Ciraparantag, an anticoagulant reversal drug

Ciraparantag, an anticoagulant reversal drug: mechanism of action, pharmacokinetics, and reversal of anticoagulants

Ansell J, Laulicht BE, Bakhru SH, Burnett A, Jiang X, Chen L, et al. Blood. 2021;137(1):115–125.

• Non-vitamin K oral anticoagulants (NOAC) are as effective as warfarin, but still associated with significant bleeding risk
• Ciraparantag is a small, synthetic, water-soluble, cationic molecule designed to reverse heparin and NOAC anticoagulation
• This preclinical study investigated the mechanism of action, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics, and proof-of-concept data for ciraparantag
• Ciraparantag is a potential anticoagulant antidote without nonspecific protein binding
• Clinical trials investigating the anticoagulation activity and utility of ciraparantag are ongoing

In 2010, dabigatran was the first non-vitamin K oral anticoagulant (NOAC) approved by the US FDA, rapidly followed by apixaban, betrixaban, edoxaban, and rivaroxaban. NOACs were determined to be as effective as warfarin, but with robust evidence suggesting they offered a safer bleeding profile (Makam et al., 2018; Chai-Adisaksopha et al., 2014). However, regardless of the benefits of NOACs, they are still associated with a significant bleeding risk (Chai-Adisaksopha et al., 2014).

In addition, NOACs were developed without specific reversal agents available to treat active bleeding or reverse anticoagulation. This absence is still a significant limitation for most currently used antithrombotic treatments.

Recently, the lack of reversal agents has been partially remedied by the availability of idarucizumab, a humanised murine monoclonal antibody fragment targeted to bind and reverse dabigatran (Pollack et al., 2017); and andexanet alfa, a recombinant Factor Xa (FXa) decoy targeted to bind and reverse the oral FXa inhibitors and enoxaparin (Connolly et al., 2019). Ciraparantag, a third reversal agent, is in clinical development.

In this preclinical report, Ansell and colleagues summarise the mechanism of action of ciraparantag, its pharmacokinetic (PK) and pharmacodynamic (PD) characteristics, and available proof-of-concept data for reversal of anticoagulant-induced bleeding in animal models.

Use of dynamic light scattering (DLS) methodology confirmed that ciraparantag has a strong ionic interaction with heparin and a physical, noncovalent binding between other anticoagulants.

DLS techniques highlight that ciraparantag does not bind to Factor IIa (FIIa), FXa, cardiac drugs (for example, diltiazem, digoxin, propranolol, clopidogrel), antiepileptic drugs, insulin and metformin, or other commonly used medications (aspirin, atorvastatin, azithromycin, and streptokinase). In addition, ciraparantag does not have binding activity with human plasma proteins.

Pharmacokinetic experiments indicate that ciraparantag fits a one-compartment model, with rapid distribution and elimination phases, and demonstrates almost zero accumulation. The main route of elimination was urinary excretion, with >90% of the total dose recovered within the first 24 hours, mainly in the initial 8 hours post-dosing.

In various animal models, ciraparantag reversed bleeding following each of the oral FXa inhibitors (apixaban, edoxaban, and rivaroxaban), an oral FIIa inhibitor (dabigatran), and both parenteral IIa/Xa inhibitors (enoxaparin and unfractionated heparin).

Dose-dependent reversal of anticoagulation has also been observed in phase 2 volunteer studies (Figure 1), where higher doses of ciraparantag were required to fully reverse anticoagulation with rivaroxaban compared with apixaban (Ansell et al., 2020).

Figure 1. Percentage change in bleeding time from baseline when ciraparantag was administered in increasing doses after edoxaban treatment (1 mg/kg) of rats.

Overall, Ansell and colleagues suggest these data support the direct binding of ciraparantag to DOACs and heparin through noncovalent hydrogen bonds and charge-charge interactions, preventing DOACs from associating with the relevant coagulation factors like FXa and permitting restoration of normal coagulation factor activity.

Thus, ciraparantag is a potential antidote for unfractionated heparin, enoxaparin, and specific oral direct FXa/FIIa inhibitors; as opposed to treatments with wider, non-targeted binding or use of alternative, non-heparin or non-FXa/FIIa anticoagulants.

Additional phase 2 trials are ongoing to assess the ability of ciraparantag to reverse anticoagulation with other DOACs before phase 3 clinical trials are initiated in patients with major bleeding or requiring urgent surgery.

Anticoagulation considerations

- Ciraparantag acts rapidly, has a short half-life, and reduces bleeding induced by heparin and DOACs in animals
- Ciraparantag is a potential antidote for unfractionated heparin, enoxaparin, and specific oral direct FXa/FIIa inhibitors

References

Ansell J, Bakkhru S, Villano S, Luo X. Efficacy and Safety of Ciraparantag in Reversing Apixaban and Rivaroxaban as Measured by Whole Blood Clotting Time in Healthy Adults. Res Pract Thromb Haemost. 2020;4(suppl1). Abstract PB0302.

Chai-Adisaksopha C, Crowther M, Isayama T, Lim W. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood. 2014;124(15):2450–2458.

Connolly SJ, Crowther M, Eikelboom JW, Gibson M, Curnutte JT, Lawrence JH, et al. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2019;380(14):1326–1335.

Makam RCP, Hoaglin DC, McManus DD, Wang V, Gore JM, Spencer FA, et al. Efficacy and safety of direct oral anticoagulants approved for cardiovascular indications: Systematic review and meta-analysis. PLoS One. 2018;13(5):e0197583.

Pollack CV Jr., Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, et al. Idarucizumab for Dabigatran Reversal – Full Cohort Analysis. N Engl J Med. 2017;377(5):431–441.