Novel Therapeutics for Thrombosis and Hemostasis

Novel Therapeutics for Thrombosis and Hemostasis

Jeffrey Weitz, M.D., F.R.C.P.(C), F.A.C.P.

McMaster University, Hamilton, Ontario

There are exciting advances in the treatment of clotting and bleeding disorders.  Not only are there many novel agents on the horizon, but there also is the potential for new indications for some recently introduced drugs.  On the thrombosis front, the non-vitamin K antagonist oral anticoagulants (NOACs), which are already streamlining the management of patients with atrial fibrillation (AF) and venous thromboembolism (VTE), are under investigation for many new indications.  These include prevention of cardiovascular events in patients with heart failure or those with coronary and/or peripheral artery disease, prevention of recurrent stroke in patient with embolic stroke of undetermined source, prevention of VTE in medically ill patients discharged from hospital, and primary and secondary prevention of VTE in cancer patients.  If positive, the results of these trials will expand the indications for NOACs. 

Anticoagulant strategies that target factor (F) XII or XI are an area of intense interest in an attempt to develop safer drugs.  The demonstration that FXI knockdown with an antisense oligonucleotide (ASO) is superior to enoxaparin for VTE prevention after elective knee surgery without increasing the risk of bleeding highlights the potential of FXI or FXII inhibitors.  Ongoing studies are evaluating the FXI ASO in hemodialysis patients, at least 15% of whom have AF, because there is equipoise about the role of warfarin in such patients and the NOACs are contraindicated.  Studies with FXIIa and XIa directed antibodies also are underway.

On the hemostasis front, phase III trials are evaluating idarucizumab and andexanet alfa for reversal of dabigatran and the oral FXa inhibitors, respectively.  When given to dabigatran-treated patients with serious bleeding or requiring urgent surgery, idarucizumab produced rapid reversal in the first 90 patients entered in the study.  Therefore, specific reversal agents for the NOACs are likely to soon be licensed, which will enhance the safety of the NOACs and increase their uptake.

Major advances in therapies for bleeding disorders focus on novel agents for management of patients with hemophilia.  Long-acting FIX and FVIII concentrates, some of which are already licensed, have the potential to simplify prophylaxis by extending the dosing interval.  Whereas the half-life of FIX is extended up to 5-fold with the new products, the half-life of FVIII is only prolonged by 1.5 fold.  Therefore, there still is a need for additional therapies.  Most promising are the rebalancing strategies that aim to enhance thrombin generation by knocking down antithrombin with GalNAc-conjugated small interfering RNA, attenuating tissue factor pathway inhibitor, or mimicking the cofactor activity of FVIII with a bispecific antibody against FIXa and FX.  Also on the horizon are new strategies for management of hemophiliacs with inhibitors.  These include long-acting recombinant FVIIa, recombinant porcine FVIII, and zymogen FXa.  Therefore, there is a rich pipeline of new therapies for management of patients with clotting and bleeding disorders.