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Andexanet Alfa: A Novel Reversal Agent for Factor Xa Inhibitors

16 Sep 2018 11:11 PM | Anonymous

Andexanet Alfa: A Novel Reversal Agent for Factor Xa Inhibitors
Author:  Christopher Kimes, Pharmacy Student, University of Kansas School of Pharmacy
Preceptor:  Amy Sipe, PharmD, Kansas City VA Medical Center

Background
In recent years, direct acting oral anticoagulants (DOACs) have been gaining increased utilization due to fewer drug and food interactions and less frequent blood monitoring required than the traditional anticoagulant of choice, warfarin. However, like warfarin, DOACs still possess a risk for acute major bleeds.

Portola Pharmaceuticals’ andexanet alfa (Andexxa®) has recently garnered significant attention for being the first FDA-approved reversal agent for the factor Xa (fXa) inhibitor class of DOACs.1 Given the limited real-world experience in the use of this drug, this overview may serve as useful source for providers to feel more comfortable with its use in practice.

Pharmacology/Mechanism of Action2,3
fXa inhibitors produce anticoagulant effects by inhibiting the serine active site of fXa, which is responsible for the conversion of prothrombin into activate thrombin during secondary hemostasis. Direct fXa inhibitors (apixaban, rivaroxaban, edoxaban, betrixaban) act by directly inhibiting the serine active site. Indirect fXa inhibitors (fondaparinux, enoxaparin) act by changing the structure of antithrombin III, which makes it more effective at binding and inhibiting the serine active site (Figure 1).

Figure 1. Interaction of Andexanet Alfa with Drugs and Proteins Involved in the Regulation of fXa Activity.


Andexanet reverses the effects of fXa inhibitors by sequestering these drugs away from fXa, allowing fXa to convert prothrombin into thrombin (Figure 1). Andexanet accomplishes this because it is a modified human fXa protein that acts as a decoy for fXa inhibitors. An important part of andexanet’s design was the removal of the procoagulant properties of fXa (Figure 2). During clinical trials, andexanet was found to possess a procoagulant effect that would potentially increase the risk of thromboembolic events in patients, however, the consequences of this property on clinical outcomes have not been fully studied.3

Figure 2. Comparison of Andexanet Alfa with Factor Xa

Indication
Currently, andexanet is FDA-approved for the reversal of anticoagulant effects in the event of life-threatening or uncontrolled bleeding for patients on either apixaban or rivaroxaban therapy.1,4 This indication was based largely on the results of the phase III ANNEXA trials, in which test subjects were given only apixaban or rivaroxaban prior to reversal by andexanet.5 Consequently, the FDA did not approve labeling of andexanet as a reversal agent for all fXa inhibitors. Although other fXa inhibitors had been used in animal studies and phase II trials, the FDA cited differences in pharmacokinetic, pharmacodynamic, and in-vivo/ex-vivo properties between anticoagulants as a reason for limiting andexanet use to agents studied in the phase III trials.3

Andexanet received breakthrough designation from the FDA, which accelerated approval based on phase III trials using healthy volunteers and surrogate biomarker as primary efficacy endpoint.  The clinical efficacy of andexanet is currently being studied through the prospective, open-label, single-group Phase IV ANNEXA-4 trial.6 Researchers intend to determine the hemostatic efficacy of andexanet in patients suffering an acute major bleed within 18 hours of taking a fXa inhibitor. To assess efficacy, the researchers have established a rating system to classify hemostasis. Given that institutions and providers may disagree with what constitutes excellent or good hemostasis, a review of this rating system is prudent prior to consideration of andexanet use (Table 1).

Table 1. Rating system for assessing hemostatic efficacy utilized in the ANNEXA-4 trial.

Based on this rating system, preliminary data from the phase IV trial indicates an 83% efficacy of achieving excellent or good hemostasis for patients of all bleed types.7 However, most patients suffered from intracerebral (61%) or gastrointestinal (27%) bleeds. Although this satisfies the FDA’s desire for the manufacturer to study the effects of andexanet in patients suffering from an intracerebral hemorrhage,1 it limits the efficacy and safety data for other types of bleeds.

Dosage and Administration
The current FDA recommended dosing guidelines were ascertained during the phase II trials and confirmed in the phase III trials. The phase II trials found that the decline in the anti-fXa activity caused by andexanet was correlated to the decline in plasma concentration of the fXa inhibitor.2 This is consistent with andexanet’s mechanism of action. Therefore, the optimal dose of andexanet is dependent upon the steady-state concentration and the volume of distribution of the fXa inhibitor.8 This led to the adoption of using a high dose regimen or low dose regimen of andexanet based on the expected plasma concentration of the fXa inhibitor (Table 2).

Table 2. Andexanet regimens developed in clinical trials and approved for use by the FDA4

Phase III trials proved that andexanet could significantly reverse the anti-fXa activity of apixaban and rivaroxaban. Andexanet showed reduced anti-fXa activity by -94% in apixaban subjects compared to -21% for placebo and by -92% for rivaroxaban subjects compared to -18% for placebo5 (Graph 1). The reduction in anti-fXa activity only took 2-5 minutes after completion of bolus infusion to reach its nadir. This reversal effect was only maintained for the duration of the infusion. Therefore, a continuous infusion after the bolus administration is necessary to maintain a sustained reduction in anti-fXa activity.

Graph 1. Anti-fXa activity of subjects over time during phase III trials. Graph 1 displays the anti-fXa activity of patients with steady state concentrations of apixaban from the phase III trials receiving either (A1) IV bolus of andexanet alone, (A2) IV bolus followed by a continuous IV infusion of andexanet, and (P) placebo. As the graph demonstrates, anti-fXa activity rapidly returns to placebo levels after cessation of andexanet infusion. 


Based on efficacy data from phase III trials, FDA labeling recommends that andexanet alfa be given as an initial IV bolus followed by a 120-minute continuous IV infusion4 (Figure 3). None of the clinical trials measured the effectiveness or safety of multidose administration or infusion administration beyond 2 hours, therefore, no efficacy or safety data exists for situations requiring infusions over that 2-hour period

Figure 3. Algorithm based on FDA package insert for andexanet4

Safety
Current data from the phase IV trial indicate that 11% of patients suffer a thromboembolic event, while 12% died within 30 days of receiving andexanet. Citing these events and the unexpected ability of andexanet to inhibit TFPI, the FDA issued a Black Box Warning that andexanet was associated with arterial and venous thromboembolic events, ischemic events (including myocardial infarction and ischemic stroke), cardiac arrest, and sudden death.3 The FDA advises that patients given andexanet are monitored for these conditions and that patients should resume anticoagulant therapy as soon as medically appropriate. 

There is limited efficacy or safety data for certain patient populations due to the design of the clinical trials. The Phase III trials were performed using only healthy test subjects. The phase IV trials excluded patients who possessed certain medical conditions or were on certain drug therapies.6 The FDA package insert takes into consideration a certain number of these exclusions, however, it does not describe all exclusions in detail. Therefore, it is important for institutions and providers to be familiar with the medical conditions that were excluded from these trials when considering andexanet use (Table 3).

Table 3. Exclusion Criteria for the ANNEXA-4 Trial

Product Availability and Cost4
Andexanet is produced from Chinese hamster ovary cells by two biotechnology companies: CMC Biologics (Copenhagen, Denmark) and Lonza (Visp, Switzerland). Concerns with manufacturing capacity and an inability to produce adequate drug quantities was a factor that prevented andexanet from gaining FDA approval in 2016.2 These concerns were addressed in subsequent reviews, however, andexanet will be produced in very limited quantities. Therefore, only a select number of medical facilities (ranging from as low as 10 to as much as 50) will carry this medication.9,10 The manufacturer has stated that andexanet will most likely be limited to medical facilities that participated in ANNEXA-4 trials. There is a possibility that a select few level 1 trauma centers and comprehensive stroke centers will be able to receive this product.9

Andexanet is produced as 100 mg lyophilized powder in single-use vials. It is sold in a package of four vials. The current estimated cost for a single package of four 100mg vials is $11,000.11 At this price point, a low and high dose andexanet regimen will cost $24,750 and $49,500, respectively.

Comparison to Other Available Treatments
Despite andexanet’s niche role as the first FDA-approved reversal agent for fXa inhibitors, bleeding caused by fXa inhibitors have previously been controlled through other pharmacological agents.12,13 While the procedure for treating bleeds varies by institution, the two most commonly recommended agents include four-factor prothrombin complex concentrates (4FPCC) and activated charcoal. A table containing information on the drug properties, FDA indications, off-label use, current recommend dosing, and research data on these two products are presented below to serve as a reference.14

Table 4. Information on off-label treatments for major bleeds caused by fXa inhibitors.15-22


Conclusion

Despite accelerated approval by the FDA, andexanet remains undergoing scrutiny, as the ANNEXA-4 trial is still underway with no final results or completion. Furthermore, the FDA felt that andexanet’s ability as a reversal agent for fXa inhibitors would be best suited for treating intracranial hemorrhages. Consequently, it has mandated the manufacturer to conduct a postmarketing study to determine the hemostatic efficacy and safety of andexanet on patients suffering from intracranial hemorrhages to be completed by October 31, 2022. 

Andexanet alfa garnered significant attention for its novelty. For many, the approval suggested a new era in which life-threatening bleeds caused by fXa inhibitors could be easily reversed with an antidote. However, an overview of andexanet’s drug design, indication, dosing regimen, safety data, and manufacturing logistics seems to paint a more complex picture. Furthermore, ever increasing research data on the off-label use of more easily accessible products may diminish the enthusiasm for the drug. Institutions and practitioners may need to consider these issues when they are reviewing andexanet for use in their patients.

References:

  1. Food and Drug Administration. Approval Letter - ANDEXXA. 2018; https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM606693.pdf.
  2. Kaatz S, Bhansali H, Gibbs J, Lavender R, Mahan CE, Paje DG. Reversing factor Xa inhibitors - clinical utility of andexanet alfa. J Blood Med. 2017;8:141-149.
  3. Food and Drug Administration. Clinical Review Memo - ANDEXXA. 2018; https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM610008.pdf.
  4. Andexxa® [package insert]. San Francisco, CA: Portola Pharmaceuticals, Inc. 2018.
  5. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015;373(25):2413-2424.
  6. Connolly SJ, Milling TJ, Jr., Eikelboom JW, et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2016;375(12):1131-1141.
  7. Andexxa-An Antidote for Apixaban and Rivaroxaban. JAMA. 2018;320(4):399-400.
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  9. Blank C. Why a New Anticoagulant Reversal Agent Is Significant. Drug Topics June 1, 2018; http://www.drugtopics.com. Accessed June 26, 2018.
  10. Palmer E. Portola's Andexxa bleeding antidote wins FDA nod but will see limited release. FiercePharma May 7, 2018; https://www.fiercepharma.com, June 26, 2018.
  11. AndexXa. (2018). IBM Micromedex® RED BOOK®. Retrieved June 26, 2018, from https://www.micromedexsolutions.com. Ann Arbor, MI: Truven Health Analytics.
  12. Lai S, Kalantari A, Mason J, Grock A. When Anticoagulants Become a Bloody Mess. Ann Emerg Med. 2017;70(6):949-952.
  13. Gulseth MP. Overview of direct oral anticoagulant therapy reversal. Am J Health Syst Pharm. 2016;73(10 Suppl 2):S5-S13.
  14. Tomaselli GF, Mahaffey KW, Cuker A, et al. 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017;70(24):3042-3067.
  15. Kcentra® [package insert]. King of Prussia, PA: CSL Behring, Inc. 2013.
  16. Levy JH, Moore KT, Neal MD, et al. Rivaroxaban reversal with prothrombin complex concentrate or tranexamic acid in healthy volunteers. J Thromb Haemost. 2018;16(1):54-64.
  17. Schultz NH, Tran HTT, Bjornsen S, Henriksson CE, Sandset PM, Holme PA. The reversal effect of prothrombin complex concentrate (PCC), activated PCC and recombinant activated factor VII against anticoagulation of Xa inhibitor. Thromb J. 2017;15:6.
  18. Schenk B, Goerke S, Beer R, Helbok R, Fries D, Bachler M. Four-factor prothrombin complex concentrate improves thrombin generation and prothrombin time in patients with bleeding complications related to rivaroxaban: a single-center pilot trial. Thromb J. 2018;16:1.
  19. Chyka PA, Seger D, Krenzelok EP, et al. Position paper: Single-dose activated charcoal. Clin Toxicol (Phila). 2005;43(2):61-87.
  20. Yeates PJ, Thomas SH. Effectiveness of delayed activated charcoal administration in simulated paracetamol (acetaminophen) overdose. Br J Clin Pharmacol. 2000;49(1):11-14.
  21. Kcentra. (2018). IBM Micromedex® RED BOOK®. Retrieved June 26, 2018, from https://www.micromedexsolutions.com. Ann Arbor, MI: Truven Health Analytics.
  22. Activated Charcoal. (2018). IBM Micromedex® RED BOOK®. Retrieved June 26, 2018, from https://www.micromedexsolutions.com. Ann Arbor, MI: Truven Health Analytics.

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