A new oral anticoagulant promising less bleeding: milvexian

In recent years, direct anticoagulants have gradually replaced warfarin in the prevention of venous thromboembolism. Their action is exerted on two factors that are involved in the coagulation cascade: thrombin, in the case of dabigatran, or activated factor X, in the case of rivaroxaban, apixaban and edoxaban.

A new oral anticoagulant targeting coagulation factor XI is now making its way through these competitors. A recent study, published in the New England Journal of Medicine, highlighted how a drug with this mechanism of action, milvexian, used in patients undergoing knee arthroplasty, was effective in the prevention of venous thromboembolism and, perhaps even more importantly , has been shown to induce a low risk of bleeding. This last aspect is particularly important, because the effectiveness in the prevention of embolic events is substantially good for all direct anticoagulants, but the element that could make the difference is the safety of the drug. A safety linked mainly to the most important of its side effects, bleeding. If a new anticoagulant proves able to prevent thrombotic events, without increasing excessively the risk of bleeding, it would obviously be the ideal drug.

Direct oral anticoagulants

Their innovative aspect was underlined in the name initially attributed to them: the new oral anticoagulants. Now, they are in use from several years, and for this reason they are currently called ‘direct anticoagulants’, recalling their mechanism of action.

This class of drugs is slowly supplanting the use of warfarin, a historic anticoagulant, however initially used as a rat poison, which acts by antagonizing the functions of vitamin K. With this mechanism it can act in different points of the coagulation cascade, inhibiting the formation of the active forms of factors II, VII, IX and X.

Direct anticoagulants exert their action more selectively. Rivaroxaban, apixaban and edoxaban work by inhibiting activated factor X, while dabigatran directly inhibits thrombin.

In the adult population, these drugs are indicated in the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and for the treatment and prevention of deep vein thrombosis and pulmonary embolism. Different studies have shown that these medications are more effective than warfarin.

Inhibitors of factor XIa

In the last years, the research shifted its focus to molecules capable of acting further upstream in the coagulation cascade, acting directly on factor XI and inhibiting its activation.

Located at the beginning of the intrinsic activation pathway, factor XI is a glycoprotein that is activated by factor XIIa, in turn activated by the lesion of the vessels and the consequent release of platelet phospholipids.

In particular, patients with genetic factor XI deficiency have been shown to have a lower risk of developing thrombosis but do not have bleeding events. From this reason the interest in developing a drug that acts precisely at the level of factor XI arises, which despite having a fundamental role in thrombi growth has a less relevant function in haemostasis.

One such drug, being developed by pharmaceutical companies Bristol Myers Squibb and Janssen, is milvexian and the first clinical results are coming.

The AXIOMATIC-TKR study

In this new phase 2 study, researchers evaluated more than 1,200 patients who had undergone knee arthroplasty. After this sort of surgery, as well as after other orthopaedic surgeries, patients are commonly initiated to a treatment with anticoagulant, for the prevention of thromboembolic events, which can be favoured by surgery itself and by the period of relative immobilization in bed.

Subjects included in the study were assigned to two different treatments: milvexian, to one of seven prescribed dosing regimens (25 mg, 50 mg, 100 mg, or 200 mg twice daily or 25 mg, 50 mg, or 200 mg once daily. day) or enoxaparin (40 mg once daily).

The main efficacy endpoint of the study was venous thromboembolism, defined as a composite of asymptomatic deep vein thrombosis, confirmed symptomatic venous thromboembolism or death from any cause. The main safety endpoint was bleeding.

Effective and safe

Among patients treated with milvexian twice daily, venous thromboembolism developed in 21% of those treated with 25 mg, in 11% of those treated with 50 mg, in 9% of those treated with 100 mg, and in 8% of those treated with 200 mg.

Among those who received milvexian once daily, venous thromboembolism developed in 25% of those treated with 25 mg, in 24% of those treated with 50 mg, and in 7% of those treated with 200 mg. Patients treated with enoxaparin developed a thrombotic event in 21% of cases.

These first results therefore seem to indicate that milvexian, at any regimen, is never inferior to enoxaparin, indeed, at higher dosages it seems decidedly more effective.

Regarding the safety of the drug, patients treated with milvexian developed bleeding of any severity in 4% of cases, exactly the same percentage found among those assigned to treatment with enoxaparin.

Clinically relevant major or non-major bleeding occurred in 1% and 2% of cases, respectively.

Precisely, the four dosing regimens of milvexian with double daily dose (25, 50, 100 or 200 mg) resulted in any bleeding in 1%, 5%, 5% and 3% of cases, respectively. The single-dose regimens (25, 50 and 200 mg) were associated with any bleeding in 0%, 5% and 6% of cases, respectively.

Comparison with other oral anticoagulant drugs

As we have already said, in this new study milvexian proved to be an effective drug in the prevention of thrombotic events, reducing them even when used once daily. Furthermore, when used in doses of 100 mg it was even superior to enoxaparin.

This study, however, revealed what was perhaps the most anticipated data for this drug, namely the low incidence of bleeding, results substantially comparable to those of the control drug.

From phase 2 trial this new drug is now set to be evaluated in phase 3 studies, when it will likely be compared not only against warfarin, but also against its closest rivals, direct anticoagulants. If even in these studies its efficacy, but above all its safety against bleeding risk, is confirmed, it could represent a fundamental turning point in the panorama of oral anticoagulants, beating the field of competitors.

With an increasing number of subjects taking oral anticoagulants for the prevention of thromboembolic events, having a drug that is not only effective, but above all safe, could drastically reduce the number of adverse haemorrhagic events, with enormous advantages for patients and for public health. A drug like this, could even guide the extension of indications for oral anticoagulants, in the light of a finally improved safety profile.

This post is also available in: Chinese (Simplified)

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