Anticoagulants are commonly used to treat blood clots, or as a prophylactic for the prevention of clot formation in high risk groups (e.g. atrial fibrillation patients).
Though the vitamin K antagonist warfarin was once the vanguard of oral anticoagulant therapy and still remains in widespread use, its multi-drug reaction profile and narrow therapeutic window require significant patient monitoring (reminding me of my late Grandmother’s regular refrain that her doctor had “upped the warfarin”), meaning it is a cumbersome therapy to administer.
Novel oral anticoagulants (NOACs) are becoming an increasingly popular therapeutic option as a prophylactic, as they demonstrate similar efficacy to that of warfarin, but may carry lower risk of complications such as intracranial bleeding.
In contrast to warfarin which inhibits the synthesis of several clotting factors, current approved NOACs block a single factor (either factor Xa or thrombin) of the common coagulation pathway. Dabigatran inhibits thrombin, whilst Apixaban, Edoxaban, and Rivaroxaban inhibit factor Xa. There are few reliable head-to-head comparisons on the safety and efficacy of the NOACs, however several trials attempting to study these aspects are currently underway. See Table 1
On the horizon, Betrixaban (Portola Pharmaceuticals Inc.), an oral factor Xa inhibitor, is being developed for extended-duration prophylaxis of venous thromboembolism in acute medically ill patients. This follows encouraging results from the Phase 3 APEX Study which concluded in January 2016.
Reversal of anticoagulation
Reversing the effects of anticoagulation therapies is important, especially in the cases that emergency surgery is required, or ahead of a planned surgical procedure. Interestingly, the approval of reversal agents to some NOACs (bringing added confidence-of-use to clinicians) may feed into a temporary competitive advantage (where indications overlap) over the NOACs without such antidotes, and has created a race-to-reversal for the remaining manufacturers in their jostle for clinical utility and market share.
Boehringer Ingelheim was first past the FDA-approval post (in October 2015), with idarucizumab, a reversal agent for dabigatran. Idarucizumab was developed from a mouse monoclonal antibody raised against dabigatran, and involved the removal of the Fc constant antibody region and humanisation of the remaining antigen-binding fragment (Fab), to produce an antibody with a shorter plasma half-life and reduced potential for immunologic reactions compared to its parent. Idarucizumab is administered I.V. and for most patients, completely neutralises the anticoagulant effects of dabigatran within minutes.
Andexanet alfa (AndexXa™)
Close to the finish line, Portola Pharmaceuticals and Daiichi Sankyo are hoping to produce the first approved reversal agent for factor Xa inhibitors, with andexanet alfa. Portola is expanding their ANNEXA-4 study of the drug as a reversal agent for edoxaban and, though not currently approved, andexanet alfa is currently under FDA and EMA review. Andexanet alfa is a modified human factor Xa molecule that acts as a decoy protein capable of mopping factor Xa inhibitors in the blood, and due to the fact that its molecular structure mimics the native factor Xa, andexanet alfa may also be efficacious in reversing factor Xa inhibitors other than edoxaban.
Ciraparantag is a small, peptide-like, water-soluble, cationic molecule under development by Perosphere Inc. as a broad spectrum (targeting both thrombin inhibitors and factor Xa inhibitors) anticoagulant reversal agent. Initially designed to bind specifically to the charged sites on unfractionated heparin, preclinical studies have shown binding to the NOACs dabigatran, edoxaban, apixaban and rivaroxaban as well. It does not bind to warfarin. A recent study in healthy male subjects showed that a single I.V. dose of ciraparantag delivered reversal of edoxaban-induced anticoagulation, and was safe and well tolerated.
The Institute for Safe Medication Practices (a US non-profit organisation dedicated to medication error prevention and safe medication use) lends a cautionary note, highlighting that anticoagulants are still the highest risk outpatient drug treatment in older patients, based on adverse drug events reported to the FDA (2015 data). Regardless of which anticoagulants turn out superior in terms of safety and efficacy, the high number of adverse events reported with this drug class emphasises the development of reversal agents as a crucial aspect of any future anticoagulant offering.