Among the bright stars of antithrombotic drugs, there are two dazzling stars that must be mentioned. One is aspirin, which is known as the "world's best-selling drug". The annual global consumption is still over 100 billion tablets, which can circle the earth 25 times if they are lined up; the other is apixaban, which has continuously broken through sales since its launch and firmly sits at the top of the small molecule drug sales list.
As a key drug category in the field of cardiovascular disease treatment, antithrombotic drugs firmly occupy the top position both in the global drug sales rankings and in the actual needs of clinical treatment. They are an indispensable "weapon" for the treatment of cardiovascular diseases.
Nowadays, as the global population aging trend becomes more and more obvious, the number of patients with cardiovascular diseases continues to rise. At the same time, the steady improvement of economic level has also made people pay more and more attention to health, and preventive anticoagulation has gradually become a trend among people at high risk of thromboembolic diseases.

More importantly, the patent cliff of the first-generation "miracle drug" apixaban is approaching, which makes people wonder: after its era gradually comes to an end, can the legend of antithrombotic drugs continue? Who will be the next generation of anticoagulant king?
Anticoagulation
The absolute protagonist in the field of anti-thrombosis

The so-called antithrombotic drugs, as the name suggests, are a class of drugs that can inhibit thrombus formation, promote thrombus dissolution or prevent thrombus expansion, thereby preventing and treating thromboembolic diseases.
According to their treatment principles, antithrombotic drugs can be roughly classified into anticoagulants, antiplatelet drugs, thrombolytic drugs and vasodilators.
Among them, thrombolytic drugs and vasodilators have clinical limitations (short application time window and temporary replacement of deep venous return in the lower limbs). Therefore, in theory, thrombolytic drugs and vasodilators are not the main anti-thrombotic drugs.
The two drugs that are truly widely used in the anti-thrombotic field are anticoagulants and antiplatelet drugs.
Anticoagulant drugs: mainly target venous thrombosis (red thrombosis and mixed thrombosis), because venous thrombosis is mostly composed of fibrin and red blood cells, usually caused by slow blood flow or congestion.
Antiplatelet drugs: mainly target arterial thrombosis (white thrombosis and mixed thrombosis), because arterial thrombosis is mainly composed of a large number of platelets and a small amount of fibrin, occurs in areas with faster blood flow, and is mainly caused by atherosclerosis.
Although both play an equally significant role in the anti-thrombotic field, antiplatelet drugs have a larger patient base but a relatively shorter medication cycle (within 12 months) because their main application scenarios are the prevention and treatment of atherosclerotic diseases (such as coronary heart disease, myocardial infarction, and stroke). The main application scenarios of anticoagulant drugs are atrial fibrillation stroke prevention, deep vein thrombosis, pulmonary embolism, and postoperative treatment of heart valve replacement. The patient base is lower, but the long-term medication value of patients is higher, and some patients may even need lifelong anticoagulant treatment.
Therefore, in comprehensive comparison, the market size of anticoagulant drugs is actually larger and growing faster. More importantly, this field has undergone a variety of technological and product changes, with new drugs having a significant substitution effect. The growth of the market size is positively correlated with the launch of new drugs.
Three major stages
Development of antithrombotic drugs
Data shows that the exploration of anticoagulant drugs can be traced back to more than 100 years ago, when German scholar Virchow proposed the three-element theory of thrombosis: damaged blood vessel walls, slowed blood flow, and changed blood components. With the joint efforts of scholars in many fields, the blood coagulation process and its regulatory mechanism have been deeply studied.
Since its development in the early 20th century, the field of anticoagulant drugs has gone through three stages, namely the initial exploration stage, the rapid development stage and the rise of new drugs stage.
Initial exploration stage (1900-2000): The discovery of heparin, aspirin and warfarin marked the gradual establishment of the cornerstone of modern anticoagulant therapy.
Rapid development stage (2001-2012): Stimulated by the market of aspirin and warfarin in the field of anticoagulation, the second-generation and third-generation anticoagulants with better efficacy, stronger safety and lower overall cost successfully entered the market, replacing the first-generation antithrombotic drugs, such as rivaroxaban and apixaban, etc.
The rise of new drugs (2012-2025): Although the clinical application of targeted anticoagulants has become more mature, the bleeding risk determined by its mechanism of action still exists, so a large number of anticoagulant drugs with new targets and new mechanisms have begun to appear.
Looking at the development of new drugs in the three stages, there are obvious commonalities in their development, namely, the selectivity of drugs is becoming stronger, the effectiveness and safety are becoming higher, and patient compliance is increasingly emphasized. In addition, in the process of development, the dominant position of MNC pharmaceutical companies such as Pfizer, BMS, Bayer, Sanofi, and GSK is particularly obvious. It can be said that the development direction of anticoagulant drugs is driven by MNCs behind the scenes, and any layout of MNCs may directly affect the future development of the entire anticoagulant field.
However, as new coagulation factor XI inhibitors have become a major research hotspot, companies that are technology-led have gradually emerged, regardless of whether they are domestic pharmaceutical companies, and are evenly distributed across various technology types, such as Hengrui's SHR-2004, Ribo Bio's RBD-4059, Hisun Pharmaceuticals' EP-7041, Corning Jeol's KN-060, and Jingyin Pharmaceutical's SRSD-107.
Four major therapies
Phased development of anticoagulant products
It is reported that in the field of anticoagulation, its main mechanism of action is centered around the inhibition of the coagulation factor family.
There are 14 coagulation factors in the human body, which together form a close and orderly network. When the upstream coagulation factors are activated, they will gradually activate the downstream factors like a waterfall effect. With each level, the number of activated coagulation factors increases exponentially, and the coagulation effect also increases. This process is vividly called the "coagulation waterfall."
Eventually, fibrinogen (factor I) is activated and converted into a fibrin network, capturing platelets, red blood cells and other components to form a stable thrombus. Among coagulation factors, most of them do not directly participate in the formation of thrombi, but play a role in transmitting signals or catalysis, but their role is equally important. In particular, factor II (thrombin) and factor X occupy a key position in drug intervention. This is why early anticoagulant targeted drugs were promoted around factors II and X.
From the early launch of heparin and warfarin to apixaban and rivaroxaban in the past 20 years, the phased development of marketed anticoagulant drugs has mainly revolved around four types of drugs, namely indirect thrombin inhibitors, vitamin K inhibitors, direct thrombin inhibitors and factor Xa inhibitors.
Indirect thrombin inhibitors

It exerts its anticoagulant effect mainly by indirectly inhibiting the activity of IIa, Xa, IXa, XIIa, and XIa through interaction with antithrombin (ATⅢ). It does not directly affect thrombin, but can react with antithrombin to greatly accelerate the rate at which antithrombin inactivates coagulation factors. Representative drugs are various types of heparin.
Its clinical advantages lie in its strong anticoagulant effect, wide therapeutic range, and low risk of immunogenicity. Its disadvantages are that due to its lack of precision (inhibiting multiple coagulation factors simultaneously), the overall anticoagulant reaction is unstable, leading to a high risk of bleeding. Long-term use will also affect the immune system and increase the risk of infection.
Vitamin K antagonists
It mainly works by inhibiting liver vitamin K epoxide reductase, blocking the cyclic conversion between vitamin K and its 2,3-epoxide (i.e., vitamin K epoxide), resulting in the inability of vitamin K-dependent coagulation factors II, VII, IX, and X to complete the carboxylation reaction, thereby inhibiting their biological activity and ultimately exerting an anticoagulant effect. In principle, it is also a type of indirect thrombin inhibitor, and its representative products are various types of warfarin.
Its biggest advantage is that it can be taken orally and is suitable for patients who need long-term anticoagulation treatment. It plays an important role in the prevention and treatment of thrombotic diseases such as venous thromboembolism (VTE), atrial fibrillation, valvular disease, artificial valve replacement, and intracardiac thrombosis. However, its narrow treatment window, high risk of bleeding, and complex management also make it a double-edged sword for anticoagulation treatment.
Direct thrombin inhibitors
It mainly inhibits thrombin directly, prevents fibrinogen from breaking down into fibrin, blocks the final step of the coagulation cascade and thrombus formation. Monovalent thrombin inhibitors (dabigatran etexilate, argatroban) can directly inhibit thrombin, and divalent thrombin inhibitors (bivalirudin, recombinant hirudin) can directly inhibit thrombin while also separating thrombin from fibrin to achieve an anticoagulant effect. It is mainly used clinically for the prevention of atrial fibrillation stroke, acute coronary syndrome, and the treatment and prevention of VTE (including primary and secondary).
Representative drugs include dabigatran etexilate, argatroban, lepirudin, bivalirudin, etc.
In terms of clinical advantages, compared with indirect thrombin inhibitors, it can inactivate both thrombin bound to fibrin and thrombin in a free state in the blood, making its theoretical anticoagulant effect better; at the same time, because it does not bind to plasma proteins, it has high bioavailability, stronger specificity, and more importantly, lower side effects, greatly reducing the risk of bleeding and thrombocytopenia (HIT). But at the same time, its injection characteristics are not friendly to the field of anticoagulant treatment, with poor compliance, high medication costs, and obvious indigestion complications.
Factor Xa inhibitors
Activated factor Xa, as a serine protease, is at the intersection of endogenous and exogenous coagulation in the coagulation cascade. Factor Xa inhibitors can interrupt the endogenous and exogenous pathways of the coagulation cascade. They can be divided into indirect and direct inhibitors according to whether they depend on ATⅢ factor. Indirect factor Xa inhibitors require ATⅢ factor as a cofactor and cannot inhibit factor Xa bound to the prothrombinase complex; direct factor Xa inhibitors act directly on the active center of the factor Xa molecule, inhibiting both free factor Xa in plasma and factor Xa bound to the prothrombinase complex to exert an anticoagulant effect.
Representative drugs include rivaroxaban, apixaban and edoxaban.
In terms of clinical advantages, its clear target and small drug-food interaction have led to its wide application in thrombotic diseases, and its priority recommendation in multiple guidelines is higher than that of traditional anticoagulants. However, even as powerful as factor Xa inhibitors are, they are still insufficient in controlling the risk of stroke.

In general, the development of new anticoagulant drugs from indirect thrombin inhibitors to factor Xa inhibitors has obvious characteristics, namely, increasingly stronger selectivity, higher effectiveness and higher safety. Under this trend, it also indicates that factor Xa inhibitors are not ideal carriers in the field of anticoagulant drugs. Anticoagulant drugs with better effects, lower bleeding risks and better compliance are still the hot spots and trends in the field of thrombosis treatment.
Factor XIa
Future trends in anticoagulant drugs
As mentioned above, the excellent efficacy, acceptable safety and almost non-existent food-drug interactions of factor Xa inhibitors have made them a successful alternative to traditional anticoagulants (such as warfarin) and become the clinical first choice.
However, with the continuous pursuit of more ideal anticoagulant drugs in clinic, more and more studies are evaluating whether targeting FXI or FXII for potential upstream inhibition of the coagulation cascade may separate the mechanism of thrombosis from hemostasis, thereby providing a safer anticoagulation method than DOAC. Among them, the incidence of stroke in patients with coagulation factor XI deficiency is significantly lower in relevant epidemiological surveys. Therefore, it is theoretically possible to further reduce the risk of bleeding on the basis of existing anticoagulant drugs.
Therefore, factor XIa inhibitors have gradually become one of the main directions of research and development of anticoagulant drugs in recent years.
According to Yaozhi data, there are currently 34 active anticoagulant drugs under development worldwide, of which more than 20 are factor XIa inhibitors, accounting for more than 60% of all anticoagulant pipelines under development, which shows its dominant position in the research of new anticoagulant drugs.
Moreover, for the same target, many factor XIa inhibitors have developed different design schemes at different levels of demand, such as factor XIa monoclonal antibodies, factor XIa small nucleic acid drugs and factor XIa small molecule inhibitors.
Factor XIa monoclonal antibody - abemacicumab
Abamix is a humanized monoclonal antibody targeting coagulation factor XI (FXI) from Novartis. It can selectively bind to FXI and coagulation factor XIa (FXIa), hindering the activation of FXI by coagulation factor XIIa (FXIIa), thereby blocking the cascade reaction process of the intrinsic coagulation pathway and exerting an anticoagulant effect. At the same time, this drug is also the fastest-progressing product in the world among factor XI monoclonal antibodies.
In early 2025, the results of an experiment comparing the efficacy and safety of abemacicab and rivaroxaban (AZALEA-TIMI 71) showed that after three months of medication, in terms of effectiveness, the free factor XI of patients in the 150 mg abemacicab group decreased by an average of 99%, and the 90 mg group decreased by 97%. In terms of safety, compared with rivaroxaban, the 150 mg abemacicab group reduced the risk of bleeding by 62%, and the 90 mg group reduced it by 69%. The reduction in bleeding events was much greater than expected, so the trial was terminated early.
It is obvious that factor XI monoclonal antibodies represented by abamacizumab have obvious advantages over factor Xa inhibitors, at least in terms of safety, and fully meet their urgent clinical needs.
Factor XIa chemical drug-Asundexian
As the main technical type of XIa inhibitors at present, small molecule XIa targeted inhibitors can quickly diffuse through the cell membrane to reach the site of action inside the cell and exert their effects quickly. In addition, small molecule drugs also have the characteristics of oral administration and renal clearance pressure.
Currently, no new drug has been successfully launched in the field of small molecule XIa targeted drugs actively under development around the world. The ones with the fastest clinical progress are Asundexian (Bayer) and Milvexian (Johnson & Johnson/BMS).

Take Asundexian as an example. As an oral chemically synthesized small molecule of Bayer, it can directly, effectively and reversibly inhibit factor Xia. The complete bioavailability of the drug is not affected by tablet formulation, gastric pH or food. In a previous Phase 2 clinical study, the results showed that the risk of bleeding (major bleeding or clinically relevant non-major bleeding according to ISTH standards) of Asundexian in patients with atrial fibrillation was lower than that of apixaban.
The PACIFIC-STROKE trial evaluated the role of Asundexian for secondary prevention of ischemic stroke in 1,800 patients with acute non-cardioembolic ischemic stroke. Compared with placebo, Asundexian did not reduce the incidence of the composite endpoint of occult cerebral infarction or ischemic stroke, nor did it increase the risk of major bleeding or clinically relevant non-major bleeding, all bleeding, or hemorrhagic transformation.
The OCEANIC-AF trial will evaluate the efficacy and safety of Asundexian versus apixaban in approximately 15,000 patients with atrial fibrillation. The Phase 3 OCEANIC-AMI trial will evaluate the effect of Asundexian on the risk of cardiovascular events and death when added to dual antiplatelet therapy.
Factor XIa small nucleic acid drug-RBD4059/SRSD-107
Given that XIa inhibitors have more effective inhibitory effects and lower bleeding risks than factor Xa inhibitors, some companies are trying to further optimize the compliance limitations of XIa monoclonal antibodies, and siRNA is one of the most promising therapies.
RBD4059 is a GalNac-coupled siRNA drug developed by RiboBio based on its liver-targeted technology platform. It achieves its anticoagulant/antithrombotic effects by inhibiting coagulation factor XI (FXI) and blocking the activation of the intrinsic coagulation pathway. Phase I clinical results have shown that RBD4059 exhibits dose-dependent, predictable pharmacokinetic properties, as well as significant (>90%) and lasting FXI activity and protein reduction effects; at the same time, it achieved the primary endpoints in terms of safety and tolerability, and no adverse safety signals were found within the dose range of the study, showing good safety.
SRSD107 is a double-stranded small interfering nucleic acid (siRNA) drug of Jingyin Pharmaceutical, which is designed to selectively inhibit coagulation factor Ⅺ (FXI). By targeting FXI, SRSD107 is expected to significantly reduce the risk of bleeding while reducing the occurrence of thrombotic events, showing a therapeutic advantage different from coagulation factor X activity (FXa) inhibitors. In its Phase I clinical trial results, SRSD107 was safe and well tolerated, and significant changes in pharmacodynamic biomarkers compared to baseline were observed. At the highest dose, the maximum decrease in FXI antigen and FXI activity exceeded 90%, and the increase in aPTT exceeded 100% (ie, aPTT ratio > 2.0). The pharmacodynamic effect after a single dose is long-lasting, maintaining nearly 90% inhibition of FXI antigen and FXI activity for more than 16 weeks.
Obviously, in addition to its more potent inhibitory effect, the biggest difference between XIa-targeted siRNA therapy and monoclonal antibodies is its long-term advantage. The frequency of medication of up to once every six months greatly improves patient compliance and reduces the risk of drug interactions.
Obviously, the three types of technology have their own advantages and limitations. The current test results cannot determine their final direction in the future. Only the head-to-head data in the three fields after the drugability is verified one by one will be truly meaningful for reference. However, roughly speaking, based on the main application scenarios of anticoagulant drugs, small nucleic acids and small molecule oral drugs may have relatively greater advantages.
summary

In summary, the development of anti-thrombotic drugs has gone through more than a hundred years of exploration. From the initial traditional drugs represented by heparin and warfarin to the new generation of innovative therapies represented by factor XIa inhibitors, its research and development path has always been centered around the three core goals of "enhanced selectivity, improved effectiveness, and optimized safety."

Judging from the current global research and development trends of anticoagulant drugs, the market has formed a competitive landscape dominated by factor Xa inhibitors and with factor XIa inhibitors as a breakthrough point. Among them, factor XIa inhibitors are becoming a hot area for multinational pharmaceutical companies (MNCs) and biotechnology companies to compete for due to their theoretically lower bleeding risk and wider potential for indications.
At the same time, in the technical development of factor XIa inhibitors, there are generally three technical directions with different advantages:
Monoclonal antibodies, such as abatacitumab, exhibit excellent safety by precisely blocking the intrinsic coagulation pathway.
Small molecule inhibitors (such as Asundexian) are advancing large-scale clinical validation due to their oral convenience and rapid onset of action.
Small nucleic acid drugs (such as RBD4059 and SRSD107) rely on long-acting mechanisms of action and liver-targeted delivery technology, attempting to break through the efficacy-safety balance of traditional drugs while reducing the frequency of dosing.
In short, today's anticoagulant drugs have clearly entered a new stage of development with precision, long-term effectiveness, and safety. In the next decade, the field will present a competitive trend of "multiple technologies in parallel and differentiated indication coverage."

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