Use of milbexian to treat or prevent cerebrovascular or cardiovascular adverse events in patients with acute coronary syndrome.

Abstract

An activated factor XI inhibitor possessing useful therapeutic properties for the prevention of cerebrovascular or cardiovascular adverse events in human patients with acute coronary syndrome.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to U.S. Provisional Application No. 63 / 497,111, filed on 19 April 2023, which is incorporated herein by reference in its entirety.

[0002] (Technical field) This disclosure relates to the use of milbexian in human patients with acute coronary syndrome (ACS) to treat or prevent cerebrovascular or cardiovascular adverse events without significantly impairing the normal blood clotting process. [Background technology]

[0003] Cardiovascular disease (CVD) remains the leading cause of death worldwide. Despite advances in modern medicine, stroke remains a major cause of death and disability globally. In 2019 alone, stroke-related disability-adjusted life years in Western countries amounted to 143 million years, deaths to 6.55 million, and accounted for a significant portion of healthcare expenditures. In the United States, an estimated 805,000 cases of first-time and recurrent myocardial infarctions (MI) occur annually. Patients who experience acute coronary syndrome (ACS) are at high risk. Despite advances in novel thin strut stents / polymers, antithrombotic therapy with aspirin and / or potent P2Y12 inhibitors, the widespread application of surgical and percutaneous revascularization, and targeted control of cardiovascular risk factors, the risk of recurrent cardiovascular (CV) adverse events (such as myocardial infarction, ischemic stroke, and cardiovascular death) in patients who have experienced acute myocardial infarction remains very high, exceeding 5% in the first year. Five percent of patients with acute myocardial infarction experience a recurrence of cardiovascular events within one year, and 60% of these events occur within the first 90 days. Atherosclerotic cardiovascular complications remain the most common cause of morbidity and mortality in Western countries and developing countries (Katan et al, Global burden of stroke, SeminNeurol., 2018, vol. 38, pp. 208-211).

[0004] Milvexian (BMS-986177 / JNJ-70033093) is a direct-acting inhibitor that shows high affinity for human activating factor XI (Dilger et al., Discovery of milvexian, a high-affinity, orally bioavailable inhibitor of factor XIa in clinical studies for antithrombotic therapy. J Med Chem 2022;65(3):1770-85). Milvexian is expressed by formula (I): [ka] It is a macrocyclic compound having the following structure.

[0005] Milbexian is its chemical name (5R,9S)-9-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazole-1-yl)phenyl)-6-oxopyrimidine-1(6H)-yl)-2 1 -(difluoromethyl)-5-methyl-2 1 Also known as H-3-aza-1(4,2)-pyridina-2(5,4)-pyrazolacronafane-4-one

[0006] Milbexian and methods for producing milbexian are described in U.S. Patent No. 9,453,018, all of which are incorporated herein by reference. Solvates, crystalline, and amorphous forms of milbexian are also known to those skilled in the art (see, for example, WO2021207659 and WO2022081473). Amorphous solid dispersion compositions of milbexian in one or more polymers are described in WO2020210629, all of which are incorporated herein by reference.

[0007] In the clinical trials of milvexian (milvexian, placebo, or comparator), 4,114 participants were involved and became the subjects of the interventional study. Among the 4,114 participants, 3,229 took milvexian, of which 660 were subjects in the phase 1 trial of milvexian, and 2,569 were subjects in the phase 2 trial of milvexian and the initial phase 2 trial. In the clinical development of milvexian, the following four types of severe bleeding: gastrointestinal bleeding, procedure-related bleeding, bleeding associated with neurological disorders (hemorrhagic transformation of ischemic stroke and subdural hematoma), and hematuria were determined to be adverse events. The results of the phase II trial of milvexian in patients who underwent TKR (total knee arthroplasty) were published in 2021 (Weitz, et al., Milvexian for the Prevention of Venous Thromboembolism, N. Engl. J. Med. 2021, vol. 385, pp. 2161-2172), and the results of the phase II trial using milvexian in addition to antiplatelet monotherapy or dual antiplatelet therapy (SAPT / DAPT) for the prevention of non-cardioembolic infarction and non-lacunar ischemic stroke were published in 2023 (Sharma et al., Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial, The Lancet Neurology, 2023, vol. 23, pp-46-59).

[0008] That is, vascular diseases and thromboembolic diseases are the main causes of death and disability worldwide. Despite the significant development of antithrombotic therapies, anticoagulant therapies are limited due to the risk of bleeding, and the thromboembolic risk remains high for many patients.

Summary of the Invention

[0009] The present disclosure provides an oral formulation of milvexian or a pharmaceutically acceptable salt or solvate thereof, a highly potent and highly selective FXIa inhibitor that modulates targeted coagulation by inhibiting activated factor XI (FXIa), and a treatment regimen comprising one or more antiplatelet therapies for the treatment and prevention of thrombus formation and embolism. As a result of the linkage of FXIa inhibition with the inhibition of platelet activation, thrombin generation is reduced, thereby reducing the risk of cerebrovascular or cardiovascular adverse events (such as cardiovascular death, myocardial infarction, or stroke in patients with a history of acute coronary syndrome and / or atherosclerosis) without impairing the hemostatic function. The treatment regimen described herein is performed to prevent (primary prevention) the formation of occlusive thrombi in patients at risk of developing thromboembolism. In some embodiments, the treatment regimen described herein is implemented for secondary prevention (e.g., secondary prevention of cardiovascular events in patients with a history of acute myocardial infarction or acute coronary syndrome) in patients after the first episode of thrombosis. The treatment regimen described herein has a better balance of ischemic risk and bleeding risk compared to rivaroxaban and other direct-acting oral anticoagulants (DOACs) in ACS patients. The treatment regimen may not only prevent coagulation activation on stents, but also potentially inhibit the stabilization and growth of thrombi via factor XI at the site of vascular injury.

[0010] In another aspect, the method of the present disclosure provides a new treatment regimen consisting of a novel immediate-release oral tablet containing milvexian and standard antiplatelet therapy to prevent coagulation in patients who develop ACS and are at high risk of bleeding. The method of the present disclosure provides an opportunity to use an FXIa inhibitor in a site or disease where anticoagulants are not fully utilized or not used at all.

[0011] In some embodiments, the Disclosure provides a method for preventing cerebrovascular or cardiovascular adverse events in human patients with acute coronary syndrome, characterized by administering to a human patient a regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof); and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; the pharmaceutical composition twice daily.

[0012] In another embodiment, the Disclosure relates to a method for preventing cardiovascular adverse events in a human patient diagnosed with acute coronary syndrome, comprising administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients; and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; the pharmaceutical composition twice daily; The above cardiovascular adverse events are selected from one or more of the following groups: all-cause mortality (ACM); cardiovascular (CV) death; myocardial infarction (MI); unstable angina (UA); any stroke or any stroke (ischemic, hemorrhagic, or of unknown cause); ischemic stroke; acute limb ischemia (ALI); large vessel (non-traumatic) limb amputation; symptomatic venous thromboembolism (VTE: pulmonary embolism (PE), deep vein thrombosis (DVT)); coronary revascularization due to ischemia; stent thrombosis; and hospitalization for any cause (classified as (1) planned or unplanned, (2) hospitalization due to arterial or venous thrombosis, or hospitalization not falling under either category). The present invention provides a method characterized by the following features.

[0013] In another embodiment, the Disclosure provides a method for reducing the incidence of one or more thrombotic adverse events selected from new-onset ischemic stroke, MI, or all-cause mortality in a human patient diagnosed with acute coronary syndrome, characterized by administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising about 25 mg to about 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients; and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; the pharmaceutical composition administered twice daily.

[0014] In yet another embodiment, the Disclosure provides a method for preventing ischemic stroke in a human patient diagnosed with acute coronary syndrome, characterized by administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients; and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; the pharmaceutical composition twice daily.

[0015] In some embodiments of the methods disclosed herein, milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered orally as a solid pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) and a pharmaceutically acceptable excipient.

[0016] In other embodiments of the method disclosed herein, administration does not statistically significantly increase the incidence of major hemorrhagic complications. [Brief explanation of the drawing]

[0017] [Figure 1]Figure 1 shows the coagulation pathway. Explanation of terms: FXII = factor XII; FXIIa = activated factor XII; FXI = factor XI; FXIa = activated factor XI; FIX = factor IX; FIXa = activated factor IX; FVIIa = activated factor VII; FVII = factor VII; FX = factor X; FXa = activated factor X. See Kakkar et al., FXI inhibition: The Holy Grail of Haemostasis-Sparing Anticoaulation, EMJ, 2021, vol. 6, pp. 12-20; and Fredenburgh et al., FXIa as a Target for New Anticoagulants, Hamostaseologie, 2021, vol. 41, pp. 104-110.

[0018] [Figure 2] Figure 2 shows the activated partial thromboplastin time, as described in Example 2. Figure 2 shows the relationship between the mean percentage change (±SD) from baseline of aPTT due to treatment and time. Within the dose range of milbexian (25 mg once daily to 200 mg twice daily), a dose-dependent increase in the percentage change from baseline of aPTT was observed. A statistical summary of the measured values ​​and percentage changes from baseline of aPTT in the PD analysis population is shown in Table 5. For the PD biomarker data analysis, values ​​from before administration of milbexian and after a specified time interval were used. At 4 hours, all test values ​​collected between 0.5 and 6 hours were included; at 12 hours, all test values ​​collected between 6 and 12 hours were included; and at 24 hours, all test values ​​collected between 12 and 72 hours were included.

[0019] [Figure 3] Figure 3 shows Kaplan-Meier curves for the time to the onset of ischemic stroke and any other stroke in all randomly selected subjects.

[0020] [Figure 4]Figure 4 shows Kaplan-Meier curves for the time to ischemic stroke and / or any other stroke in all randomly selected subjects.

[0021] [Figure 5A] Figure 5A shows the plasma concentration of milbexian on day 1, as a function of time from BID administration, for the film-coated direct-compression tablets (2 x 100 mg) of the present disclosure, compared to the plasma concentration of milbexian on day 1, as a function of time from BID administration, for capsules (2 x 100 mg) containing milbexian (see Example 3).

[0022] [Figure 5B] Figure 5B shows the plasma concentration of milbexian on day 5, function of time from BID administration, for the film-coated direct-compression tablets (2 x 100 mg) of this disclosure, compared to the plasma concentration of milbexian on day 5, function of time from BID administration, for capsules (2 x 100 mg) containing milbexian (see Example 3).

[0023] [Figure 5C] Figure 5C shows the plasma concentration of milbexian on day 1, as a function of time from BID administration, for the film-coated direct-compression tablets (1x25 mg) of this disclosure, compared to the plasma concentration of milbexian on day 1, as a function of time from BID administration, for the capsule formulation (1x25 mg) containing milbexian (see Example 3).

[0024] [Figure 5D] Figure 5D shows the plasma concentration of milbexian on day 5, function of time from BID administration, for the film-coated direct-compression tablets (1x25 mg) of this disclosure, compared to the plasma concentration of milbexian on day 5, function of time from BID administration, for the capsule formulation (1x25 mg) containing milbexian (see Example 3). [Modes for carrying out the invention]

[0025] In one embodiment, the method of the present disclosure provides a novel therapeutic regime characterized by a novel immediate-release oral tablet containing milbexian to prevent coagulation in patients at high risk of bleeding after an ACS episode.

[0026] In some embodiments, the Disclosure provides a method for preventing cerebrovascular or cardiovascular adverse events in human patients with acute coronary syndrome, characterized by a regimen of administering 25 mg of milbexian twice daily to a human patient.

[0027] In some embodiments, the Disclosure provides a method for preventing cerebrovascular or cardiovascular adverse events in human patients with acute coronary syndrome, characterized by a regimen of administering to a human patient a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) twice daily.

[0028] In certain embodiments, the Disclosure provides a method for preventing cerebrovascular or cardiovascular adverse events in human patients with acute coronary syndrome, characterized by administering to a human patient a regimen comprising (i) 25 mg of milbexian twice daily and (ii) antiplatelet therapy.

[0029] In some embodiments, the Disclosure provides a method for preventing cerebrovascular or cardiovascular adverse events in human patients with acute coronary syndrome, characterized by administering to a human patient a regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof); and (ii) antiplatelet therapy; the pharmaceutical composition administered twice daily.

[0030] In another embodiment, the present disclosure relates to a method for preventing cardiovascular adverse events in a human patient diagnosed with acute coronary syndrome, Implement a regimen in which human patients are administered approximately 25 mg of milbexian twice daily; The cardiovascular adverse event must be selected from one or more of the following groups: all-cause mortality (ACM); cardiovascular (CV) death; myocardial infarction (MI); unstable angina (UA); any stroke or any stroke (ischemic, hemorrhagic, or of unknown cause); ischemic stroke; acute limb ischemia (ALI); large vessel (non-traumatic) limb amputation; symptomatic venous thromboembolism (VTE: pulmonary embolism (PE), deep vein thrombosis (DVT)); coronary revascularization due to ischemia; stent thrombosis; or hospitalization for any cause (classified as (1) planned or unplanned, (2) hospitalization due to arterial or venous thrombosis, or hospitalization not falling under either category). This provides a method characterized by the following.

[0031] In another embodiment, the Disclosure provides a method for reducing the incidence of one or more thrombotic adverse events selected from new-onset ischemic stroke, MI, or all-cause mortality in a human patient diagnosed with acute coronary syndrome, characterized by implementing a regimen comprising administering approximately 25 mg to approximately 100 mg of milbexian twice daily to the human patient.

[0032] In yet another embodiment, the Disclosure provides a method for preventing ischemic stroke in a human patient diagnosed with acute coronary syndrome, the method comprising a regimen of administering 25 mg of milbexian twice daily to the human patient.

[0033] This disclosure provides a method for preventing cerebrovascular or cardiovascular adverse events in human patients with acute coronary syndrome (ACS), characterized by (i) administering 25.0 mg of milbexian twice daily to a human patient; and (ii) implementing a regimen comprising antiplatelet therapy. In some embodiments, the antiplatelet therapy includes antiplatelet monotherapy (SAPT). In some embodiments, the antiplatelet therapy includes dual antiplatelet therapy (DAPT). In some embodiments, the antiplatelet therapy is selected from aspirin or a P2Y12 inhibitor. In some embodiments, the antiplatelet therapy includes 21 days of DAPT comprising aspirin and clopidogrel, followed by aspirin monotherapy.

[0034] The treatment with Milbexian described in Example 1 below focuses on a different patient population than the two target patient populations (AXIOMATIC-TKR and AXIOMATIC-SSP) of the Phase II trials. For example, the treatment method described herein was performed in patients with acute coronary syndrome (ACS) to prevent cardiovascular adverse events, and the pathophysiology of ACS includes coronary atherosclerosis (such as arterial atherosclerotic plaque in the heart), while the AXIOMATIC-TKR trial was performed in patients after total knee arthroplasty to prevent the development of venous thromboembolism, and the AXIOMATIC-SSP trial was performed in patients with ischemic stroke due to atherothrombosis associated with cerebrovascular atherosclerosis (e.g., intracranial or carotid artery atherosclerotic plaque; see the above literature by Sharma et al.) to prevent secondary stroke.

[0035] Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by endothelial dysfunction, leading to lipid deposition and calcium accumulation in the subendothelial space, followed by leukocyte infiltration and smooth muscle cell proliferation. Vascular damage (e.g., erosion or rupture of atherosclerotic lesions) triggers blood clotting to stop bleeding. This leads to thrombus formation and the development of acute coronary syndrome (ACS). Atherothrombosis develops as a result of thrombus formation on ruptured or eroded atherosclerotic plaques and is clinically recognized as myocardial infarction (MI), peripheral artery disease (PAD), or ischemic stroke (not caused by an embolism from the heart) (Moliterno et al. Eds., The ESC Textbook of Thrombosis, Chapter 1, Arterial Thrombosis: Pathophysiological background, pp. 3-12, Oxford University Press, Oxford, 2023).

[0036] The relationship between coagulation and atherothrombosis has been observed in numerous animal and clinical studies (Ngo et al., Pharmacological targeting of coagulation factor XI mitigates the development of experimental atherosclerosis in low-density lipoprotein receptor-deficient mice, J Thromb Haemost. 2021;19:1001-1017). Many coagulation factors are found in human atherosclerotic lesions, strongly suggesting that coagulation activity is involved in the early stages of plaque formation. Furthermore, thrombin, tissue factor pathway inhibitors, coagulation factor (F)VIII, and activated factor X (FXa) have all been shown to contribute to plaque formation in mice. Although the mechanism is unclear, factors XII (FXII), a component of the intrinsic pathway, and more recently, factor XI (FXI), have also been shown to be involved in atherosclerosis in ApoE- / - mice.

[0037] Acute coronary syndrome (ACS) is a general term for diseases characterized by a sudden decrease in blood flow to the heart. The most common cause of this decreased blood flow is thrombosis, which can lead to other complications known as major cardiovascular adverse events, such as heart attack, stroke, and even death. The pathophysiology of ACS involves arterial thrombus formation, which consists of platelet activation and fibrin formation. Both platelets and thrombin are involved in the mechanism of thrombus formation in acute coronary syndrome (ACS). In ACS patients, thrombin production is promoted more rapidly and easily compared to patients with stable coronary artery disease or healthy controls. Sustained increases in thrombin production in both the acute and chronic phases after ACS are associated with the recurrence of adverse events. Continued increases in thrombin production year after year after ACS, and higher thrombin production levels, are associated with an increased incidence of adverse events. While both platelet and thrombin pathways are targeted in acute care, platelet inhibition has been the primary treatment in the chronic phase. However, thrombin plays a crucial role in platelet activation and fibrin formation. Some ACS patients exhibit chronically elevated thrombin production, which is associated with an increased incidence of adverse events (Bahit et al., Thrombin as target for prevention of recurrent events after acute coronary syndromes, Thrombosis Research, 2024, Vol. 235, pp. 116-121).

[0038] FXI is primarily activated by FXIIa and also by thrombin. Approximately 15% of thrombin is produced through an FXIa-mediated mechanism. Increased FXIa levels have been shown to be associated with ischemic stroke, venous thromboembolism, and ACS. FXIa and activated tissue factor (TF) in circulating blood were detected in both patients with stable CAD (76% and 6%, respectively) and ACS patients with symptom duration less than 12 hours (96% and 38%), and were also detected in patients with heart failure (Zabczyk, et al., Active tissue factor and activated factor XI in circulating blood of patients with systolic heart failure due to ischemic cardiomyopathy, Pol. Arch. Med. Wewn., 120 (2010), pp. 334-340). A SMILE study found a positive correlation between plasma FXIa and ACS (Doggen et al., Levels of intrinsic coagulation factors and the risk of myocardial infarction among men: opposite and synergistic effects of factors XI and XII, Blood, 108 (2006), pp. 4045-4051). Paszek et al. reported that activated factor XI is associated with the risk of cardiovascular events in patients with stable coronary artery disease (Atherosclerosis, 2022, vol. 346, pp. 124-132). In patients with acute ischemic stroke, activated factor XI and activated thrombin (TF) were found in 32.6% and 14.7% of patients, respectively (Goldman, et al. Activation of blood coagulation and thrombin generation in acute ischemic stroke treated with rtPA, J. Thromb. Thrombolysis, 44 (2017), pp. 362-370).Circulating TF and FXIa were associated with poor long-term prognosis in patients following ischemic cerebrovascular events. (Undas et al., Circulating activated factor XI and active tissue factor as predictors of worse prognosis in patients following ischemic cerebrovascular events, Thromb. Res., 128 (2011), pp. e62-e66).

[0039] Elevated plasma FXII, FXI activity, or kallikrein levels are associated with atherosclerosis and myocardial infarction, while severe FXI deficiency is associated with a reduced risk of stroke and deep vein thrombosis. Therefore, sustained production of FXIa may promote atherosclerosis, potentially increasing the risk of MI, stroke, and cardiovascular death.

[0040] Rupture or erosion of atherosclerotic plaque in the coronary arteries triggers platelet activation and aggregation, exposing tissue factor and initiating a coagulation cascade, leading to thrombin generation and fibrin formation. A crucial process in the enhancement of thrombin generation is the feedback activation of factor XI by thrombin (Figure 1). Fibrin and aggregated platelets form a thrombus, blocking blood flow in the coronary arteries and causing ischemic disease.

[0041] In recent years, it has become clear that CAD patients often exhibit a systemic atherosclerotic process, and more than one-third also have peripheral artery disease (PAD). Even with current standard treatment, it is estimated that approximately 5% of patients who develop ACS will experience major cardiovascular adverse events (MACE) in the first year, and another 0.5% to 1% will experience other extremely serious adverse events (e.g., major lower limb adverse events (MALE) or symptomatic venous thromboembolism (VTE)). The term "major vascular adverse events (MAVE)" comprehensively refers to arterial and vascular adverse events that are expected to be prevented by anticoagulants.

[0042] Thrombin is the most potent platelet activator. Current antithrombotic therapy for preventing recurrent thromboembolism after ACS still relies on aspirin and P2Y12 inhibitors as the basis of antiplatelet therapy; however, neither aspirin nor P2Y12 inhibitors inhibit thrombin-mediated platelet activation. The mainstream treatment for CAD is dual antiplatelet therapy with aspirin and one of the P2Y12 receptor inhibitors (clopidogrel, ticagrelor, or prasugrel). Analysis of all data from randomized trials comparing aspirin with controls for the secondary prevention of ACS or chronic CAD confirmed that aspirin reduces the risk and severity of early and late-onset recurrent MACE (Antithrombotic Trialists' Collaboration 2002). Similarly, in participants with atherosclerosis, including a subgroup that developed MI within 35 days prior to randomization, comparable results were obtained with long-term monotherapy of clopidogrel or aspirin (CAPRIE Steering Committee 1996). Despite improvements in invasive treatment and medical management in CAD patients, recurrent thrombotic adverse events after ACS occur at a very high rate of over 5% per year.

[0043] In rivaroxaban treatment after ACS, targeting activated factor X is associated with suppressing thrombin generation and reducing cardiovascular adverse events, but also with an increased risk of bleeding. Among DOACs, rivaroxaban is the only drug to complete a Phase III trial in ACS patients in combination with dual antiplatelet therapy. This reduced the risk of death from cardiovascular disease, myocardial infarction, and stroke, but increased the risk of massive bleeding. The COMPASS trial in patients with stable atherosclerosis showed that dual pathway inhibition with antiplatelet therapy and anticoagulants reduced the risk of ischemic stroke and improved efficacy, but was associated with a risk of massive bleeding (Eikelboom et al.; COMPASS Investigators. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med 2017;377:1319-30).

[0044] In managing thrombotic disorders, the significant human and economic losses associated with thromboembolism highlight the need for superior new treatment options. Developing drugs that minimize bleeding risk while exhibiting potent antithrombotic effects is challenging because they must inhibit the thrombus formation process while minimizing their impact on hemostasis. While many treatments exist for ACS, new treatment options (e.g., oral formulations of FXIa inhibitors) are needed to prevent recurrent vascular adverse events in ACS patients.

[0045] Activated coagulation factor XIa (FXIa) is a key serine protease associated with increased thrombin production. Elevated thrombin levels increase the risk of thrombosis. Inhibition of FXIa suppresses thrombin production and prevents thrombosis while maintaining normal hemostasis. Although FXIa's involvement in hemostasis is relatively limited, it is involved in thrombus formation and stabilization (see Figure 1) (Fredenburgh JC, Weitz JI, Factor XI as a target for new anticoagulants, Hamostaseologie 2021;41(2):104-10). Deficiency of human coagulation factor XI prevents venous thrombosis, stroke, and heart attack, while deficiencies in other contact factors (such as FXII, plasma prekallikrein, or kininogen) do not prevent thrombosis. FXI deficiency, inhibition of FXI production, activated FXI (FXIa) inhibitors, and antibodies against FXI that interfere with FXI / FXII interaction reduce thrombosis and inflammation in experimental models. FXI inhibitors show antithrombotic effects in patients, and FXI and FXII deficiencies show anti-atherosclerotic effects in apolipoprotein E-deficient mice (Gill D, et al. Genetically determined FXI (factor XI) levels and risk of stroke. Stroke 2018;49(11):2761-3; Salomon et al. Reduced incidence of ischemic stroke in patients with severe factor XI deficiency. Blood 2008;111(8):4113-7. Rohmann et al. Coagulation factor XII, XI, and VIII activity levels and secondary events after first ischemic stroke. J Thromb Haemost 2020;18(12):3316-244).

[0046] Analysis of genetically determined FXI levels has shown that the highest FXI levels are associated with an increased risk of ischemic stroke (Gill et al., Genetically Determined FXI (Factor XI) Levels and Risk of Stroke. Stroke. 2018;49(11):2761-2763). Patients with congenital FXI deficiency (hemophilia C) have been shown to have a lower risk of stroke and venous thromboembolism (Gailani et al., Factor XI as a therapeutic target. Arterioscler Thromb Vasc Biol. 2016;36(7):1316-1322; Peyvandi, et al; European Network of Rare Bleeding Disorders Group. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders. J Thromb Haemost. 2012 Apr;10(4):615-621).Studies on the prevention of deep vein thrombosis have shown that reducing FXI levels or inhibiting FXIa reduces the incidence of venography-assessed thrombosis and demonstrates a favorable bleeding profile (Buller et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med 2015;372(3):232-40; Weitz et al. Effect of osocimab in preventing venous thromboembolism among patients undergoing knee arthroplasty: the FOXTROT randomized clinical trial. JAMA 2020;323(2):130-9; Weitz et al. Milvexian for the prevention of venous thromboembolism. N Engl J Med 2021;385(23):2161-72).

[0047] Activated factor X inhibitors inhibit the tissue factor-mediated coagulation activation mechanism and the intrinsic pathway necessary for hemostasis. Inhibition of activated factor XI inhibits thrombus formation via the intrinsic pathway (contact pathway), which is not essential for normal hemostasis, and also inhibits thrombus formation via pathways that enhance thrombin production, which is thought to contribute to thrombus formation that causes disease. Therefore, inhibition of FXIa has a better benefit-risk ratio compared to activated factor X inhibitors and thrombin inhibitors, and may prevent vascular occlusion and embolism in patients with atherosclerotic coronary artery disease, including those who have already experienced ACS, by suppressing thrombin production while minimizing the impact on hemostasis. The risk of recurrent ACS adverse events is highest immediately after the initial ACS onset, and continues to occur as the underlying atherosclerotic disease progresses. Given the high incidence of recurrent adverse events after ACS, a new target is needed that can maintain normal hemostatic function while preventing thrombosis.

[0048] Milbexian has several features that differentiate it from other factor Xla oral inhibitors (e.g., asundexane). For example, a population pharmacokinetic model to characterize the pharmacokinetics of milbexian was constructed using plasma concentration data of milbexian collected from healthy adult subjects obtained in six phase 1 trials.

[0049] Analysis of PK data from the AXIOMATIC-SSP trial using a proprietary population pharmacokinetic model revealed that when a pharmaceutical composition containing 25 mg of milbexian is administered twice daily to human patients, the plasma concentration of milbexian reaches a steady state in approximately 3 days in the patient's exposure-response relationship. In some embodiments of the above, when 25 mg of milbexian is orally administered twice daily to human patients, the plasma concentration profile reaches a steady state in approximately 3 days. In some embodiments of the above, the steady-state plasma concentration profile is (i) steady-state C max (ii) Steady state C max (iii) The mean (standard deviation) of the ng / mL is 346 (129) ng / mL, and the steady-state AUC 0-24 (iv) Steady-state AUC 0-24 A notable feature is that the mean (standard deviation) is 7290 (2940) ng*h / mL. Furthermore, the regimen of administering 25 mg of milbexian in BID in the Phase 3 trial for ACS patients described in Example 1 was selected based on data obtained from Phase 1 and Phase 2 trials, and the results of an analysis of the exposure-response relationship of milbexian in patients using a proprietary population pharmacokinetic model.

[0050] As used herein, the term "acute coronary syndrome (ACS)" refers to coronary artery disease caused by atherothrombosis in the epicardial coronary arteries, generally triggered by rupture or erosion of plaque. Atherothrombosis is the primary pathological process that causes the vast majority of ACS cases. For example, when a plaque in a coronary artery ruptures and forms a thrombus that occludes the artery, it constitutes the underlying pathology of STEMI. ACS is divided into subgroups: ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), and unstable angina. If myocardial damage is observed, it is classified as type 1 myocardial infarction (MI). When chest pain with an unpredictable pattern is observed in clinical and electrocardiogram (ECG) findings, despite the absence of myocardial damage, it is called unstable angina (UA). ACS is further defined by the presence or absence of ST elevation on the electrocardiogram. Under appropriate clinical conditions, marked localized ST elevation generally indicates ST-elevation myocardial infarction (STEMI) associated with acute total occlusion of a major epicardial coronary artery, which can lead to transmural infarction if left untreated. Acute coronary syndrome without ST elevation (NSTE-ACS) is usually associated with transient or partial coronary artery occlusion and often presents as subendocardial myocardial infarction, non-ST-elevation myocardial infarction with minimal myocardial damage, or unstable angina without myocardial damage.

[0051] As used herein, the electrocardiogram (ECG) term "ST segment (ST)" refers to the electrically neutral region located between ventricular depolarization (QRS complex) and ventricular repolarization (T wave). Clinically, the ST segment indicates the period during which the myocardium maintains contraction and ejects blood from the ventricles. The ST segment is an important component of the electrocardiogram waveform and can provide characteristic findings useful in differentiating between normal and ischemic conditions (Kashou et al., ST Segment. [Updated 2023 Aug 14]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from www.ncbi.nlm.nih.gov / books / NBK459364 / ).

[0052] As used herein, the term "ST elevation" refers to a condition in which the ST segment is located above the baseline when the J point is displaced above the baseline. ST elevation is recognized as a sign of occlusive thrombosis in the acute phase. Early repolarization, left ventricular hypertrophy, ventricular aneurysm, left bundle branch block, and other conduction disorders have been shown to be more common causes of ST elevation than acute MI. Evaluating the waveform of the ST segment is also important. Displacement of the J point is classified into horizontal, upward-sloping, and downward-sloping types, the latter two of which are characterized as steep or slow. For example, ST elevation in lead V is expressed as a steep downward slope, which is usually benign. These ST segment features can further be useful in differentiating between normal and ischemic conditions. For example, ST elevation with an upward-sloping ST segment is generally considered normal, while ST elevation with a horizontal ST segment is considered characteristic of myocardial ischemia (see Kashou et al. above).

[0053] As used herein, the term "cerebrovascular disorder" refers to neurological disorders resulting from impaired blood flow to the brain, and signifies a condition that leads to damage or death of brain cells due to oxygen deprivation. In some embodiments, cerebrovascular disorders include transient ischemic attacks. In some embodiments, cerebrovascular disorders include strokes. How a stroke affects the body depends on which part of the brain is affected by the interruption of blood supply. In some embodiments, cerebrovascular disorders are vascular events that may be grouped into composite endpoints in various combinations, including ACM; CV death; MI; UA; any stroke or any stroke (ischemic, hemorrhagic, or of unknown cause); ischemic stroke; ALI; large vessel (non-traumatic) limb amputation; symptomatic VTE (PE, DVT); ischemia-based coronary revascularization; stent thrombosis; and hospitalization for any cause (hospitalization for arterial thrombosis or venous thrombosis, or hospitalization for neither).

[0054] In some embodiments, the term “stroke” refers to an acute neurological disorder that causes necrosis of brain tissue (cerebral infarction) due to insufficient blood flow and oxygen supply to the brain. Stroke can be either ischemic or hemorrhagic. In ischemic stroke, blood supply to a part of the brain is cut off because a blood vessel is blocked by either a locally formed thrombus in an abnormal artery (e.g., atherosclerosis) or an embolus formed upstream and traveling through the bloodstream. In hemorrhagic stroke, a blood vessel ruptures, disrupting normal blood flow and causing blood to leak into a specific area of ​​the brain, damaging that area. The vast majority of strokes are sudden and rapidly progressing, causing brain damage within minutes (complete stroke). Less common, however, is a progressive stroke in which the area of ​​necrotic brain tissue continuously expands and the stroke continues to worsen over hours to days. Ischemic stroke can also be either lacunar or non-lacunar in nature. When an ischemic stroke is caused by arterial occlusion due to an embolus presumed to originate from a thrombus formed in the heart or its valves, it may be a cardiogenic embolic stroke. In some embodiments, ischemic stroke is a non-cardiogenic embolic stroke. The definition of ischemic stroke is based on the 2013 guidelines (Sacco et al., An updated definition of stroke for the 21st century Stroke, 44 (2013), pp. 2064-2089).

[0055] In clinical trials, stroke severity is measured using the National Institutes of Health Stroke Scale (NIHSS) score (Kamel et al., Validation of the International Classification of Diseases, Tenth Revision Code for the National Institutes of Health Stroke Scale Score. Circ Cardiovasc Qual Outcomes, 2023, vol. 16, e009215). Stroke severity is classified as follows: 1-4 = mild stroke, 5-15 = moderate stroke, 16-20 = moderate to severe stroke, 21-42 = severe stroke.

[0056] In some embodiments, ischemic stroke refers to neurological disorders accompanied by clinical symptoms, resulting from non-lacunar acute cerebral infarction detected by neuroimaging (CT or MRI).

[0057] In some embodiments, “stroke” means any type of stroke (ischemic, hemorrhagic, or of unknown cause).

[0058] In some embodiments, ischemic stroke is further identified as having a National Institutes of Health Stroke Scale (NIHSS) score of 7 or less.

[0059] In another embodiment, ischemic stroke is further identified as having a National Institutes of Health Stroke Scale (NIHSS) score of 8–15.

[0060] In another embodiment, ischemic stroke is further identified as having a National Institutes of Health Stroke Scale (NIHSS) score of 15 or less.

[0061] In other embodiments, the ischemic stroke is further characterized by the presence of atherosclerotic plaque in the associated intracranial or carotid artery, ulcers or thrombi in the nutrient arteries, which are confirmed by imaging studies (either Doppler ultrasound, CTA, MRA, or catheter angiography).

[0062] In yet another embodiment, ischemic stroke is further identified by a modified Ranking Scale. For example, in some embodiments, ischemic stroke is identified by a modified Ranking Scale (mRS) score of 3 or less, 4 or less, 5 or less, or 6 or less.

[0063] In some embodiments, MI is defined according to the fourth universal definition of MI, with the exception of Type 2 myocardial infarction (Thygesen et al., Fourth universal definition of myocardial infarction (2018) Eur. Heart J., 40 (2019), pp. 237-269).

[0064] In some embodiments, cardiovascular death is classified as a death in which the primary cause of death is MI, stroke, other thromboembolism of the vascular bed, heart failure, primary arrhythmia, or cardiovascular procedure.

[0065] As used herein, the term "activated partial thromboplastin time (aPTT)" refers to an indicator of the intrinsic and common pathways of the coagulation cascade. It represents the time, in seconds, for plasma to coagulate after the addition of phospholipids, intrinsic pathway activators, and calcium. The name "activated partial thromboplastin time" originates from the original method of this test. In the original method, only phospholipid concentration was controlled (as opposed to forms that controlled both phospholipid and surface activator concentrations), and the term "partial thromboplastin" was used at the time for phospholipid preparations that promoted coagulation but did not correct the prolongation of coagulation time in hemophilic plasma. The term "partial" means that phospholipids are present but tissue factor is absent. Normal values ​​and reference ranges vary depending on the combination of reagents and instruments, particularly the phospholipid composition.

[0066] In some embodiments, aPTT is measured as follows: A plasma sample is incubated for 3 minutes with Actin FS (aPTT assay reagent) containing a standard amount of phospholipids and a contact factor (ellagic acid) that activates the intrinsic pathway. Calcium chloride is then added to initiate coagulation, and fibrin thrombus formation is optically measured. The time to thrombus formation (in seconds) is reported as activated partial thromboplastin time (aPTT). In other embodiments, fibrin thrombus formation is measured by a mechanical method (viscosity).

[0067] Multiple oral administrations of milbexian to healthy human subjects prolonged aPTT depending on the dose and concentration. The mean maximum change in aPTT from baseline increased by approximately 1.1 to 4.1 times after administration of 5 to 500 mg once daily for two weeks, and by 3.4 times after administration of 200 mg twice daily for two weeks.

[0068] The prothrombin time (PT) test used herein refers to the measurement of the time it takes for a blood clot to form in a blood sample, and the measurement result (in seconds) of the PT assay is called the prothrombin time. Single or multiple doses of milbexian administered to human subjects did not affect the prothrombin time, and the maximum mean percentage change from baseline was approximately 5%.

[0069] As used herein, "factor XI coagulation activity" is measured using a one-step coagulation method based on aPTT. Serially diluted normal plasma was mixed with FXI-deficient plasma, and coagulation time was measured according to a standard aPTT protocol to establish a reference range. Sample plasma was processed in the same manner and compared with the above reference plasma.

[0070] In some embodiments, factor XI coagulation activity is measured as follows: Factor XI (FXI) activity is measured using Actin FS (Siemens Healthcare) and applied to the principle of activated partial thromboplastin time (aPTT) measurement. (登録商標) Measurements were taken using an XP analyzer (Siemens Healthcare). A 6-point calibration curve was created using a secondary standard material (standard human plasma, Siemens Healthcare Diagnostics Inc.) with known FXI concentrations assigned by the manufacturer, covering a range of approximately 5% to 150%. Approximately 100% of the reference standard plasma was used for BCS (Body Conditioning). (登録商標)The XP analysis device was used to dilute it with physiological saline to set the calibrated level of FXI in advance. The calibration curve was plotted with the FXI activity rate (%) on the x-axis and the coagulation time (seconds) on the y-axis, and fitted with a log / lin regression curve. The sample to be tested was mixed with FXI-deficient plasma (where FXI is less than 1% and all other factors are at least 75% contained) to normalize all other factors. After adding aPTT reagent (Actin FS) and incubating the mixture, calcium chloride was added to the above mixture, and the thrombus formation time measured optically was compared with the time of the calibration curve. The sample was BCS (登録商標) It was measured by basic dilution (1:10) with physiological saline by XP. In other embodiments, the formation of fibrin thrombus is measured by a mechanical method (viscosity).

[0071] As used herein, the "thrombin generation test (TGA)" is a comprehensive coagulation test that evaluates the thrombus formation ability of plasma samples, and it has been suggested that it may more appropriately reflect thrombus tendency or bleeding tendency than conventional coagulation tests. In conventional TGA, coagulation via the extrinsic system is initiated by adding tissue factor, phospholipid, and calcium to citrated plasma. In this study, in an in vitro thrombin generation test (TGA) using human platelet-rich plasma, kaolin slurry was used to initiate intrinsic coagulation. The generation of thrombin was continuously monitored via the product released by the cleavage of a thrombin-specific fluorescent substrate. Using the obtained thrombogram, a plurality of related parameters including the ability of thrombin generation via the intrinsic system (defined as the area under the curve of thrombin concentration vs. time) were calculated. In some embodiments, when milvexian is orally administered to a human subject once or multiple times, thrombin generation via the intrinsic system is inhibited, but the inhibition of thrombin generation when initiated by the extrinsic system is negligible.

[0072] As used herein, “prevention” means reducing the occurrence of risk. In some embodiments, prevention includes eliminating the occurrence of risk (i.e., reducing the occurrence of risk to zero). Therefore, “prevention” includes prophylactic treatment to reduce the probability of clinical disease development. In some embodiments, the treatment regimens described herein are administered to patients at risk of developing thromboembolic disease to prevent the development of thromboembolic disease (primary prevention). In some embodiments, the treatment regimens described herein are administered as secondary prevention to patients after the first occurrence of thrombotic disease (e.g., secondary prevention of cardiovascular events in patients with a history of acute myocardial infarction or acute coronary syndrome). In clinical practice, aspirin and clopidogrel (or other thienopyridine derivatives) may be used in combination to prevent secondary thrombosis.

[0073] In some embodiments, “prevention” is synonymous with “reduced risk” or “reduced incidence” of adverse events of atherosclerosis (e.g., MACE). A reduction in risk or incidence means that the incidence of adverse events of atherosclerosis is reduced numerically and / or statistically significantly by at least 1%. Preferably, the reduction is 2% or more, 3% or more, 4% or more, 5% or more, 6% or more, 7% or more, 10% or more, 20% or more, 26% or more, 34% or more, 50% or more, 64% or more, and 74% or more. These reductions include those with confidence intervals of 50% or more, 75% or more, 80% or more, 90% or more, 95% or more, 98% or more, and 99% or more. A confidence interval of 95% or more is desirable.

[0074] Within the scope of this disclosure, “prevention” means prophylactic treatment to reduce and / or minimize the risk of disease and / or disease recurrence by administering to a patient a therapeutically effective amount of milbexian or a pharmaceutically acceptable salt or solvate thereof. Patients receiving prophylactic treatment may be selected based on factors known to be at higher risk of clinically developing the disease compared to the general population. Prophylactic treatment may be administered whether or not clinical symptoms of the disease are present. “Prophylactic” treatment may be classified into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment to reduce or minimize the risk of disease in patients who have not yet developed clinical disease, while secondary prevention is defined as treatment to reduce or minimize the risk of recurrence or secondary development of the same or similar clinical disease.

[0075] As used herein, the term “treatment” means improving the signs or symptoms of a patient’s disease or condition, and / or preventing the patient’s disease or condition. Unless otherwise specified, as used herein, the terms “treatment,” “procedure,” etc., include the management and care of a patient aimed at combating a disease, condition, or disorder, and include administering milbexian to prevent the onset of symptoms or complications, to alleviate symptoms or complications, or to resolve the disease, condition, or disorder. Accordingly, “treatment” or “procedure” refers to the treatment of a human disease condition and includes (a) suppression of the disease, i.e., cessation of its progression; and / or (b) relief of the disease, i.e., reduction of the condition.

[0076] As used herein, "risk factor" refers to a demographic factor that influences the underlying risk of a particular event, regardless of any drug treatment.

[0077] As used herein, the term "thrombotic event" refers to a cerebrovascular and / or cardiovascular adverse event occurring in a patient with acute coronary syndrome. In some embodiments, thrombotic events include major cardiovascular adverse events (MACE), atherothrombosis, ischemic stroke, myocardial infarction, cardiovascular death, arrhythmogenic cardiomyopathy, major vascular adverse events (MAVE), major lower extremity adverse events (MALE), all-cause mortality (ACM), symptomatic vein thromboembolic vascular accident (VTE), or a combination thereof. In some embodiments, thrombotic events include major cardiovascular adverse events. In some embodiments, thrombotic events include ischemic stroke. In some embodiments, thrombotic events include major vascular adverse events. In some embodiments, thrombotic events include arrhythmogenic cardiomyopathy. In some embodiments, thrombotic events include major lower extremity adverse events (MALE).

[0078] As used herein, the term "atherosclerosis" refers to major cardiovascular adverse events (MACE), major vascular adverse events (MAVE), arrhythmogenic cardiomyopathy, major lower extremity adverse events (MALE), or a combination thereof.

[0079] As used herein, the terms “major cardiovascular adverse event” or “MACE” mean cardiovascular death, non-fatal myocardial infarction, ischemic stroke, or a combination thereof.

[0080] As used herein, the terms “major vascular adverse events” or “MAVE” refer to cardiovascular death, non-fatal myocardial infarction, ischemic stroke, MALE, symptomatic VTE, or a combination thereof.

[0081] As used herein, the terms “Major Lower Limb Adverse Event” or “MALE” refer to acute limb ischemia (ALI), major non-traumatic vascular amputation, or a combination thereof.

[0082] As used herein, the term "symptomatic VTE" refers to pulmonary embolism, deep vein thrombosis, or a combination thereof.

[0083] As used herein, “medically acceptable salt” refers to a derivative of a compound modified by the formation of an acid salt or base salt thereof. Examples of medically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic functional groups (e.g., amines) and alkali or organic salts of acidic functional groups (e.g., carboxylic acids). Medically acceptable salts include, for example, non-toxic conventional salts or quaternary ammonium salts of parent compounds formed from non-toxic inorganic or organic acids. For example, conventional non-toxic salts include those produced from inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid) and organic acids (e.g., acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid). Medicinally acceptable salts of milbexian can be synthesized using conventional chemical methods. Generally, such salts can be produced by reacting milbexian with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture of the two. Generally, non-aqueous solvents such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are suitable. Suitable salts are listed in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, Pa. (1990), which is incorporated herein by reference.

[0084] As used herein, the term “standard treatment” refers to a treatment process that is generally considered appropriate by healthcare professionals for the treatment of a particular disease (e.g., acute coronary syndrome) and is widely used by healthcare professionals. In some embodiments, standard treatment includes antiplatelet therapy administered to patients diagnosed with acute coronary syndrome. In some embodiments, antiplatelet therapy is selected from antiplatelet monotherapy (SAPT), antiplatelet dual therapy (DAPT), or a combination thereof. In some embodiments, SAPT is selected from aspirin and P2Y12 inhibitors. In some embodiments, SAPT includes low-dose aspirin (100 mg or less per day) or a P2Y12 inhibitor. In some embodiments, SAPT includes aspirin. In some embodiments, SAPT includes a P2Y12 inhibitor. In some embodiments, the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel (alone or in combination with aspirin). In some embodiments, the P2Y12 inhibitor may be changed or discontinued. In some embodiments, de-escalation of antiplatelet therapy from DAPT to SAPT may involve discontinuing either aspirin or a P2Y12 inhibitor.

[0085] As used herein, "safe" means that, compared to antiplatelet therapy alone, the regulatory authority determines that the reduction in the risk of human atherosclerotic events outweighs the increased risk of adverse events (e.g., serious bleeding), and that a pure clinical benefit is obtained.

[0086] As used herein, "effective" means that the regimen in question demonstrates a reduction in the risk of atherosclerotic events and a therapeutic effect compared to antiplatelet therapy alone.

[0087] The absolute rate of risk reduction (ARR) is calculated by subtracting the proportion of patients with a poor prognosis in the treatment group (i.e., the group receiving the regimen) from the proportion of patients with a poor prognosis in the control group (i.e., the group not receiving the regimen). For example, if the incidence rate in the control group is 20% (i.e., 20% of patients in the control group have a poor prognosis) and the incidence rate in the treatment group is 12% (i.e., 12% of patients have a poor prognosis), then the absolute rate of risk reduction (ARR) is 8% (i.e., 20% - 12%).

[0088] In some embodiments, the "Bleeding Academic Research Consortium (BARC) bleeding criteria" are described in Roxana Mehran, et al. Standardized Bleeding Definitions for Cardiovascular Clinical Trials, Circulation. 2011;123:2736-2747, which is incorporated herein by reference.

[0089] In another embodiment, the “Bleeding Academic Research Consortium (BARC) bleeding criteria” are described in Pascal Vranckx, et al. Validation of BARC Bleeding Criteria in Patients With Acute Coronary Syndromes J Am Coll Cardiol 2016;67:2135-44, which is incorporated herein by reference.

[0090] In some embodiments, the GUSTO bleeding criteria are described in "An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. GUSTO investigators, N Engl J Med 1993;329:673-82," which is incorporated herein by reference.

[0091] In some embodiments, the GUSTO bleeding criteria are described in Pascal Vranckx, et al. Validation of BARC Bleeding Criteria in Patients With Acute Coronary Syndromes J Am Coll Cardiol 2016;67:2135-44, which disclosure is incorporated herein by reference.

[0092] In some embodiments, the TIMI bleeding criteria are described in Rao AK, Pratt C, Berke A, et al. Thrombolysis in Myocardial Infarction (TIMI) Trial-phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988;11: 1-11, which disclosure is incorporated herein by reference.

[0093] In some embodiments, the TIMI bleeding criteria are described in Pascal Vranckx, et al. Validation of BARC Bleeding Criteria in Patients With Acute Coronary Syndromes J Am Coll Cardiol 2016;67:2135-44, which disclosure is incorporated herein by reference.

[0094] In some embodiments, "Type 3 of the Bleeding Academic Research Consortium (BARC) bleeding criteria" refers to (a) obvious bleeding + a hemoglobin decrease of 3 to <5 g / dL associated with bleeding, and transfusion due to obvious bleeding; (b) obvious bleeding + a hemoglobin decrease of ≥5 g / dL associated with bleeding, cardiac tamponade, bleeding requiring surgical intervention, bleeding requiring intravenous administration of vasoactive agents, or (c) intracranial hemorrhage confirmed by subcutaneous examination, imaging, or lumbar puncture, and intraocular hemorrhage with visual impairment. See, for example, Roxana Mehran, et al. Standardized Bleeding Definitions for Cardiovascular Clinical Trials, Circulation. 2011;123:2736-2747.

[0095] In some embodiments, "Type 5 of the Bleeding Academic Research Consortium (BARC) bleeding criteria" refers to (a) bleeding that is likely to be fatal, or (b) bleeding that is clearly fatal (obvious bleeding or confirmed by autopsy or imaging). See, for example, Roxana Mehran, et al. Standardized Bleeding Definitions for Cardiovascular Clinical Trials, Circulation. 2011;123:2736-2747.

[0096] In some embodiments, "Type 2 of the Bleeding Academic Research Consortium (BARC) bleeding criteria" refers to a clear sign of bleeding that requires medical attention, diagnosis, hospitalization, or treatment by a healthcare professional. See, for example, Roxana Mehran, et al. Standardized Bleeding Definitions for Cardiovascular Clinical Trials, Circulation. 2011;123:2736-2747.

[0097] In some embodiments, the "ISTH criteria (major bleeding or clinically significant non-major bleeding (CRNM))" are as follows: Major bleeding in ISTH in non-surgical patients is characterized by the presence of clinical symptoms. i. Fatal bleeding and / or ii. Bleeding in vital sites or organs (e.g., intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular bleeding associated with compartment syndrome, and / or iii. Bleeding resulting in a decrease in hemoglobin levels of 20 g / L (1.24 mmol / L) or more, or bleeding requiring 2 or more units of whole blood transfusion or red blood cell transfusion. It is defined as follows. ISTH's definition of CRNM bleeding is a sign or symptom of bleeding (e.g., bleeding discovered solely by imaging, or bleeding greater than expected from the clinical context) that does not meet ISTH's definition of major bleeding, but follows: i. Medical intervention by healthcare professionals is required. ii. Reaching a condition requiring hospitalization or advanced medical care. iii. Face-to-face assessments should be encouraged, rather than those conducted by telephone or electronic communication. It is defined as bleeding that satisfies at least one of the following criteria.

[0098] For example, when using approximation terms (e.g., "approximately" or "about") to refer to quantity, duration, or degree of effect, it is understood that these may mean values ​​within ±5%, ±7.5%, ±10%, ±12.5%, ±15%, ±17.5%, or ±20% of a given number.

[0099] In certain embodiments, the Disclosure relates to a method for preventing cerebrovascular or cardiovascular adverse events in human patients with acute coronary syndrome (ACS), the method characterized by measuring the baseline factor XI coagulation activity of the patient, and then implementing a regimen comprising (i) a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof); and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; administering the pharmaceutical composition twice daily.

[0100] In some embodiments, the methods disclosed herein relate to the primary prevention of cerebrovascular adverse events or cardiovascular adverse events.

[0101] In some embodiments, the methods disclosed herein relate to the secondary prevention of cerebrovascular adverse events or cardiovascular adverse events.

[0102] In some embodiments of the methods of this disclosure, a cerebrovascular adverse event or a cardiovascular adverse event includes one or more of stroke, heart attack, or death.

[0103] In some embodiments of the methods of this disclosure, the cerebrovascular adverse event or cardiovascular adverse event occurs in an organ selected from the heart, brain, limbs, blood circulation system, or blood vessels.

[0104] In some embodiments of the methods of this disclosure, the cerebrovascular adverse event or cardiovascular adverse event includes one or more major cardiovascular adverse events (MACE) selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, ischemic stroke, and combinations thereof.

[0105] In other embodiments of the methods of the present disclosure, cerebrovascular or cardiovascular adverse events include one or more major vascular adverse events (MAVE) selected from the group consisting of MACE; major lower limb adverse events (MALE) including one or more selected from acute limb ischemia, chronic limb ischemia, or major amputation; symptomatic venous thromboembolic adverse events; and combinations thereof.

[0106] In some embodiments of the methods of the present disclosure, the cerebrovascular adverse event or cardiovascular adverse event is selected from the group consisting of arrhythmogenic cardiomyopathy (ACM), non-fatal myocardial infarction, ischemic stroke, and combinations thereof.

[0107] In some embodiments of the methods of this disclosure, cerebrovascular adverse events or cardiovascular adverse events include cardiovascular death.

[0108] In some embodiments of the methods disclosed herein, cerebrovascular adverse events or cardiovascular adverse events include arrhythmogenic cardiomyopathy (ACM).

[0109] In some embodiments, this disclosure relates to methods for treating or preventing cerebrovascular or cardiovascular adverse events in human patients with acute coronary syndrome.

[0110] In some embodiments, acute coronary syndrome refers to ST-elevation myocardial infarction (STEMI), non-ST-elevation acute coronary syndrome (NSTEM-ACS), non-ST-elevation myocardial infarction (NSTEMI), or unstable angina. In some embodiments, acute coronary syndrome includes ST-elevation myocardial infarction. In some embodiments, acute coronary syndrome includes non-ST-elevation acute coronary syndrome. In some embodiments, acute coronary syndrome includes non-ST-elevation myocardial infarction. In some embodiments, acute coronary syndrome includes unstable angina.

[0111] In some embodiments, the human patient is NSTEM-ACS without atrial fibrillation. In some embodiments, antiplatelet therapy includes an initial loading dose of 150-300 mg of aspirin followed by continuous administration of aspirin monotherapy at 75-100 mg once daily. In some embodiments, aspirin may be administered continuously for 3 months to 3 years. In some embodiments, aspirin may be administered continuously for 3 months to 1 year. In some embodiments, aspirin may be administered continuously for 1 year. In some embodiments, antiplatelet therapy includes aspirin and a P2Y12 inhibitor.

[0112] In some embodiments, the human patient has NSTEM-ACS and atrial fibrillation.

[0113] In some embodiments, the human patient is female. In other embodiments, the human patient is male.

[0114] In some embodiments, the human patient is at least 40 years old.

[0115] In another embodiment, the human patient is at least 50 years old.

[0116] In another embodiment, the human patient is at least 60 years old.

[0117] In another embodiment, the human patient is at least 70 years old.

[0118] In some embodiments, the method of the present disclosure is characterized by administering to a human patient (i) a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition comprising 12.5 mg to 200 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof); and (ii) implementing a regimen comprising antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof.

[0119] In some embodiments, the method of the present disclosure is characterized by administering to a human patient a regimen comprising (i) administering a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) twice daily; and (ii) implementing an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof.

[0120] In some embodiments, the pharmaceutical composition contains milbexian.

[0121] In some embodiments, the pharmaceutical composition includes a solvate of milbexian.

[0122] In another embodiment, the pharmaceutical composition contains a pharmaceutically acceptable salt of milbexian.

[0123] In embodiments of the methods disclosed herein, if a pharmaceutical composition contains a solvate or pharmaceutically acceptable salt of milbexian, the specific amount is based on milbexian. That is, the amount of solvate or pharmaceutically acceptable salt in a pharmaceutical composition contains a specific amount of milbexian. For example, a pharmaceutical composition containing 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) means a pharmaceutical composition containing 25 mg of milbexian, or an amount of a pharmaceutically acceptable salt or solvate of milbexian equivalent to 25 mg of milbexian.

[0124] In some embodiments of the methods of the present disclosure, the regimen is characterized by administering a pharmaceutical composition containing 12.5 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) twice daily.

[0125] In some embodiments of the methods of the present disclosure, the regimen is characterized by administering a pharmaceutical composition containing 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) twice daily.

[0126] In some embodiments of the methods of this disclosure, the regimen is characterized by administering a pharmaceutical composition containing 50 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) twice daily.

[0127] In some embodiments of the methods of this disclosure, the regimen is characterized by administering a pharmaceutical composition containing 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) twice daily.

[0128] In some embodiments of the methods of this disclosure, the regimen is characterized by administering a pharmaceutical composition containing 12.5 mg to 200 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) twice daily.

[0129] In some embodiments of the methods of the present disclosure, an embodiment in which a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof, in terms of milbexian) is administered to a human patient twice daily, one of the two doses being given in the morning and the other in the evening, and these doses being given at approximately the same time each day.

[0130] In some embodiments of the method of this disclosure, a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof, in terms of milbexian) is administered twice daily for at least 12 weeks.

[0131] In some embodiments of the method of this disclosure, a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof, in terms of milbexian) is administered twice daily for at least 13 weeks.

[0132] In some embodiments, a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof, calculated in terms of milbexian) is administered twice daily for 13 weeks.

[0133] In another embodiment, a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof, calculated in terms of milbexian) is administered twice daily for more than 13 weeks.

[0134] In other embodiments, a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof, calculated in terms of milbexian) is administered twice daily for at least 26 weeks, at least 52 weeks, at least 78 weeks, at least 104 weeks, at least 130 weeks, at least 156 weeks, at least 182 weeks, or at least 208 weeks.

[0135] In some embodiments, a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof, in terms of milbexian) is administered twice daily for an extended period, i.e., indefinitely.

[0136] In some embodiments, the regimens used in the methods of disclosure include antiplatelet therapies selected from the group consisting of administration of aspirin, P2Y12 inhibitors, and combinations thereof.

[0137] In some embodiments of the methods disclosed herein, antiplatelet therapy includes antiplatelet monotherapy (SAPT).

[0138] In some embodiments of the methods disclosed herein, antiplatelet therapy includes dual antiplatelet therapy (DAPT).

[0139] In some embodiments, antiplatelet therapy includes 21 days of dual antiplatelet therapy (DAPT), followed by antiplatelet monotherapy (SAPT).

[0140] In some embodiments of the method of the present disclosure, the regimen includes combination therapy with aspirin and clopidogrel for days 1 to 21, followed by aspirin monotherapy for at least 90 days.

[0141] In some embodiments of the method of the present disclosure, the regimen includes combination therapy with aspirin and clopidogrel from day 1 to day 21, followed by aspirin monotherapy from day 22 to day 90.

[0142] In some embodiments of the method of this disclosure, the regimen includes a DAPT of more than 90 days (with or without de-escalation to SAPT).

[0143] In some embodiments of the method of this disclosure, the regimen includes a DAPT of more than 90 days with de-escalation to SAPT.

[0144] In other embodiments of the method disclosed herein, the regime includes a DAPT of more than 90 days without de-escalation to SAPT.

[0145] In some embodiments of the method of this disclosure, the regime includes a DAPT of no more than 90 days, with de-escalation to SAPT.

[0146] In some embodiments of the method disclosed herein, the regimen includes SAPT.

[0147] In some embodiments of the methods of the present disclosure, the regimen includes the administration of aspirin and / or clopidogrel without any adjustment of the dose of milbexian.

[0148] In some embodiments, aspirin is used in antiplatelet monotherapy.

[0149] In some embodiments of antiplatelet monotherapy, aspirin is administered at a dose of 50 to 150 mg per day, for example, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 81 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, or 150 mg per day.

[0150] In some embodiments of antiplatelet monotherapy, aspirin is administered at a dose of 75-100 mg per day, for example, 75 mg, 80 mg, 81 mg, 85 mg, 90 mg, 95 mg, or 100 mg per day.

[0151] In some embodiments of antiplatelet monotherapy, aspirin is administered at a dose of 75 mg per day.

[0152] In some embodiments of antiplatelet monotherapy, aspirin is administered at a dose of 81 mg per day.

[0153] In some embodiments of antiplatelet monotherapy, aspirin is administered at a dose of 100 mg per day.

[0154] In another embodiment, a P2Y12 inhibitor is used for antiplatelet monotherapy.

[0155] In some embodiments of antiplatelet monotherapy, the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel.

[0156] In some embodiments of antiplatelet monotherapy, the P2Y12 inhibitor is clopidogrel.

[0157] In some embodiments of antiplatelet monotherapy, clopidogrel is administered at a dose of 75 mg to 600 mg per day, for example, 75 mg, 150 mg, 225 mg, 300 mg, 375 mg, 450 mg, 525 mg, or 600 mg per day.

[0158] In some embodiments of antiplatelet monotherapy, the P2Y12 inhibitor is ticagrelor.

[0159] In some embodiments of antiplatelet monotherapy, the P2Y12 inhibitor is prasugrel.

[0160] In some embodiments, ticlopidine is used for antiplatelet monotherapy.

[0161] In some embodiments, ticlopidine is administered at a dose of 250 to 500 mg per day, for example, 150 mg or 500 mg per day.

[0162] In other embodiments of the methods disclosed herein, antiplatelet therapy includes dual antiplatelet therapy.

[0163] In some embodiments, aspirin and ticlopidine are used in dual antiplatelet therapy.

[0164] In some embodiments, dual antiplatelet therapy uses aspirin and a P2Y12 inhibitor.

[0165] In some embodiments of dual antiplatelet therapy, aspirin is administered at a dose of 50 to 150 mg per day, for example, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 81 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, or 150 mg per day.

[0166] In some embodiments of dual antiplatelet therapy, aspirin is administered at a dose of 75-100 mg per day, for example, 75 mg, 80 mg, 81 mg, 85 mg, 90 mg, 95 mg, or 100 mg per day.

[0167] In some embodiments of dual antiplatelet therapy, aspirin is administered at a dose of 75 mg per day.

[0168] In some embodiments of dual antiplatelet therapy, aspirin is administered at a dose of 81 mg per day.

[0169] In some embodiments of dual antiplatelet therapy, aspirin is administered at a dose of 100 mg per day.

[0170] In some embodiments of dual antiplatelet therapy, the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel.

[0171] In some embodiments of dual antiplatelet therapy, the P2Y12 inhibitor is clopidogrel.

[0172] In some embodiments of dual antiplatelet therapy, clopidogrel is administered at a dose of 75 mg to 600 mg per day, for example, 75 mg, 150 mg, 225 mg, 300 mg, 375 mg, 450 mg, 525 mg, or 600 mg per day.

[0173] In some embodiments of dual antiplatelet therapy, clopidogrel is administered as an initial loading dose. This initial loading dose is administered only once at the start of treatment.

[0174] In some embodiments, the initial loading dose is 300-600 mg per day. In some embodiments, the initial loading dose is 300 mg. In other embodiments, the initial loading dose is 600 mg.

[0175] In some embodiments of dual antiplatelet therapy, clopidogrel is administered at a dose of 75 mg per day.

[0176] In some embodiments of dual antiplatelet therapy, clopidogrel is administered at a dose of 150 mg per day.

[0177] In some embodiments of dual antiplatelet therapy, clopidogrel is administered at a dose of 225 mg per day.

[0178] In some embodiments of dual antiplatelet therapy, clopidogrel is administered at a dose of 300 mg per day.

[0179] In some embodiments of dual antiplatelet therapy, clopidogrel is administered at a dose of 375 mg per day.

[0180] In some embodiments of dual antiplatelet therapy, clopidogrel is administered at a dose of 450 mg per day.

[0181] In some embodiments of dual antiplatelet therapy, clopidogrel is administered at a dose of 525 mg per day.

[0182] In some embodiments of dual antiplatelet therapy, clopidogrel is administered at a dose of 600 mg per day.

[0183] In some embodiments, antiplatelet therapy is dual antiplatelet therapy (DAPT), which involves administering 75-100 mg of aspirin once daily in combination with a P2Y12 inhibitor. In some embodiments, antiplatelet therapy is antiplatelet monotherapy (SAPT). In some embodiments, treatment methods include antiplatelet therapy consisting basically of dual antiplatelet therapy and antiplatelet monotherapy. In some embodiments, antiplatelet therapy includes DAPT.

[0184] In some embodiments, DAPT includes aspirin and prasugrel. In some embodiments, DAPT includes administering aspirin and prasugrel for 12 months.

[0185] In some embodiments, DAPT includes aspirin and clopidogrel. In some embodiments, aspirin and clopidogrel are administered for 21 days to 12 months. In some embodiments, DAPT includes aspirin and clopidogrel. In some embodiments, aspirin and clopidogrel are administered for 21 days. In some embodiments, aspirin and clopidogrel are administered for 6 months. In some embodiments, aspirin and clopidogrel are administered for 12 months.

[0186] In some embodiments, DAPT includes aspirin and ticagrelor. In some embodiments, DAPT includes a 12-month course of aspirin and ticagrelor. In some embodiments, DAPT includes administering 75-100 mg of aspirin once daily for the first 12 months, concomitantly with a P2Y12 inhibitor, followed by aspirin monotherapy for the next 6-12 months.

[0187] In some embodiments, DAPT includes administering 75-100 mg of aspirin once daily for the first 21 days, concomitantly with a P2Y12 inhibitor, followed by aspirin monotherapy for the next 6 months.

[0188] In some embodiments, DAPT includes administering 75-100 mg of aspirin once daily for the first 21 days, concomitantly with a P2Y12 inhibitor, followed by aspirin monotherapy for the next 12 months.

[0189] In some embodiments, DAPT includes administering aspirin 75-100 mg once daily and clopidogrel 75 mg once daily for the first 21 days, followed by aspirin monotherapy for the next 6 months.

[0190] In some embodiments, DAPT includes administering 75-100 mg of aspirin once daily and 90 mg of ticagrelor twice daily for the first 12 months, followed by 75-100 mg of aspirin once daily for the next 12 months.

[0191] In some embodiments, DAPT includes administering aspirin 75-100 mg once daily and ticagrelor 90 mg twice daily for the first 12 months, followed by ticagrelor 90 mg twice daily for the next 23 months.

[0192] In some embodiments, DAPT involves administering 75-100 mg of aspirin once daily and 75 mg of ticagrelor twice daily. In some embodiments, 75-100 mg of aspirin once daily and 75 mg of ticagrelor twice daily are administered for 12 months.

[0193] In some embodiments, DAPT includes administering 81-100 mg of aspirin once daily and 90 mg of ticagrelor twice daily. In some embodiments, 81-100 mg of aspirin once daily and 90 mg of ticagrelor twice daily are administered for three years.

[0194] In some embodiments, antiplatelet therapy includes a 30- to 90 day course of aspirin followed by clopidogrel monotherapy. In some embodiments, antiplatelet therapy includes a 60-day course of aspirin followed by clopidogrel monotherapy. In some embodiments, antiplatelet therapy includes a 90-day course of aspirin followed by clopidogrel monotherapy.

[0195] In some embodiments, antiplatelet therapy includes SAPT.

[0196] In some embodiments, SAPT includes the administration of aspirin. In some embodiments, aspirin monotherapy is administered once daily. In some embodiments, aspirin monotherapy is administered once daily for 3 months to 3 years. In some embodiments, aspirin monotherapy is administered once daily for 3 months. In some embodiments, aspirin monotherapy is administered once daily for 6 months. In some embodiments, aspirin monotherapy is administered once daily for 12 months. In some embodiments, aspirin monotherapy is administered once daily for 24 months. In some embodiments, aspirin monotherapy is administered once daily for 36 months. In some embodiments, aspirin monotherapy is administered twice daily.

[0197] In some embodiments, SAPT includes the administration of a P2Y12 inhibitor. In some embodiments, the P2Y12 inhibitor is selected from prasugrel, clopidogrel, seratogrel, or ticagrelor. In some embodiments, the P2Y12 inhibitor is administered as monotherapy for 3 to 6 months.

[0198] In some embodiments, SAPT includes administration of clopidogrel. In some embodiments, SAPT includes administration of ticagrelor. In some embodiments, SAPT includes ticagrelor monotherapy followed by aspirin 20 mg twice daily.

[0199] In some embodiments, SAPT includes once-daily administration of 75-100 mg of aspirin. In some embodiments, once-daily administration of 75-100 mg of aspirin is performed for 12 months.

[0200] In some embodiments, SAPT includes administration of ticagrelor 90 mg twice daily. In some embodiments, administration of ticagrelor 90 mg twice daily is performed for 3 years.

[0201] In some embodiments, SAPT includes administration of clopidogrel. In some embodiments, aspirin monotherapy is administered first, followed by clopidogrel monotherapy for at least two months.

[0202] In some embodiments, the present disclosure relates to a method for preventing cardiovascular adverse events in a human patient diagnosed with acute coronary syndrome, comprising administering to the human patient a regimen comprising (i) a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; Administering the aforementioned pharmaceutical composition twice a day; and The cardiovascular adverse event must be selected from one or more of the following groups: all-cause mortality (ACM); cardiovascular (CV) death; myocardial infarction (MI); unstable angina (UA); any stroke or any stroke (ischemic, hemorrhagic, or of unknown cause); ischemic stroke; acute limb ischemia (ALI); large vessel (non-traumatic) limb amputation; symptomatic venous thromboembolism (VTE: pulmonary embolism (PE), deep vein thrombosis (DVT)); coronary revascularization due to ischemia; stent thrombosis; hospitalization for any cause (classified as (1) planned or unplanned, (2) hospitalization due to arterial thromboembolism or venous thromboembolism, or hospitalization not falling under either category); and transient ischemic attack (TIA). This relates to a method characterized by the following.

[0203] In another embodiment of the above method, a cardiovascular adverse event is one or more of CV death, MI, or ischemic stroke.

[0204] In some embodiments, the disclosure relates to a method for reducing the incidence of one or more thrombotic adverse events selected from new-onset ischemic stroke, MI, or all-cause mortality in a human patient diagnosed with acute coronary syndrome, characterized by administering to the human patient a regimen twice daily comprising (i) a pharmaceutical composition comprising about 25 mg to about 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof.

[0205] In some embodiments of the above method, the regimen, when implemented, results in a relative risk of 0.85 or less compared to placebo, for example, 0.85, 0.84, 0.83, 0.82, 0.81, 0.8, 0.79, 0.78, 0.77, 0.76, 0.75, 0.74, 0.73, 0.72, 0.71, or 0.7 compared to placebo.

[0206] In another embodiment, the Disclosure relates to a method for preventing ischemic stroke in a human patient diagnosed with acute coronary syndrome, characterized by administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients; and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; the pharmaceutical composition twice daily.

[0207] In some embodiments of the above method, the clinical benefit of the regimen—a reduction in the incidence of ischemic stroke—is maintained over a 90-day treatment period.

[0208] In some embodiments of the methods of this disclosure, a baseline of a patient's factor XI coagulation activity is measured. As used herein, “baseline of factor XI coagulation activity” means the patient’s factor XI coagulation activity before administration of a regimen comprising a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof).

[0209] In some embodiments, factor XI (FXI) activity is measured using a modified activated partial thromboplastin time (aPTT) measurement method with Actin FS (Siemens Healthcare) and Siemens BCS. (登録商標) Measurement is performed using an XP analyzer. A 6-point calibration curve is created in the range of approximately 5-150% using a secondary standard material (standard human plasma, Siemens Healthcare Diagnostics Inc.) with a known FXI concentration assigned by the manufacturer. Approximately 100% of the reference standard plasma is used in the BCS. (登録商標) Dilute with physiological saline using an XP analyzer to a pre-set FXI calibration level. The calibration curve is fitted using a log / lin regression curve with FXI activity rate (%) plotted on the x-axis and coagulation time (seconds) on the y-axis. The sample to be tested is mixed with FXI-deficient plasma (less than 1% FXI, with at least 75% of all other factors) to normalize all other factors. After adding aPTT reagent (Actin FS) and incubating the mixture, calcium chloride is added to the mixture, and the optically measured thrombus formation time is compared to the time on the calibration curve. The sample is then processed using the BCS (Body Condition System). (登録商標) The measurement is performed by diluting the XP with physiological saline (1:10). In another embodiment, fibrin thrombus formation is measured by a mechanical method (viscosity).

[0210] In some embodiments of the method disclosed herein, the implementation of the regimen reduces the patient's factor XI coagulation activity by approximately 7% to 70% compared to baseline.

[0211] In another embodiment, the method of this disclosure results in a reduction of approximately 7% to 20% of the patient's factor XI coagulation activity compared to baseline, upon implementation of the regimen.

[0212] In some embodiments, the method of this disclosure, upon implementation of the regimen, results in the patient's factor XI coagulation activity being approximately 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, and 34% relative to baseline. It decreases by approximately 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, or approximately 68%, 69%, or approximately 70%.

[0213] In other embodiments, the methods of the present disclosure result in a reduction of approximately 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of the patient's factor XI coagulation activity compared to baseline.

[0214] In other embodiments, the methods of the present disclosure result in a reduction of the patient's factor XI coagulation activity by the rate shown in Table 6 of Example 2 upon implementation of the regimen.

[0215] In some embodiments of the method of this disclosure, the implementation of the regimen prolongs the activated partial thromboplastin time (aPTT) by approximately 27% to 64% compared to baseline.

[0216] In some embodiments of the methods of the present disclosure, the implementation of the regimen extends the activated partial thromboplastin time (aPTT) by approximately 27% to 64% relative to baseline, for example, approximately 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, or 64%. As used herein, "baseline" refers to the patient's aPTT before any regimen is administered.

[0217] In some embodiments of the method disclosed herein, the implementation of the regimen results in an extension of the activated partial thromboplastin time (aPTT) as shown in Table 5 of Example 2.

[0218] In some embodiments, aPTT is determined as follows: A plasma sample is incubated for 3 minutes with Actin FS (aPTT assay reagent) containing a standard amount of phospholipids and a contact factor (ellagic acid) that activates the intrinsic pathway. Calcium chloride is then added to initiate coagulation, and fibrin thrombus formation is optically measured. The time to thrombus formation (in seconds) is reported as the activated partial thromboplastin time (aPTT). In other embodiments, fibrin thrombus formation is measured by a mechanical method (viscosity).

[0219] In some embodiments of the methods disclosed herein, the pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is a solid oral pharmaceutical composition.

[0220] In some embodiments of the methods of this disclosure, the solid oral pharmaceutical composition includes an amorphous solid dispersion (SDP) produced by spray drying, comprising free milbexian and a pH-dependent enteric polymer as the main components.

[0221] In some embodiments of the method of this disclosure, the SDP contains free milbexian and a pH-dependent enteric polymer in a weight ratio of 3:1 (milbexian:polymer).

[0222] In some embodiments of the methods of this disclosure, the pH-dependent enteric polymer is trimellitic cellulose acetate (CAT), cellulose phthalate acetate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), ES grade of hydroxypropyl methylcellulose (HPMC ES), LF, LG, MF, MG, or HF grade of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) (e.g., Aqoat®), polyvinyl acetate phthalate (PVAP) (e.g., Sureteric® and Opadry®), and shellac resin (e.g., SSB® Aquagold), or polyvinylpyrrolidone (PVP).

[0223] In some embodiments of the method of this disclosure, the pH-dependent enteric polymer is MG grade hydroxypropyl methylcellulose-AS.

[0224] In some embodiments of the method of the present disclosure, the solid oral pharmaceutical composition further includes a binder (e.g., microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), or a combination thereof).

[0225] In some embodiments of the method of the present disclosure, the solid oral pharmaceutical composition further includes a volume extender (e.g., lactose monohydrate).

[0226] In some embodiments of the method of the present disclosure, the solid oral pharmaceutical composition further includes a disintegrant.

[0227] In some embodiments of the method of the present disclosure, the solid oral pharmaceutical composition further includes a lubricant.

[0228] In some embodiments of the method disclosed herein, the solid oral pharmaceutical composition is a tablet.

[0229] In some embodiments of the methods disclosed herein, the solid oral pharmaceutical composition is an immediate-release tablet.

[0230] In some embodiments of the methods disclosed herein, the solid oral pharmaceutical composition is a tablet obtained by direct compression.

[0231] In some embodiments of the methods disclosed herein, the solid oral pharmaceutical composition is a tablet produced by rotary compression.

[0232] In some embodiments of the methods disclosed herein, the solid oral pharmaceutical composition is a film-coated tablet.

[0233] In some embodiments of the methods of this disclosure, the film coating includes polyvinyl alcohol, titanium dioxide, polyethylene glycol-polyvinyl alcohol graft copolymer, and talc.

[0234] In some embodiments of the method of this disclosure, the film coating includes a polyethylene glycol-polyvinyl alcohol graft copolymer.

[0235] In some embodiments, the film coating includes polyvinyl alcohol, iron oxide, macrogol (PEG) polyvinyl alcohol graft copolymer, and talc.

[0236] In some embodiments, the film coating includes OpadryQX 321A220063 Yellow, a film coating material comprising polyvinyl alcohol, iron oxide, macrogol (PEG)-polyvinyl alcohol graft copolymer, and talc.

[0237] In some embodiments, the solid oral pharmaceutical composition is a tablet having the composition and / or properties shown in Table A. [Table 1]

[0238] As used herein, the term "disintegration time" refers to the time required for a tablet to disintegrate into particles under specified conditions. In some embodiments, the disintegration time is measured using a disk with distilled water at 37°C and the apparatus described in Eur. Ph. (PTZ-E Pharma Test, Hainburg, Germany).

[0239] In some embodiments where the solid pharmaceutical composition is a tablet, the disintegration time of the tablet in water is less than 60 seconds at 37°C.

[0240] In some embodiments where the solid pharmaceutical composition is a tablet, the disintegration time of the tablet in water is less than 20 seconds at 37°C.

[0241] In another embodiment where the solid pharmaceutical composition is a tablet, the disintegration time of the tablet in water is less than 15 seconds at 37°C.

[0242] In another embodiment where the solid pharmaceutical composition is a tablet, the disintegration time of the tablet in water is less than 10 seconds at 37°C.

[0243] In some embodiments of the method disclosed herein, the solid pharmaceutical composition is a capsule.

[0244] In some embodiments of the methods of this disclosure, a human patient to whom a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered is a person who is unable to swallow tablet dosage forms.

[0245] In some embodiments of the method disclosed herein, the solid oral pharmaceutical composition is dispersed in an aqueous medium for administration to form an aqueous dispersion.

[0246] In some embodiments of the method of the present disclosure, the solid oral pharmaceutical composition is a tablet dispersed in an aqueous medium for forming an aqueous dispersion for administration.

[0247] In some embodiments of the method disclosed herein, the solid oral pharmaceutical composition is a tablet for oral administration as an aqueous dispersion by dispersing it in an aqueous medium in less than one minute.

[0248] In the above embodiment, in which the solid oral pharmaceutical composition is dispersed in an aqueous medium to form an aqueous dispersion, the aqueous medium is water, physiological saline, phosphate buffer, plant juice, or fruit juice such as applesauce.

[0249] In the above embodiment, the solid oral pharmaceutical composition is a tablet dispersed in an aqueous medium to form an aqueous dispersion, the aqueous medium is water, saline solution, phosphate buffer, plant juice, or fruit juice such as applesauce.

[0250] In some embodiments of the method of the present disclosure, in which the solid oral pharmaceutical composition is dispersed in an aqueous medium to form an aqueous dispersion for administration, the aqueous dispersion is administered to a human patient via a nasogastric tube or spoon.

[0251] In some embodiments of the method of the present disclosure, the solid oral pharmaceutical composition is a tablet dispersed in an aqueous medium to form an aqueous dispersion for administration, the aqueous dispersion is administered to a human patient via a nasogastric tube or spoon.

[0252] In some embodiments of the methods of this disclosure, oral administration of a pharmaceutical composition containing milbexian (or a pharmaceutically acceptable salt or solvate thereof) results in a plasma half-life of approximately 13 to 16 hours for milbexian. Methods for measuring the half-life in the plasma of human patients are well known to those skilled in the art (or such methods are described in the protocols of the following examples).

[0253] In some embodiments of the methods of this disclosure, when a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered to a human patient, the plasma concentration of milbexian reaches a steady state in approximately 3 to 6 days. As used herein, “steady state” means a steady state plasma concentration as defined by a regulatory body (e.g., the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA)).

[0254] Milbexian differs in many ways from other oral activating factor XI inhibitors (e.g., asundexane). For example, a population pharmacokinetic model to characterize the pharmacokinetics of milbexian was constructed using plasma concentration data of milbexian collected from healthy adult subjects in six phase 1 trials.

[0255] Analysis of PK data from the AXIOMATIC-SSP trial using a proprietary population pharmacokinetic model revealed that, in the patient exposure-response relationship to milbexian, when a pharmaceutical composition containing 25 mg of milbexian was administered twice daily to human patients, the plasma concentration of milbexian reached a steady state in approximately 3 days. In some embodiments of the above, when 25 mg of milbexian is orally administered twice daily to human patients, the plasma concentration profile reaches a steady state in approximately 3 days. In some embodiments of the above, the steady-state plasma concentration profile is (i) steady-state C max (ii) Steady state C max (iii) The mean (standard deviation) of the ng / mL is 346 (129) ng / mL, and the steady-state AUC 0-24 (iv) Steady-state AUC 0-24A notable feature is that the mean (standard deviation) is 7290 (2940) ng*h / mL. Furthermore, the regimen of administering 25 mg of milbexian in BID in the Phase 3 trial for ACS patients described in Example 1 was selected based on data obtained from Phase 1 and Phase 2 trials, and the results of an analysis of the exposure-response relationship of milbexian in patients using a proprietary population pharmacokinetic model.

[0256] In some embodiments of the methods disclosed herein, a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered regardless of the timing of meals.

[0257] In some embodiments of the methods described herein, administration does not statistically significantly increase major hemorrhagic complications. In the embodiments described above, “statistically significant increase” means an increase compared to the patient’s baseline major bleeding, i.e., major bleeding before administration of the pharmaceutical composition containing milbexian (or a pharmaceutically acceptable salt or solvate thereof).

[0258] In some embodiments of the methods described herein, when evaluated based on ISTH criteria, such administration does not statistically significantly increase the incidence of major hemorrhagic complications.

[0259] In some embodiments of the methods described herein, when evaluated based on the CRNM bleeding criteria, the administration does not statistically significantly increase the incidence of major hemorrhagic complications.

[0260] In some embodiments of the methods described herein, when evaluated based on the ISTH CRNM bleeding criteria, the administration does not statistically significantly increase the incidence of major hemorrhagic complications.

[0261] In some embodiments of the methods described herein, when evaluated based on ISTH major bleeding or CRNM bleeding criteria, the administration does not statistically significantly increase the incidence of major bleeding complications.

[0262] In some aspects of the methods of the present disclosure, when evaluated based on the GUSTO, BARC, or TIMI bleeding criteria, the administration does not statistically significantly increase major hemorrhagic complications.

[0263] In some aspects of the methods of the present disclosure, when evaluated based on BARC bleeding criteria types 3c and 5, the administration does not statistically significantly increase major hemorrhagic complications.

[0264] In some aspects of the methods of the present disclosure, when evaluated based on BARC bleeding criteria types 3b, 3c, and 5, the administration does not statistically significantly increase major hemorrhagic complications.

[0265] In some aspects of the methods of the present disclosure, when evaluated based on BARC bleeding criteria type 3b, the administration does not statistically significantly increase major hemorrhagic complications.

[0266] In some aspects of the methods of the present disclosure, when evaluated based on BARC bleeding criteria type 3c, the administration does not statistically significantly increase major hemorrhagic complications.

[0267] In some aspects of the methods of the present disclosure, when evaluated based on BARC bleeding criteria type 5, the administration does not statistically significantly increase major hemorrhagic complications.

[0268] In some aspects of the methods of the present disclosure, the administration does not statistically significantly increase "severe bleeding or life - threatening bleeding" in the GUSTO bleeding criteria.

[0269] In some aspects of the methods of the present disclosure, the administration does not statistically significantly increase non - CABG - related major bleeding based on the TIMI bleeding criteria.

[0270] In some aspects of the methods of the present disclosure, the administration does not statistically significantly increase clinically important non - major bleeding.

[0271] In some embodiments of the method of this disclosure, such administration does not statistically increase clinically significant non-major bleeding based on an assessment of BARC bleeding criteria type 2, 3a, or 4.

[0272] In some embodiments of the method described herein, such administration does not statistically increase clinically significant non-major bleeding based on ISTH criteria.

[0273] In some embodiments of the methods described herein, when evaluated based on moderate bleeding according to the GUSTO bleeding criteria, the administration does not statistically increase clinically significant non-major bleeding.

[0274] In some embodiments of the methods described herein, when evaluated based on CABG-related major bleeding according to the TIMI bleeding criteria, the administration does not statistically increase clinically significant non-major bleeding.

[0275] In some embodiments of the methods described herein, when evaluated based on minor bleeding according to the TIMI bleeding criteria, the administration does not statistically increase clinically significant non-major bleeding.

[0276] In some embodiments of the methods described herein, when evaluated based on the TIMI bleeding criteria for "bleeding requiring treatment," the administration does not statistically increase clinically significant non-major bleeding.

[0277] In some aspects of the methods of this disclosure, the relative risk of bleeding meeting type 3 or 5 of the Bleeding Academic Research Consortium (BARC) bleeding criteria with this regimen is 3 or less, for example, ≤3.0, ≤2.9, ≤2.8, ≤2.7, ≤2.6, ≤2.5, ≤2.4, ≤2.3, ≤2.2, ≤2.1, ≤2.0, ≤1.9, ≤1.8, ≤1.7, ≤1.6, ≤1.5, ≤1.4, ≤1.3, ≤1.2, ≤1.1, ≤1.0, ≤0.9, ≤0.8, ≤0.7, ≤0.6, or ≤0.5, compared to placebo with antiplatelet therapy.

[0278] In some aspects of the methods of this disclosure, the relative risk of bleeding meeting type 3 or 5 of the Bleeding Academic Research Consortium (BARC) bleeding criteria with this regimen is 3 or less, for example, ≤3.0, ≤2.9, ≤2.8, ≤2.7, ≤2.6, ≤2.5, ≤2.4, ≤2.3, ≤2.2, ≤2.1, ≤2.0, ≤1.9, ≤1.8, ≤1.7, ≤1.6, ≤1.5, ≤1.4, ≤1.3, ≤1.2, ≤1.1, ≤1.0, ≤0.9, ≤0.8, ≤0.7, ≤0.6, or ≤0.5, compared to placebo with antiplatelet therapy.

[0279] In some embodiments of the method of this disclosure, the relative risk of serious bleeding corresponding to type 3 or 5 of the Bleeding Academic Research Consortium (BARC) bleeding criteria is independent of the amount of milbexian administered.

[0280] In other embodiments of the method of this disclosure, the human patient does not have severe bleeding that corresponds to type 3 or 5 of the Bleeding Academic Research Consortium (BARC) bleeding criteria.

[0281] In some aspects of the methods of this disclosure, the relative risk of bleeding meeting type 2 of the Bleeding Academic Research Consortium (BARC) bleeding criteria with this regimen is 2.6 or less, for example, 2.6 or less, 2.5 or less, 2.4 or less, 2.3 or less, 2.2 or less, 2.1 or less, 2.0 or less, 1.9 or less, 1.8 or less, 1.7 or less, 1.6 or less, 1.5 or less, 1.4 or less, 1.3 or less, 1.2 or less, 1.1 or less, 1.0 or less, 0.9 or less, 0.8 or less, 0.7 or less, 0.6 or less, or 0.5 or less.

[0282] In some aspects of the methods of this disclosure, the relative risk of bleeding meeting type 2 of the Bleeding Academic Research Consortium (BARC) bleeding criteria with this regimen is 2.6 or less, compared to placebo administered with antiplatelet therapy, for example, 2.6 or less, 2.5 or less, 2.4 or less, 2.3 or less, 2.2 or less, 2.1 or less, 2.0 or less, 1.9 or less, 1.8 or less, 1.7 or less, 1.6 or less, 1.5 or less, 1.4 or less, 1.3 or less, 1.2 or less, 1.1 or less, 1.0 or less, 0.9 or less, 0.8 or less, 0.7 or less, 0.6 or less, or 0.5 or less.

[0283] In some embodiments of the method of this disclosure, the relative risk of bleeding corresponding to type 2 of the Bleeding Academic Research Consortium (BARC) bleeding criteria is independent of the amount of milbexian administered.

[0284] In other embodiments of the method of this disclosure, the human patient does not have bleeding that falls under type 2 of the Bleeding Academic Research Consortium (BARC) bleeding criteria.

[0285] In some aspects of the methods of this disclosure, the relative risk of bleeding meeting the ISTH criteria for major bleeding or clinically significant non-major bleeding (CRNM) with this regimen is 3 or less, for example, ≤3.0, ≤2.9, ≤2.8, ≤2.7, ≤2.6, ≤2.5, ≤2.4, ≤2.3, ≤2.2, ≤2.1, ≤2.0, ≤1.9, ≤1.8, ≤1.7, ≤1.6, ≤1.5, ≤1.4, ≤1.3, ≤1.2, ≤1.1, ≤1.0, ≤0.9, ≤0.8, ≤0.7, ≤0.6, or ≤0.5, compared to placebo in addition to standard treatment.

[0286] In some aspects of the methods of this disclosure, the relative risk of bleeding meeting the ISTH criteria for major bleeding or clinically significant non-major bleeding (CRNM) with this regimen is 3 or less, for example, ≤3.0, ≤2.9, ≤2.8, ≤2.7, ≤2.6, ≤2.5, ≤2.4, ≤2.3, ≤2.2, ≤2.1, ≤2.0, ≤1.9, ≤1.8, ≤1.7, ≤1.6, ≤1.5, ≤1.4, ≤1.3, ≤1.2, ≤1.1, ≤1.0, ≤0.9, ≤0.8, ≤0.7, ≤0.6, or ≤0.5, compared to placebo with antiplatelet therapy.

[0287] Administration of milvexian as described in the present disclosure is generally safe and well tolerated. For example, no clinically significant prolongation of the QTc interval is observed even when milvexian is administered at a dose of 25 mg, 50 mg, or 100 mg. For example, ΔΔQTc does not exceed 10 milliseconds even when milvexian is administered at a dose of 25 mg, 50 mg, or 100 mg. In some embodiments, when milvexian is administered at a dose of 25 mg, 50 mg, or 100 mg, ΔΔQT is less than 10 milliseconds. In some embodiments, when milvexian is administered at a dose of 25 mg, 50 mg, or 100 mg, ΔΔQTc is less than 9 milliseconds. In some embodiments, when milvexian is administered at a dose of 25 mg, 50 mg, or 100 mg, ΔΔQTc is less than 8 milliseconds. In some embodiments, when milvexian is administered at a dose of 25 mg, 50 mg, or 100 mg, ΔΔQTc of QTc is less than 7 milliseconds. In some embodiments, when milvexian is administered at a dose of 25 mg, 50 mg, or 100 mg, ΔΔQTc is less than 6 milliseconds. In some embodiments, when milvexian is administered at a dose of 25 mg, 50 mg, or 100 mg, ΔΔQTc is less than 5 milliseconds. In some embodiments, when milvexian is administered at a dose of 25 mg, 50 mg, or 100 mg, ΔΔQTc is less than 4 milliseconds.

[0288] Administration of milbexian at a dose of 25 mg does not result in clinically significant QTc interval prolongation. In some embodiments, administration of milbexian at a dose of 25 mg results in a ΔΔQTc of less than 10 milliseconds. In some embodiments, administration of milbexian at a dose of 25 mg results in a ΔΔQTc of less than 9 milliseconds. In some embodiments, administration of milbexian at a dose of 25 mg results in a ΔΔQTc of less than 8 milliseconds. In some embodiments, administration of milbexian at a dose of 25 mg results in a ΔΔQTc of less than 7 milliseconds. In some embodiments, administration of milbexian at a dose of 25 mg results in a ΔΔQTc of less than 6 milliseconds. In some embodiments, administration of milbexian at a dose of 25 mg results in a ΔΔQTc of less than 5 milliseconds. In some embodiments, administration of milbexian at a dose of 25 mg results in a ΔΔQTc of less than 4 milliseconds.

[0289] Administration of milbexian at a dose of 50 mg does not result in clinically significant QTc interval prolongation. In some embodiments, administration of milbexian at a dose of 50 mg results in a ΔΔQTc of less than 10 milliseconds. In some embodiments, administration of milbexian at a dose of 50 mg results in a ΔΔQTc of less than 9 milliseconds. In some embodiments, administration of milbexian at a dose of 50 mg results in a ΔΔQTc of less than 8 milliseconds. In some embodiments, administration of milbexian at a dose of 50 mg results in a ΔΔQTc of less than 7 milliseconds. In some embodiments, administration of milbexian at a dose of 50 mg results in a ΔΔQTc of less than 6 milliseconds. In some embodiments, administration of milbexian at a dose of 50 mg results in a ΔΔQTc of less than 5 milliseconds. In some embodiments, administration of milbexian at a dose of 50 mg results in a ΔΔQTc of less than 4 milliseconds.

[0290] Administration of milbexian at a dose of 100 mg does not result in a clinically significant QTc interval prolongation. In some embodiments, administration of milbexian at a dose of 100 mg results in a ΔΔQTc of less than 10 milliseconds. In some embodiments, administration of milbexian at a dose of 100 mg results in a ΔΔQTc of less than 9 milliseconds. In some embodiments, administration of milbexian at a dose of 100 mg results in a ΔΔQTc of less than 8 milliseconds. In some embodiments, administration of milbexian at a dose of 100 mg results in a ΔΔQTc of less than 7 milliseconds. In some embodiments, administration of milbexian at a dose of 100 mg results in a ΔΔQTc of less than 6 milliseconds. In some embodiments, administration of milbexian at a dose of 100 mg results in a ΔΔQTc of less than 5 milliseconds. In some embodiments, administration of milbexian at a dose of 100 mg results in a ΔΔQTc of less than 4 milliseconds.

[0291] This disclosure relates to one method for preventing one thrombotic event in adult patients with acute coronary syndrome (ACS), characterized by administering 25 mg of milbexian in a BID in combination with antiplatelet therapy. This disclosure relates to multiple methods for preventing multiple thrombotic events in adult patients with acute coronary syndrome (ACS), characterized by administering 25 mg of milbexian in a BID in combination with antiplatelet therapy.

[0292] [Pattern] In this specification, references to methods of using milbexian or compositions containing milbexian for treating or preventing the symptoms of the Disclosure are understood to also refer to (i) milbexian or compositions containing milbexian for use in methods of treating or preventing the symptoms of the Disclosure; and / or (ii) the use of milbexian or compositions containing milbexian in the manufacture of a medicament for treating or preventing the symptoms of the Disclosure.

[0293] Method of use Embodiment 1. A method for preventing cerebrovascular or cardiovascular adverse events in human patients with acute coronary syndrome, the method comprising administering to a human patient a regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof); and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; the pharmaceutical composition twice daily. Embodiment 2. The method of Embodiment 1, wherein the antiplatelet therapy is the administration of a P2Y12 inhibitor. Embodiment 3. The method of Embodiment 2, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel. Embodiment 4. Any one of Embodiments 1 to 3, wherein the antiplatelet therapy is the administration of aspirin. Embodiment 5. One of embodiments 1 to 4, wherein a human patient is treated with a combination of aspirin and clopidogrel from day 1 to day 21, followed by aspirin monotherapy for at least 90 days. Embodiment 6. The method of Embodiment 5, wherein the patient is treated with aspirin and / or clopidogrel without adjusting the dose of milbexian. Embodiment 7. Any one of the above embodiments for the primary prevention of cerebrovascular adverse events or cardiovascular adverse events. Embodiment 8. Any one of the above embodiments for secondary prevention of cerebrovascular adverse events or cardiovascular adverse events. Embodiment 9. Any one of Embodiments 1 to 8, wherein the cerebrovascular adverse event or cardiovascular adverse event includes one or more of stroke, heart attack, or death. Embodiment 10. Any one of Embodiments 1 to 9, wherein the cerebrovascular adverse event or cardiovascular adverse event occurs in an organ selected from the heart, brain, limbs, blood circulation system, or blood vessels. Embodiment 11. One of the methods from Embodiments 1 to 10, wherein the cerebrovascular adverse event or cardiovascular adverse event includes one or more major cardiovascular adverse events (MACE) selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, ischemic stroke, and combinations thereof. Embodiment 12. One of the methods in Embodiments 1 to 11, wherein the cerebrovascular adverse event or cardiovascular adverse event includes one or more major lower limb adverse events (MALE) including one or more of acute limb ischemia, chronic limb ischemia, or major amputation; symptomatic venous thromboembolic adverse events; and combinations thereof, comprising one or more major vascular adverse events (MAVE). Embodiment 13. One of the methods from Embodiments 1 to 12, wherein the cerebrovascular adverse event or cardiovascular adverse event is selected from the group consisting of arrhythmogenic cardiomyopathy (ACM), non-fatal myocardial infarction, ischemic stroke, and combinations thereof. Embodiment 14. Any one of Embodiments 1 to 11, wherein the cerebrovascular adverse event or cardiovascular adverse event includes cardiovascular death. Embodiment 15. Any one of Embodiments 1 to 10, wherein the cerebrovascular adverse event or cardiovascular adverse event includes arrhythmogenic cardiomyopathy (ACM). Embodiment 16. A method for preventing cardiovascular adverse events in a human patient diagnosed with acute coronary syndrome, comprising administering to the human patient a regimen comprising (i) a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; i. Administering the pharmaceutical composition twice a day; and ii. The cardiovascular adverse event is selected from one or more of the following groups: all-cause mortality (ACM); cardiovascular (CV) death; myocardial infarction (MI); unstable angina (UA); any stroke or any stroke (ischemic, hemorrhagic, or of unknown cause); ischemic stroke; acute limb ischemia (ALI); large vessel (non-traumatic) limb amputation; symptomatic venous thromboembolism (VTE: pulmonary embolism (PE), deep vein thrombosis (DVT)); coronary revascularization due to ischemia; stent thrombosis; hospitalization for any cause (classified as (1) planned or unplanned, (2) hospitalization due to arterial thromboembolism or venous thromboembolism, or hospitalization not falling under either category); and transient ischemic attack (TIA). A method characterized by the following. Apparatus 17. The method of Apparatus 16, wherein the cardiovascular adverse event is one or more of CV death, MI, or ischemic stroke. Embodiment 18. A method for reducing the incidence of one or more thrombotic adverse events selected from new-onset ischemic stroke, MI, or all-cause mortality in a human patient diagnosed with acute coronary syndrome, characterized by administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising about 25 mg to about 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients; and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; the pharmaceutical composition administered twice daily. Embodiment 19. A method for preventing ischemic stroke in a human patient diagnosed with acute coronary syndrome, characterized by administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients; and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; the pharmaceutical composition twice daily. Embodiment 20. The method of Embodiment 19, wherein the regimen maintains a clinical benefit of reduced incidence of ischemic stroke over a 90-day treatment period. Embodiment 21. Any one of the embodiments described above, wherein the implementation of the regimen reduces the patient's factor XI coagulation activity by approximately 7% to approximately 20% compared to baseline. Embodiment 22. Any one of the above embodiments, wherein the regimen is implemented to prolong the activated partial thromboplastin time (aPTT) by approximately 27% to approximately 64% compared to baseline. Embodiment 23. Any one of the above embodiments, wherein administration does not statistically significantly increase the incidence of major hemorrhagic complications. Embodiment 24. Any one of the above embodiments, wherein the pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is a solid oral pharmaceutical composition. Embodiment 25. The method of Embodiment 24, wherein the solid oral pharmaceutical composition is a tablet. Embodiment 26. The method of Embodiment 25, wherein the tablets are immediately released. Embodiment 27. The method of Embodiment 25 or Embodiment 26, wherein the disintegration time of the tablet in water is less than 20 seconds. Embodiment 28. Any one of the above embodiments, wherein administration results in a plasma half-life of milbexian of approximately 13 hours to approximately 16 hours. Embodiment 29. Any one of the above embodiments, wherein the plasma concentration of milbexian reaches a steady state in approximately 3 to 6 days after administration. Embodiment 30. Any one of the above embodiments, wherein a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered regardless of the timing of meals. Embodiment 31. Any one of the above embodiments, wherein the human patient is unable to swallow tablet dosage forms. Embodiment 32. Any one of Embodiments 25 to 31, wherein tablets are dispersed in an aqueous medium to form an aqueous dispersion. Embodiment 33. The method of Embodiment 32, wherein the aqueous medium is water, saline solution, phosphate buffer, plant juice, or fruit juice such as applesauce. Embodiment 34. The method according to Embodiment 32 or Embodiment 33, wherein the aqueous dispersion is administered to a human patient via a nasogastric tube or spoon. Embodiment 35. Any one of Embodiments 25 to 34, wherein the pharmaceutical composition, which is an oral tablet, is administered orally as an aqueous dispersion by dispersing it in an aqueous medium in less than one minute. Embodiment 36. A method for preventing cerebrovascular or cardiovascular adverse events in human patients with acute coronary syndrome, characterized in that a regime is administered orally to a human patient comprising (i) a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and (ii) antiplatelet therapy, wherein the pharmaceutical composition is administered twice daily. Embodiment 37. The method of Embodiment 36, wherein the antiplatelet therapy is the administration of a P2Y12 inhibitor. Embodiment 38. The method of Embodiment 37, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel. Embodiment 39. Any one of embodiments 36 to 38, wherein the antiplatelet therapy is the administration of aspirin. Embodiment 40. Any one of embodiments 36 to 39, wherein a human patient is treated with a combination of aspirin and clopidogrel from day 1 to day 21, followed by aspirin monotherapy for at least 90 days. Embodiment 41. The method of Embodiment 40, wherein treatment with aspirin and / or clopidogrel is performed on the patient without adjusting the dose of milbexian. Embodiment 42. Any one of Embodiments 36 to 41 for the primary prevention of cerebrovascular adverse events or cardiovascular adverse events. Embodiment 43. Any one of Embodiments 36 to 42 for the secondary prevention of cerebrovascular adverse events or cardiovascular adverse events. Embodiment 44. Any one of embodiments 36 to 43, wherein the cerebrovascular adverse event or cardiovascular adverse event includes one or more of stroke, heart attack, or death. Embodiment 45. Any one of Embodiments 36 to 44, wherein the cerebrovascular adverse event or cardiovascular adverse event occurs in an organ selected from the heart, brain, limbs, blood circulation system, or blood vessels. Embodiment 46. Any one of Embodiments 36 to 45, wherein the cerebrovascular adverse event or cardiovascular adverse event includes one or more major cardiovascular adverse events (MACE) selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, ischemic stroke, and combinations thereof. Aspect 47. Any one of the methods in Aspects 36 to 46, wherein the cerebrovascular adverse event or cardiovascular adverse event includes one or more major lower limb adverse events (MALE) including one or more of acute limb ischemia, chronic limb ischemia, or major amputation; symptomatic venous thromboembolic adverse events; and major vascular adverse events (MAVE) selected from the group consisting of a combination thereof. Embodiment 48. Any one of Embodiments 36 to 47, wherein the cerebrovascular adverse event or cardiovascular adverse event is selected from the group consisting of arrhythmogenic cardiomyopathy (ACM), non-fatal myocardial infarction, ischemic stroke, and combinations thereof. Embodiment 49. Any one of Embodiments 36 to 47, wherein the cerebrovascular adverse event or cardiovascular adverse event includes cardiovascular death. Embodiment 50. Any one of embodiments 36 to 49, wherein the cerebrovascular adverse event or cardiovascular adverse event includes arrhythmogenic cardiomyopathy (ACM). Apparatus 51. A method for preventing cardiovascular adverse events in a human patient diagnosed with acute coronary syndrome, comprising administering to the human patient (i) 25.0 mg of milbexian twice daily, and (ii) implementing a regimen including antiplatelet therapy; The cardiovascular adverse event is one or more of the following: all-cause mortality (ACM); cardiovascular (CV) death; myocardial infarction (MI); unstable angina (UA); any stroke or any stroke (ischemic, hemorrhagic, or of unknown cause); ischemic stroke; acute limb ischemia (ALI); large vessel (non-traumatic) limb amputation; symptomatic venous thromboembolism (VTE: pulmonary embolism (PE), deep vein thrombosis (DVT)); coronary revascularization due to ischemia; stent thrombosis; hospitalization for any cause (classified as (1) planned or unplanned, (2) hospitalization due to arterial thromboembolism or venous thromboembolism, or hospitalization not falling under either of the above); or transient ischemic attack (TIA); and The following clinical outcomes: (1) The plasma concentration profile of milbexian reaches a steady state in approximately 6 days; (2)(i) Steady state C max (ii) Steady state C max (iii) The mean (standard deviation) of the ng / mL is 346 (129) ng / mL, and the steady-state AUC 0-24 (iv) Steady-state AUC 0-24 Reaching a steady-state plasma concentration profile of mirbexian characterized by a mean (standard deviation) of 7290 (2940) ng*h / mL; (3) The patient's QTc change from baseline is less than 10 milliseconds; (4) AUC or C in a steady state maxNo clinically relevant effects are observed for any bleeding resulting from exposure to Milbexian, as assessed by the following criteria; (5) Minimal impairment of hemostatic function in human patients; (6) No clinically significant change in prothrombin time is observed, and the maximum mean change from baseline is approximately 5%; or (7) Any combination of the clinical outcomes described above Achieve at least one of the following A method characterized by the following. Apparatus 52. A method for preventing cardiovascular adverse events in a human patient diagnosed with acute coronary syndrome, comprising administering to the human patient (i) 25.0 mg of milbexian twice daily, and (ii) implementing a regimen including antiplatelet therapy; The cardiovascular adverse event is one or more of the following: all-cause mortality (ACM); cardiovascular (CV) death; myocardial infarction (MI); unstable angina (UA); any stroke or any stroke (ischemic, hemorrhagic, or of unknown cause); ischemic stroke; acute limb ischemia (ALI); large vessel (non-traumatic) limb amputation; symptomatic venous thromboembolism (VTE: pulmonary embolism (PE), deep vein thrombosis (DVT)); coronary revascularization due to ischemia; stent thrombosis; hospitalization for any cause (classified as (1) planned or unplanned, (2) hospitalization due to arterial thromboembolism or venous thromboembolism, or hospitalization not falling under either category); or transient ischemic attack (TIA). A method characterized by the following. Embodiment 53. A method for preventing all-cause mortality in a human patient diagnosed with acute coronary syndrome, characterized by (i) administering 25.0 mg of milbexian twice daily to the human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 54. A method for preventing cardiovascular death in a human patient diagnosed with acute coronary syndrome, characterized by (i) administering 25.0 mg of milbexian twice daily to the human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 55. A method for preventing myocardial infarction in a human patient diagnosed with acute coronary syndrome, characterized by (i) administering 25.0 mg of milbexian twice daily to the human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 56. A method for preventing stroke in a human patient diagnosed with acute coronary syndrome, characterized by administering to the human patient (i) 25.0 mg of milbexian twice daily, and (ii) implementing a regimen including antiplatelet therapy. Apparatus 57. A method for preventing ischemic stroke in a human patient diagnosed with acute coronary syndrome, characterized by (i) administering 25.0 mg of milbexian twice daily to the human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 58. A method for preventing ischemic stroke in a human patient diagnosed with acute coronary syndrome, characterized by (i) administering 25.0 mg of milbexian twice daily to the human patient, and (ii) implementing a regimen including antiplatelet therapy. Apparatus 59. A method for preventing unstable angina in a human patient diagnosed with acute coronary syndrome, characterized by (i) administering 25.0 mg of milbexian twice daily to the human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 60. A method for preventing acute limb ischemia in a human patient diagnosed with acute coronary syndrome, characterized by (i) administering 25.0 mg of milbexian twice daily to the human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 61. A method for preventing major vascular (non-traumatic) limb amputation in a human patient diagnosed with acute coronary syndrome, characterized by (i) administering 25.0 mg of milbexian twice daily to the human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 62. A method for preventing symptomatic venous thromboembolism in a human patient diagnosed with acute coronary syndrome, characterized by (i) administering 25.0 mg of milbexian twice daily to the human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 63. A method for preventing pulmonary embolism in a human patient diagnosed with acute coronary syndrome, characterized by (i) administering 25.0 mg of milbexian twice daily to the human patient, and (ii) implementing a regimen including antiplatelet therapy. Apparatus 64. A method for preventing deep vein thrombosis in a human patient diagnosed with acute coronary syndrome, characterized by (i) administering 25.0 mg of milbexian twice daily to the human patient, and (ii) implementing a regimen including antiplatelet therapy. Apparatus 65. A method for preventing deep vein thrombosis in a human patient diagnosed with acute coronary syndrome, characterized by (i) administering 25.0 mg of milbexian twice daily to the human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 66. A method for preventing ischemia-based revascularization in a human patient diagnosed with acute coronary syndrome, characterized by (i) administering 25.0 mg of milbexian twice daily to the human patient, and (ii) implementing a regimen including antiplatelet therapy. Apparatus 67. A method for preventing stent thrombosis in a human patient diagnosed with acute coronary syndrome, characterized by (i) administering 25.0 mg of milbexian twice daily to the human patient, and (ii) implementing a regimen including antiplatelet therapy. Apparatus 68. A method for preventing hospitalization for any cause in a human patient diagnosed with acute coronary syndrome, which is classified as (a) planned or unplanned, (b) hospitalization due to arterial or venous thromboembolism, or hospitalization not falling under either category, characterized in that the human patient is (i) administered 25.0 mg of milbexian twice daily, and (ii) given a regimen including antiplatelet therapy. Apparatus 69. A method for preventing transient ischemic attack in a human patient diagnosed with acute coronary syndrome, characterized by (i) administering 25.0 mg of milbexian twice daily to the human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 70. A method for preventing cerebrovascular adverse events in human patients with acute coronary syndrome, characterized by administering a regimen to a human patient orally twice daily, comprising (i) 25.0 mg of milbexian and (ii) antiplatelet therapy. Embodiment 71. A method for preventing cardiovascular adverse events in human patients with acute coronary syndrome, characterized by administering a regimen to a human patient orally twice daily, comprising (i) 25.0 mg of milbexian and (ii) antiplatelet therapy. Embodiment 72. A method for preventing cerebrovascular adverse events in human patients with acute coronary syndrome, comprising administering to a human patient orally a regimen comprising (i) a pharmaceutical composition comprising 25 mg of milbexian and a pharmaceutically acceptable excipient; and (ii) antiplatelet therapy; the pharmaceutical composition being administered twice daily. Embodiment 73. A method for preventing cardiovascular adverse events in a human patient with acute coronary syndrome, characterized by administering to the human patient a regimen comprising (i) a pharmaceutical composition comprising 25 mg of milbexian and a pharmaceutically acceptable excipient; and (ii) antiplatelet therapy; the pharmaceutical composition being administered twice daily. Embodiment 74. Any one of embodiments 70 to 73, wherein the cerebrovascular adverse event or cardiovascular adverse event includes ischemic stroke. Embodiment 75. Any one of embodiments 70 to 74, wherein the cerebrovascular adverse event or cardiovascular adverse event includes one or more of stroke, heart attack, or death. Embodiment 76. Any one of Embodiments 70 to 75, wherein the cerebrovascular adverse event or cardiovascular adverse event occurs in an organ selected from the heart, brain, limbs, blood circulation system, or blood vessels. Embodiment 77. Any one of Embodiments 70 to 76, wherein the cerebrovascular adverse event or cardiovascular adverse event includes one or more major cardiovascular adverse events (MACE) selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, ischemic stroke, and combinations thereof. Embodiment 78. Any one of Embodiments 70 to 77, wherein the cerebrovascular adverse event or cardiovascular adverse event includes one or more major lower limb adverse events (MALE) including one or more of acute limb ischemia, chronic limb ischemia, or major amputation; symptomatic venous thromboembolic adverse events; and major vascular adverse events (MAVE) selected from the group consisting of a combination thereof. Apparatus 79. Any one of the methods described in Apparatus 70 to 78, wherein the cerebrovascular adverse event or cardiovascular adverse event is selected from the group consisting of arrhythmogenic cardiomyopathy (ACM), non-fatal myocardial infarction, ischemic stroke, and combinations thereof. Embodiment 80. Any one of Embodiments 70 to 79, wherein the cerebrovascular adverse event or cardiovascular adverse event includes cardiovascular death. Embodiment 81. Any one of Embodiments 70 to 80, wherein the cerebrovascular adverse event or cardiovascular adverse event includes arrhythmogenic cardiomyopathy (ACM). Embodiment 82. A method for preventing ischemic stroke in human patients with acute coronary syndrome, characterized by administering a regimen to a human patient orally twice daily, comprising (i) 25.0 mg of milbexian and (ii) antiplatelet therapy. Embodiment 83. Any one of the above embodiments, wherein the plasma concentration profile of milbexian reaches a steady state in approximately 3 days after administration. Apparatus 84. Upon administration, the steady-state plasma concentration profile of milbexian is as follows: (i) Steady state C max The range is approximately 217 ng / mL to approximately 475 ng / mL. (ii) Steady state C max The mean (standard deviation) is 346 (129) ng / mL. (iii) AUC in steady state 0-24 The values ​​are approximately 4350 ng*h / mL to approximately 10230 ng*h / mL, and (iv) Steady-state AUC 0-24 The mean (standard deviation) is 7290 (2940) ng*h / mL. A method of any one of the above embodiments characterized by the following. Embodiment 85. Any one of the above embodiments, wherein administration does not result in a clinically significant prolongation of the QTc interval. Apparatus 86. Administration brings about a steady-state AUC or C max One of the above-described methods, which evaluates that no clinically relevant effect is observed for any bleeding caused by exposure to Milbexian. Embodiment 87. Any one of the above embodiments, wherein the impairment of hemostatic function due to administration is minimized in a human patient. Embodiment 88. Any one of the above embodiments, wherein the regimen includes an immediate-release tablet. Embodiment 89. The method of Embodiment 88, wherein the disintegration time of the immediate-release tablet in water is less than 20 seconds at 37°C. Embodiment 90. Any one of the above embodiments, wherein administration results in a terminal phase half-life of milbexian in plasma of approximately 13 hours to approximately 16 hours. Embodiment 91. Any one of the embodiments described above, wherein the regimen is implemented regardless of the timing of meals. Embodiment 92. Any one of Embodiments 88 to 91, wherein an immediate-release tablet is dispersed in an aqueous medium to form an aqueous dispersion. Embodiment 93. The method of Embodiment 92, wherein the aqueous medium contains water or applesauce. Embodiment 94. Any one of the above embodiments, characterized in that antiplatelet therapy is performed as antiplatelet monotherapy (SAPT) for approximately 1 month to approximately 36 months. Embodiment 95. The method of Embodiment 94, characterized in that antiplatelet therapy (SAPT) is performed for approximately 3 to 12 months. Embodiment 96. The method of Embodiment 94, characterized in that antiplatelet therapy (SAPT) is performed for approximately 6 to 12 months. Appearance 97. The method of Appearance 94, wherein antiplatelet therapy is characterized by the implementation of SAPT for 3 months. Embodiment 98. The method of Embodiment 94, wherein antiplatelet therapy is characterized by the implementation of SAPT for 6 months. Apparatus 99. The method of Apparatus 94, wherein antiplatelet therapy is characterized by the implementation of SAPT for 12 months. Apparatus 100. The method of Apparatus 94, wherein antiplatelet therapy is characterized by the implementation of SAPT for 24 months. Embodiment 101. Any one of Embodiments 94 to 100, wherein SAPT is selected from aspirin and a P2Y12 inhibitor. Embodiment 102. Any one of Embodiments 94 to 101, wherein SAPT includes the administration of aspirin. Embodiment 103. The method of Embodiment 102, wherein aspirin is administered once a day. Embodiment 104. The method of Embodiment 102, wherein aspirin is administered once a day for approximately 3 months to approximately 3 years. Embodiment 105. The method of Embodiment 102, wherein aspirin is administered once a day for three months. Embodiment 106. The method of Embodiment 102, wherein aspirin is administered once a day for six months. Embodiment 107. The method of Embodiment 102, wherein aspirin is administered once daily for 12 months. Embodiment 108. The method of Embodiment 102, wherein aspirin is administered once daily for 24 months. Embodiment 109. The method of Embodiment 102, wherein aspirin is administered once daily for 36 months. Embodiment 110. The method of Embodiment 102, wherein aspirin is administered twice a day. Embodiment 111. The method of Embodiment 102, wherein 75 mg to 100 mg of aspirin is administered twice a day. Embodiment 112. The method of Embodiment 102, wherein 75 mg to 100 mg of aspirin is administered once daily for 12 months. Embodiment 113. Any one of Embodiments 94 to 101, wherein SAPT includes the administration of a P2Y12 inhibitor. Embodiment 114. Any one of embodiments 94 to 101, wherein SAPT includes the administration of a P2Y12 inhibitor selected from prasugrel, clopidogrel, seratogrel, or ticagrelor. Embodiment 115. The method according to Embodiment 113 or 114, wherein the P2Y12 inhibitor is administered for approximately 3 to 6 months. Embodiment 116. The method of Embodiment 113 or 114, wherein the P2Y12 inhibitor includes clopidogrel. Embodiment 117. The method of Embodiment 113 or 114, wherein the P2Y12 inhibitor includes ticagrelor. Embodiment 118. The method of Embodiment 113 or 114, wherein the administration of a P2Y12 inhibitor includes administering 90 mg of ticagrelor twice daily. Embodiment 119. The method of Embodiment 113 or 114, wherein the administration of a P2Y12 inhibitor includes administering 90 mg of ticagrelor twice daily for 3 years. Embodiment 120. The method of Embodiment 113 or 114, wherein the administration of the P2Y12 inhibitor includes administering ticagrelor first, followed by administering 20 mg of aspirin monotherapy twice daily. Embodiment 121. The SAPT is a method of any one of Embodiments 113 or 114, wherein the SAPT includes first administering aspirin monotherapy for 30 to 90 days, followed by clopidogrel monotherapy. Embodiment 122. The SAPT is a method of any one of Embodiments 113 or 114, wherein the SAPT includes first administering aspirin monotherapy for 60 days, followed by clopidogrel monotherapy. Embodiment 123. Any one of Embodiments 94 to 122, wherein SAPT includes first administering aspirin monotherapy for 90 days, followed by clopidogrel monotherapy. Embodiment 124. Any one of embodiments 94 to 123, wherein SAPT includes first administering aspirin monotherapy followed by clopidogrel monotherapy for at least two months. Embodiment 125. Any one of Embodiments 94 to 123, wherein SAPT includes first administering aspirin monotherapy for 30 to 90 days, followed by clopidogrel monotherapy for at least 2 months. Embodiment 126. Any one of Embodiments 1 to 93, wherein the antiplatelet therapy includes dual antiplatelet therapy (DAPT). Embodiment 127. The method of Embodiment 126, wherein DAPT includes the administration of aspirin and prasugrel. Embodiment 128. The method of Embodiment 126, wherein DAPT includes a 12-month administration of aspirin and prasugrel. Embodiment 129. The method of Embodiment 126, wherein DAPT includes the administration of aspirin and clopidogrel. Embodiment 130. The method of Embodiment 126, wherein DAPT includes administration of aspirin and clopidogrel for 21 days to 12 months. Embodiment 131. The method of Embodiment 126, wherein DAPT includes a 21-day administration of aspirin and clopidogrel. Embodiment 132. The method of Embodiment 126, wherein DAPT includes a 6-month administration of aspirin and clopidogrel. Embodiment 133. The method of Embodiment 126, wherein DAPT includes a 12-month administration of aspirin and clopidogrel. Embodiment 134. The method of Embodiment 126, wherein DAPT includes the administration of aspirin and ticagrelor. Embodiment 135. The method of Embodiment 126, wherein DAPT includes a 12-month administration of aspirin and ticagrelor. Embodiment 136. The method of Embodiment 126, wherein antiplatelet therapy includes DAPT consisting of once-daily administration of aspirin 75 mg to 100 mg and administration of a P2Y12 inhibitor. Embodiment 137. The method of Embodiment 126, wherein antiplatelet therapy includes first performing DAPT followed by SAPT. Embodiment 138. The method of Embodiment 126, wherein antiplatelet therapy includes first administering DAPT followed by aspirin monotherapy. Embodiment 139. The method of Embodiment 126, wherein antiplatelet therapy includes DAPT consisting of once-daily administration of aspirin 75 mg to 100 mg and administration of a P2Y12 inhibitor for the first 12 months, followed by aspirin monotherapy for 6 months. Embodiment 140. The method of Embodiment 126, wherein antiplatelet therapy includes DAPT consisting of once-daily administration of aspirin 75 mg to 100 mg and administration of a P2Y12 inhibitor for the first 21 days, followed by aspirin monotherapy for 6 months. Embodiment 141. The method of Embodiment 126, wherein antiplatelet therapy includes DAPT consisting of once-daily administration of 75 mg to 100 mg of aspirin and once-daily administration of 75 mg of clopidogrel for the first 21 days, followed by aspirin monotherapy for 6 months. Embodiment 142. The method of Embodiment 126, wherein antiplatelet therapy includes DAPT consisting of once-daily administration of aspirin 75 mg to 100 mg and administration of a P2Y12 inhibitor for the first 21 days, followed by aspirin monotherapy for 12 months. Embodiment 143. The method of Embodiment 126, wherein the antiplatelet therapy includes DAPT consisting of once-daily administration of 75 mg to 100 mg of aspirin and twice-daily administration of 90 mg of ticagrelor. Embodiment 144. The method of Embodiment 126, wherein the antiplatelet therapy includes DAPT consisting of administering 75 mg to 100 mg of aspirin once daily and 90 mg of ticagrelor twice daily for 12 months. Embodiment 145. The method of Embodiment 126, wherein the antiplatelet therapy includes DAPT consisting of once-daily administration of 81-100 mg of aspirin and twice-daily administration of 90 mg of ticagrelor. Embodiment 146. The method of Embodiment 126, wherein the antiplatelet therapy includes DAPT consisting of administering 81-100 mg of aspirin once daily and 90 mg of ticagrelor twice daily for three years. Embodiment 147. The method of Embodiment 126, wherein antiplatelet therapy includes DAPT consisting of once-daily administration of 75-100 mg of aspirin and twice-daily administration of 90 mg of ticagrelor for the first 12 months, followed by administration of 75-100 mg of aspirin monotherapy once daily for 12 months. Embodiment 148. The method of Embodiment 126, wherein antiplatelet therapy includes DAPT consisting of once-daily administration of 75 mg to 100 mg of aspirin and twice-daily administration of 90 mg of ticagrelor for the first 12 months, followed by administration of 90 mg of ticagrelor twice-daily for 23 months. Embodiment 149. Any one of the embodiments wherein the regimen maintains a clinical benefit of reduced incidence of ischemic stroke over a 90-day treatment period. Embodiment 150. Any one of the embodiments wherein the clinical benefit of a reduced incidence of ischemic stroke is maintained over a 180-day treatment period. Embodiment 151. Any one of the embodiments wherein the clinical benefit of a reduced incidence of ischemic stroke is maintained over a 12-month treatment period. Embodiment 152. Any one of the embodiments described above, wherein the implementation of the regimen reduces the patient's factor XI coagulation activity by approximately 7% to approximately 20% compared to baseline. Embodiment 153. Any one of the above embodiments, wherein the regimen is implemented to prolong the activated partial thromboplastin time (aPTT) by approximately 27% to approximately 64% compared to baseline. Embodiment 154. Any one of the above embodiments, wherein administration does not statistically significantly increase the incidence of major hemorrhagic complications. Embodiment 155. Any one of the above embodiments, wherein the pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is a solid oral pharmaceutical composition. Embodiment 156. The method of Embodiment 155, wherein the solid oral pharmaceutical composition is a tablet. Embodiment 157. The method of Embodiment 156, wherein the tablets are immediately released. Embodiment 158. Any one of the embodiments described above, wherein the human patient is unable to swallow tablet dosage forms. Embodiment 159. Any one of embodiments 156 to 158, wherein tablets are dispersed in an aqueous medium to form an aqueous dispersion. Embodiment 160. The method of Embodiment 159, wherein the aqueous medium is water, saline solution, phosphate buffer, plant juice, or fruit juice such as applesauce. Embodiment 161. The method according to Embodiment 159 or Embodiment 160, wherein the aqueous dispersion is administered to a human patient via a nasogastric tube or spoon. Embodiment 162. Any one of the above embodiments, wherein the pharmaceutical composition, which is an oral tablet, is administered orally as an aqueous dispersion by dispersing it in an aqueous medium in less than one minute. Embodiment 163. Any one of the above embodiments, wherein the pharmaceutical composition includes an amorphous milbexian formed by mixing polymers. Embodiment 164. Any one of the above embodiments, wherein the pharmaceutical composition comprises an amorphous solid dispersion prepared by spray drying, comprising 75% w / w milbexian and 25% w / w HPMC-AS. Embodiment 165. Any one of the above embodiments, wherein no clinically significant QTc interval prolongation is observed by the above method.

[0294] Usage of Milbexian Embodiment 1. Use of milbexian in a method for preventing cerebrovascular or cardiovascular adverse events in human patients with acute coronary syndrome, characterized in that the method involves administering to a human patient a regimen comprising: (i) administration of a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof); and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; the pharmaceutical composition administered twice daily. Embodiment 2. Use of Milbexian according to Embodiment 1, wherein the antiplatelet therapy is the administration of a P2Y12 inhibitor. Embodiment 3. Use of milbexian according to Embodiment 2, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel. Embodiment 4. Use of milbexian according to any one of Embodiments 1 to 3, wherein the antiplatelet therapy is the administration of aspirin. Embodiment 5. Use of milbexian according to any one of Embodiments 1 to 4, in which a human patient is treated with a combination of aspirin and clopidogrel from day 1 to day 21, followed by aspirin monotherapy for at least 90 days. Embodiment 6. Use of milbexian according to Embodiment 5, wherein the patient is treated with aspirin and / or clopidogrel without adjusting the dose of milbexian. Embodiment 7. Use of milbexian in any one of the embodiments described above, wherein milbexian is used for the primary prevention of cerebrovascular adverse events or cardiovascular adverse events. Embodiment 8. Use of milbexian in any one of the embodiments described above, wherein milbexian is used for secondary prevention of cerebrovascular adverse events or cardiovascular adverse events. Apparatus 9. Use of any one of the milbexian in Apparatus 1 to 8, wherein the cerebrovascular adverse event or cardiovascular adverse event includes one or more strokes, heart attacks, or death. Appearance 10. A milbexian according to any one of Appearances 1 to 9, wherein the cerebrovascular adverse event or cardiovascular adverse event occurs in an organ selected from the heart, brain, limbs, blood circulation system, or blood vessels. Apparatus 11. Use of any one of the milbexian from Apparatus 1 to 10, wherein the cerebrovascular adverse event or cardiovascular adverse event includes one or more major cardiovascular adverse events (MACE) selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, ischemic stroke, and combinations thereof. Apparatus 12. Use of any one of the milbexian in Apparatus 1 to 11, wherein cerebrovascular adverse events or cardiovascular adverse events include one or more major lower limb adverse events (MALE) including one or more of acute limb ischemia, chronic limb ischemia, or major amputation; symptomatic venous thromboembolic adverse events; and major vascular adverse events (MAVE) selected from the group consisting of these and combinations thereof. Embodiment 13. Use of any one of the milbexian embodiments 1 to 12, wherein the cerebrovascular adverse event or cardiovascular adverse event is selected from the group consisting of arrhythmogenic cardiomyopathy (ACM), non-fatal myocardial infarction, ischemic stroke, and combinations thereof. Embodiment 14. Use of any one of the milbexian embodiments 1 to 11, wherein the cerebrovascular adverse event or cardiovascular adverse event includes cardiovascular death. Apparatus 15. Use of any one of the milbexian formulations from Apparatus 1 to 10, wherein the cerebrovascular adverse event or cardiovascular adverse event includes arrhythmogenic cardiomyopathy (ACM). Embodiment 16. Use of milbexian in a method for preventing cardiovascular adverse events in a human patient diagnosed with acute coronary syndrome, the method comprising administering to the human patient a regimen comprising (i) a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; i. Administer the pharmaceutical composition twice a day; and ii. The cardiovascular adverse event must be selected from one or more of the following groups: all-cause mortality (ACM); cardiovascular (CV) death; myocardial infarction (MI); unstable angina (UA); any stroke or any stroke (ischemic, hemorrhagic, or of unknown cause); ischemic stroke; acute limb ischemia (ALI); large vessel (non-traumatic) limb amputation; symptomatic venous thromboembolism (VTE: pulmonary embolism (PE), deep vein thrombosis (DVT)); coronary revascularization due to ischemia; stent thrombosis; hospitalization for any cause (classified as (1) planned or unplanned, (2) hospitalization due to arterial thromboembolism or venous thromboembolism, or hospitalization not falling under either category); and transient ischemic attack (TIA). It is characterized by the following. Apparatus 17. Use of milbexian as in Apparatus 16, wherein the cardiovascular adverse event is one or more of CV death, MI, or ischemic stroke. Embodiment 18. Use of milbexian in a method for reducing the incidence of one or more thrombotic adverse events selected from newly occurring ischemic stroke, MI, or all-cause mortality, wherein in a human patient diagnosed with acute coronary syndrome, the method is characterized by administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising about 25 mg to about 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients; and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; the pharmaceutical composition administered twice daily. Embodiment 19. Use of milbexian in a method for preventing ischemic stroke, wherein in a human patient diagnosed with acute coronary syndrome, the method is characterized by administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients; and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; the pharmaceutical composition twice daily. Apparatus 20. Use of milbexian according to Apparatus 18 or Apparatus 19, wherein the regimen maintains a clinical benefit of reduced incidence of ischemic stroke over a 90-day treatment period. Embodiment 21. Use of any one of the above embodiments, wherein the implementation of the regimen reduces the patient's factor XI coagulation activity by approximately 7% to approximately 20% from baseline. Embodiment 22. Use of any one of the above embodiments of a milbexian, wherein the regimen, upon implementation, prolongs the activated partial thromboplastin time (aPTT) by approximately 27% to approximately 64% compared to baseline. Embodiment 23. Use of milbexian in any one of the embodiments described above, wherein administration does not statistically significantly increase the incidence of major hemorrhagic complications. Embodiment 24. Use of milbexian according to any one of the embodiments described above, wherein the pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is a solid oral pharmaceutical composition. Embodiment 25. Use of milbexian according to Embodiment 24, wherein the solid oral pharmaceutical composition is a tablet. Embodiment 26. Use of milbexian according to Embodiment 25, wherein the tablets are immediately released. Embodiment 27. Use of milbexian according to Embodiment 25 or Embodiment 26, wherein the disintegration time of the tablet in water is less than 20 seconds. Embodiment 28. Use of milbexian in any one of the embodiments described above, wherein administration results in a plasma half-life of milbexian of approximately 13 hours to approximately 16 hours. Embodiment 29. Use of milbexian in any one of the embodiments described above, wherein the plasma concentration of milbexian reaches a steady state in approximately 3 to 6 days after administration. Embodiment 30. Use of milbexian according to any one of the embodiments described above, wherein a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered regardless of the timing of meals. Embodiment 31. Use of milbexian in any one of the embodiments described above, wherein the human patient is unable to swallow tablet dosage forms. Embodiment 32. Use of any one of the milbexian embodiments 25 to 31, wherein the tablets are dispersed in an aqueous medium to form an aqueous dispersion. Embodiment 33. Use of the milbexian of Embodiment 32, wherein the aqueous medium is water, saline solution, phosphate buffer, plant juice, or fruit juice such as applesauce. Embodiment 34. Use of milbexian according to Embodiment 32 or Embodiment 33, wherein the aqueous dispersion is administered to a human patient via a nasogastric tube or spoon. Embodiment 35. Use of milbexian according to any one of Embodiments 25 to 34, wherein the pharmaceutical composition, which is an oral tablet, is administered orally as an aqueous dispersion by dispersing it in an aqueous medium in less than one minute. Embodiment 36. Use of milbexian in a method for preventing cerebrovascular or cardiovascular adverse events in human patients with acute coronary syndrome, the method comprising administering to a human patient, by oral administration, a regimen comprising (i) a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and (ii) antiplatelet therapy, wherein the pharmaceutical composition is administered twice daily. Embodiment 37. Use of milbexian according to Embodiment 36, wherein the antiplatelet therapy is the administration of a P2Y12 inhibitor. Embodiment 38. Use of milbexian according to Embodiment 37, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel. Embodiment 39. Use of milbexian according to any one of Embodiments 36-38, wherein the antiplatelet therapy is the administration of aspirin. Embodiment 40. Use of milbexian according to any one of Embodiments 36-39, wherein a human patient is treated with a combination of aspirin and clopidogrel from day 1 to day 21, followed by aspirin monotherapy for at least 90 days. Embodiment 41. Use of milbexian according to Embodiment 40, wherein the patient is treated with aspirin and / or clopidogrel without adjusting the dose of milbexian. Embodiment 42. Use of milbexian according to any one of Embodiments 36 to 41, wherein milbexian is used for the primary prevention of cerebrovascular adverse events or cardiovascular adverse events. Embodiment 43. Use of milbexian according to any one of Embodiments 36 to 42, wherein milbexian is used for secondary prevention of cerebrovascular adverse events or cardiovascular adverse events. Apparatus 44. Use of any one of the milbexian described in Apparatus 36 to 43, wherein the cerebrovascular adverse event or cardiovascular adverse event includes one or more of stroke, heart attack, or death. Apparatus 45. Use of any one of the milbexian in Apparatus 36 to 44, wherein the cerebrovascular adverse event or cardiovascular adverse event occurs in an organ selected from the heart, brain, limbs, blood circulation system, or blood vessels. Appearance 46. Use of any one of the milbexian described in Appearances 36 to 45, wherein the cerebrovascular adverse event or cardiovascular adverse event includes one or more major cardiovascular adverse events (MACE) selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, ischemic stroke, and combinations thereof. Appearance 47. Use of any one of the milbexian in Appearances 36 to 46, wherein cerebrovascular adverse events or cardiovascular adverse events include one or more major lower limb adverse events (MALE) including one or more of acute limb ischemia, chronic limb ischemia, or major amputation; symptomatic venous thromboembolic adverse events; and combinations thereof, of which are major vascular adverse events (MAVE). Appearance 48. Use of any one of the milbexian in Appearances 36 to 47, wherein the cerebrovascular adverse event or cardiovascular adverse event is selected from the group consisting of arrhythmogenic cardiomyopathy (ACM), non-fatal myocardial infarction, ischemic stroke, and combinations thereof. Appearance 49. Use of any one of the milbexian in Appearances 36 to 47, wherein the cerebrovascular adverse event or cardiovascular adverse event includes cardiovascular death. Apparatus 50. Use of any one of the milbexian formulations from Apparatus 36 to 48, wherein the cerebrovascular adverse event or cardiovascular adverse event includes arrhythmogenic cardiomyopathy (ACM). Appearance 51. Use of milbexian in a method for preventing cardiovascular adverse events in a human patient diagnosed with acute coronary syndrome, the method comprising (i) administering 25.0 mg of milbexian twice daily to the human patient, and (ii) implementing a regimen including antiplatelet therapy; The cardiovascular adverse event is one or more of the following: all-cause mortality (ACM); cardiovascular (CV) death; myocardial infarction (MI); unstable angina (UA); any stroke or any stroke (ischemic, hemorrhagic, or of unknown cause); ischemic stroke; acute limb ischemia (ALI); large vessel (non-traumatic) limb amputation; symptomatic venous thromboembolism (VTE: pulmonary embolism (PE), deep vein thrombosis (DVT)); coronary revascularization due to ischemia; stent thrombosis; hospitalization for any cause (classified as (1) planned or unplanned, (2) hospitalization due to arterial thromboembolism or venous thromboembolism, or hospitalization not falling under either of the above); or transient ischemic attack (TIA); and The following clinical outcomes: (1) The plasma concentration profile of milbexian reaches a steady state in approximately 6 days; (2)(i) Steady state C max (ii) Steady state C max (iii) The mean (standard deviation) of the ng / mL is 346 (129) ng / mL, and the steady-state AUC 0-24 (iv) Steady-state AUC 0-24 Reaching a steady-state plasma concentration profile of mirbexian characterized by a mean (standard deviation) of 7290 (2940) ng*h / mL; (3) The patient's QTc change from baseline is less than 10 milliseconds; (4) AUC or C in a steady statemax No clinically relevant effects are observed for any bleeding resulting from exposure to Milbexian, as assessed by the following criteria; (5) Minimal impairment of hemostatic function in human patients; (6) No clinically significant change in prothrombin time is observed, and the maximum mean change from baseline is approximately 5%; or (7) Any combination of the clinical outcomes described above Achieve at least one of the following It is characterized by the following. Appearance 52. Use of milbexian in a method for preventing cardiovascular adverse events in a human patient diagnosed with acute coronary syndrome, the method comprising (i) administering 25.0 mg of milbexian twice daily to the human patient, and (ii) implementing a regimen including antiplatelet therapy; The cardiovascular adverse event is one or more of the following: all-cause mortality (ACM); cardiovascular (CV) death; myocardial infarction (MI); unstable angina (UA); any stroke or any stroke (ischemic, hemorrhagic, or of unknown cause); ischemic stroke; acute limb ischemia (ALI); large vessel (non-traumatic) limb amputation; symptomatic venous thromboembolism (VTE: pulmonary embolism (PE), deep vein thrombosis (DVT)); coronary revascularization due to ischemia; stent thrombosis; hospitalization for any cause (classified as (1) planned or unplanned, (2) hospitalization due to arterial thromboembolism or venous thromboembolism, or hospitalization not falling under either category); or transient ischemic attack (TIA). It is characterized by the following. Embodiment 53. Use of milbexian in a method for preventing all-cause mortality in a human patient diagnosed with acute coronary syndrome, the method characterized by (i) administering 25.0 mg of milbexian twice daily to a human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 54. Use of milbexian in a method for preventing cardiovascular death in a human patient diagnosed with acute coronary syndrome, the method characterized by (i) administering 25.0 mg of milbexian twice daily to a human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 55. Use of milbexian in a method for preventing myocardial infarction in a human patient diagnosed with acute coronary syndrome, the method characterized by (i) administering 25.0 mg of milbexian twice daily to a human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 56. Use of milbexian in a method for preventing stroke in a human patient diagnosed with acute coronary syndrome, the method characterized by (i) administering 25.0 mg of milbexian twice daily to a human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 57. Use of milbexian in a method for preventing ischemic stroke in a human patient diagnosed with acute coronary syndrome, the method characterized by (i) administering 25.0 mg of milbexian twice daily to a human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 58. Use of milbexian in a method for preventing ischemic stroke in a human patient diagnosed with acute coronary syndrome, the method characterized by (i) administering 25.0 mg of milbexian twice daily to a human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 59. Use of milbexian in a method for preventing unstable angina in a human patient diagnosed with acute coronary syndrome, the method characterized by (i) administering 25.0 mg of milbexian twice daily to a human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 60. Use of milbexian in a method for preventing acute limb ischemia in a human patient diagnosed with acute coronary syndrome, the method being characterized by (i) administering 25.0 mg of milbexian twice daily to a human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 61. Use of milbexian in a method for preventing macrovascular (non-traumatic) limb amputation in a human patient diagnosed with acute coronary syndrome, the method characterized by (i) administering 25.0 mg of milbexian twice daily to a human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 62. Use of milbexian in a method for preventing symptomatic venous thromboembolism in a human patient diagnosed with acute coronary syndrome, the method characterized by (i) administering 25.0 mg of milbexian twice daily to a human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 63. Use of milbexian in a method for preventing pulmonary embolism in a human patient diagnosed with acute coronary syndrome, the method characterized by (i) administering 25.0 mg of milbexian twice daily to a human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 64. Use of milbexian in a method for preventing deep vein thrombosis in a human patient diagnosed with acute coronary syndrome, the method characterized by (i) administering 25.0 mg of milbexian twice daily to a human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 65. Use of milbexian in a method for preventing deep vein thrombosis in a human patient diagnosed with acute coronary syndrome, the method characterized by (i) administering 25.0 mg of milbexian twice daily to a human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 66. Use of milbexian in a method for preventing ischemia-based coronary revascularization in a human patient diagnosed with acute coronary syndrome, the method characterized by (i) administering 25.0 mg of milbexian twice daily to a human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 67. Use of milbexian in a method for preventing stent thrombosis in a human patient diagnosed with acute coronary syndrome, the method characterized by (i) administering 25.0 mg of milbexian twice daily to a human patient, and (ii) implementing a regimen including antiplatelet therapy. Apparatus 68. Use of milbexian in a method for preventing hospitalization for any cause in a human patient diagnosed with acute coronary syndrome, which is classified as (a) planned or unplanned, (b) hospitalization due to arterial or venous thromboembolism, or hospitalization not falling under either category, the method being characterized by (i) administering 25.0 mg of milbexian twice daily to a human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 69. Use of milbexian in a method for preventing transient ischemic attacks in human patients diagnosed with acute coronary syndrome, the method characterized by (i) administering 25.0 mg of milbexian twice daily to a human patient, and (ii) implementing a regimen including antiplatelet therapy. Embodiment 70. A method for preventing cerebrovascular adverse events in human patients with acute coronary syndrome, comprising administering a regimen to a human patient orally twice daily, comprising (i) 25.0 mg of milbexian and (ii) antiplatelet therapy. Embodiment 71. Use of milbexian in a method for preventing cardiovascular adverse events in human patients with acute coronary syndrome, the method characterized by administering a regimen to a human patient orally twice daily, comprising (i) 25.0 mg of milbexian and (ii) antiplatelet therapy. Embodiment 72. Use of milbexian in a method for preventing cerebrovascular adverse events in human patients with acute coronary syndrome, the method comprising administering to a human patient orally a regimen comprising (i) a pharmaceutical composition comprising 25 mg of milbexian and a pharmaceutically acceptable excipient; and (ii) antiplatelet therapy; the pharmaceutical composition being administered twice daily. Embodiment 73. Use of milbexian in a method for preventing cardiovascular adverse events in human patients with acute coronary syndrome, the method comprising administering to a human patient a regimen comprising (i) a pharmaceutical composition comprising 25 mg of milbexian and a pharmaceutically acceptable excipient; and (ii) antiplatelet therapy; the pharmaceutical composition being administered twice daily. Appearance 74. Use of any one of the milbexian embodiments 70 to 73, wherein cerebrovascular adverse events or cardiovascular adverse events include ischemic stroke. Apparatus 75. Use of any one of the milbexian in Apparatus 70 to 74, wherein the cerebrovascular adverse event or cardiovascular adverse event includes one or more of stroke, heart attack, or death. Apparatus 76. Use of any one of the milbexian described in Apparatus 70 to 75, wherein the cerebrovascular adverse event or cardiovascular adverse event occurs in an organ selected from the heart, brain, limbs, blood circulation system, or blood vessels. Appearance 77. Use of any one of the milbexian described in Appearances 70 to 76, wherein the cerebrovascular adverse events or cardiovascular adverse events include one or more major cardiovascular adverse events (MACE) selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, ischemic stroke, and combinations thereof. Appearance 78. Use of any one of the milbexian in Appearances 70 to 77, wherein cerebrovascular adverse events or cardiovascular adverse events include one or more major lower limb adverse events (MALE) including one or more of acute limb ischemia, chronic limb ischemia, or major amputation; symptomatic venous thromboembolic adverse events; and major vascular adverse events (MAVE) selected from the group consisting of a combination thereof. Appearance 79. Use of any one of the milbexian described in Appearances 70 to 78, wherein the cerebrovascular adverse event or cardiovascular adverse event is selected from the group consisting of arrhythmogenic cardiomyopathy (ACM), non-fatal myocardial infarction, ischemic stroke, and combinations thereof. Appearance 80. Use of milbexian according to any one of Appearances 70 to 79, wherein the cerebrovascular adverse event or cardiovascular adverse event includes cardiovascular death. Apparatus 81. Use of any one of the milbexian of Apparatus 70 to 80, wherein the cerebrovascular adverse event or cardiovascular adverse event includes arrhythmogenic cardiomyopathy (ACM). Embodiment 82. Use of milbexian in a method for preventing ischemic stroke in human patients with acute coronary syndrome, the method characterized by administering a regimen to a human patient orally twice daily, comprising (i) 25.0 mg of milbexian and (ii) antiplatelet therapy. Embodiment 83. Use of milbexian in any one of the embodiments described above, wherein the plasma concentration profile of milbexian reaches a steady state in approximately 3 days after administration. Apparatus 84. Upon administration, the steady-state plasma concentration profile of milbexian is as follows: (i) Steady state C max The range is approximately 217 ng / mL to approximately 475 ng / mL. (ii) Steady state C max The mean (standard deviation) is 346 (129) ng / mL. (iii) AUC in steady state 0-24 The values ​​are approximately 4350 ng*h / mL to approximately 10230 ng*h / mL, and (iv) Steady-state AUC 0-24 The mean (standard deviation) is 7290 (2940) ng*h / mL. The use of any one of the above embodiments of the Milbexian, characterized by the following: Embodiment 85. Use of any one of the above embodiments of milbexian, wherein administration does not result in a clinically significant prolongation of the QTc interval. Apparatus 86. Administration brings about a steady-state AUC or C max The use of any one of the above-described embodiments of milbexian, in which no clinically relevant effects are observed for any bleeding due to milbexian exposure, as evaluated by [method]. Embodiment 87. Use of any one of the above embodiments of milbexian in which administration causes minimal impairment of hemostatic function in human patients. Embodiment 88. Use of milbexian in any one of the embodiments described above, wherein the regimen includes an immediate-release tablet. Appearance 89. Use of Milbexian according to Appearance 88, wherein the disintegration time of the immediate-release tablet in water is less than 20 seconds at 37°C. Embodiment 90. Use of milbexian in any one of the embodiments described above, wherein administration results in a terminal phase half-life of milbexian in plasma of approximately 13 hours to approximately 16 hours. Embodiment 91. Use of any one of the above embodiments of the Milbexian, wherein the regimen is implemented regardless of the timing of meals. Embodiment 92. Use of milbexian according to any one of Embodiments 88 to 91, wherein the immediate-release tablets are dispersed in an aqueous medium to form an aqueous dispersion. Embodiment 93. Use of the Milbexian of Embodiment 92, wherein the aqueous medium contains water or applesauce. Embodiment 94. Use of milbexian according to any one of the embodiments described above, characterized in that antiplatelet therapy is performed as antiplatelet monotherapy (SAPT) for approximately 1 month to approximately 36 months. Embodiment 95. Use of milbexian according to Embodiment 94, characterized in that antiplatelet therapy is performed for approximately 3 months to approximately 12 months using SAPT. Embodiment 96. Use of milbexian according to Embodiment 94, characterized in that antiplatelet therapy is performed for approximately 6 to 12 months using SAPT. Appearance 97. Use of milbexian according to Appearance 94, wherein antiplatelet therapy is characterized by the implementation of a 3-month SAPT. Appearance 98. Use of milbexian according to Appearance 94, wherein antiplatelet therapy is characterized by the implementation of a 6-month SAPT. Appearance 99. Use of milbexian according to Appearance 94, wherein antiplatelet therapy is characterized by the implementation of SAPT for 12 months. Apparatus 100. Use of milbexian according to Apparatus 94, wherein antiplatelet therapy is characterized by the implementation of SAPT for 24 months. Embodiment 101. Use of any one of the milbexian embodiments 94-100, wherein the SAPT is selected from aspirin and a P2Y12 inhibitor. Embodiment 102. Use of milbexian according to any one of Embodiments 94-101, wherein the SAPT includes the administration of aspirin. Embodiment 103. Use of milbexian according to Embodiment 102, in which aspirin is administered once daily. Embodiment 104. Use of milbexian according to Embodiment 102, in which aspirin is administered once a day for approximately 3 months to approximately 3 years. Embodiment 105. Use of milbexian according to Embodiment 102, wherein aspirin is administered once daily for three months. Embodiment 106. Use of milbexian according to Embodiment 102, wherein aspirin is administered once daily for six months. Embodiment 107. Use of milbexian according to Embodiment 102, wherein aspirin is administered once daily for 12 months. Embodiment 108. Use of milbexian according to Embodiment 102, wherein aspirin is administered once daily for 24 months. Embodiment 109. Use of milbexian according to Embodiment 102, wherein aspirin is administered once daily for 36 months. Embodiment 110. Use of milbexian according to Embodiment 102, in which aspirin is administered twice daily. Embodiment 111. Use of milbexian according to Embodiment 102, in which 75 mg to 100 mg of aspirin is administered twice a day. Embodiment 112. Use of milbexian according to Embodiment 102, in which 75 mg to 100 mg of aspirin is administered once daily for 12 months. Embodiment 113. Use of any one of the milbexian embodiments 94-101, wherein SAPT includes the administration of a P2Y12 inhibitor. Embodiment 114. Use of milbexian in any one of Embodiments 94-101, wherein SAPT includes the administration of a P2Y12 inhibitor selected from prasugrel, clopidogrel, seratogrel, or ticagrelor. Embodiment 115. Use of milbexian according to Embodiment 113 or 114, wherein the P2Y12 inhibitor is administered for approximately 3 to 6 months. Embodiment 116. Use of milbexian according to Embodiment 113 or 114, wherein the P2Y12 inhibitor contains clopidogrel. Embodiment 117. Use of milbexian according to Embodiment 113 or 114, wherein the P2Y12 inhibitor contains ticagrelor. Embodiment 118. Use of milbexian according to Embodiment 113 or 114, wherein the administration of a P2Y12 inhibitor includes administering 90 mg of ticagrelor twice daily. Embodiment 119. Use of milbexian according to Embodiment 113 or 114, wherein the administration of a P2Y12 inhibitor includes administering 90 mg of ticagrelor twice daily for 3 years. Embodiment 120. Use of milbexian according to Embodiment 113 or 114, wherein the administration of a P2Y12 inhibitor includes administering ticagrelor first, followed by 20 mg of aspirin monotherapy twice daily. Embodiment 121. Use of milbexian in either Embodiment 113 or 114, wherein the SAPT includes first administering aspirin monotherapy for 30 to 90 days, followed by clopidogrel monotherapy. Embodiment 122. Use of milbexian in either Embodiment 113 or 114, wherein the SAPT includes first administering aspirin monotherapy for 60 days, followed by clopidogrel monotherapy. Embodiment 123. Use of milbexian as described in any one of Embodiments 94-122, wherein SAPT includes first administering aspirin monotherapy for 90 days, followed by clopidogrel monotherapy. Embodiment 124. Use of milbexian according to any one of Embodiments 94-122, wherein the SAPT includes first administering aspirin monotherapy followed by clopidogrel monotherapy for at least two months. Embodiment 125. Use of milbexian according to any one of Embodiments 94-122, wherein the SAPT includes first administering aspirin monotherapy for 30 to 90 days, followed by clopidogrel monotherapy for at least 2 months. Embodiment 126. Use of milbexian as described in any one of Embodiments 1 to 93, wherein antiplatelet therapy includes dual antiplatelet therapy (DAPT). Embodiment 127. Use of milbexian according to Embodiment 126, wherein DAPT includes the administration of aspirin and prasugrel. Embodiment 128. Use of milbexian according to Embodiment 126, wherein DAPT includes a 12-month administration of aspirin and prasugrel. Embodiment 129. Use of milbexian according to Embodiment 126, wherein DAPT includes the administration of aspirin and clopidogrel. Embodiment 130. Use of milbexian according to Embodiment 126, wherein DAPT includes administration of aspirin and clopidogrel for 21 days to 12 months. Embodiment 131. Use of milbexian according to Embodiment 126, wherein DAPT includes a 21-day administration of aspirin and clopidogrel. Embodiment 132. Use of milbexian according to Embodiment 126, wherein DAPT includes a 6-month administration of aspirin and clopidogrel. Embodiment 133. Use of milbexian according to Embodiment 126, wherein DAPT includes a 12-month administration of aspirin and clopidogrel. Embodiment 134. Use of milbexian according to Embodiment 126, wherein DAPT includes the administration of aspirin and ticagrelor. Embodiment 135. Use of milbexian according to Embodiment 126, wherein DAPT includes a 12-month administration of aspirin and ticagrelor. Embodiment 136. Use of milbexian according to Embodiment 126, wherein antiplatelet therapy includes DAPT consisting of once-daily administration of aspirin 75 mg to 100 mg and administration of a P2Y12 inhibitor. Embodiment 137. Use of milbexian according to Embodiment 126, wherein antiplatelet therapy includes first DAPT followed by SAPT. Embodiment 138. Use of milbexian according to Embodiment 126, wherein antiplatelet therapy includes first DAPT followed by aspirin monotherapy. Embodiment 139. Use of milbexian as in Embodiment 126, wherein antiplatelet therapy includes DAPT consisting of once-daily administration of aspirin 75 mg to 100 mg and administration of a P2Y12 inhibitor for the first 12 months, followed by aspirin monotherapy for 6 months. Embodiment 140. Use of milbexian according to Embodiment 126, wherein antiplatelet therapy includes DAPT consisting of once-daily administration of aspirin 75 mg to 100 mg and administration of a P2Y12 inhibitor for the first 21 days, followed by aspirin monotherapy for 6 months. Embodiment 141. Use of milbexian according to Embodiment 126, wherein antiplatelet therapy includes DAPT consisting of once-daily administration of aspirin 75 mg to 100 mg and once-daily administration of 75 mg clopidogrel for the first 21 days, followed by aspirin monotherapy for 6 months. Embodiment 142. Use of milbexian according to Embodiment 126, wherein antiplatelet therapy includes DAPT consisting of once-daily administration of aspirin 75 mg to 100 mg and administration of a P2Y12 inhibitor for the first 21 days, followed by aspirin monotherapy for 12 months. Embodiment 143. Use of milbexian according to Embodiment 126, wherein antiplatelet therapy includes DAPT consisting of once-daily administration of 75 mg to 100 mg of aspirin and twice-daily administration of 90 mg of ticagrelor. Embodiment 144. Use of milbexian according to Embodiment 126, wherein antiplatelet therapy includes DAPT consisting of administering aspirin 75 mg to 100 mg once daily and ticagrelor 90 mg twice daily for 12 months. Embodiment 145. Use of milbexian according to Embodiment 126, wherein antiplatelet therapy includes DAPT consisting of 81-100 mg of aspirin once daily and 90 mg of ticagrelor twice daily. Embodiment 146. Use of milbexian according to Embodiment 126, wherein antiplatelet therapy includes DAPT consisting of administering 81-100 mg of aspirin once daily and 90 mg of ticagrelor twice daily for three years. Embodiment 147. Use of milbexian according to Embodiment 126, wherein antiplatelet therapy includes DAPT consisting of once-daily administration of 75-100 mg of aspirin and twice-daily administration of 90 mg of ticagrelor for the first 12 months, followed by administration of 75-100 mg of aspirin monotherapy once daily for 12 months. Embodiment 148. Use of milbexian according to Embodiment 126, wherein antiplatelet therapy includes DAPT consisting of once-daily administration of aspirin 75 mg to 100 mg and twice-daily administration of ticagrelor 90 mg for the first 12 months, followed by administration of 90 mg of ticagrelor twice-daily for 23 months. Embodiment 149. Use of any one of the above embodiments of milbexian, wherein the regimen maintains a clinical benefit of reduced incidence of ischemic stroke over a 90-day treatment period. Embodiment 150. Use of any one of the above embodiments of milbexian, wherein the clinical benefit of reduced incidence of ischemic stroke is maintained over a 180-day treatment period. Embodiment 151. Use of any one of the above embodiments of milbexian, wherein the clinical benefit of reduced incidence of ischemic stroke is maintained over a 12-month treatment period. Embodiment 152. Use of any one of the above embodiments, wherein the implementation of the regimen reduces the patient's factor XI coagulation activity by approximately 7% to approximately 20% compared to baseline. Embodiment 153. Use of any one of the above embodiments of a milbexian, wherein the implementation of the regimen prolongs the activated partial thromboplastin time (aPTT) by approximately 27% to approximately 64% compared to baseline. Embodiment 154. Use of milbexian in any one of the embodiments described above, wherein administration does not statistically significantly increase the incidence of major hemorrhagic complications. Embodiment 155. Use of milbexian according to any one of the embodiments described above, wherein the pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is a solid oral pharmaceutical composition. Embodiment 156. Use of milbexian according to Embodiment 155, wherein the solid oral pharmaceutical composition is a tablet. Embodiment 157. Use of milbexian according to Embodiment 156, wherein the tablets are immediate-release tablets. Embodiment 158. Use of milbexian in any one of the embodiments described above, wherein the human patient is unable to swallow tablet dosage forms. Embodiment 159. Use of milbexian according to any one of Embodiments 156 to 158, wherein the tablets are dispersed in an aqueous medium to form an aqueous dispersion. Embodiment 160. Use of the milbexian of Embodiment 159, wherein the aqueous medium is water, saline solution, phosphate buffer, plant juice, or fruit juice such as applesauce. Embodiment 161. Use of milbexian according to Embodiment 159 or Embodiment 160, wherein the aqueous dispersion is administered to a human patient via a nasogastric tube or spoon. Embodiment 162. Use of milbexian according to any one of the embodiments described above, wherein the pharmaceutical composition, which is an oral tablet, is administered orally as an aqueous dispersion by dispersing it in an aqueous medium in less than one minute. Embodiment 163. Use of milbexian according to any one of the above embodiments, wherein the pharmaceutical composition contains amorphous milbexian formed by mixing a polymer. Embodiment 164. Use of milbexian according to any one of the embodiments described above, wherein the pharmaceutical composition comprises an amorphous solid dispersion of 75% w / w milbexian and 25% w / w HPMC-AS, prepared by a spray-drying method. Embodiment 165. Use of milbexian in any one of the embodiments described above, wherein the use of milbexian does not result in a clinically significant prolongation of the QTc interval.

[0295] Other aspects Embodiment 1. A method for preventing cerebrovascular or cardiovascular adverse events in human patients with acute coronary syndrome, the method comprising administering to a human patient a regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof); and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; the pharmaceutical composition twice daily. Embodiment 2. The method of Embodiment 1, wherein the antiplatelet therapy is the administration of a P2Y12 inhibitor. Embodiment 3. The method of Embodiment 2, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel. Embodiment 4. Any one of Embodiments 1 to 3, wherein the antiplatelet therapy is the administration of aspirin. Embodiment 5. One of embodiments 1 to 4, wherein a human patient is treated with a combination of aspirin and clopidogrel from day 1 to day 21, followed by aspirin monotherapy for at least 90 days. Embodiment 6. The method of Embodiment 5, wherein the patient is treated with aspirin and / or clopidogrel without adjusting the dose of milbexian. Embodiment 7. Any one of the above embodiments for the primary prevention of cerebrovascular adverse events or cardiovascular adverse events. Embodiment 8. Any one of the above embodiments for secondary prevention of cerebrovascular adverse events or cardiovascular adverse events. Embodiment 9. Any one of Embodiments 1 to 8, wherein the cerebrovascular adverse event or cardiovascular adverse event includes one or more of stroke, heart attack, or death. Embodiment 10. Any one of Embodiments 1 to 9, wherein the cerebrovascular adverse event or cardiovascular adverse event occurs in an organ selected from the heart, brain, limbs, blood circulation system, or blood vessels. Embodiment 11. One of the methods from Embodiments 1 to 10, wherein the cerebrovascular adverse event or cardiovascular adverse event includes one or more major cardiovascular adverse events (MACE) selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, ischemic stroke, and combinations thereof. Embodiment 12. One of the methods in Embodiments 1 to 11, wherein the cerebrovascular adverse event or cardiovascular adverse event includes one or more major lower limb adverse events (MALE) including one or more of acute limb ischemia, chronic limb ischemia, or major amputation; symptomatic venous thromboembolic adverse events; and combinations thereof, comprising one or more major vascular adverse events (MAVE). Embodiment 13. One of the methods from Embodiments 1 to 12, wherein the cerebrovascular adverse event or cardiovascular adverse event is selected from the group consisting of arrhythmogenic cardiomyopathy (ACM), non-fatal myocardial infarction, ischemic stroke, and combinations thereof. Embodiment 14. Any one of Embodiments 1 to 11, wherein the cerebrovascular adverse event or cardiovascular adverse event includes cardiovascular death. Embodiment 15. Any one of Embodiments 1 to 10, wherein the cerebrovascular adverse event or cardiovascular adverse event includes arrhythmogenic cardiomyopathy (ACM). Embodiment 16. A method for preventing cardiovascular adverse events in a human patient diagnosed with acute coronary syndrome, comprising administering to the human patient a regimen comprising (i) a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; Administering the aforementioned pharmaceutical composition twice a day; and The cardiovascular adverse event must be selected from one or more of the following groups: all-cause mortality (ACM); cardiovascular (CV) death; myocardial infarction (MI); unstable angina (UA); any stroke or any stroke (ischemic, hemorrhagic, or of unknown cause); ischemic stroke; acute limb ischemia (ALI); large vessel (non-traumatic) limb amputation; symptomatic venous thromboembolism (VTE: pulmonary embolism (PE), deep vein thrombosis (DVT)); coronary revascularization due to ischemia; stent thrombosis; hospitalization for any cause (classified as (1) planned or unplanned, (2) hospitalization due to arterial thromboembolism or venous thromboembolism, or hospitalization not falling under either category); and transient ischemic attack (TIA). A method characterized by the following. Embodiment 17. The method of Embodiment 16, wherein the implementation of the regimen results in at least a 25% reduction in the relative risk (RRR) of symptomatic venous thromboembolism (VTE: pulmonary embolism (PE), deep vein thrombosis (DVT)) in patients compared to the placebo group, without an increased risk of bleeding. Apparatus 18. The method of Apparatus 16, wherein the cardiovascular adverse event is one or more of CV death, MI, or ischemic stroke. Embodiment 19. A method for reducing the incidence of one or more thrombotic adverse events selected from new-onset ischemic stroke, MI, or all-cause mortality in a human patient diagnosed with acute coronary syndrome, characterized by administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising about 25 mg to about 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients; and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; the pharmaceutical composition administered twice daily. Embodiment 20. The method of Embodiment 19, wherein the implementation of the regimen results in a relative risk of 0.85 or less compared to placebo. Embodiment 21. A method for preventing ischemic stroke in a human patient diagnosed with acute coronary syndrome, characterized by administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients; and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; the pharmaceutical composition twice daily. Embodiment 22. The method of Embodiment 21, wherein the implementation of the regimen results in at least a 25% reduction in the relative risk (RRR) of clinical ischemic stroke incidence in patients compared to the placebo group, without an increased risk of bleeding. Embodiment 23. The method of Embodiment 21 or Embodiment 22, wherein the regimen maintains a clinical benefit of reduced incidence of ischemic stroke over a 90-day treatment period. Embodiment 24. Any one of the embodiments described above, wherein the implementation of the regimen reduces the patient's factor XI coagulation activity by approximately 7% to approximately 20% compared to baseline. Embodiment 25. Any one of the above embodiments, wherein the regimen is implemented to prolong the activated partial thromboplastin time (aPTT) by approximately 27% to approximately 64% compared to baseline. Embodiment 26. Any one of the above embodiments, wherein administration does not statistically significantly increase the incidence of major hemorrhagic complications. Embodiment 27. Any one of the above embodiments, wherein the pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is a solid oral pharmaceutical composition. Embodiment 28. The method of Embodiment 27, wherein the solid oral pharmaceutical composition is a tablet. Embodiment 29. The method of Embodiment 28, wherein the tablets are immediately released. Embodiment 30. The method of Embodiment 28 or Embodiment 29, wherein the disintegration time of the tablet in water is less than 20 seconds. Embodiment 31. Any one of the above embodiments, wherein administration results in a plasma half-life of milbexian of approximately 13 hours to approximately 16 hours. Embodiment 32. Any one of the above embodiments, wherein the plasma concentration of milbexian reaches a steady state in approximately 3 to 6 days after administration. Embodiment 33. Any one of the above embodiments, wherein a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered regardless of the timing of meals. Embodiment 34. Any one of the embodiments described above, wherein the human patient is unable to swallow tablet dosage forms. Embodiment 35. Any one of Embodiments 28 to 34, wherein tablets are dispersed in an aqueous medium to form an aqueous dispersion. Embodiment 36. The method of Embodiment 35, wherein the aqueous medium is water, saline solution, phosphate buffer, plant juice, or fruit juice such as applesauce. Embodiment 37. The method according to Embodiment 35 or Embodiment 36, wherein the aqueous dispersion is administered to a human patient via a nasogastric tube or spoon. Embodiment 38. A method of administering the pharmaceutical composition, which is an oral tablet, orally as an aqueous dispersion by dispersing it in an aqueous medium in less than one minute, as described in any one of Embodiments 28 to 37.

[0296] Those skilled in the art will be able to recognize or confirm, within the scope of ordinary experimentation, many equivalents to the embodiments described herein.

[0297] All publications, patents, and patent applications referenced herein are incorporated by reference to the same extent as when each individual publication, patent, or patent application is specifically and individually indicated to be incorporated by reference.

[0298] [Examples] Example 1. A placebo-controlled, event-driven, phase 3 randomized, double-blind trial to evaluate the efficacy and safety of the oral activated factor XI inhibitor milbexian in patients who have recently developed acute coronary syndrome. This Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group, event-driven, superiority, sequential-group trial is designed to evaluate the efficacy and safety of Milbexian in subjects enrolled within 7 days of the onset of ACS (defined as biomarker-positive STEMI, NSTEMI, or UA). These subjects either underwent cardiac catheterization via PCI or were managed with conservative treatment regardless of catheterization, and were also receiving standard antiplatelet therapy at the discretion of the principal investigator.

[0299] Number of subjects Approximately 16,000 subjects will be randomized within 7 days of ACS onset, and further randomization will be performed until the number of subjects meeting one or more primary efficacy endpoints reaches a pre-defined 875.

[0300] Criteria for study patients Each candidate participant must meet all of the following criteria in order to be enrolled in this study. age 1. 18 years of age or older Subject type and disease characteristics 2. Participants must have an indicative event that meets all three of the following criteria within 7 days prior to randomization. a) Clinical syndromes consistent with spontaneous ischemic heart disease b) Diagnosis of ACS (i.e., STEMI, non-STEMI, or UA) c) Elevated cardiac biomarkers (e.g., troponin I, troponin T, CK-MB) exceeding the upper limit of normal as defined by the laboratory of the facility conducting the test. 3. The subjects have at least two of the following risk factors: a) 65 years of age or older b) Diabetes c) A history of MI (other than events that are indicators of ACS) d) CAD in multiple vessels (Note: This may indicate a history of CAD in multiple vessels, or it may indicate a history of CAD in a single vessel, but that an event indicative of ACS occurred in another coronary artery, leading to confirmation of CAD in multiple vessels.) e) A history of CABG surgery prior to the onset of an event that would be an indicator of ACS. f) A history of PAD or cerebrovascular disease (e.g., carotid atherosclerosis, intracranial artery stenosis) (however, patients with a history of TIA or stroke will not be enrolled). g) Conservative treatment (i.e., no PCI or CABG performed after the onset of an event indicative of ACS) h) One or more of the following high-risk angiographic findings: a. The total diameter of the stent is >30mm b. Thrombotic target lesions c. Bifurcation lesions treated with one or more stents d. Calcified target lesions treated with atheromatectomy e. Treatment of left main coronary artery occlusion or proximal left anterior descending artery occlusion that is an indicator of ACS (or clinical diagnosis of anterior wall STEMI) body weight Not applicable Gender and contraception / barrier requirements 4. All female subjects of childbearing age must have a negative result on either a high-sensitivity serum β-hCG test or a urine test during screening. 5. Female subjects must not be pregnant, breastfeeding, or planning to become pregnant within four days (five half-lives) of the final dose of the intervention trial. 6. Female subjects, a. No possibility of pregnancy b. You are capable of becoming pregnant, but you use a highly effective method of contraception (with an annual failure rate of less than 1% when used correctly at all times), and you agree to continue using that method until 4 days (5 half-lives) have passed since the last dose of the intervention trial (i.e., the associated exposure has ended). It is necessary. 7. Female subjects using hormonal contraceptives must use an alternative method of contraception (exceeding the criteria required in 6b above) until four days (five half-lives) have elapsed since the last dose of the intervention study (i.e., the relevant exposure has ended).

[0301] Exclusion criteria Any prospective participant who meets any of the following criteria will not be permitted to participate in this study. Medical condition 1. Individuals with ischemia-associated MI (Type 2 MI due to either increased oxygen demand or decreased oxygen supply) or perioperative MI, which are indicators of ACS. 2. Patients with mild or no occlusive CAD in angiography performed prior to PCI for an event indicative of ACS (i.e., those whose stenosis rate is judged to be less than 50% by visual evaluation by the principal investigator). 3. Patients scheduled for planned CABG or staged PCI after randomization (Note: After completion of planned staged PCI, subjects may be evaluated for enrollment). 4. Individuals with any condition requiring long-term anticoagulant therapy, as determined by the principal investigator and / or the guidelines of the institution conducting the study. (Note: Individuals who are candidates for long-term antiplatelet therapy after replacement with a bioprosthetic valve (non-mechanical valve) (e.g., transcatheter aortic valve replacement) do not meet this exclusion criterion and are eligible to participate in this study.) 5. Individuals with a significantly increased risk of bleeding (e.g., clinically significant bleeding within the past three months, or a known bleeding diathesis). 6. Requires permanent dialysis or has an eGFR of 15 mL / min / 1.73 m² at screening. 2 Those who are less than 7. Individuals currently suffering from active liver disease (e.g., acute hepatitis and known cirrhosis) (including those receiving antiviral treatment for hepatitis) 8. Individuals with active cancer who have received chemotherapy, radiation therapy, or immunotherapy. 9. Individuals who underwent CABG during the onset of a benchmark event. 10. Individuals with a history of ischemic stroke or transient ischemic attack (TIA) 11. Individuals whose Killip classification is Class 3 or 4 at the time of randomization. 12. Individuals with a history of any one of the following serious drug allergies (e.g., anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS). 13. Individuals with a known allergy, hypersensitivity, or intolerance to Milbexian or its excipients (see Milbexian IB). 14. Individuals whose aPTT prolongation exceeds 1.5 times the ULN, or who have a known congenital factor XI deficiency. Pre-treatment / simultaneous treatment 15. Anyone planning any prohibited treatment or combination therapy, such as isoniazid (INH). Pre-clinical / parallel clinical trials 16. Anyone who has received a clinical trial intervention, used an invasive investigational medical device, or is currently participating in another clinical trial within four weeks of the planned first dose. Diagnostic evaluation 17. If, prior to randomization, any of the following test results at the testing site meet the specific criteria below and are confirmed by retesting: - Platelet amount <75,000 / μL -ALT is more than 3 times ULN - Total bilirubin level is 1.5 times or more the ULN level (except when other factors such as Gilbert's syndrome have been identified). - Hemoglobin level less than 8.0 g / dL Other exclusion criteria 18. Any employee of the principal investigator or the research site who is directly involved in the proposed trial or any other trial under the direction of the principal investigator or the research site, as well as any family member of such employee or researcher. 19. In the opinion of the principal investigator, any condition that is not in the best interests of the subject (e.g., would impair their health), a condition that could interfere with, limit, or disrupt the evaluations specified in the protocol, or a condition in which the subject has a life expectancy of less than 12 months. 20. Participants who discontinue the investigational drug administration early or discontinue participation in the study during screening, or who do not consider adhering to the study contact schedule until the end of the study, or who do not consent to being contacted by themselves, a designated family member, or a healthcare professional for the purpose of confirming endpoint events and / or survival status, will be excluded from the study. 21. Participants with a mental condition or cognitive impairment / dementia that makes it difficult to understand the content, potential risks, and benefits of the study. 22. Persons in custody (including prisoners or persons in compulsory detention for the treatment of mental illness) 23. Persons currently known to be using drugs

[0302] Treatment and visits in the trial Participants will receive either milbexian (25 mg orally twice daily) or a corresponding placebo, based on standard antiplatelet therapy. Randomization will be stratified to one of the following groups based on an antiplatelet therapy strategy predetermined by the principal investigator: 1) DAPT for more than 90 days (with or without de-escalation to SAPT), 2) DAPT for 90 days or less with de-escalation to SAPT, or 3) SAPT. Under the current protocol, the trial is expected to run for approximately 3.5 years in total.

[0303] Underlying antiplatelet therapy The treatment plan for SAPT or DAPT and the duration of DAPT will be determined at the discretion of the principal investigator in accordance with standard treatment guidelines and will be recorded at the time of randomization.

[0304] SAPT may also involve the administration of low-dose aspirin (100 mg or less per day) or a P2Y12 inhibitor.

[0305] The P2Y12 inhibitor (either alone or in combination with aspirin) may be clopidogrel, ticagrelor, or prasugrel.

[0306] P2Y12 inhibitors may be changed or discontinued. Such changes must be recorded in the eCRF.

[0307] During de-escalation from DAPT to SAPT, it is possible to discontinue either aspirin or a P2Y12 inhibitor, and this must be recorded in the eCRF.

[0308] For example, the underlying antiplatelet therapy regimen and duration are: SAPT: Administering less than 100 mg of aspirin per day until the end of the trial; SAPT: Administering 75 mg of clopidogrel per day until the end of the trial; DAPT consisting of 100 mg or less of aspirin per day and 75 mg of clopidogrel per day for 90 days, followed by 75 mg of clopidogrel per day until the end of the study; or All of the above It can be composed of.

[0309] This trial consists of three phases: a screening period from within 7 days of the onset of an ACS-defining event until randomization, a double-blind trial period, and a 30-day follow-up period. Treatment begins on the day of randomization and continues until the target number of subjects develops at least one of the primary efficacy endpoints (within 30 days of the GTED date, a treatment end-of-treatment (EOT) visit is conducted thereafter). In other words, the duration of treatment with the trial intervention will differ depending on when the subjects are randomized. Subjects who are randomized last are expected to receive treatment with the trial intervention for at least approximately 3 months until GTED.

[0310] The trial intervention may be performed regardless of meal timing. In subjects unable to swallow the medication, it may be administered dissolved in water via a nasogastric tube or dissolved in applesauce.

[0311] Milbexian is available in the form of film-coated, direct-compression tablets as described in Table 1 below. a That is the case. [Table 2]

[0312] As used herein, the term "disintegration time" refers to the time required for a tablet to disintegrate into particles under specified conditions. In some embodiments, the disintegration time is measured using a disk with distilled water at 37°C and the apparatus described in Eur. Ph. (PTZ-E Pharma Test, Hainburg, Germany).

[0313] The SDP (spray-dried powder) in the tablets (Examples 17 and 18) was prepared as follows: A solution containing approximately 12.3% by weight of milbexian P1 acetone solvate (equivalent to approximately 11.25% by weight of free milbexian) and approximately 3.75% by weight of HPMC-AS MG (AQOAT® AS-MG, Shin-Etsu Chemical Co., Ltd. (Niigata, Japan)) was prepared in a mixed solvent containing DCM / MeOH (80 / 20 w / w%). The transparent solution was spray-dried at 21°C using a spray dryer (Buchi B-290, parameters set as follows) with a drying gas flow rate of 35 kg / hr. Parameters: Atomizing gas flow rate 25 mm (301 L / hr); liquid delivery rate 7.7 g / min; inlet / outlet temperature 67 / 44°C; condenser temperature -19°C; spray nozzle opening diameter 0.7 mm; spray nozzle cap diameter 1.4 mm Spray drying was performed for 11 minutes to obtain wet SDP (11.5 g, yield 89%). The wet SDP was dried in a vacuum oven (Heraeus, VT6130M, 40°C, nitrogen gas, under reduced pressure of approximately 200 mbar) for 24 hours to obtain the desired dry SDP (10.7 g, yield 83%). The SDP product is a white powder with a content of 98.8% and a purity of 99.9% by HPLC. The PXRD diffraction pattern shows a halo pattern without crystalline peaks, indicating that the product is amorphous.

[0314] Effectiveness evaluation The primary, secondary, and exploratory efficacy endpoints include the following individual events, which may be combined in various ways to form composite endpoints: ACM; CV death; MI; UA; any stroke or any stroke (ischemic, hemorrhagic, or of unknown cause); ischemic stroke; ALI; major vessel (non-traumatic) limb amputation; symptomatic VTE (PE, DVT); coronary revascularization due to ischemia; stent thrombosis; hospitalization for any cause (classified as (1) planned or unplanned, (2) hospitalization due to arterial or venous thromboembolism, or hospitalization not falling under either category); and TIA. An independent CEC determines the efficacy events as defined in the CEC Charter (Table 2). [Table 3]

[0315] Pharmacokinetic evaluation Plasma samples were collected from approximately 5,000 subjects. Milbexian concentrations in samples collected from subjects treated with milbexian were measured using validated, specific, and highly sensitive methods (e.g., LC-MS / MS) under the supervision of the sponsor. Residual plasma PK samples may be stored for future analysis and metabolite profiling. Based on the plasma concentration-time data, population PK modeling will be used to calculate the exposure-response analysis of Milbexian and PK parameters (such as apparent clearance) for related variables, using actual doses and sampling times.

[0316] Pharmacodynamic evaluation and biomarker evaluation Plasma samples for PD assays and biomarker assays were collected from approximately 1,000 subjects during the study. The PD assay involves measuring aPTT. Exploratory biomarkers for disease pathogenesis include proteomics and D-dimers.

[0317] Safety evaluation Bleeding assessment items include the following: types 2, 3a, 3b, 3c, 4, and 5 of the BARC bleeding criteria; major bleeding and CRNM in the ISTH criteria; (1) severe or life-threatening bleeding and (2) moderate bleeding in the GUSTO bleeding criteria; and events including non-CABG-related major bleeding, CABG-related major bleeding, minor bleeding, and bleeding requiring treatment in the TIMI bleeding criteria, which may be grouped in various combinations. These bleeding assessment items are determined by an independent CEC as defined in the CEC Charter. Overall safety and tolerability are assessed by AEs, laboratory values, and vital signs.

[0318] statistical methods Aggregations by treatment group will be performed for all test variables, including demographic and baseline characteristics, using appropriate descriptive statistics. Unless otherwise specified in SAP, no data substitution will be performed. For continuous variables, descriptive statistics such as mean, median, standard deviation, minimum, and maximum will be used. For categorical variables, count and percentage will be used. For time-dependent variables (such as time to event occurrence), the Kaplan-Meier method will be used. Data will also be presented in charts and graphs as needed. Unless otherwise specified, all statistical tests are interpreted at a nominal two-sided significance level of 0.05 without adjustment for multiples, and all confidence intervals are calculated at the nominal two-sided 95th percentile level.

[0319] The stratified log-rank test is used to test the primary hypothesis. In testing the primary and secondary efficacy endpoints, to control the probability of a Type I error for each set of null hypotheses at a two-sided significance level α=0.05, if the superiority of Milbexian over placebo is established for the primary efficacy endpoint, the superiority of Milbexian for the secondary efficacy endpoints is sequentially tested using a closed procedure in a predefined hierarchical order.

[0320] Stratified Cox regression analysis is used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of the treatment effect for the primary efficacy endpoint.

[0321] An interim analysis of ineffectiveness will be conducted when the number of subjects experiencing the primary efficacy event is observed in approximately 60% of the target population. Since this trial will not be terminated based on superiority, adjustment for the probability of Type I error is not necessary.

[0322] Example 2. Prevention of new-onset ischemic stroke or new-onset cryptogenic stroke following acute ischemic stroke or transient ischemic attack. The AXIOMATIC-SSP trial, which uses activated factor XI inhibitors for antithrombotic treatment to optimize the management of acute thromboembolic events in secondary stroke prevention, was a phase 2, multicenter, randomized, double-blind, placebo-controlled, dose-finding study of milbexian to prevent new-onset ischemic stroke or cryptogenic stroke in subjects treated with aspirin and clopidogrel after acute ischemic stroke or TIA. The primary objective was to estimate the dose-response relationship of milbexian by evaluating a composite endpoint of new-onset ischemic stroke during the treatment period and new-onset cryptogenic stroke detected by magnetic resonance imaging (MRI) (central review) at day 90 in subjects with ischemic stroke or TIA treated with aspirin and clopidogrel. The target randomization ratio at the end of the trial was 2:1:1:1:1:1 (placebo, milbexian 25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, and 200 mg twice daily). The original design included two additional dosing groups (milbexian 50 mg once daily and milbexian 100 mg once daily), but the protocol was modified to eliminate randomization to these groups in order to achieve the trial objectives, minimize the number of subjects exposed to the new investigational drug, reduce the burden on subjects and research facilities, streamline the trial procedure, and simplify the trial design while maintaining scientific rigor (Revised Protocol 05). Enrollment in the 50 mg once daily and 100 mg once daily treatment groups was terminated early, and the number of subjects in both groups was limited. Therefore, these groups are not included in the efficacy analysis, but they are included in the baseline characteristics (total for the milbexian administration group), subject status, and safety analysis.

[0323] The study enrolled subjects aged 40 years or older who had experienced an ischemic stroke or transient ischemic attack (TIA). Ischemic stroke was defined as a neurological deficit resulting from a non-lacunar acute ischemic infarction detected by neuroimaging, consistent with clinical symptoms and a National Institutes of Health Stroke Scale (NIHSS) score of 7 or less at the time of randomization. A TIA was defined as an acute-onset neurological deficit resulting from focal ischemia of the brain, as determined by medical history or physical examination, without infarct findings on neuroimaging, with complete disappearance of the deficit, and an ABCD score of 6 or greater or the presence of motor symptoms. Imaging must confirm the presence of atherosclerotic plaque, ulceration, or thrombus in the associated intracranial or carotid artery, and the index event may be an ischemic stroke or a TIA. In addition, all subjects were required to have a modified Ranking Scale score of 3 or less prior to the occurrence of the index event. Eligible subjects were screened for eligibility to participate in the study as soon as possible after their visit and randomized within 48 hours of the occurrence of a benchmark event. After obtaining informed consent, subjects who were not receiving standard treatment were administered aspirin (100 mg) once daily and an initial loading dose of clopidogrel (300 mg). Subjects were then randomized to receive either milbexian or placebo, in addition to a 21-day combination therapy of uncoated aspirin (100 mg) and clopidogrel (75 mg) once daily, as in the open trial. From day 22 to day 90, subjects continued to receive either milbexian or placebo, in addition to 100 mg of uncoated aspirin, as in the open trial. A baseline MRI scan was performed before randomization within 48 hours of the occurrence of the benchmark event. A second MRI scan was performed on day 90 ± 6 days. All subjects were required to continue the trial until the 90-day MRI scan (up to day 96).

[0324] Between January 27, 2019 and December 24, 2021, 2,799 subjects were enrolled, and 2,366 subjects were randomized to eight treatment groups. The group receiving 200 mg twice daily was established on June 5, 2021, after approximately 1,387 subjects were enrolled and the DMC reviewed open-label data to assess the safety of establishing the treatment group. Randomization of subjects to the 50 mg once daily (N=22) and 100 mg once daily (N=18) treatment groups was completed with the implementation of the revised protocol 05 described above. Overall, the mean age (standard deviation [SD]) of subjects was 69.6 (±10.81) years. The majority of subjects were white males. Overall, the majority of indicator adverse events (75.7%) were ischemic stroke, and approximately 96% of randomized subjects had an NIHSS score of 5 or less. TIAs accounted for 24.1% of indicator events, and 53.4% ​​of TIA subjects had an ABCD2 score of 6 or higher. While baseline disease characteristics were generally balanced across treatment groups, the proportion of subjects with an NIHSS score of 6-7 was higher in the 200 mg twice daily dose group (4.7%) than in the other groups (2.1-4.0%). More subjects with an NIHSS score of 6 or 7 were placed in the highest dose group due to the phased introduction of this treatment group and the expansion of the NIHSS inclusion criteria from ≤5 to ≤7 following the protocol revision. The most common comorbidities / risk factors were hypertension, diabetes, smoking history, and hypercholesterolemia. All baseline characteristics were balanced across treatment groups.

[0325] The dose-response relationship between the Milbexian treatment groups (including placebo) for the primary composite endpoint, which consisted of symptomatic ischemic stroke during the study period and newly occurring cryptogenic stroke detected at MRI on day 90, was analyzed based on general multiple comparisons and dose-response relationship modeling (MCP-Mod), and the results are presented for each treatment group.

[0326] In the AXIOMATIC-TKR trial, the group receiving milbexian 25 mg twice daily demonstrated efficacy comparable to enoxaparin and showed a favorable safety profile. In the AXIOMATIC-SSP trial, the group receiving milbexian 25 mg twice daily showed numerical superiority over the placebo group in preventing ischemic stroke (hazard ratio 0.69, 95% confidence interval 0.36–1.30). No further improvement in efficacy was observed at higher doses.

[0327] In the groups receiving 50 mg and 100 mg twice daily, the primary endpoint was numerically lower, but no dose-response relationship was observed. With milbexian, the incidence of ischemic stroke (acute IS, excluding cryptogenic stroke) in the ITT population was numerically reduced in all dose groups except the 200 mg twice daily group (see Table 3 below). Milbexian effectively reduced the incidence of ischemic stroke in patients who had experienced ischemic stroke or TIA at doses ranging from 25 mg twice daily to 100 mg twice daily. At these doses, the relative risk reduction (RRR) for ischemic stroke in the treatment group compared to the placebo group was approximately 30% (see Figure 3). [Table 4]

[0328] Subgroup analyses of symptomatic ischemic stroke by stroke subtype confirmed that the majority of new-onset ischemic strokes in both the mirbexian treatment group and the placebo group were caused by large vessel atherosclerosis.

[0329] The incidence of the composite event of new-onset ischemic stroke, MI, and all-cause mortality, a secondary efficacy endpoint, was lower in the milbexian group than in the placebo group (dosage: 25 mg once daily to 100 mg twice daily) (Table 5). The relative risk of this composite event in the milbexian group compared to placebo was 0.78 to 0.85 in the range of 25 mg once daily to 100 mg twice daily, but no clear dose-response relationship was observed. [Table 5]

[0330] In the dosage range of 25 mg once daily to 100 mg twice daily, the proportion of participants who completed the treatment period was similar in the placebo group and the milbexian treatment group. In the milbexian group (25 mg once daily to 100 mg twice daily), 20.7% to 25.8% of subjects discontinued treatment early, compared to 23.4% in the placebo group. In the group receiving 200 mg twice daily, the rate of early treatment discontinuation was highest (31.6%), mainly due to adverse events (AEs). Similarly, in the other dosage groups, AEs were the most common reason for subjects not completing the treatment period.

[0331] Statistical analysis, tabulation, and chart creation were performed using SAS® version 9 or later. The DoseFinding package for R (version 3.1.3 or later) was also used for multiple comparisons and dose-response relationship modeling analysis.

[0332] A subset of the ITT population, including subjects (1995 in total) who had at least one PD endpoint after the first dose of milbexian, was evaluated. Percentage changes (%) from baseline in aPTT and factor XI coagulation activity were summarized by treatment group and key time point. Furthermore, exposure-response (ER) analysis was performed to examine the association between milbexian exposure and percentage changes (%) from baseline in aPTT and factor XI coagulation activity using data collected from all treated subjects (2334 in total). In the milbexian-treated group, aPTT increased in a dose-dependent manner, and factor XI coagulation activity decreased in a dose-dependent manner.

[0333] The activated partial thromboplastin time (aPTT) and the percentage change from baseline in the pharmacodynamic population are shown in Table 5 below. [Table 6]

[0334] The factor XI coagulation activity observed in this study was as follows: [Table 7] Nominal time points were used for the analysis of PD biomarker data. N at post-baseline time points represents the number of subjects with baseline and post-baseline values ​​at that time point. Measurements exceeding the upper limit of the quantitative threshold were replaced with the upper limit in the calculation of summary statistics. Baseline refers to the "pre-administration baseline," which is a complete set of measurements collected before the date of the first effective dose administration in each treatment group. Randomization of subjects to the 50 mg once daily (N=22) and 100 mg once daily (N=18) treatment groups was completed with the implementation of the revised protocol 05 described above.

[0335] Example 3. Bioavailability study and results comparing 25 mg and 100 mg film-coated DC tablets with 25 mg and 100 mg SDP oral capsules in healthy subjects. The Phase 1 trial is an open-source, randomized, crossover comparative study designed to evaluate the relative oral bioavailability, pharmacokinetics, and effects of food after single doses (Parts 1, 3, and 4) or multiple doses (Part 2). Part 1 of this Phase 1 trial aims to compare and evaluate the relative bioavailability and effects of food under fasting and post-feed conditions when administering a single dose of 200 mg of milbexian as a film-coated DC tablet versus a single dose of 100 mg of SDP oral capsules. Part 2 of this Phase 1 trial aims to compare and evaluate the pharmacokinetics (PK) of administering 200 mg of milbexian as a film-coated DC tablet twice daily over 5 days versus administering 25 mg or 200 mg of SDP oral capsules twice daily. The 100 mg and 25 mg capsules (see Table 7 below) are described in WO 2020210629, and these capsules contain MCC and anhydrous lactose DC in a weight ratio of 1:1 (binder (MCC):bulizer (anhydrous lactose)). The composition and physical properties of the 25 mg and 100 mg film-coated DC tablets are as shown in Table 1 above.

[0336] Blood samples were collected at the designated time after drug administration, as specified in the clinical trial protocol. Sample concentrations were measured using an effective analytical method (liquid chromatography by tandem mass spectrometry). Phoenix TM WinNonlin (登録商標) Software (version 8.1, Pharsight, Certara) TM Using the pharmacokinetic parameters (e.g., C) of each subject (Company, LP, Princeton, NJ, USA), max AUC last , and AUC inf The following was derived from the time-concentration profile using non-compartmental analysis. [Table 8]

[0337] The treatment regimens for Part 1 and Part 2 are summarized in Table 7 below. TIFF2026514837000011.tif108164

[0338] The absolute bioavailability of a 100 mg comparative SDP capsule is 52% when fasting and 72% when eating, at a 200 mg dose.

[0339] In the Part 1 single-dose regimen, film-coated DC tablets (100 mg) showed an efficacy of approximately 9.0% to 11% compared to oral SDP capsules at a 200 mg dose. Film-coated DC* oral tablets (100 mg) are less affected by food. To improve patient adherence, it is desirable to be able to administer milbexian regardless of whether food has been consumed. Formulations that are less affected by food contribute to improved patient adherence.

[0340] In the Part 2 BID administration regimen, film-coated DC tablets (2 x 100 mg) were shown to have approximately 5-7% lower bioavailability compared to SDP oral capsules (2 x 100 mg). 25 mg film-coated DC tablets (DC tablets) were shown to have approximately 11-13% lower bioavailability compared to 25 mg SDP oral capsules (see Figures 5A-5D for milbexian dose curves as a function of time after BID administration).

[0341] In the second Phase 1 trial, Part 1 is an open-ended, randomized, three-condition crossover comparative study in healthy subjects comparing 2 x 100 mg SDP DC tablets and 2 x 100 mg SDP granule capsules with a single oral dose of 200 mg milbexian, aiming to evaluate the relative oral bioavailability, pharmacokinetics, and effects of food under fasting conditions, as well as the effect of food on bioavailability after a single dose of 200 mg milbexian (as 2 x 100 mg SDP DC tablets). Part 2 is an open-ended, randomized, two-condition crossover comparative study in healthy subjects comparing 2 x 25 mg SDP tablets and 2 x 25 mg SDP granule capsules with a single oral dose of 50 mg milbexian, aiming to evaluate PK and relative bioavailability under fasting conditions.

[0342] PK data (AUC) obtained in two Phase 1 trials for 2x100 mg and 1x25 mg SDP DC tablets and 25 mg and 100 mg SDP granule capsule formulations, both under ingested and fasted conditions. inf and C max In a pooled analysis, the study showed that among healthy subjects, tablets resulted in less variability in pharmacokinetics (PK) between subjects compared to capsules.

[0343] Clinical trial results showed that for tablets with similar dissolution rates, the area under the blood drug concentration-time curve (AUC) of 2 x 100 mg film-coated DC* oral tablets was the same. inf The formulation (also known as 2x100mg granular capsules) has been shown to meet the criteria for bioequivalence.

[0344] Example 4. Delayed myocardial repolarization is an undesirable side effect seen with some non-antiarrhythmic drugs. Considering the potential clinical impact of delayed myocardial repolarization, rigorous characterization of the QT / QTc interval prolongation potential of new drugs is recommended.

[0345] In vitro studies showed that milbexian inhibited cardiac potassium (hERG / IKr) channel currents with a weak to moderate effect at concentrations significantly higher than the free plasma concentrations in subjects administered clinically appropriate doses. This study was conducted in response to the results of the in vitro studies to evaluate the effect of milbexian on myocardial repolarization in healthy subjects, a key aspect of cardiovascular safety.

[0346] This placebo- and positive control TQT trial was conducted in healthy subjects to evaluate the effects of repeated administration of milbexian at therapeutic and over-therapeutic doses on QT / QTc interval duration and electrocardiograms at steady state. [Table 9]

[0347] When administered at therapeutic doses (100 mg capsules twice daily) and doses exceeding therapeutic doses (200 mg liquid twice daily), the upper limit of the two-sided 90% confidence interval (ΔΔQTc) for the mean difference in QTc change from baseline (ΔQTc; based on the primary correction formula QTcF) between milbexian and placebo was less than 10 milliseconds.

[0348] A total of 66 subjects were enrolled in the trial and randomly assigned to one of four treatment sequences. The safety and PD analysis population included all 66 subjects enrolled in the trial (100.0%). The breakdown was 55 subjects each in the milbexian 100 mg and 200 mg groups, 58 subjects in the moxifloxacin group, and 57 subjects in the placebo group.

[0349] Pharmacokinetic analyses were performed on the plasma concentrations of each subject. The PK analysis group included 61 subjects, i.e., all randomized subjects who received at least one dose of the effective investigational drug and had a PK profile for which at least one PK parameter could be accurately calculated. The PK / PD analysis was performed on subjects in the PD analysis group, whose milbexian concentration was measured at least once.

[0350] All 66 subjects enrolled in the trial (100.0%) received at least one full dose of the trial intervention.

[0351] 45 subjects (68.2%) completed all four intervention trials as planned. In each intervention group, 52 subjects received milbexian 100 mg capsules twice daily for 4 days, 54 subjects received milbexian 200 mg liquid twice daily for 4 days, 58 subjects received a single dose of moxifloxacin 400 mg, and 56 subjects received a placebo for 4 days.

[0352] No consistent or clinically significant changes were observed in mean vital signs over time.

[0353] During the study period, no cases were observed where treatment-induced QTcF or QTcB values ​​exceeded 480 milliseconds, or where the change from baseline exceeded 60 milliseconds. No electrocardiogram abnormalities were reported as TEAEs in this study.

[0354] In the group administered 100 mg twice daily as a capsule (Treatment A) and the group administered 200 mg twice daily as a liquid (Treatment B), the exposure to milbexian (i.e., C during the dosing interval) was observed. max The AUC (and other metrics) increased by approximately 2 to 3 times on day 4 compared to day 1.

[0355] [Pharmacodynamic analysis results] In the administration of 100 mg and 200 mg of milbexian, the upper limit of the two-sided 90% confidence interval for ΔΔQTcF during the measurement period on days 1 and 4 post-administration was below the protocol-defined 10 ms limit at all measurement points (i.e., the upper limit was 5.16 ms in the 100 mg milbexian group and 4.57 ms in the 200 mg group). This is in accordance with the ICH E14 guidelines and indicates that no clinical or regulatory concern was observed in the QT interval. These results support the efficacy of milbexian in the QT max This was confirmed based on ΔΔQTcF in the following case. Specifically, the T of milbexian after administration of 100 mg or 200 mg twice daily. max In this case, T on day 1 and day 4 max Analysis combining the two, or T1 and T4. max In all analyses using the two methods separately, the upper limit of the 90% confidence interval was less than 10 ms.

[0356] No clinical or regulatory concern effects on the QT interval were observed with the correction methods used in the study or the Bazett method, in accordance with the ICH E14 guidelines. The assay sensitivity of moxifloxacin was demonstrated when using either the Bazett method or the power-law correction method used in the study for HR.

[0357] During the study period, no measured QTc values ​​exceeding 480 milliseconds due to treatment were observed. Furthermore, no cases of QTcF or QTcP changes of 60 milliseconds or more from baseline due to treatment were observed. One subject (1.7%) experienced a treatment-related change of 60 milliseconds or more from baseline in QTcB during the study period (after moxifloxacin administration).

[0358] No consistent, clinically significant changes were observed over time in HR, RR interval, PR interval, or QRS width. Furthermore, no clinically significant differences were observed between treatment groups.

[0359] [Pharmacokinetic / pharmacodynamic analysis results] Based on the results of the linear mixed-effects model, no statistically significant association was found between milbexian concentration and ΔΔQTcF (p=0.8454), ΔΔQTcP (p=0.7102), or ΔΔQTcB (p=0.8670). max In this study, no statistically significant effect was observed between treatment (administration of 100 mg or 200 mg of milbexian) and ΔΔQTc (p>0.5).

[0360] result The sponsor did not allow any notable restrictions in this examination.

[0361] In healthy adult subjects, multiple doses of milbexian at 100 mg and 200 mg were generally safe and well-tolerated.

[0362] The upper limit of all two-sided 90% confidence intervals for the change in QTcF from baseline between the milbexian 100 mg group and placebo, and between the milbexian 200 mg group and placebo, was less than 10 ms. Therefore, in accordance with the ICH E14 guidelines, administration of milbexian at therapeutic doses (100 mg) and doses exceeding therapeutic doses (200 mg) did not result in any findings of QT / QTc interval prolongation that would raise clinical or regulatory concerns.

[0363] The sensitivity of the assay was confirmed using moxifloxacin as a positive control.

[0364] Based on the results of a linear mixed-effects model, no statistically significant association was found between milbexane concentration and ΔΔQTcF (p=0.8454).

Claims

1. A method for preventing cerebrovascular adverse events or cardiovascular adverse events in human patients with acute coronary syndrome, wherein the method is applied to human patients. (i) A pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof); and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; administering the pharmaceutical composition twice daily. The regimen is characterized by implementing a regimen that includes the following:

2. The method according to claim 1, wherein the antiplatelet therapy is the administration of a P2Y12 inhibitor.

3. The method according to claim 2, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel.

4. The method according to claim 1, wherein the antiplatelet therapy is the administration of aspirin.

5. The method according to claim 1, wherein a human patient is treated with a combination of aspirin and clopidogrel from day 1 to day 21, followed by treatment with aspirin monotherapy for at least 90 days.

6. A method for preventing cardiovascular adverse events in human patients diagnosed with acute coronary syndrome, wherein the method is used in human patients. (i) a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients; and (ii) implementing a regimen comprising antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; The aforementioned pharmaceutical composition is characterized by being administered twice a day; further The cardiovascular adverse event is selected from one or more of the following groups: all-cause mortality (ACM); cardiovascular (CV) death; myocardial infarction (MI); unstable angina (UA); any stroke or any stroke (ischemic, hemorrhagic, or of unknown cause); ischemic stroke; acute limb ischemia (ALI); large vessel (non-traumatic) limb amputation; symptomatic venous thromboembolism (VTE: pulmonary embolism (PE), deep vein thrombosis (DVT)); coronary revascularization due to ischemia; stent thrombosis; hospitalization for any cause (classified as (1) planned or unplanned, (2) hospitalization due to arterial thromboembolism or venous thromboembolism, or hospitalization not falling under either category); and transient ischemic attack (TIA).

7. The method according to claim 6, wherein the cardiovascular adverse event is one or more of cardiovascular death, myocardial infarction, or ischemic stroke.

8. A method for reducing the incidence of one or more thrombotic adverse events selected from new-onset ischemic stroke, MI, or all-cause mortality in a human patient diagnosed with acute coronary syndrome, the method comprising administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising about 25 mg to about 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients; and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; the pharmaceutical composition twice daily.

9. A method for preventing ischemic stroke in a human patient diagnosed with acute coronary syndrome, the method comprising administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients; and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; the pharmaceutical composition twice daily.

10. The method according to claim 9, wherein the regimen maintains a clinical benefit of reduced incidence of ischemic stroke over a 90-day treatment period.

11. The method according to claim 1, wherein the implementation of the regimen reduces the patient's factor XI coagulation activity by approximately 7% to approximately 20% compared to baseline.

12. The method according to claim 1, wherein the regimen is implemented to extend the activated partial thromboplastin time (aPTT) by approximately 27% to approximately 64% compared to baseline.

13. The method according to claim 1, wherein administration does not statistically significantly increase the incidence of major hemorrhagic complications.

14. The method according to claim 1, wherein the pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is a solid oral pharmaceutical composition.

15. The method according to claim 1, wherein administration results in a plasma half-life of milbexian of approximately 13 to 16 hours.

16. The method according to claim 1, wherein, upon administration, the plasma concentration of milbexian reaches a steady state in approximately 3 to 6 days.

17. The method according to claim 1, wherein a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered regardless of the timing of meals.

18. The method according to claim 1, wherein no clinically significant prolongation of the QTc interval is observed by the above method.

Images