrhage, thus expanding treatment to a greater number of patients and potentially decreasing the number of strokes in this untreated population. PER977, andexanet alfa, and idarucizumab show promise, but significant questions remain regarding safety, dosing, and impact on re-anticoagulation.

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