Application of MILVEXIAN in treating or preventing ischemic stroke

Abstract

The present invention relates to a factor XIa inhibitor having therapeutic properties suitable for use in a method of treating or preventing ischemic stroke.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 370,031, filed on August 1, 2022; U.S. Provisional Application No. 63 / 401,361, filed on August 26, 2022; U.S. Provisional Application No. 63 / 379,848, filed on October 17, 2022; and U.S. Provisional Application No. 63 / 498,945, filed on April 28, 2023. The disclosures of each of the foregoing applications are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to the use of milvexian for treating or preventing ischemic stroke in patients suffering from acute ischemic stroke or transient ischemic attack (TIA) while maintaining hemostasis. Background Art

[0004] Ischemic stroke is a common and devastating condition. Data from the Global Burden of Disease study estimated that the number of people with ischemic stroke worldwide in 2019 was 77 million, with the highest age-based incidence in Southeast Asia / East Asia / Central Asia, Central / Eastern Europe, North Africa, and the Middle East. Across Europe, stroke accounts for more than 1 / 10 of all deaths each year, and it is the third leading cause of disability-adjusted years lost (Feigin et al., Global Burden of Stroke. Circ Res. 2017; 120: 439-448). In the United States, an estimated 7.6 million Americans aged >20 years self-report having had a stroke, with an additional 3.4 million American adults expected to experience a stroke by 2030 (Tsao et al., Heart Disease and Stroke Statistics-2022 Update: A Report From the American Heart Association. Circulation. 2022.; 145(8): e153-e639). Thromboembolic complications are the leading cause of death worldwide in patients with coronary, peripheral, or cerebrovascular atherosclerosis.

[0005] Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by endothelial cell dysfunction, leading to lipid deposition, calcium accumulation in the subendothelial space, followed by leukocyte infiltration and smooth muscle proliferation. Vascular damage, such as during erosion or rupture of atherosclerotic lesions, triggers blood coagulation in an attempt to maintain hemostasis (prevent bleeding). This can lead to thrombosis and acute coronary syndrome (ACS). Atherothrombosis occurs because thrombi form on ruptured or eroded atherosclerotic plaques, and manifests clinically as myocardial infarction (MI), peripheral artery disease (PAD), or ischemic stroke (not due to embolism to the heart).

[0006] The connection between coagulation and atherosclerotic thrombosis has been confirmed in many 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). There are many coagulation components in human atherosclerotic lesions, which strongly indicates the role of coagulation activity during early plaque development. In addition, thrombin, tissue factor pathway inhibitors, coagulation factor (F) VIII and activated FX (FXa) have been shown to contribute to the development of plaques in mice. Components of the intrinsic pathway, such as factor XII (FXII) and the recent factor XI (FXI), have also been shown to play a role in the formation of atherosclerosis in ApoE- / - mice via unclear mechanisms.

[0007] The cause of ischemic stroke is attributed to thrombotic or embolic events that reduce blood flow to the brain. In thrombotic events, due to endovascular dysfunction, blood flow to the brain is blocked in the blood vessels, which is usually secondary to atherosclerotic disease, arterial dissection, fibromuscular dysplasia or inflammatory conditions. In embolic events, debris from other parts of the body blocks blood flow through the affected blood vessels. The cause of stroke affects prognosis and results (Ntaios G. Embolic Stroke of Undetermined Source: JACC Review Topic of the Week. J Am Coll Cardiol. January 28, 2020; 75 (3): 333-340; Pierik et al., Distribution of Cardioembolic Stroke: A Cohort Study. Cerebrovasc Dis. 2020; 49 (1): 97-104).

[0008] The key element in the pathophysiology of cerebrovascular ischemic stroke events is activated platelets (Field et al., Antiplatelet Therapy for Secondary Prevention of Stroke, Stroke, 4th edition, Vancouver, 2015, Chapter 61, pages 992 to 1013). Accordingly, antiplatelet therapy is the basis for preventing such events. After the first ischemic stroke, the risk of recurrent ischemic stroke is high (see Tsao et al. above). The current standard-of-care for secondary prevention of cerebrovascular events after noncardioembolic ischemic stroke or TIA is single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT) combined with patient-level risk factor modification by increasing physical activity and smoking cessation, and management of vascular risk factors including arterial hypertension, hyperlipidemia, hypertriglyceridemia, and glycemic control (Rothwell et al., Effects of aspirin on risk and severity of early recurrent stroke after transient ischemic attack and ischemic stroke: time-course analysis of randomized trials. Lancet. 2016; 388(10042): 365-375. Epub 2016 May 18; Dawson et al., European Stroke Organization. European Stroke Organization expedited recommendation for the use of short-term dual antiplatelet therapy early after minor stroke and high-risk TIA. Eur Stroke J. 2021 Jun;6(2):VI. Epub 2021 Jun 18). Although the risk of recurrent ischemic stroke can be reduced by implementing these guideline-directed approaches, the residual risk of recurrent stroke remains high even when patients are treated with aspirin plus clopidogrel (see Field et al., supra), and intensification or prolonged duration of antiplatelet therapy is limited by increased risk of bleeding.

[0009] Researchers are testing various strategies to achieve better outcomes in patients, such as using more potent or longer-lasting antiplatelet therapy, or a combination of antiplatelet therapy with anticoagulant therapy. However, long-term use of DAPT has not been supported by evidence from randomized studies. The MATCH study compared clopidogrel plus aspirin with clopidogrel alone as chronic therapy, started up to 3 months after ischemic stroke, and did not show an efficacy benefit over a treatment period of 18 months. The CHARISMA study compared clopidogrel plus aspirin with aspirin alone as chronic therapy, started any time up to 5 years after ischemic stroke or TIA, and did not show an overall efficacy benefit over a median follow-up period of 28 months.

[0010] The risk of recurrent stroke represents a significant and ongoing unmet need for more effective treatment options (Johnston et al., Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA. N Engl J Med. 2020; 383(3):207-217).

[0011] Activated coagulation factor XIa (FXIa) is a key serine protease involved in the amplification of thrombin generation. Increased thrombin levels carry the risk of thrombosis. Inhibition of FXIa reduces thrombin generation and prevents thrombi while maintaining normal hemostasis. Although the contribution of FXIa to hemostasis is relatively small, it is involved in clot growth and stability (see Figure 1). (Fredenburgh JC et al. Factor XI as a target for new anticoagulants. Hamostaseologie 2021; 41(2): 104-10). Epidemiological and Bayesian randomized studies of individuals born with FXI deficiency suggest that FXI(a) inhibition is a promising strategy for preventing secondary stroke. (Gill D et al. Genetically determined FXI (factor XI) levels and risk of stroke. Stroke 2018; 49(11): 2761-3; Salomon O, Steinberg DM, Koren-Morag N et al. Reduced incidence of ischemic stroke in patients with severe factor XI deficiency. Blood 2008; 111(8): 4113-7). Patients with FXI deficiency have a significantly lower risk of stroke than matched controls with normal FXI levels, while patients with high FXI levels have an increased risk of recurrent stroke (Rohmann JL et al. Coagulation factor XII, XI, and VIII activity levels and secondary events after first ischemic stroke. J Thromb Haemost 2020; 18(12): 3316-24).

[0012] Analysis of genetically determined FXI has shown that the highest levels of FXI 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). It has been shown that patients with congenital FXI deficiency (hemophilia C) 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 April; 10(4): 615-621). Studies on the prevention of deep vein thrombosis have demonstrated that by reducing FXI content or inhibiting FXIa, thrombi defined by venography are reduced and the bleeding profile is good (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). FXI and FXIa have the potential for therapeutic effects with low bleeding risk, making them promising targets for preventing secondary strokes.

[0013] The high human and financial costs of thromboembolic events emphasize the need for newer and better treatment options for managing thrombotic disorders. The challenge is to develop an agent with a potent antithrombotic effect but with a minimal risk of bleeding, because it requires a very delicate balance in regulating hemostasis. Dual pathway inhibition of antiplatelet therapy and anticoagulants is another strategy to potentially improve the efficacy in patients after a recent ischemic stroke or TIA. Although data from the WARSS study did not show the benefits of anticoagulant therapy with warfarin relative to antiplatelet therapy with aspirin alone, exploratory results from subjects with stable atherosclerotic vascular disease in the COMPASS trial showed that the dual pathway mechanism of antiplatelet therapy and anticoagulants can improve efficacy by reducing the risk of ischemic stroke that increases the possibility of major bleeding (Eikelboom et al.; COMPASS Investigators. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med 2017; 377: 1319-30). Although many treatments are available for ischemic stroke, new treatment options, such as oral formulations of FXIa inhibitors, are needed for preventing recurrent adverse vascular events in patients who have or have had an ischemic stroke or transient ischemic attack (TIA).

[0014] Milvexian (BMS-986177 / JNJ-70033093) is a high-affinity inhibitor of human coagulation FXIa (Dilger et al. Discovery of milvexian, a high-affinity, generally bioavailable inhibitor of factor XIa in clinical studies for antithrombotic therapy. J MedChem 2022; 65(3): 1770-85). Milvexian is a macrocyclic compound having the structure of formula (I):

[0015]

[0016] Milvexian is also known by its chemical name (5R,9S)-9-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-2 1 -(Difluoromethyl)-5-methyl-2 1It is known as H-3-aza-1(4,2)-pyridine-2(5,4)-pyrazolo[upsilon]naphthalen-4-one.

[0017] Milvexian and a method for preparing milvexian are described in U.S. Patent No. 9,453,018, which is incorporated herein by reference in its entirety. Milvexian solvates, crystalline forms, and amorphous forms are also known in the art. See, for example, WO2021207659 and WO2022081473. Amorphous solid dispersion compositions containing one or more polymers of milvexian have been described in WO2020210629, which is incorporated herein by reference in its entirety.

[0018] 4,114 participants have been enrolled and exposed to the study intervention (milvexian, placebo, or comparator) in the milvexian clinical program. Of the 4,114 participants, 3,229 received milvexian, of which 660 participants were exposed to milvexian in the Phase 1 study and 2,569 participants were exposed to milvexian in the Phase 2 study. Four types of serious bleeding in the milvexian clinical development program were evaluated as adverse drug reactions: gastrointestinal bleeding, surgical bleeding, bleeding in neurological disorders (ischemic stroke and hemorrhagic transformation of subdural hematoma), and hematuria. The results of a Phase II clinical trial of milvexian in patients undergoing total knee replacement (TKR) were published in 2021 (Weitz, JI; et al., supra).

[0019] A variety of other small molecule FXIa inhibitors have been explored in many studies in humans for secondary prevention of ischemic stroke in patients who have or have had ischemic stroke or transient ischemic attack (TIA). For example, in the PACIFIC-Stroke Phase II trial, the safety and efficacy of three doses of asundexian (10 mg, 20 mg, or 50 mg, once daily for 26 to 52 weeks) when added to standard care antiplatelet therapy were evaluated in patients after acute non-cardioembolicischaemic stroke. Compared with placebo, asundexian plus antiplatelet therapy did not reduce the composite symptoms of hidden cerebral infarction or ischemic stroke and did not increase the composite symptoms of major bleeding or clinically relevant non-major bleeding. (Shoamanesh et al., Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke (PACIFIC-Stroke): an international, randomized, double-blind, placebo-controlled, phase 2b trial, Lancet, Vol. 400, No. 10357, pp. 997-1007, DOI: https: / / doi.org / 10.1016 / S0140-6736(22)01588-4). However, the PACIFIC-AMI and PACIFIC-Stroke trials were not statistically designed to test the clinical efficacy of asundexian at a dose of 50 mg once daily to reduce thrombotic events (e.g., ischemic vascular events) in patients after acute heart attack or acute non-cardioembolic ischaemic stroke, particularly by virtue of its ability to reduce FXIa activity in the blood.

[0020] Small molecule FXIa inhibitors have been explored in many studies in humans. The results of a Phase II clinical trial of Milvexian in patients undergoing total knee replacement (TKR) were published in 2021 (Weitz, JI; et al., supra). In the PACIFIC-AF Phase II trial, the safety of Asundexian (20mg, 50mg QD for 12 weeks) compared to apixaban was evaluated in patients with atrial fibrillation (Piccini, JP; et al., Safety of the Oral Factor XIa Inhibitor Asundexian Compared with Apixaban in Patients with Atrial Fibrillation (PACIFIC-AF): a Multicentre, Randomised, Double-blind, Double-dummy, Dose-finding Phase 2 Study. Lancet, 2022, 399, 1383-1390).

[0021] As a result, vascular and thromboembolic diseases remain the leading causes of death and disability worldwide. Despite significant advances in antithrombotic therapy, anticoagulant therapy is still limited by bleeding and many patients remain at high risk of thrombosis. Summary of the invention

[0022] The present invention provides a therapeutic regimen comprising an oral formulation of milvexian (a potent and highly selective FXIa inhibitor as described above) or a pharmaceutically acceptable salt or solvate thereof for targeted regulation of coagulation by inhibiting activated factor XI (FXIa) through inhibition of the contact pathway, and one or more antiplatelet therapies for treating and preventing thrombosis and embolism, thereby reducing the risk of adverse cerebrovascular events (e.g., recurrent ischemic stroke) in patients who have or have had ischemic stroke or transient ischemic attack (TIA), maintaining hemostasis while reducing thrombin generation by inhibiting FXIa and inhibiting platelet activation. Compared with antiplatelet therapy alone, the therapeutic regimen as described herein provides a more favorable balance between ischemia and bleeding risks.

[0023] The present invention generally relates to methods of treating or preventing ischemic stroke in patients who have or have had ischemic stroke or transient ischemic attack (TIA). More specifically, the present invention relates to the use of milvexian (or a pharmaceutically acceptable salt or solvate thereof) in reducing the risk of ischemic stroke in patients who have or have had ischemic stroke or TIA, as compared to placebo, without causing a clinically significant increase in the risk of bleeding.

[0024] In a first aspect, a method is disclosed herein, comprising administering an amount of milvexian (or a pharmaceutically acceptable salt or solvate thereof) and DAPT to a patient suffering from or having had an ischemic stroke or TIA in an experimental group in a randomized double-blind clinical trial to effectively reduce the risk of ischemic stroke in the patient, wherein the risk in the experimental group is numerically reduced compared to the risk reduction caused by the administration of placebo and DAPT to the patient in the placebo comparator group suffering from or having had an ischemic stroke or TIA. In some embodiments of the first aspect, a pharmaceutical composition comprising 25 mg, 50 mg, 100 mg or 200 mg of milvexian (or a pharmaceutically acceptable salt or solvate thereof) and a pharmaceutically acceptable carrier is administered to the experimental group twice daily. In some embodiments of the first aspect, a pharmaceutical composition comprising 25 mg of milvexian (or a pharmaceutically acceptable salt or solvate thereof) and a pharmaceutically acceptable carrier is administered to the experimental group once daily. In some embodiments of the first aspect, the experimental group is administered a pharmaceutical composition comprising 25 mg to 200 mg of milvexian (or a pharmaceutically acceptable salt or solvate thereof) and a pharmaceutically acceptable carrier twice daily.

[0025] In some aspects, the present invention provides a method for preventing ischemic stroke in a human patient who has or has had ischemic stroke or transient ischemic attack, wherein the method comprises administering milvexian (or a pharmaceutically acceptable salt or solvate thereof) to the human patient, wherein milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered in an amount of 25 mg once daily or in an amount of 25 mg to 200 mg twice daily, and wherein standard care is administered in addition to the administration of milvexian (or a pharmaceutically acceptable salt or solvate thereof).

[0026] In other aspects, the present invention provides a method for reducing the risk of ischemic stroke in a human patient who has or has had ischemic stroke or transient ischemic attack, the method comprising administering milvexian (or a pharmaceutically acceptable salt or solvate thereof) to the human patient, wherein milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered in an amount of 25 mg once a day or in an amount of 20 mg to 200 mg twice a day; and standard care is performed in addition to the administration of milvexian (or a pharmaceutically acceptable salt or solvate thereof).

[0027] In some aspects, the present invention provides a method of preventing ischemic stroke in a human patient having or having had an ischemic stroke or transient ischemic attack, wherein the method comprises administering to the human patient a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg once daily or in an amount of 25 mg to 200 mg twice daily, and standard of care, wherein the regimen is effective in preventing ischemic stroke in the human patient having or having had an ischemic stroke or transient ischemic attack relative to standard of care alone.

[0028] In some aspects, the present invention provides a method of reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg once daily or in an amount of 25 mg to 200 mg twice daily, and standard of care, wherein the regimen is effective in reducing the risk of ischemic stroke in the human patient who has or has had an ischemic stroke or transient ischemic attack relative to standard of care alone.

[0029] In some aspects, the present invention provides a method of treating a human patient who has or has had an ischemic stroke or transient ischemic attack, wherein the method comprises administering to the human patient a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg once daily or in an amount of 25 mg to 200 mg twice daily, and standard of care; wherein the regimen is effective to reduce the risk of ischemic stroke in the human patient who has or has had an ischemic stroke or transient ischemic attack, and wherein the human patient does not experience an ischemic stroke during the duration of the regimen.

[0030] In other aspects, the present invention provides methods of treating a patient population, wherein the patients in the population have or have had ischemic stroke or transient ischemic attack, the method comprising administering to the patients in the population a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg once daily or in an amount of 25 mg to 200 mg twice daily, and standard of care; wherein the percentage of patients in the population who experience ischemic stroke within 90 days of initiation of the regimen is less than 5%.

[0031] In other aspects, the present invention provides milvexian for use in a method of preventing ischemic stroke in a human patient having or having had ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg once daily or in an amount of 25 mg to 200 mg twice daily, and standard of care.

[0032] In other aspects, the present invention provides milvexian (or a pharmaceutically acceptable salt or solvate thereof) for use in preventing ischemic stroke in a human patient having or having had ischemic stroke or transient ischemic attack, wherein milvexian is administered in a regimen comprising 25 mg once daily or 25 mg to 200 mg twice daily; and standard of care.

[0033] In other aspects, the present invention provides a composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) for use in a method of preventing ischemic stroke in a human patient suffering from or having suffered from ischemic stroke or transient ischemic attack, wherein the composition is administered in a regimen comprising a unit dose of 25 mg of milvexian (or a pharmaceutically acceptable salt or solvate thereof) once daily or a unit dose of 25 mg to 200 mg of milvexian twice daily; and standard of care.

[0034] In other aspects, the present invention provides milvexian (or a pharmaceutically acceptable salt or solvate thereof) for use in a method of reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg once daily or in an amount of 25 mg to 200 mg twice daily, and standard of care; wherein the regimen is effective in reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack relative to standard of care alone.

[0035] In other aspects, the present invention provides milvexian (or a pharmaceutically acceptable salt or solvate thereof) for use in reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack, wherein milvexian is administered in a regimen comprising 25 mg once daily or 25 mg to 200 mg twice daily; and standard of care; wherein the regimen is effective in reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack relative to standard of care alone.

[0036] In other aspects, the present invention provides a composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) for use in a method of reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack, wherein the composition is administered in a regimen comprising a unit dose of 25 mg of milvexian (or a pharmaceutically acceptable salt or solvate thereof) once daily or a unit dose of 25 mg to 200 mg of milvexian twice daily; and standard of care; wherein the regimen is effective in reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack relative to standard of care alone.

[0037] In other aspects, the present invention provides milvexian (or a pharmaceutically acceptable salt or solvate thereof) for use in a method of treating a human patient who has or has had an ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg once daily or 25 mg to 200 mg twice daily, and standard of care; wherein the human patient does not experience an ischemic stroke during the duration of the regimen.

[0038] In other aspects, the present invention provides milvexian (or a pharmaceutically acceptable salt or solvate thereof) for use in treating a human patient having or having had an ischemic stroke or transient ischemic attack, wherein milvexian is administered in a regimen comprising 25 mg once daily or 25 mg to 200 mg twice daily, and standard of care, wherein the human patient does not experience an ischemic stroke during the duration of the regimen.

[0039] In other aspects, the present invention provides a composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) for use in a method of treating a human patient having or having had an ischemic stroke or transient ischemic attack, wherein the composition is administered in a regimen comprising a unit dose of 25 mg of milvexian (or a pharmaceutically acceptable salt or solvate thereof) once daily or a unit dose of 25 mg to 200 mg of milvexian twice daily, and standard of care, wherein the human patient does not experience an ischemic stroke during the duration of the regimen.

[0040] In other aspects, the present invention provides milvexian (or a pharmaceutically acceptable salt or solvate thereof) for use in a method of treating a patient population, wherein the patient suffers from or has suffered from ischemic stroke or transient ischemic attack, the method comprising administering to the patients in the population a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg once daily or in an amount of 25 mg to 200 mg twice daily, and standard of care; wherein the percentage of patients in the population who experience ischemic stroke within 90 days of the start of the regimen is less than 5%.

[0041] In other aspects, the present invention provides milvexian (or a pharmaceutically acceptable salt or solvate thereof) for use in treating a human patient having or having had an ischemic stroke or transient ischemic attack, wherein milvexian is administered in a regimen comprising 25 mg once daily or 25 mg to 200 mg twice daily, and standard of care, wherein the percentage of patients in said population experiencing an ischemic stroke within 90 days of initiation of the regimen is less than 5%.

[0042] In other aspects, the present invention provides a composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) for use in a method of treating a human patient having or having had an ischemic stroke or transient ischemic attack, wherein the composition is administered in a regimen comprising a unit dose of 25 mg of milvexian (or a pharmaceutically acceptable salt or solvate thereof) once daily or a unit dose of 25 mg to 200 mg of milvexian twice daily, and standard of care, wherein the percentage of patients in said population experiencing an ischemic stroke within 90 days of the start of the regimen is less than 5%. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 The coagulation pathway is shown. Legend: 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.

[0044] Figure 2 The AXIOMATIC-SSP study design described in Example 1 is shown. Legend: BID, twice daily; MRI, magnetic resonance imaging; QD, once daily; SOC, standard of care; PD, pharmacodynamics; PK, pharmacokinetic; LD, loading dose. *Within 48 hours of the index event and before randomization. Clopidogrel LD + 100mg aspirin. 600 mg clopidogrel LD was permitted. § Clinical neuroimaging for eligibility assessment is recommended within 72 hours of the index event and up to 24 hours after randomization; if MRI is completed after randomization (to minimize protocol deviation in the event of negative imaging results). Relative to the 1st or 2nd dose of study drug. || The 200-mg BID cohort will be added after 450 participants from the lower dose complete the Day 21 follow-up.

[0045] Figure 3 The incidence of ischemic stroke and major bleeding in the clinical study group described in Example 1 is shown. Figure 3 Milvexian numerically reduced the incidence of clinical ischemic stroke in patients with a pre-existing ischemic stroke or high-risk TIA in all treatment groups except 200 mg BID. Doses of 25-100 mg BID showed similar relative risk reductions (RRR) of ischemic stroke of approximately 30% compared to placebo, with similar trends observed over 21 days (the expected treatment period with DAPT). Figure 3 It was also depicted that for both the 25 mg QD and BID doses of milvexian, the incidence of major bleeding (BARC types 3 and 5) was the same as placebo (0.6%).

[0046] Figure 4Kaplan-Meier plot depicting the time to ischemic stroke and unexplained stroke in all randomized subjects in the placebo, 25 mg QD, 25 mg BID, 50 mg BID and 100 mg BID dose groups. The Kaplan-Meier plot depicts the time from randomization to the first occurrence of any ischemic stroke event for the combined dose of milvexian. The vertical line indicates the time point at which milvexian treatment showed a significant clinical benefit relative to participants taking placebo (approximately 10 days, early significant benefit). The reduction in the incidence of ischemic stroke events occurred relatively early after the start of treatment. Compared with placebo, the benefits conferred by milvexian were maintained throughout the treatment period (e.g., 90 days).

[0047] Figure 5 Kaplan-Meier plots depicting the time course of symptomatic ischemic stroke in the intent-to-treat population in the placebo, 25 mg QD, 25 mg BID, 50 mg BID, 100 mg BID, and 200 mg BID dose groups.

[0048] Figure 6 Depicted are the incidences (%, 95% CI) of symptomatic ischemic stroke and BARC type 3c hemorrhage in the placebo, 25 mg QD, 25 mg BID, 50 mg BID, 100 mg BID, and 200 mg BID dose groups.

[0049] Figure 7 Depicts the combined incidence (%, 95% CI) of ischemic stroke (IS) and transient ischemic attack (TIA) in the placebo, 25 mg QD, 25 mg BID, 50 mg BID, 100 mg BID and 200 mg BID dose groups. These data show that except for 200 mg BID, the incidence of recurrent symptomatic ischemic stroke and TIA is low for all doses of milvexian. Relative to placebo, doses of 25 mg QD to 100 mg BID reduce symptomatic ischemic stroke and TIA by 27% to 40% (Wald 95% CI within the group. 95% CI of RR was constructed using Wald Confidence Limits. Clinical events until day 90 are included).

[0050] Fig. 8AShown is the change in milvexian plasma concentration over time on day 1 after BID administration of a film-coated direct compression tablet of the invention (2 x 100 mg) compared to the change in milvexian plasma concentration over time on day 1 after BID administration of a capsule containing milvexian (2 x 100 mg). See Example 2.

[0051] Figure 8B Shown is the change in milvexian plasma concentration over time on day 5 following BID administration of the film-coated direct compression tablets of the present invention (2 x 100 mg) compared to the change in milvexian plasma concentration over time on day 5 following BID administration of capsules containing milvexian (2 x 100 mg). See Example 2.

[0052] Figure 8C Shown is the change in milvexian plasma concentration over time on day 1 following BID administration of a film-coated direct compression tablet of the invention (1 x 25 mg) compared to the change in milvexian plasma concentration over time on day 1 following BID administration of a capsule containing milvexian (1 x 25 mg).

[0053] Fig.8D Shown is the change in milvexian plasma concentration over time on day 5 following BID administration of a film-coated direct compression tablet of the invention (1 x 25 mg) compared to the change in milvexian plasma concentration over time on day 5 following BID administration of a capsule containing milvexian (1 x 25 mg).

[0054] Fig. 9 The benefit-risk profile of milvexian in the Phase II AXIOMATIC-SSP study is shown. See Example 1. DETAILED DESCRIPTION

[0055] As used herein, "prevention" refers to reducing the risk of occurrence. In some embodiments, prevention encompasses eliminating the risk of occurrence (i.e., reducing the risk of occurrence to zero). Therefore, "prevention" encompasses preventive treatments intended to reduce the incidence of clinical disease conditions. In some embodiments, for any of the methods described herein, "prevention" encompasses reducing the recurrence of ischemic stroke or TIA.

[0056] In some embodiments, "prevention" is synonymous with "reducing the risk of adverse cerebrovascular events (e.g., non-cardioembolic ischemic stroke) occurring" or "reducing the incidence of adverse cerebrovascular events (e.g., non-cardioembolic ischemic stroke) occurring." Reducing the risk or reducing the incidence means that the incidence of adverse cerebrovascular events is numerically and / or statistically significantly reduced or decreased by at least 1% or greater. Preferably, the reduction is 2% or greater, 3% or greater, 4% or greater, 5% or greater, 6% or greater, 7% or greater, 10% or greater, 20% or greater, 26% or greater, 34% or greater, 50% or greater, 64% or greater, and 74% or greater. The reduction includes confidence intervals of equal to or greater than 50%, equal to or greater than 75%, equal to or greater than 80%, equal to or greater than 90%, equal to or greater than 95%, equal to or greater than 98%, and equal to or greater than 99%. A confidence interval of equal to or greater than 95% is more preferred.

[0057] Within the scope of the present invention, "prevention" is a protective treatment of a disease condition by reducing and / or minimizing the risk of recurrence of a disease condition and / or reducing the risk by administering a therapeutically effective amount of milvexian or a pharmaceutically acceptable salt or solvate thereof to a patient. Patients for preventive and therapeutic therapy can be selected based on factors known to increase the risk of developing clinical disease conditions compared to the general population. For preventive and therapeutic treatments, the condition of a clinical disease condition may or may not have yet been presented. "Prevention" treatments can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment that reduces or minimizes the risk of a disease condition in a patient who has not yet presented a clinical disease condition, while secondary prevention is defined as minimizing or reducing the risk of recurrence or a second occurrence of the same or similar clinical disease condition.

[0058] As used herein, the term "treat" refers to alleviating the signs or symptoms of a disease or condition in a patient and / or preventing a disease or condition in a patient. Unless otherwise indicated, as used herein, the terms "treating," "treatment," and the like shall include managing and caring for a patient for the purpose of combating a disease, condition, or disorder, and include administering milvexian to prevent the onset of symptoms or complications, alleviate symptoms or complications, or eliminate a disease, condition, or disorder. Thus, "treating" or "treatment" encompasses treating a disease condition in a human and includes: (a) inhibiting a disease condition, i.e., curbing its development; and / or (b) alleviating a disease condition, i.e., regression of a disease condition.

[0059] As used herein, the term "patient population" refers to a specific group of individual patients suffering from an indication, such as the group of patients in a specific treatment arm of a clinical trial.

[0060] As used herein, a "risk factor" is a demographic factor that influences the potential risk of an event independent of any medication.

[0061] As used herein, the term "cerebrovascular disorder" or "cerebrovascular disease" refers to a neurological problem caused by a disruption in blood flow to the brain, which causes brain cells to become damaged or die due to lack of oxygen. In some embodiments, a cerebrovascular disorder includes a transient ischemic attack. In some embodiments, a cerebrovascular disorder includes a stroke. The extent to which a stroke or transient ischemic attack affects the body depends on the exact location in the brain where the blood supply is cut off.

[0062] As used herein, the term "stroke" (also referred to as cerebrovascular accident) refers to an acute onset of neurological dysfunction that causes brain tissue death (cerebral infarction) due to insufficient blood flow and insufficient oxygen supply to the brain. Stroke can be ischemic or hemorrhagic. In ischemic stroke, due to a thrombus formed locally in an abnormal artery (such as atherosclerosis) or an embolism formed upstream and moved via blood flow, a blood clot blocks a blood vessel, thereby causing the blood supply of part of the brain to be cut off. In hemorrhagic stroke, blood vessels rupture, hindering normal blood flow, and causing blood to leak into and damage the brain region. Most strokes occur suddenly, develop rapidly, and cause brain damage (complete stroke) within minutes. Less commonly, as the area of ​​brain tissue death continues to expand, a stroke may continue to worsen for hours to days (evolving stroke). Ischemic stroke can be lacunar or non-lacunar in nature. If the ischemic stroke is attributable to an arterial occlusion caused by an embolism that may have resulted from a blood clot formed in the heart or one of its valves, the ischemic stroke may be a cardiogenic embolic ischemic stroke. In some embodiments, the ischemic stroke is a non-cardiogenic embolic ischemic stroke. In some embodiments, the terms "ischemic stroke" and "symptomatic ischemic stroke" are used interchangeably.

[0063] In some embodiments, ischemic stroke refers to a neurological deficit attributable to a non-lacunar acute cerebral infarction detected by neuroimaging (CT or MRI) and associated with clinical symptoms.

[0064] In some embodiments, the ischemic stroke is further characterized by a National Institutes of Health Stroke Score (NIHSS) ≤7.

[0065] In other embodiments, the ischemic stroke is further characterized by a National Institutes of Health Stroke Scale (NIHSS) of 8-15.

[0066] In other embodiments, the ischemic stroke is further characterized by a National Institutes of Health Stroke Scale (NIHSS) ≤15.

[0067] In other embodiments, ischemic stroke is further characterized by evidence of atherosclerotic plaques, ulcers, or thrombi in the feeding arteries of the relevant intracranial or carotid arteries as documented by imaging (Doppler ultrasound or CTA or MRA or catheter angiography).

[0068] In still other embodiments, the ischemic stroke is further characterized by a Modified Rankin Score. For example, in some embodiments, the ischemic stroke is further characterized by a Modified Rankin Score of ≤3, ≤4, ≤5, or ≤6.

[0069] As used herein, the term "transient ischemic attack (TIA)" (also called a mini-stroke) refers to a short-term, focal neurological symptom similar to a stroke. TIAs do not cause permanent damage. TIAs are caused by a brief decrease in blood supply to part of the brain, which may last for several minutes. Like ischemic strokes, TIAs occur when clots or debris reduce or block blood flow to part of the nervous system. (e.g., high-risk TIAs).

[0070] In some embodiments, a TIA may be a "high-risk transient ischemic attack," which is an acute onset of neurological deficits attributable to cerebral ischemia based on history or examination, with complete resolution of the deficits on neuroimaging (CT or MRI) and without cerebral infarction.

[0071] In some embodiments, high risk transient ischemic attack is further characterized by an ABCD2 score ≥ 6 or by motor symptoms. See Rothwell PM et al. A simple score (ABCD) to identify individuals at high early risk of stroke after transient ischaemic attack. Lancet. 2005 Jul 2-8; 366(9479): 29-36.

[0072] In other embodiments, the high risk transient ischemic attack is further characterized by evidence of atherosclerotic plaques, ulcers, or thrombi in the feeding arteries of the relevant intracranial or carotid arteries as documented by imaging (Doppler ultrasound or CTA or MRA or catheter angiography).

[0073] As used herein, "pharmaceutically acceptable salts" refer to derivatives wherein a compound is modified by preparing an acidic or basic salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and basic or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid; and salts prepared from organic acids such as 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, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid and isethionic acid. Pharmaceutically acceptable salts of milvexian can be synthesized using conventional chemical methods. Generally, such salts can be prepared by reacting milvexian with a certain stoichiometric amount of an appropriate base or acid in water or in an organic solvent or in a mixture of the two; generally, non-aqueous media (such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile) are more preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences 18th ed., Mack Publishing Company, Easton, PA (1990), the disclosure of which is incorporated herein by reference.

[0074] As used herein, the term "standard of care" refers to a method of treatment that is generally accepted by medical experts and widely used by health care professionals as an appropriate treatment for a certain type of disease (e.g., stroke). The current standard of care for secondary prevention of recurrent cerebrovascular events after non-cardioembolic ischemic stroke or TIA is SAPT or DAPT, while changing patient-level risk factors by increasing physical activity and quitting smoking, and managing vascular risk factors including arterial hypertension, hyperlipidemia, hypertriglyceridemia, and glycemic control (Antithrombotic Trialists'Collaboration 2002, Antithrombotic Trialists'Collaboration 2009, Rothwell 2016, Kleindorfer 2021, Dawson 2021, Fonseca 2021). Current AHA / ASA guidelines recommend early initiation (ideally within 12 to 24 hours of symptom onset and at least within 7 days of onset) of short-term (21 to 90 days) DAPT with ASA plus clopidogrel followed by antiplatelet monotherapy for patients with a recent mild (NIHSS score ≤3) noncardioembolic ischemic stroke or high-risk TIA (ABCD2 score ≥4) followed by antiplatelet monotherapy (Kleindorfer 2021). As specified in the guidelines, DAPT with ticagrelor plus ASA for 30 days may be considered for patients with a recent (<24 hours) mild to moderate stroke (NIHSS score ≤5), high-risk TIA (ABCD2 score ≥6), or symptomatic intracranial or extracranial stenosis (Kleindorfer 2021). ESO guidelines recommend DAPT with ASA and clopidogrel for 21 days followed by SAPT for patients with mild non-cardioembolic ischemic stroke (NIHSS score ≤3) or high-risk TIA (ABCD2 score ≥4), or DAPT with ASA plus ticagrelor for 30 days followed by SAPT for patients with mild to moderate non-cardioembolic ischemic stroke (NIHSS score ≤5) or high-risk TIA (ABCD2 score ≥6 or other high-risk features) (Dawson 2021). In some embodiments, standard of care for stroke is the standard of care that clinicians typically follow when treating ischemic stroke in human patients who have recently (within 0 to 48 hours) had an ischemic stroke or transient ischemic attack.See, e.g., AHA / ASA Guideline for the Prevention of Stroke in PatientsWith Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association / American Stroke Association, Stroke, 2021;52:e364-e467. DOI:10.1161 / STR.0000000000000375.

[0075] As used herein, the term "placebo administration" or "placebo" refers to standard care as defined above. In some embodiments, "placebo administration" or "placebo" refers to an antiplatelet administration regimen comprising dual antiplatelet therapy (DAPT) or single antiplatelet therapy (SAPT). In some embodiments, "placebo administration" or "placebo" refers to a daily dose of DAPT comprising 75 mg clopidogrel and 100 mg aspirin (see Figure 2 ). In some aspects, the placebo is referred to as a "control."

[0076] As used herein, "safe" means that the regimen provides a net clinical benefit such that the reduced risk of ischemic stroke (or cardiovascular death or myocardial infarction) in humans outweighs the increased risk of adverse events (e.g., major bleeding) compared to antiplatelet therapy alone, as determined by regulatory authorities.

[0077] As used herein, "effective" means that the regimen reduces the risk of ischemic stroke (or cardiovascular death or myocardial infarction) and provides treatment compared to antiplatelet therapy alone.

[0078] As used herein, the term "clinically confirmed" means that the safety and / or efficacy of the regimen is confirmed by clinical studies, such as at least one clinical trial.

[0079] The absolute risk reduction (ARR) is the percentage of patients with adverse outcomes in the control group (i.e., the group that did not receive the regimen) minus the percentage of patients with adverse outcomes in the treatment group (i.e., the group that received the regimen). For example, if the incidence in the control group is 20% (i.e., if 20% of the patients in the control group experienced adverse outcomes) and the incidence in the treatment group is 12% (i.e., 12% of the patients experienced adverse outcomes), the absolute risk reduction (ARR) is 8% (i.e., 20%-12%).

[0080] The "relative risk" (RR) is the proportion of adverse outcomes (e.g., suffering ischemic stroke) in the treatment group (i.e., the group receiving the regimen) divided by the proportion of adverse outcomes in the control group (i.e., the group not receiving the regimen). For example, if 20% of the patients in the control group experience an adverse outcome and 12% of the patients in the treatment group experience an adverse outcome, then RR = 0.12 / 0.20 = 0.6. Therefore, an RR of less than 1 indicates a reduced risk.

[0081] As used herein, the term "relative risk reduction" (RRR) refers to the extent to which the regimen reduces the risk of adverse outcomes relative to a control group that did not receive the regimen. For example, if 20% of the patients in the control group experience adverse outcomes and 12% of the patients in the treatment group experience adverse outcomes, then RRR = (1-RR) × 100% = [1-(0.12 / 0.20)] × 100% = 0.4 × 100% = 40%. Therefore, an RRR greater than 0% indicates a reduced risk.

[0082] As used herein, the term "dose-dependent manner" means that the risk occurs inversely proportional to the amount of milvexian administered.

[0083] As used herein, the term "duration of a regimen" refers to the period during which a regimen is administered to a patient.

[0084] As used herein, the "Bleeding Academic Research Consortium (BARC) Type 3 criteria" are: a. Overt bleeding plus a drop in hemoglobin of 3 to <5 g / dL (with the proviso that the drop in hemoglobin is associated with bleeding); blood transfusion with overt bleeding; b. Overt bleeding plus a drop in hemoglobin ≥5 g / dL (with the proviso that the drop in hemoglobin is associated with bleeding); cardiac tamponade; bleeding requiring surgical intervention for control; bleeding requiring IV vasopressors; or c. Intracranial hemorrhage confirmed by autopsy, imaging, or lumbar puncture; intraocular hemorrhage that impairs vision. See, e.g., Roxana Mehran et al. Standardized Bleeding Definitions for Cardiovascular Clinical Trials, Circulation. 2011; 123: 2736-2747.

[0085] As used herein, "Bleeding Academic Research Consortium (BARC) Type 5 criteria" are: a. Potentially fatal bleeding; or b. Definitely fatal bleeding (overt or confirmed by autopsy or imaging). See, e.g., Roxana Mehran et al. Standardized Bleeding Definitions for Cardiovascular Clinical Trials, Circulation. 2011; 123: 2736-2747.

[0086] As used herein, "Bleeding Academic Research Consortium (BARC) Type 2 criteria" are: any clinically significant sign of bleeding that is "actionable" and requires diagnostic investigations, hospitalization, or treatment by a health care professional. See, e.g., Roxana Mehran et al. Standardized Bleeding Definitions for Cardiovascular Clinical Trials, Circulation. 2011; 123: 2736-2747.

[0087] As used herein, the "ISTH criteria (major bleeding or clinically relevant non-major bleeding (CRNM) criteria)" are as follows:

[0088] ISTH major bleeding in nonsurgical patients is defined as symptomatic bleeding with:

[0089] i. Fatal bleeding, and / or

[0090] ii. Bleeding into critical areas or organs, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, or pericardial, or intramuscular with compartment syndrome, and / or

[0091] iii. Causes hemoglobin level to drop by 20 g L -1 (1.24mmol L -1 ) or more, or bleeding requiring transfusion of two or more units of whole blood or red blood cells

[0092] ISTH CRNM bleeding is any sign or symptom of bleeding (e.g., bleeding in excess of that expected in the clinical setting, including bleeding detected by imaging alone) that does not meet the criteria for the ISTH definition of major bleeding but meets at least one of the following criteria:

[0093] i. Requires medical intervention by a healthcare professional

[0094] ii. Resulting in hospitalization or increased level of care

[0095] iii. Requires a face-to-face (i.e., not just telephone or electronic communication) assessment

[0096] It should be understood that when referring to, for example, amount, duration, extent of action and the like, the use of approximate terms, such as "substantially" or "about" may refer to a value within 5% (greater than or less than), or within 7.5% (greater than or less than), or within 10% (greater than or less than), or within 12.5% ​​(greater than or less than), or within 15% (greater than or equal to), or within 17.5% (greater than or equal to), or within 20% (greater than or equal to) of the specified value.

[0097] It should be understood that when referring to, for example, amount, duration, extent of action and similar terms, the term "equivalent" can be used as a value within 0% (greater than or less than), or within 0.5% (greater than or less than); or within 1.0% (greater than or less than); or within 2.0% (greater than or less than); or within 3.0% (greater than or equal to); or within 4.0% (greater than or equal to); or within 5.0% (greater than or equal to). In some embodiments, "equivalent" refers to the extent of action measured by a value within 0% (greater than or less than) of a specific value, for example, for milvexian 25 mg QD and BID doses, the incidence (%) of major bleeding (BARC type 3 and type 5) is the same as placebo (0.6%). In some embodiments, "equivalent" means that there is no statistical difference. Statistical data can be interpreted at a two-sided significance level of 0.05, and all confidence intervals are calculated at a two-sided confidence level of 95%.

[0098] As used herein, the term "intention to treat population" (ITT population) refers to all randomized participants who are (i) randomized to treatment, regardless of whether they receive study drug. For the primary efficacy endpoint analysis, the population includes all randomized participants who: have a primary endpoint event (a new ischemic stroke during the study period or a new hidden cerebral infarction detected by MRI at day 90); or (ii) have an evaluable MRI image at day 90. All other efficacy analyses will be performed on the ITT population during the double-blind treatment period. This population will be analyzed according to the treatment assigned at randomization. All treated participants include all participants who received at least one dose of study drug. This will be the main population for safety analysis and will be analyzed according to the treatment assigned at randomization.

[0099] As used herein, the term "a patient who has or has had an ischemic stroke or transient ischemic attack" refers to a patient who had an ischemic stroke or transient ischemic attack prior to starting a treatment regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof).

[0100] As used herein, the term "activated partial thromboplastin time (activated partial thromboplastin time; aPTT)" refers to the measurement of the intrinsic and final common pathway of the coagulation cascade. It represents the time (in seconds) for plasma to clot after the addition of phospholipids (an intrinsic pathway activator) and calcium. The name "activated partial thromboplastin time" comes from the original form of the test, in which only the phospholipid concentration of the test was controlled (relative to the phospholipid and surfactant concentrations), and the name "partial thromboplastin" is applied when the phospholipid preparation accelerates coagulation but does not correct for the prolonged clotting time of hemophilic plasma. The term "partial" refers to the presence of phospholipids but the absence of tissue factor. Normal and reference ranges vary depending on the reagent and instrument combination (especially the phospholipid composition).

[0101] In some embodiments, aPTT is determined as follows: Plasma samples are incubated with Actin FS aPTT detection reagent containing a standard amount of phospholipids and a contact activator (ellagic acid), which activates the intrinsic coagulation pathway. After 3 minutes of incubation, calcium chloride is added to initiate coagulation and the formation of a fibrin clot is determined optically. The time for clot formation (measured in seconds) is reported as the activated partial thromboplastin time (aPTT).

[0102] As used herein, "factor XI clotting activity" is determined using an aPTT-based 1-stage clotting time assay. Serial dilutions of normal pooled plasma are mixed with FXI-depleted plasma, and clotting times are measured according to a standard aPTT protocol to determine a reference range. Subject test plasma is processed in the same manner and compared to reference plasma.

[0103] In some embodiments, factor XI coagulation activity is determined as follows: Factor XI (FXI) activity was determined on the analyzer using Actin FS (Siemens Healthcare) modified activated partial thromboplastin time (aPTT). A 6-point calibration curve (approximately 5% to 150%) was prepared using a secondary calibrator (standard human plasma, Siemens Healthcare Diagnostics Inc.) and known concentrations of human FXI as specified by the manufacturer. The analyzer dilutes approximately 100% of the reference standard in saline to produce a preselected calibration level of FXI. A calibration curve is plotted with FXI activity in percent (%) on the x-axis and clotting time in seconds on the y-axis. A log / linear (log / lin) regression curve fit is used. The sample being tested is mixed with plasma lacking FXI (containing less than 1% FXI and at least 75% of all other factors) to normalize all other factors. APTT reagent (Actin FS) is added and the mixture is incubated. After incubation, calcium chloride is added to the mixture and the time for clot formation (measured optically) is compared to the time on the calibration curve. The clotting time is measured using a flow cytometer. Samples were tested at a base dilution (1:10) prepared in saline.

[0104] In some aspects, the methods of the invention relate to preventing ischemic stroke in adult patients after acute ischemic stroke or high-risk transient ischemic attack. In other aspects, the methods of the invention relate to reducing the risk of ischemic stroke in adult patients after acute ischemic stroke or high-risk transient ischemic attack. As used herein, "after" is synonymous with "have or have had".

[0105] In other aspects, the methods described herein are directed to preventing ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack.

[0106] In some aspects, the methods described herein relate to reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack.

[0107] In some aspects, the invention provides methods of treating a human patient who has or has had an ischemic stroke or transient ischemic attack.

[0108] In other aspects, the invention provides methods of treating a patient population in which the patient suffers or has suffered an ischemic stroke or transient ischemic attack.

[0109] The methods of the present invention are performed on human patients. In some embodiments, the human patients are female. In other embodiments, the human patients are male.

[0110] In some embodiments, the human patient is at least 40 years old.

[0111] In other embodiments, the human patient is at least 50 years old.

[0112] In other embodiments, the human patient is at least 60 years old.

[0113] In other embodiments, the human patient is at least 70 years old.

[0114] In some aspects of the disclosed methods, a regimen comprising milvexian, or a pharmaceutically acceptable salt or solvate thereof, is administered to the patient.

[0115] In some embodiments, the regimen comprises milvexian.

[0116] In some embodiments, the milvexian in the scheme comprises a milvexian solvate.

[0117] In other embodiments, the regimen comprises a pharmaceutically acceptable salt of milvexian.

[0118] In embodiments of the disclosed methods, where the regimen comprises a solvate or a pharmaceutically acceptable salt of milvexian, the specified amount is based on milvexian. That is, a certain amount of solvate or pharmaceutically acceptable salt in the regimen contains a specified amount of milvexian. For example, a regimen comprising 50 mg of milvexian (or a pharmaceutically acceptable salt or solvate thereof) refers to a regimen comprising 50 mg of milvexian, or an amount of a pharmaceutically acceptable salt or solvate of milvexian equivalent to 50 mg of milvexian.

[0119] In some aspects, the methods described herein comprise administering to a human patient (or patients in a patient population) a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 12.5 mg to 200 mg twice daily; and standard of care.

[0120] In some embodiments, the methods described herein comprise administering to a human patient (or patients in a patient population) a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg once daily or in an amount of 25 to 200 mg twice daily; and standard of care.

[0121] In some embodiments, the regimen comprises milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 12.5 mg twice daily in combination with standard of care.

[0122] In some embodiments, the regimen comprises milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg once daily in combination with standard of care.

[0123] In some embodiments, the regimen comprises milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg twice daily in combination with standard of care, wherein the standard of care allows for a loading dose of an antiplatelet agent.

[0124] In other embodiments, the regimen comprises milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 12.5 mg to 200 mg twice daily along with standard of care. Thus, in some embodiments, the regimen comprises milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of, for example, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 70 mg, milvexian administered in an amount of one of 75 mg, 80 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, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg or 200 mg twice daily, and standard of care.

[0125] In other embodiments, the regimen comprises milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg to 200 mg twice daily and standard of care. Thus, in some embodiments, the regimen comprises milvexian administered in an amount of, for example, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 70 mg, 75 mg, 80 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, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg twice daily and standard of care.

[0126] In other embodiments, the regimen comprises milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 12.5 mg to less than 200 mg twice daily along with standard of care. Thus, in some embodiments, the regimen comprises milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of, for example, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg , 70 mg, 75 mg, 80 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, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg or 190 mg twice daily, and standard of care.

[0127] In other embodiments, the regimen comprises milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg to less than 200 mg twice daily and standard of care. Thus, in some embodiments, the regimen comprises milvexian administered in an amount of, for example, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 70 mg, 75 mg, 80 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, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, or 190 mg twice daily and standard of care.

[0128] In some embodiments of the disclosed methods, milvexian is administered in an amount of 25 mg once daily.

[0129] In some embodiments of the disclosed methods, milvexian is administered in an amount of 12.5 mg twice daily.

[0130] In some embodiments of the disclosed methods, milvexian is administered in an amount of 25 mg twice daily.

[0131] In some embodiments of the disclosed methods, milvexian is administered in an amount of 50 mg twice daily.

[0132] In some embodiments of the disclosed methods, milvexian is administered in an amount of 100 mg twice daily.

[0133] In some embodiments of the disclosed methods, milvexian is administered daily in an amount of 200 mg twice daily.

[0134] In some embodiments of the disclosed methods, milvexian is administered in an amount of less than 200 mg twice daily.

[0135] In some aspects, the present invention relates to a method for preventing ischemic stroke or reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg twice daily and (ii) single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT).

[0136] In other aspects, the present invention relates to milvexian for use in preventing ischemic stroke in a human patient who has previously suffered an ischemic stroke or transient ischemic attack, or reducing the risk of ischemic stroke in a human patient who has previously suffered an ischemic stroke or transient ischemic attack, wherein milvexian is administered in an amount of 25 mg twice daily in conjunction with single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT).

[0137] In some aspects, the regimen used in the disclosed methods comprises standard of care.

[0138] In some embodiments, the standard of care comprises antiplatelet therapy.

[0139] In some embodiments, for any of the methods disclosed herein, the patient is administered personalized standard of care, antiplatelet therapy (DAPT or SAPT), and a specific P2Y12 inhibitor (clopidogrel, ticagrelor, ticlopidine, cangrelor, or prasugrel).

[0140] In some embodiments, for any of the methods disclosed herein, the standard of care comprises clopidogrel and aspirin for 21 days, followed by clopidogrel alone or aspirin alone from day 22 to day 90.

[0141] In some embodiments, for any of the methods disclosed herein, the standard of care comprises clopidogrel and aspirin for 90 days or aspirin alone for 90 days.

[0142] In some embodiments, for any of the methods disclosed herein, the standard of care comprises clopidogrel and aspirin for 90 days.

[0143] In some embodiments, for any of the methods disclosed herein, the standard of care comprises ticagrelor alone for 90 days, or aspirin alone for 90 days.

[0144] In some embodiments, for any of the methods disclosed herein, the standard of care comprises ticagrelor alone for 90 days.

[0145] In some embodiments, for any of the methods disclosed herein, the standard of care comprises ticagrelor and aspirin for 30 days.

[0146] In some embodiments, for any of the methods disclosed herein, the antiplatelet therapy comprises a selective phosphodiesterase type 3 (PDE3) inhibitor that inhibits blood clot formation by increasing cAMP. In some embodiments, the selective PDE3 inhibitor is cilostazol.

[0147] In some embodiments, for any of the methods disclosed herein, the antiplatelet therapy comprises a dual inhibitor of nucleoside transport and PDE3 that inhibits clot formation. In some embodiments, the dual inhibitor of nucleoside transport and PDE3 is dipyridamole.

[0148] In some embodiments, for any of the methods disclosed herein, the antiplatelet therapy comprises cilostazol or dipyridamole alone. In some embodiments, for any of the methods disclosed herein, the antiplatelet therapy comprises cilostazol and a P2Y12 inhibitor. In some embodiments, for any of the methods disclosed herein, the antiplatelet therapy comprises cilostazol and clopidogrel alone.

[0149] In some embodiments, the standard of care comprises single antiplatelet therapy (SAPT).

[0150] In some embodiments, the standard of care comprises dual antiplatelet therapy (DAPT).

[0151] In some embodiments, the standard of care comprises dual antiplatelet therapy (DAPT) for 21 days, followed by single antiplatelet therapy (SAPT).

[0152] In some aspects, the regimen used in the disclosed methods comprises milvexian and antiplatelet therapy.

[0153] In some embodiments, the antiplatelet therapy comprises a single antiplatelet therapy.

[0154] In some embodiments, the single antiplatelet therapy is aspirin.

[0155] In some embodiments of single antiplatelet therapy, aspirin is administered in an amount of 50 to 150 mg per day, for example: one of 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.

[0156] In some embodiments of single antiplatelet therapy, aspirin is administered in an amount of 75 to 100 mg per day, for example, one of 75 mg, 80 mg, 81 mg, 85 mg, 90 mg, 95 mg, or 100 mg per day.

[0157] In some embodiments of single antiplatelet therapy, aspirin is administered in an amount of 75 mg per day.

[0158] In some embodiments of single antiplatelet therapy, aspirin is administered in an amount of 81 mg per day.

[0159] In some embodiments of single antiplatelet therapy, aspirin is administered in an amount of 100 mg per day.

[0160] In other embodiments, the single antiplatelet therapy is a P2Y12 inhibitor.

[0161] In some embodiments of single antiplatelet therapy, the P2Y12 inhibitor is clopidogrel, ticagrelor, ticlopidine, cangrelor, or prasugrel.

[0162] In some embodiments of single antiplatelet therapy, the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel.

[0163] In some embodiments of the single antiplatelet therapy, the P2Y12 inhibitor is clopidogrel.

[0164] In some embodiments of single antiplatelet therapy, clopidogrel is administered in an amount of 75 mg to 600 mg per day, for example, one of 75 mg, 150 mg, 225 mg, 300 mg, 375 mg, 450 mg, 525 mg, or 600 mg per day.

[0165] In some embodiments of the single antiplatelet therapy, the P2Y12 inhibitor is ticagrelor.

[0166] In some embodiments of single antiplatelet therapy, the P2Y12 inhibitor is ticlopidine.

[0167] In some embodiments of single antiplatelet therapy, the P2Y12 inhibitor is cangrelor.

[0168] In some embodiments, the single antiplatelet therapy is ticlopidine.

[0169] In some embodiments, ticlopidine is administered in an amount of 250 to 500 mg per day, such as 150 mg or 500 mg per day.

[0170] In other embodiments of the disclosed methods, the antiplatelet therapy comprises dual antiplatelet therapy.

[0171] In some embodiments, the dual antiplatelet therapy is aspirin and ticlopidine.

[0172] In some embodiments, the dual antiplatelet therapy is aspirin and a P2Y12 inhibitor.

[0173] In some embodiments of dual antiplatelet therapy, aspirin is administered in an amount of 50 to 150 mg per day, for example: one of 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.

[0174] In some embodiments of dual antiplatelet therapy, aspirin is administered in an amount of 75 to 100 mg per day, such as one of 75 mg, 80 mg, 81 mg, 85 mg, 90 mg, 95 mg, or 100 mg per day.

[0175] In some embodiments of dual antiplatelet therapy, aspirin is administered in an amount of 75 mg per day.

[0176] In some embodiments of dual antiplatelet therapy, aspirin is administered in an amount of 81 mg per day.

[0177] In some embodiments of dual antiplatelet therapy, aspirin is administered in an amount of 100 mg per day.

[0178] In some embodiments of dual antiplatelet therapy, the P2Y12 inhibitor is clopidogrel, ticagrelor, ticlopidine, cangrelor, or prasugrel.

[0179] In some embodiments of dual antiplatelet therapy, the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel.

[0180] In some embodiments of dual antiplatelet therapy, the P2Y12 inhibitor is clopidogrel.

[0181] In some embodiments of dual antiplatelet therapy, clopidogrel is administered in an amount of 75 mg to 600 mg per day, for example, one of 75 mg, 150 mg, 225 mg, 300 mg, 375 mg, 450 mg, 525 mg, or 600 mg per day.

[0182] In some embodiments of dual antiplatelet therapy, clopidogrel is administered as a loading dose.

[0183] In some embodiments, the loading dose is between 300 and 600 mg per day.

[0184] In some embodiments of the dual antiplatelet therapy, clopidogrel is administered in an amount of 75 mg per day.

[0185] In some embodiments of the dual antiplatelet therapy, clopidogrel is administered in an amount of 150 mg per day.

[0186] In some embodiments of the dual antiplatelet therapy, clopidogrel is administered in an amount of 225 mg per day.

[0187] In some embodiments of the dual antiplatelet therapy, clopidogrel is administered in an amount of 300 mg per day.

[0188] In some embodiments of the dual antiplatelet therapy, clopidogrel is administered in an amount of 375 mg per day.

[0189] In some embodiments of the dual antiplatelet therapy, clopidogrel is administered in an amount of 450 mg per day.

[0190] In some embodiments of the dual antiplatelet therapy, clopidogrel is administered in an amount of 525 mg per day.

[0191] In some embodiments of the dual antiplatelet therapy, clopidogrel is administered in an amount of 600 mg per day.

[0192] In some embodiments, the antiplatelet therapy comprises Aggrenox, a combination of aspirin and dipyridamole (persantine).

[0193] In some embodiments, the antiplatelet therapy comprises a combination of single antiplatelet therapy and dual antiplatelet therapy.

[0194] In some embodiments of the disclosed methods, the dual antiplatelet therapy is administered for up to 21 consecutive days, followed by administration of a single antiplatelet therapy.

[0195] In some aspects, the regimens used in the methods described herein are effective in preventing ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack.

[0196] In some aspects, the regimens used in the methods described herein are effective in reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack.

[0197] In some aspects, the regimens used in the methods described herein are safe and effective for preventing ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack.

[0198] In some aspects, the regimens used in the methods described herein are safe and effective in reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack.

[0199] In some aspects, the regimens used in the methods described herein are clinically demonstrated to be safe and effective for preventing ischemic stroke in human patients who have or have had an ischemic stroke or transient ischemic attack.

[0200] In some aspects, the regimens used in the methods described herein are clinically demonstrated to be safe and effective in reducing the risk of ischemic stroke in human patients who have or have had an ischemic stroke or transient ischemic attack.

[0201] In some embodiments of the methods described herein, the regimen reduces the risk of ischemic stroke compared to administration of a placebo and standard of care.

[0202] In some embodiments of the disclosed methods, the relative risk of ischemic stroke for the regimen compared to placebo together with standard of care is about 0.9 to 0.6, e.g., about 0.9 to 0.85, about 0.85 to 0.8, about 0.85 to 0.75, about 0.85 to 0.7, about 0.85 to 0.65, about 0.8 to 0.75, about 0.8 to 0.7, about 0.8 to 0.65, about 0.8 to 0.6, about 0.75 to 0.7, about 0.75 to 0.65, about 0.75 to 0.6, about 0.75 to 0.65, about 0.75 to 0.6, about 0.75 to 0.65, about 0.75 to 0.6. 65 to 0.6, or one of about 0.9, about 0.89, about 0.88, about 0.87, about 0.86, about 0.85, about 0.84, about 0.83, about 0.82, about 0.81, about 0.80, about 0.79, about 0.78, about 0.77, about 0.76, about 0.75, about 0.74, about 0.73, about 0.72, about 0.71, about 0.7, about 0.69, about 0.68, about 0.67, about 0.66, about 0.65, about 0.64, about 0.63, about 0.62, about 0.61, or about 0.6.

[0203] In some embodiments of the disclosed methods, the relative risk reduction for ischemic stroke of the regimen compared to placebo together with standard of care is about 10% to 40%, such as about 10% to 15%, about 15% to 20%, about 15% to 25%, about 15% to 30%, about 15% to 35%, about 20% to 25%, about 20% to 30%, about 20% to 35%, about 20% to 40%, about 25% to 30%, about 25% to 35%, about 25% to 40%, about 30% to 35%, about 30% to 35%. %, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, or about 40%.

[0204] In some embodiments of the disclosed methods, the absolute risk reduction in ischemic stroke for the regimen compared to placebo together with standard of care is about 1% to 10%, such as about 1% to 2%, about 1% to 3%, about 1% to 4%, about 1% to 5%, about 1% to 6%, about 1% to 7%, about 1% to 8%, about 1% to 9%, about 2% to 3%, about 2% to 4%, about 2% to 5%, about 2% to 6%, about 2% to 7%, about 2% to 8%, about 2% to 9%, about 2% to 10%, about 3% to 4%, about 3% to 5%, about 3% to 6%, about 3% to 7%, about 3% to 8%, about 3% to 9%. , about 3% to 10%, about 4% to 5%, about 4% to 6%, about 4% to 7%, about 4% to 8%, about 4% to 9%, about 4% to 10%, about 5% to 6%, about 5% to 7%, about 5% to 8%, about 5% to 9%, about 5% to 10%, about 6% to 7%, about 6% to 8%, about 6% to 9%, about 6% to 10%, about 7% to 8%, about 7% to 9%, about 7% to 10%, about 8% to 9%, about 8% to 10%, or about 9% to 10%, or one of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%.

[0205] In some embodiments of the methods described herein, the regimen reduces the risk of ischemic stroke compared to administration of a placebo along with the antiplatelet therapy.

[0206] In some embodiments of the disclosed methods, the relative risk of ischemic stroke for the regimen compared to placebo together with antiplatelet therapy is about 0.9 to 0.6, e.g., about 0.9 to 0.85, about 0.85 to 0.8, about 0.85 to 0.75, about 0.85 to 0.7, about 0.85 to 0.65, about 0.8 to 0.75, about 0.8 to 0.7, about 0.8 to 0.65, about 0.8 to 0.6, about 0.75 to 0.7, about 0.75 to 0.65, about 0.75 to 0.6, about 0.75 to 0.65, about 0.75 to 0.6, about 0.75 to 0.65, about 0.75 to 0.6. .65 to 0.6, or one of about 0.9, about 0.89, about 0.88, about 0.87, about 0.86, about 0.85, about 0.84, about 0.83, about 0.82, about 0.81, about 0.80, about 0.79, about 0.78, about 0.77, about 0.76, about 0.75, about 0.74, about 0.73, about 0.72, about 0.71, about 0.7, about 0.69, about 0.68, about 0.67, about 0.66, about 0.65, about 0.64, about 0.63, about 0.62, about 0.61, or about 0.6.

[0207] In some embodiments of the disclosed methods, the relative risk reduction for ischemic stroke of the regimen compared to placebo in combination with antiplatelet therapy is about 10% to 40%, for example, about 10% to 15%, about 15% to 20%, about 15% to 25%, about 15% to 30%, about 15% to 35%, about 20% to 25%, about 20% to 30%, about 20% to 35%, about 20% to 40%, about 25% to 30%, about 25% to 35%, about 25% to 40%, about 30% to 35%, about 35% to 30%. In some embodiments, the present invention relates to an agent that is at least about 0.05% to 0.06% of the present invention, wherein the agent is at least about 0.05% to 0.06% of the present invention, wherein the agent is at least about 0.05% to 0.06% of the present invention, or wherein the agent is at least about 0.05% to 0.06% of the present invention, wherein the agent is at least about 0.05% to 0.06% of the present invention, or wherein the agent is at least about 0.05% to 0.06% of the present invention,

[0208] In some embodiments of the disclosed methods, the absolute risk reduction in ischemic stroke for the regimen compared to placebo in combination with antiplatelet therapy is about 1% to 10%, such as about 1% to 2%, about 1% to 3%, about 1% to 4%, about 1% to 5%, about 1% to 6%, about 1% to 7%, about 1% to 8%, about 1% to 9%, about 2% to 3%, about 2% to 4%, about 2% to 5%, about 2% to 6%, about 2% to 7%, about 2% to 8%, about 2% to 9%, about 2% to 10%, about 3% to 4%, about 3% to 5%, about 3% to 6%, about 3% to 7%, about 3% to 8%, about 3% to 9%. In some embodiments, the present invention relates to a pharmaceutical composition that is at least about 1% to about 2% of the pharmaceutical composition. The pharmaceutical composition may be selected from the group consisting of about 1% to about 10%; about 2% to about 3%; about 3% to about 10%; about 4% to about 5%; about 4% to about 6%; about 4% to about 7%; about 4% to about 8%; about 4% to about 9%; about 4% to about 10%; about 5% to about 6%; about 5% to about 7%; about 5% to about 8%; about 5% to about 9%; about 5% to about 10%; about 6% to about 7%; about 6% to about 8%; about 6% to about 9%; about 6% to about 10%; about 7% to about 8%; about 7% to about 9%; about 7% to about 10%; about 8% to about 9%; or about 9% to 10%; or one of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10%.

[0209] In some embodiments of the disclosed methods, the risk of ischemic stroke is reduced in a dose-dependent manner with the amount of milvexian administered.

[0210] In some aspects of the methods described herein, the human patient administered the regimen does not experience an ischemic stroke during the duration of the regimen.

[0211] In some embodiments, the duration of the regimen is about 4 weeks to 52 weeks, for example one of 4, 5, 6, 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, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks.

[0212] In other embodiments, the duration of the regimen is one of at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 14 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, at least 26 weeks, at least 28 weeks, at least 30 weeks, at least 32 weeks, at least 34 weeks, at least 36 weeks, at least 38 weeks, at least 40 weeks, at least 42 weeks, at least 44 weeks, at least 46 weeks, at least 48 weeks, at least 50 weeks, or at least 52 weeks.

[0213] In some embodiments, the regimen is administered chronically, ie, the duration of the regimen is the remaining life span of the patient.

[0214] In some embodiments, the duration of the regimen is one of at least 0.5 years, at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years, at least 9 years, at least 10 years, at least 11 years, at least 12 years, at least 13 years, at least 14 years, at least 15 years, at least 16 years, at least 17 years, at least 18 years, at least 19 years, or at least 20 years.

[0215] In some aspects of the disclosed methods, wherein the regimen is administered to a patient population, the percentage of patients in the population experiencing ischemic stroke within 90 days of initiation of the regimen is about 10% or less, such as about 10% or less, about 9.9% or less, about 9.8% or less, about 9.7% or less, about 9.6% or less, about 9.5% or less, about 9.4% or less, about 9.3% or less, about 9.2% or less, about 9.1% or less, about 9% or less, about 8.9% or less, about 8.9% or less, or about 8.8% or less. 8% or less, about 8.7% or less, about 8.6% or less, about 8.5% or less, about 8.4% or less, about 8.3% or less, about 8.2% or less, about 8.1% or less, about 8% or less, about 7.9% or less, about 7.8% or less, about 7.7% or less, about 7.6% or less, about 7.5% or less, about 7.4% or less, about 7.3% or less, about 7.2% or less, about 7.1% or less, about 7% or less, about 6.9% or less, about 6.8% or less, about 6.7% or less, about 6.6% or less, about 6.5% or less, about 6.4% or less, about 6.3% or less, about 6.2% or less, about 6.1% or less, about 6% or less, about 5.9% or less, about 5.8% or less, about 5.7% or less, about 5.6% or less, about 5.5% or less, about 5.4% or less, about 5.3% or less, about 5.2% or less, about 5.1% or less, about 5% or less, about 4.9% or less. % or less, about 4.8% or less, about 4.7% or less, about 4.6% or less, about 4.5% or less, about 4.4% or less, about 4.3% or less, about 4.2% or less, about 4.1% or less, about 4.0% or less, about 3.9% or less, about 3.8% or less, about 3.7% or less, about 3.6% or less, about 3.5% or less, about 3.4% or less, about 3.3% or less, about 3.2% or less, about 3.1% or less, or about 3.0% or less.

[0216] In some embodiments of the methods described herein, the relative risk of bleeding according to the Bleeding Academic Research Consortium (BARC) type 3 or type 5 criteria for the regimen compared to placebo together with standard of care is no more than 3, e.g., no more than one of 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.

[0217] In some embodiments of the methods described herein, the relative risk of bleeding according to the Bleeding Academic Research Consortium (BARC) type 3 or type 5 criteria for the regimen compared to placebo in combination with antiplatelet therapy is no more than 3, e.g., no more than one of 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.

[0218] In some embodiments of the disclosed methods, the relative risk of major bleeding according to the Bleeding Academic Research Consortium (BARC) Type 3 or Type 5 criteria is independent of the amount of milvexian administered.

[0219] In other embodiments of the disclosed methods, the human patient does not experience major bleeding according to the Bleeding Academic Research Consortium (BARC) type 3 and 5 criteria.

[0220] In some embodiments of the methods described herein, the relative risk of bleeding according to the Bleeding Academic Research Consortium (BARC) type 2 criteria of the regimen compared to placebo together with standard of care is no more than 2.6, e.g., no more than one of 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.

[0221] In some embodiments of the methods described herein, the relative risk of bleeding according to the Bleeding Academic Research Consortium (BARC) type 2 criteria for the regimen compared to placebo in combination with antiplatelet therapy is no more than 2.6, e.g., no more than one of 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.

[0222] In some embodiments of the disclosed methods, the relative risk of bleeding according to the Bleeding Academic Research Consortium (BARC) Type 2 criteria is independent of the amount of milvexian administered.

[0223] In other embodiments of the disclosed methods, the human patient does not experience bleeding according to Bleeding Academic Research Consortium (BARC) type 2.

[0224] In some embodiments of the methods described herein, the relative risk of bleeding according to ISTH criteria (major bleeding or clinically relevant non-major bleeding (CRNM)) of the regimen compared to placebo together with standard of care is no more than 3, for example no more than one of the following: 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.

[0225] In some embodiments of the methods described herein, the relative risk of bleeding according to ISTH criteria (major bleeding or clinically relevant non-major bleeding (CRNM)) of the regimen compared to placebo in combination with antiplatelet therapy is no more than 3, for example no more than one of the following: 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.

[0226] In some aspects of the disclosed methods, wherein the regimen is administered to a patient population, the percentage of patients in the population who experience major bleeding according to the Bleeding Academic Research Consortium (BARC) type 3 or type 5 criteria within 90 days is about 2% or less, such as one of about 2% or less, about 1.9% or less, about 1.8% or less, about 1.7% or less, about 1.6% or less, about 1.5% or less, about 1.4% or less, about 1.3% or less, about 1.2% or less, about 1.1% or less, about 1% or less, about 0.9% or less, about 0.8% or less, about 0.7% or less, about 0.6% or less, about 0.5% or less, about 0.4% or less, about 0.3% or less, about 0.2% or less, or about 0.1% or less.

[0227] In some aspects of the disclosed methods, wherein the regimen is administered to a patient population, the percentage of patients in the population who experience bleeding according to the Bleeding Academic Research Consortium (BARC) Type 2 criteria within 90 days is about 3.5% or less, e.g., about 3.5% or less, about 3.4% or less, about 3.3% or less, about 3.2% or less, about 3.1% or less, about 3.0% or less, about 2.9% or less, about 2.8% or less, about 2.7% or less, about 2.6% or less, about 2.5% or less, about 2.4% or less, about 2.3% or less, about 2.4% or less, about 2.5% or less, about 2.6% or less, about 2.7% or less, about 2.8% or less, about 2.9% or less, about 2.9% or less, about 2.8 ... In some embodiments, the present invention relates to one of about 2.2% or less, about 2.1% or less, about 2% or less, about 1.9% or less, about 1.8% or less, about 1.7% or less, about 1.6% or less, about 1.5% or less, about 1.4% or less, about 1.3% or less, about 1.2% or less, about 1.1% or less, about 1% or less, about 0.9% or less, about 0.8% or less, about 0.7% or less, about 0.6% or less, about 0.5% or less, about 0.4% or less, about 0.3% or less, about 0.2% or less, or about 0.1% or less.

[0228] In some aspects of the disclosed methods, wherein the regimen is administered to a patient population, the percentage of patients in the population who experience bleeding according to ISTH criteria (major bleeding or clinically relevant non-major bleeding (CRNM) criteria) within 90 days is about 5% or less, such as about 5% or less, about 4.9% or less, about 4.8% or less, about 4.7% or less, about 4.6% or less, about 4.5% or less, about 4.4% or less, about 4.3% or less, about 4.2% or less, about 4.1% or less, about 4% or less, about 3.9% or less, about 3.8% or less, about 3.7% or less, about 3.6% or less, about 3.5% or less, about 3.4% or less, about 3.3% or less, about 3.2% or less, about 3.1% or less, about 3.2% or less, about 3.3% or less, about 3.4% or less, about 3.5% or less, about 3.6% or less, about 3.7% or less, about 3.8% or less, about 3.9% or less, about 3.9% or less, about 3.8% or less, about 3.7% or less, about 3.6% or less, about 3.5% or less, about 3.4% or less, about 3.3% or less, about 3.2% or less, about 3. In some embodiments, the present invention relates to one of about 1% or less, about 2.0% or less, about 2.9% or less, about 2.8% or less, about 2.7% or less, about 2.6% or less, about 2.5% or less, about 2.4% or less, about 2.3% or less, about 2.2% or less, about 2.1% or less, about 2% or less, about 1.9% or less, about 1.8% or less, about 1.7% or less, about 1.6% or less, about 1.5% or less, about 1.4% or less, about 1.3% or less, about 1.2% or less, about 1.1% or less, about 1% or less, about 0.9% or less, about 0.8% or less, about 0.7% or less, about 0.6% or less, about 0.5% or less, about 0.4% or less, about 0.3% or less, about 0.2% or less, or about 0.1% or less.

[0229] In some aspects of the disclosed methods, administration of the regimen reduces FXI coagulation activity in the patient.

[0230] In some embodiments, in Siemens Factor XI (FXI) activity was determined on the analyzer using Actin FS (Siemens Healthcare) modified activated partial thromboplastin time (aPTT). A 6-point calibration curve (approximately 5% to 150%) was prepared using a secondary calibrator (standard human plasma, Siemens Healthcare Diagnostics Inc.) and known concentrations of human FXI as specified by the manufacturer. The analyzer dilutes approximately 100% of the reference standard in saline to produce a pre-selected calibration level of FXI. A calibration curve is plotted with FXI activity in percent (%) on the x-axis and clotting time in seconds on the y-axis. A log / linear regression curve fit is used. The tested sample is mixed with plasma lacking FXI (containing less than 1% FXI and at least 75% of all other factors) to normalize all other factors. APTT reagent (Actin FS) is added and the mixture is incubated. After incubation, calcium chloride is added to the mixture and the time for clot formation (measured optically) is compared to the time on the calibration curve. The clotting time is measured using the calibration curve. Samples were tested at a base dilution (1:10) prepared in saline.

[0231] In some embodiments of the methods described herein, administration of the regimen results in a dose-dependent decrease in the patient's FXI coagulation activity relative to baseline.

[0232] In some embodiments of the methods described herein, administration of the regimen results in a decrease in the patient's FXI coagulation activity from about 7% to about 70% relative to baseline.

[0233] In other aspects, in the methods described herein, administration of the regimen results in a decrease in the patient's FXI coagulation activity from about 7% to about 43% relative to baseline.

[0234] In other aspects, in the methods described herein, administration of the regimen results in a decrease in the patient's FXI coagulation activity from about 7% to about 20% relative to baseline.

[0235] In some embodiments, in the methods described herein, administration of the regimen results in a decrease in the patient's FXI coagulation activity relative to baseline of about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about About 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67% or about 68%, about 69% or about 70%.

[0236] In some embodiments, in the methods described herein, administration of the regimen results in a decrease in the patient's FXI coagulation activity relative to baseline by about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, or about 43%.

[0237] In other embodiments, in the methods described herein, administration of the regimen results in a decrease in the patient's FXI coagulation activity relative to baseline by about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%.

[0238] In other embodiments, in the methods described herein, administration of the regimen reduces the patient's FXI coagulation activity by an amount shown in Table 16 of Example 1.

[0239] In some aspects of the disclosed methods, administration of the regimen results in a dose-dependent prolongation of activated partial thromboplastin time (aPTT) relative to baseline.

[0240] In some aspects of the disclosed methods, administration of the regimen results in an increase in activated partial thromboplastin time (aPTT) within a range of about 27% to about 115% relative to baseline.

[0241] In some embodiments of the disclosed methods, administration of the regimen results in an activated partial thromboplastin time (aPTT) being prolonged by about 27% to about 115% relative to baseline, e.g., about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about , about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, About 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111%, about 112%, about 113%, about 114%, or about 115%. As used herein, "baseline" refers to a patient's aPTT prior to administration of any regimen.

[0242] In some aspects of the disclosed methods, administration of the regimen results in an increase in activated partial thromboplastin time (aPTT) within a range of about 27% to about 64% relative to baseline.

[0243] In some embodiments of the disclosed methods, administration of the regimen results in an activated partial thromboplastin time (aPTT) that is prolonged by about 27% to about 64% relative to baseline, e.g., about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, or about 64%. As used herein, "baseline" refers to the aPTT of a patient prior to administration of any regimen.

[0244] In some embodiments of the disclosed methods, administration of the regimen prolongs the activated partial thromboplastin time (aPTT) by the amount shown in Table 15 in Example 1.

[0245] In some embodiments, aPTT is determined as follows: Plasma samples are incubated with Actin FS aPTT detection reagent containing a standard amount of phospholipids and a contact activator (ellagic acid), which activates the intrinsic coagulation pathway. After 3 minutes of incubation, calcium chloride is added to initiate coagulation and the formation of a fibrin clot is determined optically. The time for clot formation (measured in seconds) is reported as the activated partial thromboplastin time (aPTT).

[0246] In some aspects of the methods of the present invention, the pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) is a solid oral pharmaceutical composition.

[0247] In some embodiments, the dose of milvexian or a pharmaceutically acceptable salt thereof administered may be formulated as an immediate release formulation.

[0248] In some embodiments, the dose of milvexian administered may be formulated as an immediate release capsule formulation.

[0249] In some embodiments, the dose of milvexian administered may be formulated as an amorphous solid dispersion composition comprising one or more polymers of milvexian.

[0250] In some embodiments, the polymer in the amorphous solid dispersion is hydroxypropylmethylcellulose acetate succinate (HPMCAS).

[0251] In some embodiments, the amorphous solid dispersion composition containing the milvexian polymer or polymers is prepared by spray drying.

[0252] In some embodiments, an amorphous solid dispersion of milvexian or polymers comprises milvexian molecularly dispersed in one or more polymers.

[0253] In some embodiments of the methods described herein, the solid oral pharmaceutical composition comprises a spray-dried amorphous solid dispersion (SDP) consisting essentially of milvexian free form and a pH-dependent enteric polymer.

[0254] In some embodiments, the SDP is a spray-dried amorphous solid dispersion prepared according to the composition and method described in WO 2020210629. The SDP consists essentially of milvexian free form and hydroxypropylmethylcellulose acetate succinate (HPMCAS-MG) in a weight ratio of 3:1 (milvexian:HPMCAS-MG).

[0255] In some embodiments of the methods described herein, the SDP comprises milvexian free form and a pH-dependent enteric polymer in a weight ratio of 3:1 (milvexian:polymer).

[0256] In some embodiments of the methods of the present invention, the pH-dependent enteric polymer is cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose ES grade (HPMC ES), e.g. Hydroxypropyl methylcellulose acetate succinate (HPMC-AS) LF, LG, MF, MG or HF grade, such as and polyvinyl acetate phthalate (PVAP), and for example Aquagold's Shellac resin, or polyvinyl pyrrolidone (PVP).

[0257] In some embodiments of the methods of the present invention, the pH-dependent enteric polymer is hydroxypropylmethylcellulose-AS MG.

[0258] In some embodiments of the methods described herein, the solid oral pharmaceutical composition further comprises a binder, such as microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), or a combination thereof.

[0259] In some embodiments of the methods described herein, the solid oral pharmaceutical composition further comprises a filler, such as lactose monohydrate.

[0260] In some embodiments of the methods described herein, the solid oral pharmaceutical composition further comprises a disintegrant.

[0261] In some embodiments of the methods described herein, the solid oral pharmaceutical composition further comprises a lubricant.

[0262] In some embodiments of the methods described herein, the solid oral pharmaceutical composition is a tablet.

[0263] In some embodiments of the methods described herein, the solid oral pharmaceutical composition is an immediate release tablet.

[0264] In some embodiments of the methods described herein, the solid oral pharmaceutical composition is a direct compression tablet.

[0265] In some embodiments of the methods described herein, the solid oral pharmaceutical composition is a roller-compressed granulation tablet.

[0266] In some embodiments of the methods described herein, the solid oral pharmaceutical composition is a film-coated tablet.

[0267] In some embodiments of the methods described herein, the film coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol-polyvinyl alcohol graft copolymer, and talc.

[0268] In some embodiments of the methods described herein, the film coating comprises a polyethylene glycol-polyvinyl alcohol graft copolymer.

[0269] In some embodiments, the film coating comprises Opadry.

[0270] In some embodiments, the film coating comprises polyvinyl alcohol, iron oxide, polyethylene glycol (PEG) polyvinyl alcohol graft copolymer, and talc.

[0271] In some embodiments, the film coating comprises Opadry QX 321A220063 Yellow, a film coating material comprising polyvinyl alcohol, iron oxide, polyethylene glycol (PEG) polyvinyl alcohol graft copolymer, and talc.

[0272] In some embodiments, the solid oral pharmaceutical composition is a tablet having the composition and / or properties shown in Table A:

[0273]

[0274] b SDP: A spray-dried amorphous solid dispersion prepared according to the composition and method described in WO 2020210629. The SDP consists essentially of milvexian free form and hydroxypropylmethylcellulose acetate succinate (HPMCAS-MG) in a weight ratio of 3:1 (milvexian:HPMCAS-MG).

[0275] c Opadry QX 321A220063 Yellow: A film coating material comprising polyvinyl alcohol, iron oxide, polyethylene glycol (PEG) polyvinyl alcohol graft copolymer and talc.

[0276] In some embodiments where the solid pharmaceutical composition is a tablet, the disintegration time of the tablet in water is less than 20 seconds.

[0277] In other embodiments where the solid pharmaceutical composition is a tablet, the tablet has a disintegration time in water of less than 15 seconds.

[0278] In other embodiments where the solid pharmaceutical composition is a tablet, the tablet has a disintegration time in water of less than 10 seconds.

[0279] In some embodiments of the methods described herein, the solid pharmaceutical composition is a capsule.

[0280] In some aspects of the methods described herein, the human patient to whom the pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered is unable to swallow a tablet dosage form.

[0281] In some embodiments of the disclosed methods, a solid oral pharmaceutical composition is dispersed in an aqueous medium to form an aqueous dispersion for administration.

[0282] In some embodiments of the disclosed methods, the solid oral pharmaceutical composition is a tablet that is dispersed in an aqueous medium to form an aqueous dispersion for administration.

[0283] In some embodiments of the disclosed methods, the solid oral pharmaceutical composition is a tablet that is orally administered as an aqueous dispersion by dispersing the tablet in an aqueous medium for less than 1 minute.

[0284] In those embodiments where the solid oral pharmaceutical composition is dispersed in an aqueous medium to form an aqueous dispersion, the aqueous medium is water, saline, phosphate buffered saline, vegetable or fruit juice, including, for example, applesauce.

[0285] In those embodiments where the solid oral pharmaceutical composition is a tablet that is dispersed in an aqueous medium to form an aqueous dispersion, the aqueous medium is water, saline, phosphate buffered saline, vegetable or fruit juice, including, for example, applesauce.

[0286] In some embodiments of the disclosed methods of dispersing a solid oral pharmaceutical composition 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 a spoon.

[0287] In some embodiments of the disclosed methods where 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 a spoon.

[0288] In some embodiments of the disclosed methods, oral administration of a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) results in a plasma half-life of milvexian in the range of about 13 hours to about 16 hours. In some embodiments of the disclosed methods, oral administration of a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) results in a plasma half-life of milvexian in the range of about 13 hours to about 16 hours during repeated dosing. As used herein, “half-life (t 1 / 2 )" refers to the apparent terminal elimination half-life, the average value of which is calculated using the formula t 1 / 2 =log e 2 / 1, where λ is the apparent terminal elimination rate constant, which is estimated by linear regression using the terminal log-linear phase of the log-transformed concentration versus time data. In some embodiments, the half-life (t 1 / 2 ) has an average value in the range of about 8 hours to about 16 hours. In some embodiments, the half-life (t 1 / 2 ) has an average value in the range of about 11 hours to about 16 hours. In a preferred embodiment, the half-life (t 1 / 2 ) is in the range of about 13 hours to about 16 hours.

[0289] In some embodiments of the disclosed methods, a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered to a human patient such that the plasma concentration of milvexian reaches a steady state in about 3 to 6 days. As used herein, the term "steady state" refers to a steady-state plasma concentration as defined by regulatory agencies such as the US Food & Drug Administration (FDA) and the European Medicines Agency (EMA).

[0290] In some embodiments of the disclosed methods, administration of a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) to a human patient results in a steady-state milvexian plasma concentration in about 3 days.

[0291] In some embodiments of the disclosed methods, administration of a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) to a human patient results in a steady-state milvexian plasma concentration in about 4 days.

[0292] In some embodiments of the disclosed methods, administration of a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) to a human patient results in a steady-state milvexian plasma concentration in about 5 days.

[0293] In some embodiments of the disclosed methods, administration of a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) to a human patient results in a steady state of milvexian plasma concentration in about 6 days.

[0294] In some embodiments of the disclosed methods, the pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered without regard to the timing of food intake.

[0295] In some aspects, the regimen used in the methods of the present invention may be administered using separate dosage forms of milvexian and antiplatelet therapy components, or using a combination dosage form containing both milvexian and antiplatelet therapy components. These dosage forms further comprise a pharmaceutically acceptable excipient. If a combination dosage form is used in a method of administering milvexian twice a day, the present invention includes using the combination dosage form in one daily administration, and using a dosage form containing milvexian but not antiplatelet therapy as the second dosage form in the daily regimen. The present invention also includes using a combination dosage form containing antiplatelet therapy and milvexian in both daily administrations.

[0296] For the purposes of the present invention, "combination" refers not only to a dosage form comprising all components (i.e., a fixed dose combination), but also to a combination package or kit comprising components that are independent of each other in a package, optionally including instructions for use according to one of the methods of treatment or risk reduction of a disorder or injury disclosed herein, and also to components that are administered simultaneously or sequentially, as long as they are used to prevent and / or treat the same disease. The combination of the present invention can also be used in the manufacture of medicaments.

[0297] The individual active ingredients of the combination are known in the art. When used alone without the other elements of the claimed combination, the active ingredients are used in dosage forms lower than the therapeutically effective dose.

[0298] The formulation of Milvexian is described in U.S. Pat. No. 9,453,018, WO2021207659, WO2022081473, WO2020210629, which are incorporated herein by reference in their entirety. A combination dosage form containing both milvexian and an antiplatelet therapy can be prepared by following examples of the formulation of milvexian, known formulations of antiplatelet therapy, and the understanding of pharmaceutical formulations by those skilled in the art.

[0299] The methods disclosed herein can be used in combination with another cardiovascular drug or multiple cardiovascular drugs. For example, the methods and combinations involving milvexian and antiplatelet therapy disclosed herein can be used with one or more of the following other cardiovascular drugs: (1) angiotensin converting enzyme (ACE) inhibitors, such as benazepril Captopril Enalapril Fosinopril Lisinopril Moexipril Perindopril Quinapril Ramipril and trandolapril (2) Angiotensin II (AII) receptor antagonists, such as embusartan and losartan Valsartan Irbesartan Candesartan Eprosartan and telmisartan (3) Statins, such as atorvastatin Rosuvastatin and simvastatin ( and ); (4) niacin, such as lovastatin (5) Cholesterol absorption inhibitors, such as ezetimibe / simvastatin and (6) beta-adrenergic blockers, such as acebutolol Atenolol Betaxolol Bisoprolol / hydrochlorothiazide Bisoprolol Metoprolol XL), nadolol Propranolol and sotalol

[0300] All common administration forms are suitable for administering the regimen of the present invention. Preferably, the administration is carried out orally, lingually, sublingually, buccally, rectally, topically or parenterally (i.e. avoiding the intestine, i.e. intravenously, intracardially, intradermally, subcutaneously, transdermally, intraperitoneally or intramuscularly), preferably oral administration of milvexian and antiplatelet therapy.

[0301] In some aspects, the present invention provides milvexian (or a pharmaceutically acceptable salt or solvate thereof) for use in the methods disclosed herein.

[0302] In other aspects, the present invention provides compositions comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) for use in the methods disclosed herein.

[0303] The present invention includes pharmaceutical products or dosage forms that contain milvexian, antiplatelet therapy, or both milvexian and antiplatelet therapy, in addition to non-toxic, pharmaceutically suitable inert excipients and / or carriers. Methods for making these pharmaceutical products are also contemplated. In addition to milvexian, antiplatelet therapy, or both milvexian and antiplatelet therapy, these pharmaceutical products may contain other active pharmaceutical ingredients, such as the cardiovascular drugs discussed herein for use with the combinations and methods of use of the present invention.

[0304] As used herein, the term "dosage form" refers to a physical manifestation containing milvexian and one or more pharmaceutically acceptable excipients that deliver a dose of milvexian to a patient. In some embodiments, the amount of milvexian in the dosage form is preferably from about 25 mg to about 100 mg. More preferably, such dosage forms contain about 25 mg, about 50 mg, about 75 mg, or about 100 mg of milvexian. Most preferably, such dosage forms contain about 25 mg of milvexian. In some embodiments, the dosage form is preferably a unit dosage form, such as a tablet, pill, capsule, powder, granule, sterile parenteral solution or suspension; which is used for oral, parenteral, intranasal, sublingual administration. In some embodiments, the drug product is prepared according to the compositions and methods described in WO2020210629.

[0305] As used herein, the term "drug product" refers to a dosage form containing milvexian that is administered to a patient multiple times daily in an amount that reduces the incidence of clinical ischemic stroke events in the patient by about 27% to about 36% over 90 days compared to a placebo group.

[0306] In some embodiments, the drug product is a dosage form containing milvexian that is administered to a patient multiple times daily in an amount that results in a relative risk reduction of about 27% to about 36% in the incidence of clinical ischemic stroke within 90 days relative to placebo along with standard of care.

[0307] In some embodiments, the drug product is a dosage form containing milvexian that is administered to a patient multiple times daily in an amount that results in a relative risk reduction of about 27% to about 36% in the incidence of clinical ischemic stroke within 90 days compared to placebo in combination with antiplatelet therapy.

[0308] In some embodiments, the amount of milvexian in the dosage form is from about 20 mg to less than 200 mg.

[0309] In some embodiments, the amount of milvexian in the dosage form is from about 25 mg to less than 200 mg.

[0310] In some embodiments, the amount of milvexian in the dosage form is from about 25 mg to about 100 mg.

[0311] In some embodiments, the amount of milvexian in the dosage form is from about 25 mg to about 50 mg.

[0312] In some embodiments, the amount of milvexian in the dosage form is from about 75 mg to about 100 mg.

[0313] In some embodiments, the amount of milvexian in the dosage form is about 20 mg.

[0314] In some embodiments, the amount of milvexian in the dosage form is about 25 mg.

[0315] In some embodiments, the amount of milvexian in the dosage form is about 50 mg.

[0316] In some embodiments, the amount of milvexian in the dosage form is about 75 mg.

[0317] In some embodiments, the amount of milvexian in the dosage form is about 100 mg.

[0318] In some embodiments, the amount of milvexian in the dosage form is about 125 mg.

[0319] In some embodiments, the amount of milvexian in the dosage form is about 150 mg.

[0320] In some embodiments, the amount of milvexian in the dosage form is about 175 mg.

[0321] In some embodiments, the dosage form is administered twice daily to a patient at risk for clinical ischemic stroke.

[0322] In one embodiment, the invention provides a pharmaceutical product for administration twice daily to a patient who suffers or has suffered an ischemic stroke or transient ischemic attack.

[0323] In some embodiments, for any of the drug products described herein, the amount of milvexian in the drug product is in the range of about 25 mg to about 100 mg per administration.

[0324] In some embodiments, for any of the drug products described herein, the amount of milvexian in the drug product is about 25 mg per administration.

[0325] In some embodiments, for any of the drug products described herein, the drug product reduces the relative risk (RRR) of clinical ischemic stroke events in patients by about 30% relative to the placebo group without increasing bleeding.

[0326] In one embodiment, the present invention provides a method for preventing adverse cerebrovascular events or adverse cardiovascular events in a human patient suffering from atherosclerosis, wherein the method comprises administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milvexian (or a pharmaceutically acceptable salt or solvate thereof); and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and a combination thereof; wherein the pharmaceutical composition is administered twice daily.

[0327] In some embodiments, the antiplatelet therapy is a P2Y12 inhibitor.

[0328] In some embodiments, the P2Y12 inhibitor is clopidogrel, ticagrelor, ticlopidine, cangrelor, or prasugrel.

[0329] In some embodiments, the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel.

[0330] In some embodiments, the antiplatelet therapy is aspirin.

[0331] In some embodiments, the human patient is treated with aspirin and clopidogrel combination therapy from day 1 to day 21, followed by treatment with aspirin monotherapy for at least 90 days.

[0332] In some embodiments, the patient is treated with aspirin and / or clopidogrel without milvexian dose adjustment.

[0333] In some embodiments, the adverse cerebrovascular event or adverse cardiovascular event comprises one or more of stroke, heart attack, or death.

[0334] In some embodiments, the adverse cerebrovascular event or adverse cardiovascular event occurs in an organ selected from the group consisting of the heart, brain, limbs, blood supply system, or blood vessels.

[0335] In some embodiments, the adverse cerebrovascular event or adverse cardiovascular event comprises one or more major adverse cardiovascular events (MACE) selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, ischemic stroke, and combinations thereof.

[0336] In some embodiments, the adverse cerebrovascular event or adverse cardiovascular event comprises one or more major adverse vascular events (MAVE) selected from the group consisting of: MACE; major adverse limb event (MALE), including one or more selected from acute limb ischemia, chronic limb ischemia or major amputation; symptomatic venous thromboembolic events, and combinations thereof.

[0337] In some embodiments, the adverse cerebrovascular event or adverse cardiovascular event is selected from the group consisting of arrhythmogenic cardiomyopathy (ACM), non-fatal myocardial infarction, ischemic stroke, and combinations thereof.

[0338] In some embodiments, the adverse cerebrovascular event or adverse cardiovascular event comprises cardiovascular death.

[0339] In some embodiments, the adverse cerebrovascular event or adverse cardiovascular event comprises arrhythmogenic cardiomyopathy (ACM).

[0340] In one embodiment, the present invention provides a method for preventing adverse cardiovascular events in a human patient diagnosed with atherosclerosis, wherein the method comprises administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milvexian (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, a P2Y12 inhibitor, and a combination thereof.

[0341] In some embodiments, the pharmaceutical composition is administered twice daily.

[0342] In some embodiments, the adverse cardiovascular event is selected from one or more of the group consisting of: all-cause mortality (ACM); cardiovascular (CV) death; myocardial infarction (MI); unstable angina (UA); "all strokes" or "any stroke" (ischemic, hemorrhagic, or of unknown cause); ischemic stroke; acute limb ischemia (ALI); major vascular (non-traumatic) limb amputation; symptomatic venous thromboembolism (VTE: (pulmonary embolism (PE), deep vein thrombosis (DVT)); ischemia-driven coronary revascularization; stent thrombosis; hospitalization for any reason, which can be divided into (1) planned or unplanned, (2) due to arterial or venous thrombotic events or neither; and transient ischemic attack (TIA).

[0343] In some embodiments, administration of the regimen results in a relative risk reduction (RRR) of at least 25% in patients developing symptomatic venous thromboembolism (VTE: (pulmonary embolism (PE), deep vein thrombosis (DVT)) relative to a placebo group without increasing bleeding.

[0344] In some embodiments, the adverse cardiovascular event is one or more of CV death, MI, or ischemic stroke.

[0345] A method for reducing the incidence of one or more adverse thrombotic events selected from new ischemic stroke, MI, or all-cause death in a human patient diagnosed with atherosclerosis, wherein the method comprises administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising from about 25 mg to about 100 mg of milvexian (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, a P2Y12 inhibitor, and a combination thereof; wherein the pharmaceutical composition is administered twice daily.

[0346] In some embodiments, the regimen is administered such that the relative risk relative to placebo is 0.85 or less.

[0347] A method for preventing ischemic stroke in a human patient diagnosed with atherosclerosis, wherein the method comprises administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milvexian (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, a P2Y12 inhibitor, and a combination thereof; wherein the pharmaceutical composition is administered twice daily.

[0348] In some embodiments, administration of the regimen results in a relative risk reduction (RRR) of at least 25% in a patient experiencing a clinical ischemic stroke event relative to a placebo group without increasing bleeding.

[0349] In some embodiments, the clinical benefit of reducing the incidence of clinical ischemic stroke by the regimen is maintained throughout the 90-day treatment period.

[0350] In some embodiments, administration of the regimen results in a decrease in the patient's FXI coagulation activity from about 7% to about 20% relative to baseline.

[0351] In some embodiments, administration of the regimen results in an increase in activated partial thromboplastin time (aPTT) in the range of about 27% to about 64% relative to baseline.

[0352] In some embodiments, administration does not result in a statistically significant increase in major bleeding complications.

[0353] In some embodiments, the pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) is a solid oral pharmaceutical composition. In some embodiments, the solid oral pharmaceutical composition is a tablet. In some embodiments, the tablet is an immediate release tablet. In some embodiments, the disintegration time of the tablet in water is less than 20 seconds.

[0354] In some embodiments, administration results in a milvexian plasma half-life in the range of about 13 hours to about 16 hours. In some embodiments, administration results in a milvexian plasma half-life in the range of about 13 hours to about 16 hours during repeated dosing.

[0355] In some embodiments, administration is such that milvexian plasma concentrations reach steady state in about 3 to 6 days.

[0356] In some embodiments, the pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered regardless of the timing of food intake.

[0357] In some embodiments, the human patient is unable to swallow a tablet dosage form.

[0358] In some embodiments, the tablet is dispersed in an aqueous medium to form an aqueous dispersion. In some embodiments, the aqueous medium is water, saline, phosphate buffer, vegetable juice or fruit juice, including, for example, applesauce. In some embodiments, the aqueous dispersion is administered to a human patient via a nasogastric tube or spoon. In some embodiments, the pharmaceutical composition is orally administered as an aqueous dispersion by dispersing the oral tablet in an aqueous medium for less than 1 minute.

[0359] In some embodiments, for any of the drug products described herein, wherein the clinical benefit of reducing the incidence of clinical ischemic stroke by the drug product is maintained throughout the 90-day treatment period.

[0360] The present invention also relates to the following aspects:

[0361] Aspect 1. A method for preventing ischemic stroke in a human patient who has or has had ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising: milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg once daily or in an amount of 12.5 mg to 200 mg twice daily; and standard of care; wherein the regimen is effective in preventing ischemic stroke in the human patient.

[0362] Aspect 2. A method for reducing the risk of ischemic stroke in a human patient who has or has had ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising: milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg once daily or in an amount of 12.5 mg to 200 mg twice daily; and standard of care; wherein the regimen is effective in reducing the risk of ischemic stroke in the human patient relative to placebo together with standard of care.

[0363] Aspect 3. The method according to Aspect 1 or Aspect 2, wherein the standard of care comprises antiplatelet therapy.

[0364] Aspect 4. The method according to Aspect 3, wherein the antiplatelet therapy comprises a single antiplatelet therapy.

[0365] Aspect 5. The method according to aspect 4, wherein the single antiplatelet therapy is aspirin.

[0366] Aspect 6. The method according to aspect 5, wherein aspirin is administered in an amount of 75 to 100 mg per day.

[0367] Aspect 7. The method according to aspect 6, wherein aspirin is administered in an amount of 75 mg per day.

[0368] Aspect 8. The method according to aspect 6, wherein aspirin is administered in an amount of 81 mg per day.

[0369] Aspect 9. The method according to aspect 6, wherein aspirin is administered in an amount of 100 mg per day.

[0370] Aspect 10. The method according to aspect 4, wherein the single antiplatelet therapy is a P2Y12 inhibitor.

[0371] Aspect 11. The method according to aspect 10, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor or prasugrel.

[0372] Aspect 12. The method according to aspect 11, wherein the P2Y12 inhibitor is clopidogrel.

[0373] Aspect 13. The method according to aspect 12, wherein clopidogrel is administered in an amount of 75 mg per day.

[0374] Aspect 14. The method according to aspect 4, wherein the single antiplatelet therapy is ticlopidine.

[0375] Aspect 15. The method according to aspect 14, wherein ticlopidine is administered in an amount of 250 to 500 mg per day.

[0376] Aspect 16. The method according to aspect 3, wherein the antiplatelet therapy comprises dual antiplatelet therapy.

[0377] Aspect 17. The method according to aspect 16, wherein the dual antiplatelet therapy is aspirin and a P2Y12 inhibitor.

[0378] Aspect 18. The method according to aspect 17, wherein aspirin is administered in an amount of 75 to 100 mg per day.

[0379] Aspect 19. The method according to aspect 18, wherein aspirin is administered in an amount of 75 mg per day.

[0380] Aspect 20. The method according to aspect 18, wherein aspirin is administered in an amount of 81 mg per day.

[0381] Aspect 21. The method according to aspect 18, wherein aspirin is administered in an amount of 100 mg per day.

[0382] Aspect 22. The method according to any one of aspects 17 to 21, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor or prasugrel.

[0383] Aspect 23. The method according to aspect 22, wherein the P2Y12 inhibitor is clopidogrel.

[0384] Aspect 24. The method according to aspect 23, wherein clopidogrel is administered in an amount of 75 mg per day.

[0385] Aspect 25. The method according to aspect 3, wherein the antiplatelet therapy comprises cefotaxime, which is a combination of aspirin and dipyridamole (dipyridamole).

[0386] Aspect 26. The method according to any one of aspects 1 to 25, wherein milvexian is administered in an amount of 25 mg once daily.

[0387] Aspect 27. The method according to any one of aspects 1 to 25, wherein milvexian is administered in an amount of 25 mg twice daily.

[0388] Aspect 28. The method according to any one of aspects 1 to 25, wherein milvexian is administered in an amount of 50 mg twice daily.

[0389] Aspect 29. The method according to any one of aspects 1 to 25, wherein milvexian is administered in an amount of 100 mg twice daily.

[0390] Aspect 30. The method according to any one of aspects 1 to 25, wherein milvexian is administered in an amount of 200 mg twice daily.

[0391] Aspect 31. The method according to any one of aspects 1 to 25, wherein milvexian is administered in an amount of less than 200 mg twice daily.

[0392] Aspect 32. The method according to any one of Aspects 1 to 31, wherein the risk of ischemic stroke is reduced compared to administration of a placebo together with standard of care.

[0393] Aspect 33. The method according to any one of Aspects 1 to 32, wherein the risk of ischemic stroke is reduced compared to administration of a placebo together with antiplatelet therapy.

[0394] Aspect 34. The method according to aspect 32 or aspect 33, wherein the relative risk is about 0.9 to 0.6.

[0395] Aspect 35. The method according to aspect 32 or aspect 33, wherein the relative risk reduction is about 10% to 40%.

[0396] Aspect 36. The method according to any one of the preceding aspects, wherein the risk of ischemic stroke is reduced in a dose-dependent manner with the amount of milvexian administered.

[0397] Aspect 37. A method for preventing ischemic stroke in a human patient having or having had ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising: milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg once daily; and standard of care; wherein the regimen is effective in preventing ischemic stroke in the human patient.

[0398] Aspect 38. A method of reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising: milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg twice daily; and standard of care; wherein the regimen is effective in reducing the risk of ischemic stroke in the human patient relative to placebo together with standard of care.

[0399] Aspect 39. The method according to any one of Aspects 1 to 38, wherein the relative risk of bleeding according to Bleeding Academic Research Consortium (BARC) type 3 and type 5 criteria is no more than 3 compared to placebo together with standard of care.

[0400] Aspect 40. The method according to any one of Aspects 1 to 39, wherein the relative risk of bleeding according to Bleeding Academic Research Consortium (BARC) type 3 and type 5 criteria is no more than 3 compared to placebo together with antiplatelet therapy.

[0401] Aspect 41. The method according to any one of aspects 1 to 40, wherein the relative risk of major bleeding according to the Bleeding Academic Research Consortium (BARC) Type 3 and Type 5 criteria is independent of the amount of milvexian administered.

[0402] Aspect 42. The method according to any one of Aspects 1 to 41, wherein the relative risk of bleeding according to the Bleeding Academic Research Consortium (BARC) type 2 criteria does not exceed 2.6 compared to placebo together with standard of care.

[0403] Aspect 43. The method according to any one of Aspects 1 to 42, wherein the relative risk of bleeding according to the Bleeding Academic Research Consortium (BARC) Type 2 criteria is no more than 2.6 compared to placebo together with antiplatelet therapy.

[0404] Aspect 44. The method according to any one of aspects 1 to 43, wherein the risk of bleeding according to the Bleeding Academic Research Consortium (BARC) Type 2 criteria is independent of the amount of milvexian administered.

[0405] Aspect 45. The method according to any one of Aspects 1 to 44, wherein the relative risk of bleeding according to ISTH criteria (major bleeding or clinically relevant non-major bleeding (CRNM)) is no more than 3 compared to placebo together with standard of care.

[0406] Aspect 46. The method according to any one of Aspects 1 to 45, wherein the relative risk of bleeding according to ISTH criteria (major bleeding or clinically relevant non-major bleeding (CRNM)) is no more than 3 compared to placebo together with antiplatelet therapy.

[0407] Aspect 47. A method of treating a human patient who has or has had an ischemic stroke or transient ischemic attack, comprising administering to the human patient a regimen comprising: milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg once daily or 12.5 mg to 200 mg twice daily, and standard of care; wherein the regimen is effective to reduce the risk of ischemic stroke in the human patient, and wherein the human patient does not experience an ischemic stroke during the duration of the regimen.

[0408] Aspect 48. A method of treating a human patient who has or has had an ischemic stroke or transient ischemic attack, comprising administering to the human patient a regimen comprising: milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg twice daily, and standard of care; wherein the regimen is effective to reduce the risk of ischemic stroke in the human patient, and wherein the human patient does not experience an ischemic stroke during the duration of the regimen.

[0409] Aspect 49. The method according to aspect 47 or aspect 48, wherein the standard of care comprises antiplatelet therapy.

[0410] Aspect 50. The method according to aspect 49, wherein the antiplatelet therapy comprises a single antiplatelet therapy.

[0411] Aspect 51. The method according to aspect 50, wherein the single antiplatelet therapy is aspirin.

[0412] Aspect 52. The method according to aspect 51, wherein aspirin is administered in an amount of 75 to 100 mg per day.

[0413] Aspect 53. The method according to aspect 51, wherein aspirin is administered in an amount of 75 mg per day.

[0414] Aspect 54. The method according to aspect 51, wherein aspirin is administered in an amount of 81 mg per day.

[0415] Aspect 55. The method according to aspect 51, wherein aspirin is administered in an amount of 100 mg per day.

[0416] Aspect 56. The method according to aspect 50, wherein the single antiplatelet therapy is a P2Y12 inhibitor.

[0417] Aspect 57. The method according to aspect 56, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor or prasugrel.

[0418] Aspect 58. The method according to aspect 57, wherein the P2Y12 inhibitor is clopidogrel.

[0419] Aspect 59. The method according to aspect 58, wherein clopidogrel is administered in an amount of 75 mg per day.

[0420] Aspect 60. The method according to aspect 50, wherein the single antiplatelet therapy is ticlopidine.

[0421] Aspect 61. The method according to aspect 60, wherein ticlopidine is administered in an amount of 250 to 500 mg per day.

[0422] Aspect 62. The method according to Aspect 49, wherein the antiplatelet therapy comprises dual antiplatelet therapy.

[0423] Aspect 63. The method according to aspect 62, wherein the dual antiplatelet therapy is aspirin and a P2Y12 inhibitor.

[0424] Aspect 64. The method according to aspect 63, wherein aspirin is administered in an amount of 75 to 100 mg per day.

[0425] Aspect 65. The method according to aspect 64, wherein aspirin is administered in an amount of 75 mg per day.

[0426] Aspect 66. The method according to aspect 64, wherein aspirin is administered in an amount of 81 mg per day.

[0427] Aspect 67. The method according to aspect 64, wherein aspirin is administered in an amount of 100 mg per day.

[0428] Aspect 68. The method according to any one of aspects 63 to 67, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor or prasugrel.

[0429] Aspect 69. The method according to aspect 68, wherein the P2Y12 inhibitor is clopidogrel.

[0430] Aspect 70. The method according to aspect 69, wherein clopidogrel is administered in an amount of 75 mg per day.

[0431] Aspect 71. The method according to aspect 49, wherein the antiplatelet therapy comprises cefotaxime, a combination of aspirin and dipyridamole (dipyridamole).

[0432] Aspect 72. The method according to any one of aspects 47 or 49 to 71, wherein milvexian is administered in an amount of 25 mg once daily.

[0433] Aspect 73. The method according to any one of aspects 47 to 71, wherein milvexian is administered in an amount of 25 mg twice daily.

[0434] Aspect 74. The method according to any one of aspects 47 or 49 to 71, wherein milvexian is administered in an amount of 50 mg twice daily.

[0435] Aspect 75. The method according to any one of aspects 47 or 49 to 71, wherein milvexian is administered in an amount of 100 mg twice daily.

[0436] Aspect 76. The method according to any one of aspects 47 or 49 to 71, wherein milvexian is administered in an amount of less than 200 mg twice daily.

[0437] Aspect 77. The method according to any one of aspects 47 or 49 to 71, wherein milvexian is administered in an amount of 200 mg twice daily.

[0438] Aspect 78. The method according to any one of aspects 47 to 77, wherein the administration regimen is at least 12 weeks.

[0439] Aspect 79. The method according to any one of aspects 47 to 77, wherein the administration regimen is at least 24 weeks.

[0440] Aspect 80. The method according to any one of aspects 47 to 77, wherein the administration regimen is at least 36 weeks.

[0441] Aspect 81. The method according to any one of aspects 47 to 77, wherein the administration regimen is at least 48 weeks.

[0442] Aspect 82. The method according to any one of aspects 47 to 81, wherein the relative risk of bleeding according to Bleeding Academic Research Consortium (BARC) type 3 and type 5 criteria is no more than 3 compared to placebo together with standard of care.

[0443] Aspect 83. The method according to any one of Aspects 47 to 81, wherein the relative risk of bleeding according to Bleeding Academic Research Consortium (BARC) type 3 and type 5 criteria is no more than 3 compared to placebo together with antiplatelet therapy.

[0444] Aspect 84. The method according to any one of aspects 47 to 81, wherein the risk of major bleeding according to Bleeding Academic Research Consortium (BARC) Type 3 and Type 5 criteria is independent of the amount of milvexian administered.

[0445] Aspect 85. The method according to any one of aspects 47 to 84, wherein the relative risk of bleeding according to the Bleeding Academic Research Consortium (BARC) type 2 criteria does not exceed 2.6 compared to placebo together with standard of care.

[0446] Aspect 86. The method according to any one of Aspects 47 to 85, wherein the relative risk of bleeding according to the Bleeding Academic Research Consortium (BARC) Type 2 criteria is no more than 2.6 compared to placebo together with antiplatelet therapy.

[0447] Aspect 87. The method according to any one of aspects 47 to 86, wherein the risk of bleeding according to the Bleeding Academic Research Consortium (BARC) Type 2 criteria is independent of the amount of milvexian administered.

[0448] Aspect 88. The method according to any one of Aspects 47 to 87, wherein the relative risk of bleeding according to ISTH criteria (major bleeding or clinically relevant non-major bleeding (CRNM)) is no more than 3 compared to placebo together with standard of care.

[0449] Aspect 89. The method according to any one of Aspects 47 to 88, wherein the relative risk of bleeding according to ISTH criteria (major bleeding or clinically relevant non-major bleeding (CRNM)) is no more than 3 compared to placebo together with antiplatelet therapy.

[0450] Aspect 90. The method according to any one of aspects 47 to 88, wherein the human patient does not experience bleeding according to the Bleeding Academic Research Consortium (BARC) type 3 and type 5 criteria.

[0451] Aspect 91. A method of treating a patient population wherein the patients have or have had an ischemic stroke or transient ischemic attack, the method comprising administering to the patients in the population a regimen comprising: milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg once daily or in an amount of 12.5 mg to 200 mg twice daily; and standard of care; wherein the percentage of patients in the population who experience an ischemic stroke within 90 days of initiation of the regimen is less than 10%.

[0452] Aspect 92. A method of treating a patient population, wherein the patients have or have had ischemic stroke or transient ischemic attack, the method comprising administering to the patients in the population a regimen comprising: milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg once daily; and standard of care; wherein the percentage of patients in the population who experience ischemic stroke within 90 days of initiation of the regimen is less than 10%.

[0453] Aspect 93. The method according to aspect 91 or aspect 92, wherein the percentage of patients in said population experiencing ischemic stroke within 90 days of initiation of the regimen is less than 4%.

[0454] Aspect 94. The method according to any one of Aspects 91 to 93, wherein the standard of care comprises antiplatelet therapy.

[0455] Aspect 95. The method according to Aspect 94, wherein the antiplatelet therapy is a single antiplatelet therapy.

[0456] Aspect 96. The method according to aspect 95, wherein the single antiplatelet therapy is aspirin.

[0457] Aspect 97. The method according to aspect 96, wherein aspirin is administered in an amount of 75 to 100 mg per day.

[0458] Aspect 98. The method according to aspect 97, wherein aspirin is administered in an amount of 75 mg per day.

[0459] Aspect 99. The method according to aspect 97, wherein aspirin is administered in an amount of 81 mg per day.

[0460] Aspect 100. The method according to aspect 97, wherein aspirin is administered in an amount of 100 mg per day.

[0461] Aspect 101. The method according to aspect 95, wherein the single antiplatelet therapy is a P2Y12 inhibitor.

[0462] Aspect 102. The method according to aspect 101, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor or prasugrel.

[0463] Aspect 103. The method according to aspect 102, wherein the P2Y12 inhibitor is clopidogrel.

[0464] Aspect 104. The method according to aspect 103, wherein clopidogrel is administered in an amount of 75 mg per day.

[0465] Aspect 105. The method according to aspect 95, wherein the single antiplatelet therapy is ticlopidine.

[0466] Aspect 106. The method according to aspect 105, wherein ticlopidine is administered in an amount of 250 to 500 mg per day.

[0467] Aspect 107. The method according to aspect 94, wherein the antiplatelet therapy is dual antiplatelet therapy.

[0468] Aspect 108. The method according to aspect 107, wherein the dual antiplatelet therapy is aspirin and a P2Y12 inhibitor.

[0469] Aspect 109. The method according to aspect 108, wherein aspirin is administered in an amount of 75 to 100 mg per day.

[0470] Aspect 110. The method according to aspect 109, wherein aspirin is administered in an amount of 75 mg per day.

[0471] Aspect 111. The method according to aspect 109, wherein aspirin is administered in an amount of 81 mg per day.

[0472] Aspect 112. The method according to aspect 109, wherein aspirin is administered in an amount of 100 mg per day.

[0473] Aspect 113. The method according to any one of aspects 108 to 112, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor or prasugrel.

[0474] Aspect 114. The method according to aspect 113, wherein the P2Y12 inhibitor is clopidogrel.

[0475] Aspect 115. The method according to aspect 114, wherein clopidogrel is administered in an amount of 75 mg per day.

[0476] Aspect 116. The method according to aspect 94, wherein the antiplatelet therapy comprises cefotaxime, a combination of aspirin and dipyridamole (dipyridamole).

[0477] Aspect 117. The method according to any one of aspects 91 or 93 to 116, wherein milvexian is administered in an amount of 25 mg once daily.

[0478] Aspect 118. The method according to any one of aspects 91 to 116, wherein milvexian is administered in an amount of 25 mg twice daily.

[0479] Aspect 119. The method according to any one of aspects 91 or 93 to 116, wherein milvexian is administered in an amount of 50 mg twice daily.

[0480] Aspect 120. The method according to any one of aspects 91 or 93 to 116, wherein milvexian is administered in an amount of 100 mg twice daily.

[0481] Aspect 121. The method according to any one of aspects 91 or 93 to 116, wherein milvexian is administered in an amount of less than 200 mg twice daily.

[0482] Aspect 122. The method according to any one of aspects 91 or 93 to 116, wherein milvexian is administered in an amount of 200 mg twice daily.

[0483] Aspect 123. The method according to any one of Aspects 91 to 122, wherein the percentage of patients in the population experiencing severe bleeding according to Bleeding Academic Research Consortium (BARC) type 3 or 5 criteria within 90 days is about 2% or less.

[0484] Aspect 124. The method according to any one of Aspects 91 to 122, wherein the percentage of patients in the population experiencing bleeding according to the Bleeding Academic Research Consortium (BARC) Type 2 criteria within 90 days is about 3.5% or less.

[0485] Aspect 125. The method according to any one of Aspects 91 to 122, wherein the percentage of patients in the population experiencing bleeding according to ISTH criteria (major bleeding or clinically relevant non-major bleeding (CRNM) criteria) within 90 days is about 5% or less.

[0486] Aspect 126. A method for preventing ischemic stroke in an adult patient following acute ischemic stroke or high-risk transient ischemic attack, wherein the method comprises administering to the adult patient a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg once daily or in an amount of 12.5 mg to 200 mg twice daily.

[0487] Aspect 127. A method of reducing the risk of ischemic stroke in an adult patient following acute ischemic stroke or high-risk transient ischemic attack, wherein the method comprises administering to the adult patient a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg once daily or in an amount of 12.5 mg to 200 mg twice daily.

[0488] Aspect 128. A method of preventing ischemic stroke in an adult patient following acute ischemic stroke or high-risk transient ischemic attack, wherein the method comprises administering to the adult patient a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg twice daily.

[0489] Aspect 129. A method of reducing the risk of ischemic stroke in an adult patient following acute ischemic stroke or high-risk transient ischemic attack, wherein the method comprises administering to the adult patient a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg twice daily.

[0490] Aspect 130. The method according to any one of aspects 126 to 129, further comprising administering standard of care to the adult patient.

[0491] Aspect 131. The method according to Aspect 130, wherein the standard of care comprises antiplatelet therapy.

[0492] Aspect 132. The method according to Aspect 131, wherein the antiplatelet therapy comprises a single antiplatelet therapy.

[0493] Aspect 133. The method according to aspect 132, wherein the single antiplatelet therapy is aspirin.

[0494] Aspect 134. The method according to aspect 133, wherein aspirin is administered in an amount of 75 to 100 mg per day.

[0495] Aspect 135. The method according to aspect 134, wherein aspirin is administered in an amount of 75 mg per day.

[0496] Aspect 136. The method according to aspect 134, wherein aspirin is administered in an amount of 81 mg per day.

[0497] Aspect 137. The method according to aspect 134, wherein aspirin is administered in an amount of 100 mg per day.

[0498] Aspect 138. The method according to aspect 132, wherein the single antiplatelet therapy is a P2Y12 inhibitor.

[0499] Aspect 139. The method according to aspect 138, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor or prasugrel.

[0500] Aspect 140. The method according to aspect 139, wherein the P2Y12 inhibitor is clopidogrel.

[0501] Aspect 141. The method according to aspect 140, wherein clopidogrel is administered in an amount of 75 mg per day.

[0502] Aspect 142. The method according to aspect 132, wherein the single antiplatelet therapy is ticlopidine.

[0503] Aspect 143. The method according to aspect 142, wherein ticlopidine is administered in an amount of 250 to 500 mg per day.

[0504] Aspect 144. The method according to aspect 131, wherein the antiplatelet therapy comprises dual antiplatelet therapy.

[0505] Aspect 145. The method according to aspect 144, wherein the dual antiplatelet therapy is aspirin and a P2Y12 inhibitor.

[0506] Aspect 146. The method according to aspect 145, wherein aspirin is administered in an amount of 75 to 100 mg per day.

[0507] Aspect 147. The method according to aspect 146, wherein aspirin is administered in an amount of 75 mg per day.

[0508] Aspect 148. The method according to aspect 146, wherein aspirin is administered in an amount of 81 mg per day.

[0509] Aspect 149. The method according to aspect 146, wherein aspirin is administered in an amount of 100 mg per day.

[0510] Aspect 150. The method according to any one of aspects 145 to 149, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor or prasugrel.

[0511] Aspect 151. The method according to aspect 150, wherein the P2Y12 inhibitor is clopidogrel.

[0512] Aspect 152. The method according to aspect 151, wherein clopidogrel is administered in an amount of 75 mg per day.

[0513] Aspect 153. The method according to aspect 131, wherein the antiplatelet therapy comprises cefotaxime, a combination of aspirin and dipyridamole (dipyridamole).

[0514] Aspect 154. The method according to any one of aspects 126, 127, or 130 to 153, wherein milvexian is administered in an amount of 25 mg once daily.

[0515] Aspect 155. The method according to any one of aspects 126 to 153, wherein milvexian is administered in an amount of 25 mg twice daily.

[0516] Aspect 156. The method according to any one of aspects 126, 127, or 130 to 153, wherein milvexian is administered in an amount of 50 mg twice daily.

[0517] Aspect 157. The method according to any one of aspects 126, 127, or 130 to 153, wherein milvexian is administered in an amount of 100 mg twice daily.

[0518] Aspect 158. The method according to any one of aspects 126, 127, or 130 to 153, wherein milvexian is administered in an amount of 200 mg twice daily.

[0519] Aspect 159. The method according to any one of aspects 126, 127, or 130 to 153, wherein milvexian is administered in an amount of less than 200 mg twice daily.

[0520] Aspect 160. The method according to any one of aspects 126 to 159, wherein the risk of ischemic stroke is reduced compared to administration of a placebo together with standard of care.

[0521] Aspect 161. The method according to any one of aspects 126 to 160, wherein the risk of ischemic stroke is reduced compared to administration of a placebo together with antiplatelet therapy.

[0522] Aspect 162. The method according to aspect 160 or aspect 161, wherein the relative risk is about 0.9 to 0.6.

[0523] Aspect 163. The method according to aspect 160 or aspect 161, wherein the relative risk reduction is about 10% to 40%.

[0524] Aspect 164. The method according to any one of aspects 126 to 163, wherein the risk of ischemic stroke is reduced in a dose-dependent manner with the amount of milvexian administered.

[0525] Aspect 165. The method according to any one of Aspects 126 to 164, wherein the relative risk of bleeding according to Bleeding Academic Research Consortium (BARC) type 3 and type 5 criteria is no more than 3 compared to placebo together with standard of care.

[0526] Aspect 166. The method according to any one of Aspects 126 to 165, wherein the relative risk of bleeding according to Bleeding Academic Research Consortium (BARC) type 3 and type 5 criteria is no more than 3 compared to placebo together with antiplatelet therapy.

[0527] Aspect 167. The method according to any one of Aspects 126 to 166, wherein the risk of major bleeding according to Bleeding Academic Research Consortium (BARC) Type 3 and Type 5 criteria is independent of the amount of milvexian administered.

[0528] Aspect 168. The method according to any one of Aspects 126 to 167, wherein the relative risk of bleeding according to the Bleeding Academic Research Consortium (BARC) type 2 criteria does not exceed 2.6 compared to placebo together with standard of care.

[0529] Aspect 169. The method according to any one of Aspects 126 to 167, wherein the relative risk of bleeding according to the Bleeding Academic Research Consortium (BARC) type 2 criteria does not exceed 2.6 compared to placebo together with antiplatelet therapy.

[0530] Aspect 170. The method according to any one of aspects 126 to 169, wherein the risk of bleeding according to the Bleeding Academic Research Consortium (BARC) Type 2 criteria is independent of the amount of milvexian administered.

[0531] Aspect 171. The method according to any one of Aspects 126 to 170, wherein the relative risk of bleeding according to ISTH criteria (major bleeding or clinically relevant non-major bleeding (CRNM)) is no more than 3 compared to placebo together with standard of care.

[0532] Aspect 172. The method according to any one of Aspects 126 to 171, wherein the relative risk of bleeding according to ISTH criteria (major bleeding or clinically relevant non-major bleeding (CRNM)) is no more than 3 compared to placebo together with antiplatelet therapy.

[0533] Aspect 173. A pharmaceutical product for administration twice daily to a patient suffering from or having suffered from an ischemic stroke or transient ischemic attack.

[0534] Aspect 174. The pharmaceutical product according to aspect 173, wherein the amount of milvexian per administration is in the range of about 25 mg to about 100 mg.

[0535] Aspect 175. The pharmaceutical product according to aspect 174, wherein the amount of milvexian administered per time is about 25 mg.

[0536] Aspect 176. The pharmaceutical product according to any one of aspects 173 to 175, wherein the pharmaceutical product reduces the relative risk (RRR) of a clinical ischemic stroke event in a patient by about 30% relative to a placebo group without increasing bleeding.

[0537] Aspect 177. The pharmaceutical product according to any one of aspects 173 to 176, wherein the clinical benefit of reducing the incidence of clinical ischemic stroke by the pharmaceutical product is maintained throughout the 90-day treatment period.

[0538] Aspect 178. The method according to any one of aspects 1 to 172, wherein administration of the regimen results in a decrease in the patient's FXI coagulation activity by about 7% to about 20% relative to baseline.

[0539] Aspect 179. The method according to any one of aspects 1 to 172 or 178, wherein administration of the regimen results in an increase in activated partial thromboplastin time (aPTT) from about 27% to about 64% relative to baseline.

[0540] Aspect 180. The method according to any one of aspects 1 to 172 or 178 to 179, wherein administration does not result in a statistically significant increase in major bleeding complications.

[0541] Aspect 181. The method according to any one of aspects 1 to 172 or 178 to 180, wherein milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered in the form of a pharmaceutical composition, wherein the pharmaceutical composition is a solid oral pharmaceutical composition.

[0542] Aspect 182. The method according to aspect 181, wherein the solid oral pharmaceutical composition is a tablet.

[0543] Aspect 183. The method according to aspect 182, wherein the tablet is an immediate release tablet.

[0544] Aspect 184. The method according to aspect 182 or aspect 183, wherein the tablet has a disintegration time in water of less than 20 seconds.

[0545] Aspect 185. The method according to any one of aspects 1 to 172 or 178 to 184, wherein the administration results in a milvexian plasma half-life in the range of about 13 hours to about 16 hours.

[0546] Aspect 186. The method according to any one of aspects 1 to 172 or 178 to 185, wherein the administration is such that the milvexian plasma concentration reaches a steady state in about 3 to 6 days.

[0547] Aspect 187. The method according to any one of aspects 1 to 172 or 178 to 186, wherein milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered without regard to the timing of food intake.

[0548] Aspect 188. The method according to any one of aspects 1 to 172 or 178 to 187, wherein the human patient is unable to swallow a tablet dosage form.

[0549] Aspect 189. The method according to any one of aspects 182 to 188, wherein the tablet is dispersed in an aqueous medium to form an aqueous dispersion.

[0550] Aspect 190. The method according to aspect 189, wherein the aqueous medium is water, saline, phosphate buffered saline, vegetable juice or fruit juice, including, for example, applesauce.

[0551] Aspect 191. The method according to aspect 189 or aspect 190, wherein the aqueous dispersion is administered to the human patient via a nasogastric tube or a spoon.

[0552] Aspect 192. The method according to any one of aspects 182 to 191, wherein the milvexian is orally administered as an aqueous dispersion by dispersing the oral tablet in an aqueous medium for less than 1 minute.

[0553] Aspect 193. A method for preventing ischemic stroke or reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg twice daily and (ii) single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT), wherein the method achieves at least one of the following efficacy results: (i) a relative risk of ischemic stroke of about 0.6 to about 0.9 relative to placebo administration; (ii) a numerical reduction in the absolute risk of ischemic stroke relative to placebo administration; (iii) a numerical reduction in the Kaplan-Meier incidence rate of ischemic stroke compared to placebo administration; (iv) a numerical reduction in the percentage of patients suffering from ischemic stroke relative to placebo administration; or (v) a relative risk reduction of ischemic stroke of about 10% to about 40% relative to placebo administration.

[0554] Aspect 194. A method for preventing ischemic stroke or reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg twice daily and (ii) single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT), preferably wherein the method achieves a relative risk of ischemic stroke of about 0.6 to about 0.9 relative to placebo administration.

[0555] Aspect 195. A method for reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg twice daily and (ii) single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT), preferably wherein the method achieves a relative risk reduction of ischemic stroke of about 10% to about 40% relative to placebo administration.

[0556] Aspect 196. The method according to aspect 195, wherein the method achieves a relative risk reduction of ischemic stroke of about 28% to about 32% relative to placebo administration.

[0557] Aspect 197. The method according to aspect 195, wherein the method achieves a relative risk reduction of ischemic stroke of about 30% relative to placebo administration.

[0558] Aspect 198. The method according to any one of Aspects 193 to 196, wherein the method further achieves at least one of the following safety outcomes: (i) no fatal bleeding events comparable to placebo administration; (ii) no intracranial bleeding events comparable to placebo administration; or (iii) an incidence of major bleeding (BARC types 3 and 5) comparable to placebo administration.

[0559] Aspect 199. The method according to any one of aspects 193 to 198, wherein administration of the regimen results in a decrease in the patient's FXI coagulation activity by about 7% to about 20% relative to baseline.

[0560] Aspect 200. The method according to any one of aspects 193 to 198, wherein administration of the regimen results in an increase in the patient's activated partial thromboplastin time (aPTT) in the range of about 27% to about 64% relative to baseline.

[0561] Aspect 201. The method according to any one of aspects 193 to 196, wherein milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered in the form of a pharmaceutical composition, wherein the pharmaceutical composition is a solid oral pharmaceutical composition.

[0562] Aspect 202. The method according to aspect 201, wherein the solid oral pharmaceutical composition is a tablet.

[0563] Aspect 203. The method according to aspect 202, wherein the tablet is an immediate release tablet.

[0564] Aspect 204. The method according to aspect 202 or aspect 203, wherein the disintegration time of the tablet in water is less than 20 seconds.

[0565] Aspect 205. The method according to any one of aspects 193 to 198 or aspects 201 to 204, wherein during repeated dosing, administration is such that the plasma half-life of milvexian is in the range of about 13 hours to about 16 hours.

[0566] Aspect 206. The method according to any one of aspects 193 to 198 or aspects 201 to 205, wherein the administration is such that the milvexian plasma concentration reaches a steady state in about 3 to 6 days.

[0567] Aspect 207. The method according to any one of aspects 193 to 196 or aspects 201 to 205, wherein the administration of milvexian (or a pharmaceutically acceptable salt or solvate thereof) is without regard to the timing of food intake.

[0568] Aspect 208. The method according to any one of aspects 193 to 198 or aspects 201 to 206, wherein the patient is unable to swallow a tablet dosage form.

[0569] Aspect 209. The method according to any one of aspects 193 to 198, wherein the tablet is dispersed in an aqueous medium to form an aqueous dispersion.

[0570] Aspect 210. The method according to aspect 209, wherein the aqueous medium is water, saline, phosphate buffered saline, vegetable juice or fruit juice, including, for example, applesauce.

[0571] Aspect 211. The method according to aspect 209 or aspect 210, wherein the aqueous dispersion is administered to the human patient via a nasogastric tube or a spoon.

[0572] Aspect 212. The method according to any one of aspects 209 to 211, wherein the milvexian is orally administered as an aqueous dispersion by dispersing the oral tablet in an aqueous medium for less than 60 seconds.

[0573] Aspect 213. A milvexian for use in a method of reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg twice daily and (ii) single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT), wherein the method achieves at least one of the following efficacy outcomes: (i) a relative risk of ischemic stroke of about 0.6 to about 0.9 relative to placebo administration; (ii) a numerical reduction in the absolute risk of ischemic stroke relative to placebo administration; (iii) a numerical reduction in the Kaplan-Meier rate of ischemic stroke compared to placebo administration; (iv) a numerical reduction in the percentage of patients who suffer ischemic stroke relative to placebo administration; or (v) a relative risk reduction of ischemic stroke of about 10% to about 40% relative to placebo administration.

[0574] Aspect 214. Milvexian for use in a method of reducing the risk of ischemic stroke in a human patient who has or has had ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg twice daily and (ii) single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT), preferably wherein the method achieves a relative risk of ischemic stroke of about 0.6 to about 0.9 relative to placebo administration.

[0575] Aspect 215. Milvexian for use in a method of reducing the risk of ischemic stroke in a human patient who has or has had ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg twice daily and (ii) single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT), preferably wherein the method achieves a relative risk reduction of ischemic stroke of about 10% to about 40% relative to placebo administration.

[0576] Aspect 216. Milvexian for use according to Aspect 215, wherein the method achieves a relative risk reduction of ischemic stroke of about 10% to about 40% relative to placebo administration.

[0577] Aspect 217. Milvexian for use according to Aspect 215, wherein the method achieves a relative risk reduction of ischemic stroke of about 28% to about 32% relative to placebo administration.

[0578] Aspect 218. Milvexian for use according to any one of Aspects 213 to 217, wherein the method further achieves at least one of the following safety outcomes: (i) no fatal bleeding events comparable to placebo administration; (ii) no intracranial bleeding events comparable to placebo administration; or (iii) an incidence of major bleeding (BARC type 3 and type 5) comparable to placebo administration.

[0579] Aspect 219. Milvexian for use according to any one of aspects 213 to 217, wherein administration of the regimen results in a decrease in the patient's FXI coagulation activity by about 7% to about 20% relative to baseline.

[0580] Aspect 220. Milvexian for use according to any one of aspects 213 to 217, wherein administration of the regimen results in the patient's activated partial thromboplastin time (aPTT) being prolonged in the range of about 27% to about 64% relative to baseline.

[0581] Aspect 221. Milvexian for use according to any one of aspects 213 to 217, wherein the milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered in the form of a pharmaceutical composition, wherein the pharmaceutical composition is a solid oral pharmaceutical composition.

[0582] Aspect 222. Milvexian for use according to aspect 221, wherein the solid oral pharmaceutical composition is a tablet.

[0583] Aspect 223. The method according to aspect 202, wherein the tablet is an immediate release tablet.

[0584] Aspect 224. The method according to aspect 202 or aspect 203, wherein the tablet has a disintegration time in water of less than 20 seconds.

[0585] Aspect 225. The method according to any one of aspects 213 to 217 or aspects 221 to 224, wherein during repeated dosing, administration is such that the plasma half-life of milvexian is in the range of about 13 hours to about 16 hours.

[0586] Aspect 226. The method according to any one of aspects 213 to 217 or aspects 221 to 225, wherein administration is such that the milvexian plasma concentration reaches steady state in about 3 to 6 days.

[0587] Aspect 227. The method according to any one of aspects 213 to 217 or aspects 221 to 226, wherein milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered without regard to the timing of food intake.

[0588] Aspect 228. The method according to any one of aspects 213 to 217 or aspects 221 to 227, wherein the patient is unable to swallow a tablet dosage form.

[0589] Aspect 229. The method according to any one of aspects 213 to 217, wherein the tablet is dispersed in an aqueous medium to form an aqueous dispersion.

[0590] Aspect 230. The method according to aspect 229, wherein the aqueous medium is water, saline, phosphate buffer, vegetable juice or fruit juice, including, for example, applesauce.

[0591] Aspect 231. The method according to aspect 229 or aspect 230, wherein the aqueous dispersion is administered to the human patient via a nasogastric tube or a spoon.

[0592] Aspect 232. The method according to any one of aspects 229 to 231, wherein the milvexian is orally administered as an aqueous dispersion by dispersing the oral tablet in an aqueous medium for less than 60 seconds.

[0593] Aspect 233. The method according to any one of aspects 193 to 232, wherein the antiplatelet therapy is a single antiplatelet therapy.

[0594] Aspect 234. The method according to aspect 233, wherein the single antiplatelet therapy is aspirin.

[0595] Aspect 235. The method according to aspect 234, wherein aspirin is administered in an amount of 75 to 100 mg per day.

[0596] Aspect 236. The method according to aspect 235, wherein aspirin is administered in an amount of 75 mg per day.

[0597] Aspect 237. The method according to aspect 235, wherein aspirin is administered in an amount of 81 mg per day.

[0598] Aspect 238. The method according to aspect 235, wherein aspirin is administered in an amount of 100 mg per day.

[0599] Aspect 239. The method according to any one of aspects 193 to 232, wherein the single antiplatelet therapy is a P2Y12 inhibitor.

[0600] Aspect 240. The method according to aspect 239, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor or prasugrel.

[0601] Aspect 241. The method according to aspect 240, wherein the P2Y12 inhibitor is clopidogrel.

[0602] Aspect 242. The method according to aspect 242, wherein clopidogrel is administered in an amount of 75 mg per day.

[0603] Aspect 243. The method according to any one of aspects 193 to 232, wherein the single antiplatelet therapy is ticlopidine.

[0604] Aspect 244. The method according to aspect 243, wherein ticlopidine is administered in an amount of 250 to 500 mg per day.

[0605] Aspect 245. The method according to any one of aspects 193 to 232, wherein the antiplatelet therapy is dual antiplatelet therapy.

[0606] Aspect 246. The method according to aspect 245, wherein the dual antiplatelet therapy is aspirin and a P2Y12 inhibitor.

[0607] Aspect 247. The method according to aspect 246, wherein aspirin is administered in an amount of 75 to 100 mg per day.

[0608] Aspect 248. The method according to aspect 247, wherein aspirin is administered in an amount of 75 mg per day.

[0609] Aspect 249. The method according to aspect 247, wherein aspirin is administered in an amount of 81 mg per day.

[0610] Aspect 250. The method according to aspect 247, wherein aspirin is administered in an amount of 100 mg per day.

[0611] Aspect 251. The method according to any one of aspects 245 to 250, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor or prasugrel.

[0612] Aspect 252. The method according to aspect 251, wherein the P2Y12 inhibitor is clopidogrel.

[0613] Aspect 253. The method according to aspect 252, wherein clopidogrel is administered in an amount of 75 mg per day.

[0614] Aspect 254. The method according to any one of aspects 193 to 232, wherein the antiplatelet therapy comprises cephalosporin, a combination of aspirin and dipyridamole (dipyridamole).

[0615] Aspect 255. The method according to any one of aspects 193 to 254, wherein the pharmaceutical composition is a tablet having the composition and / or properties shown in Table A.

[0616] Aspect 256. The method according to aspect 255, wherein the tablet comprises a spray-dried amorphous solid dispersion (SDP).

[0617] Aspect 257. The method according to aspect 255, wherein the tablet comprises about 22.0% w / w of the spray-dried amorphous solid dispersion (SDP) based on the total weight of the tablet.

[0618] Aspect 258. The method according to aspect 255, wherein the tablet comprises about 43.0% w / w silicified microcrystalline cellulose based on the total weight of the tablet.

[0619] Aspect 259. The method according to aspect 255, wherein the tablet comprises about 22.0% w / w SDP and about 43.0% w / w silicified microcrystalline cellulose, based on the total weight of the tablet.

[0620] Aspect 260. The method of any one of aspects 255 to 259, wherein the SDP consists essentially of milvexian free form and hydroxypropylmethylcellulose acetate succinate MG grade (HPMCAS-MG) in a weight ratio of 3:1 (milvexian:HPMCAS-MG).

[0621] Aspect 261. The method according to aspect 255, wherein the tablet consists essentially of 25 mg of milvexian, HPMCAS-MG, silicified microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate.

[0622] Aspect 262. The method according to aspect 261, wherein the tablet further has a film coating comprising polyvinyl alcohol, iron oxide, polyethylene glycol (PEG) polyvinyl alcohol graft copolymer and talc.

[0623] Aspect 263. A method for preventing ischemic stroke or reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg twice daily and (ii) single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT), wherein the method achieves at least one of the following efficacy results: (i) a relative risk of ischemic stroke of about 0.6 to about 0.9 relative to placebo administration; (ii) a numerical reduction in the absolute risk of ischemic stroke relative to placebo administration; (iii) a numerical reduction in the Kaplan-Meier incidence rate of ischemic stroke compared to placebo administration; (iv) a numerical reduction in the percentage of patients who suffer from ischemic stroke relative to placebo administration; or (v) a relative risk reduction of ischemic stroke of about 10% to about 40% relative to placebo administration.

[0624] Aspect 264. A method for preventing ischemic stroke or reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg twice daily and (ii) single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT), wherein the method achieves a relative risk of ischemic stroke of about 0.6 to about 0.9 relative to placebo administration.

[0625] Aspect 265. A method of reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg twice daily and (ii) single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT), wherein the method achieves a relative risk reduction of ischemic stroke of about 10% to about 40% relative to placebo administration.

[0626] Aspect 266. The method according to aspect 265, wherein the method achieves a relative risk reduction of ischemic stroke of about 28% to about 32% relative to placebo administration.

[0627] Aspect 267. The method according to aspect 265, wherein the method achieves a relative risk reduction of ischemic stroke of about 30% relative to placebo administration.

[0628] Aspect 268. The method according to any one of Aspects 263 to 266, wherein the method further achieves at least one of the following safety outcomes: (i) no fatal bleeding events comparable to placebo administration; (ii) no intracranial bleeding events comparable to placebo administration; or (iii) an incidence of major bleeding (BARC types 3 and 5) comparable to placebo administration.

[0629] Aspect 269. The method according to any one of aspects 263 to 268, wherein administration of the regimen results in a decrease in the patient's FXI coagulation activity by about 7% to about 20% relative to baseline.

[0630] Aspect 270. The method according to any one of aspects 263 to 268, wherein administration of the regimen prolongs the patient's activated partial thromboplastin time (aPTT) by about 27% to about 64% relative to baseline.

[0631] Aspect 271. The method according to any one of aspects 263 to 266, wherein milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered in the form of a pharmaceutical composition, wherein the pharmaceutical composition is a solid oral pharmaceutical composition.

[0632] Aspect 272. The method according to aspect 271, wherein the solid oral pharmaceutical composition is a tablet.

[0633] Aspect 273. The method according to aspect 272, wherein the tablet is an immediate release tablet.

[0634] Aspect 274. The method according to aspect 272 or aspect 273, wherein the disintegration time of the tablet in water is less than 20 seconds.

[0635] Aspect 275. The method according to any one of aspects 263 to 268 or aspects 271 to 274, wherein during repeated dosing, administration is such that the plasma half-life of milvexian is in the range of about 13 hours to about 16 hours.

[0636] Aspect 276. The method according to any one of aspects 263 to 268 or aspects 271 to 275, wherein administration is such that the milvexian plasma concentration reaches steady state in about 3 to 6 days.

[0637] Aspect 277. The method according to any one of aspects 263 to 266 or aspects 271 to 275, wherein milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered without regard to the timing of food intake.

[0638] Aspect 278. The method according to any one of aspects 263 to 268 or aspects 271 to 276, wherein the patient is unable to swallow a tablet dosage form.

[0639] Aspect 279. The method according to any one of aspects 263 to 268, wherein the tablet is dispersed in an aqueous medium to form an aqueous dispersion.

[0640] Aspect 280. The method according to aspect 279, wherein the aqueous medium is water, saline, phosphate buffer, vegetable juice or fruit juice, including, for example, applesauce.

[0641] Aspect 281. The method according to aspect 279 or aspect 280, wherein the aqueous dispersion is administered to the human patient via a nasogastric tube or a spoon.

[0642] Aspect 282. The method according to any one of aspects 279 to 281, wherein the milvexian is orally administered as an aqueous dispersion by dispersing the oral tablet in an aqueous medium for less than 60 seconds.

[0643] Aspect 283. Milvexian for use in a method of reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg twice daily and (ii) single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT), wherein the method achieves at least one of the following efficacy outcomes: (i) a relative risk of ischemic stroke of about 0.6 to about 0.9 relative to placebo administration; (ii) a numerical reduction in the absolute risk of ischemic stroke relative to placebo administration; (iii) a numerical reduction in the Kaplan-Meier rate of ischemic stroke compared to placebo administration; (iv) a numerical reduction in the percentage of patients who suffer from ischemic stroke relative to placebo administration; or (v) a relative risk reduction of ischemic stroke of about 10% to about 40% relative to placebo administration.

[0644] Aspect 284. Milvexian for use in a method of reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg twice daily and (ii) single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT), wherein the method achieves a relative risk of ischemic stroke of about 0.6 to about 0.9 relative to placebo administration.

[0645] Aspect 285. Milvexian for use in a method of reducing the risk of ischemic stroke in a human patient who has or has had ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg twice daily and (ii) single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT), wherein the method achieves a relative risk reduction of ischemic stroke of about 10% to about 40% relative to placebo administration.

[0646] Aspect 286. Milvexian for use according to Aspect 285, wherein the method achieves a relative risk reduction of ischemic stroke of about 10% to about 40% relative to placebo administration.

[0647] Aspect 287. Milvexian for use according to Aspect 285, wherein the method achieves a relative risk reduction of ischemic stroke of about 28% to about 32% relative to placebo administration.

[0648] Aspect 288. Milvexian for use according to any one of Aspects 283 to 287, wherein the method further achieves at least one of the following safety outcomes: (i) no fatal bleeding events comparable to placebo administration; (ii) no intracranial bleeding events comparable to placebo administration; or (iii) an incidence of major bleeding (BARC type 3 and type 5) comparable to placebo administration.

[0649] Aspect 289. Milvexian for use according to any one of aspects 283 to 287, wherein administration of the regimen results in a decrease in the patient's FXI coagulation activity by about 7% to about 20% relative to baseline.

[0650] Aspect 290. Milvexian for use according to any one of aspects 283 to 287, wherein administration of the regimen results in the patient's activated partial thromboplastin time (aPTT) being prolonged in the range of about 27% to about 64% relative to baseline.

[0651] Aspect 291. Milvexian for use according to any one of aspects 283 to 287, wherein the milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered in the form of a pharmaceutical composition, wherein the pharmaceutical composition is a solid oral pharmaceutical composition.

[0652] Aspect 292. Milvexian for use according to aspect 291, wherein the solid oral pharmaceutical composition is a tablet.

[0653] Aspect 293. The method according to aspect 272, wherein the tablet is an immediate release tablet.

[0654] Aspect 294. The method according to aspect 272 or aspect 273, wherein the tablet has a disintegration time in water of less than 20 seconds.

[0655] Aspect 295. The method according to any one of aspects 283 to 287 or aspects 291 to 294, wherein administration is such that during repeated dosing the plasma half-life of milvexian is in the range of about 13 hours to about 16 hours.

[0656] Aspect 296. The method according to any one of aspects 283 to 287 or aspects 291 to 295, wherein administration is such that the milvexian plasma concentration reaches steady state in about 3 to 6 days.

[0657] Aspect 297. The method according to any one of aspects 283 to 287 or aspects 291 to 296, wherein milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered without regard to the timing of food intake.

[0658] Aspect 298. The method according to any one of aspects 283 to 287 or aspects 291 to 297, wherein the patient is unable to swallow a tablet dosage form.

[0659] Aspect 299. The method according to any one of aspects 283 to 287, wherein the tablet is dispersed in an aqueous medium to form an aqueous dispersion.

[0660] Aspect 300. The method according to aspect 299, wherein the aqueous medium is water, saline, phosphate buffered saline, vegetable juice or fruit juice, including, for example, applesauce.

[0661] Aspect 301. The method according to aspect 299 or aspect 300, wherein the aqueous dispersion is administered to the human patient via a nasogastric tube or a spoon.

[0662] Aspect 302. The method according to any one of aspects 299 to 301, wherein the milvexian is orally administered as an aqueous dispersion by dispersing the oral tablet in an aqueous medium for less than 60 seconds.

[0663] Aspect 303. The method according to any one of aspects 263 to 302, wherein the antiplatelet therapy is a single antiplatelet therapy.

[0664] Aspect 304. The method according to aspect 303, wherein the single antiplatelet therapy is aspirin.

[0665] Aspect 305. The method according to aspect 304, wherein aspirin is administered in an amount of 75 to 100 mg per day.

[0666] Aspect 306. The method according to aspect 305, wherein aspirin is administered in an amount of 75 mg per day.

[0667] Aspect 307. The method according to aspect 305, wherein aspirin is administered in an amount of 81 mg per day.

[0668] Aspect 308. The method according to aspect 305, wherein aspirin is administered in an amount of 100 mg per day.

[0669] Aspect 309. The method according to any one of aspects 263 to 302, wherein the single antiplatelet therapy is a P2Y12 inhibitor.

[0670] Aspect 310. The method according to aspect 309, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor or prasugrel.

[0671] Aspect 311. The method according to aspect 310, wherein the P2Y12 inhibitor is clopidogrel.

[0672] Aspect 312. The method according to aspect 312, wherein clopidogrel is administered in an amount of 75 mg per day.

[0673] Aspect 313. The method according to any one of aspects 263 to 302, wherein the single antiplatelet therapy is ticlopidine.

[0674] Aspect 314. The method according to aspect 313, wherein ticlopidine is administered in an amount of 250 to 500 mg per day.

[0675] Aspect 315. The method according to any one of aspects 263 to 302, wherein the antiplatelet therapy is dual antiplatelet therapy.

[0676] Aspect 316. The method according to aspect 315, wherein the dual antiplatelet therapy is aspirin and a P2Y12 inhibitor.

[0677] Aspect 317. The method according to aspect 316, wherein aspirin is administered in an amount of 75 to 100 mg per day.

[0678] Aspect 318. The method according to aspect 317, wherein aspirin is administered in an amount of 75 mg per day.

[0679] Aspect 319. The method according to aspect 317, wherein aspirin is administered in an amount of 81 mg per day.

[0680] Aspect 320. The method according to aspect 317, wherein aspirin is administered in an amount of 100 mg per day.

[0681] Aspect 321. The method according to any one of aspects 315 to 320, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor or prasugrel.

[0682] Aspect 322. The method according to aspect 311, wherein the P2Y12 inhibitor is clopidogrel.

[0683] Aspect 323. The method according to aspect 312, wherein clopidogrel is administered in an amount of 75 mg per day.

[0684] Aspect 324. The method according to any one of aspects 263 to 302, wherein the antiplatelet therapy comprises cefotaxime, a combination of aspirin and dipyridamole (dipyridamole).

[0685] Aspect 325. The method according to any one of aspects 263 to 314, wherein the pharmaceutical composition is a tablet having the composition and / or properties shown in Table A.

[0686] Aspect 326. The method according to aspect 325, wherein the tablet comprises a spray-dried amorphous solid dispersion (SDP).

[0687] Aspect 327. The method according to aspect 325, wherein the tablet comprises about 22.0% w / w of the spray-dried amorphous solid dispersion (SDP) based on the total weight of the tablet.

[0688] Aspect 328. The method according to aspect 325, wherein the tablet comprises about 43.0% w / w silicified microcrystalline cellulose based on the total weight of the tablet.

[0689] Aspect 329. The method according to aspect 325, wherein the tablet comprises about 22.0% w / w SDP and about 43.0% w / w silicified microcrystalline cellulose, based on the total weight of the tablet.

[0690] Aspect 330. The method of any one of aspects 325 to 329, wherein the SDP consists essentially of milvexian free form and hydroxypropylmethylcellulose acetate succinate MG grade (HPMCAS-MG) in a weight ratio of 3:1 (milvexian:HPMCAS-MG).

[0691] Aspect 331. The method of aspect 325, wherein the tablet consists essentially of 25 mg of milvexian, HPMCAS-MG, silicified microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate.

[0692] Aspect 332. The method according to aspect 331, wherein the tablet further has a film coating comprising polyvinyl alcohol, iron oxide, polyethylene glycol (PEG) polyvinyl alcohol graft copolymer and talc.

[0693] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the embodiments described herein.

[0694] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference into the specification to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference herein.

[0695] Example

[0696] Example 1. Antithrombotic Therapy by Factor XIa Inhibition to Optimize Management of Secondary Stroke Prevention in Acute Thromboembolic Events (AXIOMATIC-SSP)

[0697] The AXIOMATIC-SSP study is an international, Phase II, randomized, double-blind, placebo-controlled, dose-ranging clinical trial investigating the safety and efficacy of milvexian, an oral FXIa inhibitor, for the prevention of new ischemic stroke in patients receiving aspirin and clopidogrel following acute ischemic stroke or high-risk TIA. The primary objective was to determine the dose-response relationship of milvexian in participants with acute ischemic stroke or TIA treated with aspirin and clopidogrel. The main secondary objective was to assess the incidence of major bleeding in this population compared to placebo.

[0698] Study Group

[0699] Key inclusion criteria for patient participation are listed in Table 1 .

[0700] Table 1. Key inclusion criteria

[0701]

[0702]

[0703] CT, computed tomography; MRI, magnetic resonance imaging; NIHSS, National Institutes of Health Stroke Scale; CTA, computed tomography angiography; MRA, magnetic resonance angiography; mRS, modified Rankin score; TIA, transient ischemic attack; IV, intravenous; INR, international normalized ratio; aPTT, activated partial thromboplastin time; ULN, upper limit of normal.

[0704] Individuals aged ≥40 years who had suffered an ischemic stroke or high-risk TIA were recruited and randomized within 48 hours of symptom onset. A qualifying stroke was defined as a symptomatic non-lacunar acute cerebral infarction visible on neuroimaging (computed tomography [CT] or magnetic resonance imaging [MRI]) and associated with clinical symptoms. Participants were required to have a National Institutes of Health Stroke Scale (NIHSS) score of ≤7 at the time of randomization (scores range from 0 to 42, with higher scores indicating greater stroke severity). Point-like hemorrhagic transformation of index infarction and cerebral microbleeds was allowed. A qualifying TIA was defined as an acute onset of neurological deficits attributable to cerebral ischemia, with complete resolution of the deficits and no cerebral infarction on neuroimaging, and an ABCD2 score of ≥6 (scores range from 0 to 7, with higher scores indicating greater stroke risk) or with motor symptoms. See Johnston SC et al. Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 2007; 369(9558): 283-92. All participants were required to have any degree of visible intracranial or extracranial atherosclerotic plaques, but not completely blocked on imaging studies, and a modified Reye's score (mRS) ≤ 3 before the onset of the disease.

[0705] The exclusion criteria for patient participation are summarized in Table 2 .

[0706] Table 2. Key exclusion criteria for patient participation

[0707]

[0708]

[0709] AVM, arteriovenous malformation; CT, computed tomography; MRI, magnetic resonance imaging; NVAF, nonvalvular atrial fibrillation; DVT, deep venous thrombosis; PE, pulmonary embolism; DAPT, dual antiplatelet therapy; CMB, cerebral microbleed; HI1, hemorrhagic infarction type 1; aPTT, activated partial thromboplastin time; ULN, upper limit of normal; INR, international normalized ratio; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ESRD, end-stage renal disease; eGFR, estimated glomerular filtration rate; LMWH, low-molecular-weight heparin; NSAID, nonsteroidal anti-inflammatory drug; COX-2, cyclooxygenase 2; P-gp, P-glycoprotein; CYP3A4, cytochrome P4503A4; PPI, proton pump inhibitor; ECG, electrocardiogram.

[0710] Potential participants were excluded if there were signs of major vessel dissection, intracranial tumors (other than meningiomas), or arteriovenous malformations that could explain their symptoms. Participants with a history of cerebral or spinal cord bleeding were also excluded, as were participants with conditions that, in the opinion of the investigator, would conflict with anticoagulant therapy. Participants who required dual antiplatelet therapy for more than 21 days or planned use of anticoagulants (except heparin or low molecular weight heparin to maintain patency of indwelling catheters) were excluded. Participants with known SARS-CoV-2 infection within 4 weeks prior to screening were also excluded.

[0711] Study Treatment and Follow-up

[0712] After signing informed consent, participants were randomized to milvexian or matching placebo plus open-label uncoated aspirin 100 mg and clopidogrel (loading dose of 300 to 600 mg, followed by 75 mg / day). Clopidogrel was administered for 21 days, while aspirin and milvexian or matching placebo were continued until day 90 (see Figure 2 ). Initial randomization was to milvexian 25 mg QD and milvexian 25 mg, 50 mg, 100 mg BID, and after independent DMC review of safety and efficacy data, also to 200 mg BID. Although randomization to the 200 mg BID dose was delayed, the study goal was to achieve a 2:1 randomization between placebo and each milvexian dose at the end of enrollment.

[0713] Dosing with milvexian was initiated within 6 hours of the baseline scan. In the event that a baseline MRI could not be obtained within 48 hours of symptom onset, it could be obtained after randomization, but no later than 72 hours after symptom onset. Study follow-up was conducted at 21 and 90 days, with a telephone contact at 60 days. Central laboratory testing was also performed on approximately 450 patients at 60 days. An end-of-study MRI brain scan was performed at 90 days, with a telephone contact at 97 days. The NIHSS, Montreal Cognitive Assessment (MoCA), and Digit Symbol Substitution Test (DSST) were collected at Day 1, Day 21, and Day 90 follow-up visits, as well as after any new clinical stroke.

[0714] Study objectives and endpoints

[0715] The primary efficacy endpoint was a combination of sudden ischemic stroke occurring during the treatment period or new hidden cerebral infarction detected by comparing 90-day MRI with baseline MRI. All images were read independently by 2 blinded neuroradiologists, and disagreements were resolved by consensus. If the 90-day MRI showed new lesions on the diffusion weighted imaging (DWI) sequence or fluid attenuated inversion recovery (FLAIR) sequence consistent with ischemic infarction, it was determined as a new infarction. Clinically obvious stroke was determined by the on-site investigator following a standardized definition. In brief, in order to be eligible as an outcome event, the clinical diagnosis of stroke required a continuous increase in the NIHSS score of ≥3 points and was not explained by other factors such as infection or confirmed as a new infarction by imaging. Hidden cerebral infarction was defined as a small ischemic brain lesion detected on the 90-day MRI in the absence of a symptomatic ischemic stroke event.

[0716] The secondary endpoint of major bleeding was determined by the occurrence of type 3 and type 5 bleeding according to the Bleeding Academic Research Consortium (BARC) classification system. Roxana Mehran et al. Standardized Bleeding Definitions for Cardiovascular Clinical Trials, Circulation. 2011; 123: 2736-2747. Secondary endpoints also included the volume and number of new infarcts detected by MRI imaging, and the incidence of any type of clinical bleeding with milvexian compared to placebo. In addition, bleeding was assessed using the International Society on Thrombosis and Haemostasis (ISTH) and Platelet inhibition and patient Outcomes (PLATO) criteria. Dose-response relationships with PD markers and the PK of milvexian were determined using central laboratory samples.

[0717] Statistical considerations

[0718] Simulations were performed using the dose-finding package in R statistical analysis software, with sample size calculations for the primary endpoint performed by generalized multiple comparisons and modeling (gMCP-Mod) to detect dose-response effects. Bornkamp B, Pinheiro J, Bretz FR: Dose-finding package, version 0.9-16. Comprehensive R archivenetwork. Vienna, Austra: The R Foundation; 2018; CRAN. R-project. Comprehensive Rarchive network. Vienna, Austra: The R Foundation. 2500 clinical trials were simulated, assuming a true placebo incidence of 15%, a stationary dose-response relationship, a maximum relative risk reduction of 32% for milvexian 100 or 200 mg BID relative to placebo, and 25 mg QD as the lowest dose added to the ordered BID dose regimen. Bretz F, Pinheiro JC, Branson M. Combining multiple comparisons and modeling techniques in dose-response studies. Biometrics 2005; 61 (3): 738-48; Pinheiro J, Bornkamp B, Glimm E et al. Model-based dose finding under model uncertainty using general parametric models. Stat Med 2014; 33 (10): 1646-61. Candidate models include E max Models, logistic models, and exponential models.

[0719] Using these assumptions, a total of 2100 participants assigned to placebo and milvexian 25 mg QD, 25 mg BID, 50 mg BID, 100 mg BID, and 200 mg BID in a ratio of 2:1:1:1:1:1 would provide approximately 80% power to demonstrate a dose-response relationship with a one-sided type I error of 0.049. With up to 10% of participants missing from imaging at Day 90, the targeted sample size was approximately 2350 patients.

[0720] All randomized participants will be included in the analysis of the primary endpoint if they have a symptomatic ischemic stroke event at Day 90 or an evaluable MRI at Day 90 follow-up. Due to the COVID-19 pandemic, all Day 90 follow-up MRIs will be included in the primary analysis regardless of timing. All other efficacy analyses will be performed up to Day 90 in the randomized (intention-to-treat, ITT) population.

[0721] If there is a dose-response relationship, the fitted estimate of the primary endpoint incidence rate is calculated in each treatment group using the weighted average of the fitted model, and the weight of each model is determined according to the Akaike information criteria (AIC). The observed primary endpoint incidence rate will be summarized by treatment group using the fitted model from the gMCP-Mod program. gMCP-Mod will combine the event proportions for each dose level, and then the logarithmic scale will be used in the rest of the gMCP-Mod program.

[0722] The population for the primary efficacy endpoint analysis included all randomized participants with (i) a primary endpoint event (new ischemic stroke during the study period or new occult cerebral infarction detected by MRI at Day 90) or (ii) an evaluable MRI at Day 90.

[0723] The population for safety analyses included all participants who received at least one dose of study drug. This is the primary population for safety analyses and will be analyzed according to the treatment assigned at randomization.

[0724] To assess the robustness of the primary efficacy analysis, additional sensitivity analyses will be performed using the following methods:

[0725] Sensitivity analyses will repeat the primary analysis but include MRIs obtained up to day 106.

[0726] The primary analysis will be repeated using all randomized participants, with any event-free participant who did not undergo an MRI at Day 90 counted as having no event (Analysis #1) or having an event (Analysis #2).

[0727] The primary analysis will be repeated excluding participants with protocol deviations that meet predefined criteria and that, if present in ≥5% of participants, could affect the interpretation of the primary safety or efficacy end point analysis.

[0728] Key subgroup analyses will be performed for demographic variables, index event type (ischemic stroke or TIA), time from onset to first dose, baseline NIHSS score, prior ischemic stroke or TIA, hypertension, thrombolysis / thrombectomy, prior antiplatelet therapy, and prior statin therapy.

[0729] For other events, the incidence within each treatment group and the associated relative risk reduction between each milvexian group and placebo will be presented. NIHSS, mRS, MoCA, and DSST (a subtest of the WAIS-IV) will be summarized at baseline, at 21 and 90 days, and at the time of a new stroke event.

[0730] All safety data will be analyzed for participants treated with ≥1 dose of double-blind medication. The proportion of participants with major bleeding events (BARC types 3 and 5), as well as criteria defined by BARC, ISTH, and PLATO will be summarized by treatment group. Other summaries will include the characteristics of cerebral microbleeds, hemorrhagic transformation of ischemic stroke, and asymptomatic intracranial hemorrhage. Adverse events and laboratory data will be summarized, as well as PK and PD data.

[0731] result

[0732] (i) Participants

[0733] The Phase II AXIOMATIC-SSP study randomized 2,366 participants ≥40 years of age with non-lacunar, non-cardioembolic ischemic stroke (NIHSS score ≤7) or high-risk TIA within 48 hours of sign or symptom onset. The trial was conducted at 367 sites in 27 countries. Eligible participants were randomized to receive one of 5 doses of double-blind milvexian (25, 50, 100, 200 mg twice daily, 25 mg once daily) or placebo. A 16-fold dose range (25 mg to 400 mg total daily dose) of milvexian was compared to placebo on a background of 21 days of aspirin and clopidogrel (DAPT) followed by 69 days of aspirin monotherapy (see Figure 2 ).

[0734] All participants received background treatment with open-label ASA and clopidogrel for 21 days, followed by open-label ASA from day 22 to day 90. All 2366 randomized subjects were included in the ITT analysis set. As shown in Table 3, in the ITT analysis set, 859 (36.3%) participants were female and 1884 (79.6%) participants were white. The mean (SD) of participant age was 69.8 (10.9). As shown in Table 6, in the ITT analysis set, 1675 (74.7%) of the 2366 subjects received at least 1 dose of study drug and were therefore in the safety analysis set. In the ITT analysis set, 2272 (96.0%) participants completed the study, and 94 (4.0%) participants discontinued the study early. In the safety analysis set, 1252 (74.7%) subjects completed the study treatment, and 423 (25.3%) participants discontinued the study treatment early. Demographic characteristics and baseline characteristics were balanced between the groups. Patients were well treated with other therapies to manage glycemic and cardiovascular risk (see Tables 1 and 2). The baseline characteristics of milvexian were balanced and directly comparable compared to the placebo group, as shown in Tables 3 and 5 below. The baseline characteristics of the participants are summarized in Tables 3 to 6 below.

[0735]

[0736] a. 22 subjects in the discontinued 50QD group and 18 subjects in the discontinued 100QD group were included in the combined milvexian set (40 subjects total).

[0737] SD, standard deviation.

[0738]

[0739]

[0740] a. 22 subjects in the discontinued 50QD group and 18 subjects in the discontinued 100QD group were included in the combined milvexian set (40 subjects total).

[0741]

[0742]

[0743] a. 22 subjects in the discontinued 50QD group and 18 subjects in the discontinued 100QD group were included in the combined milvexian set (40 subjects total).

[0744]

[0745] a. 22 subjects in the discontinued 50QD group and 18 subjects in the discontinued 100QD group were included in the combined milvexian set (40 subjects total).

[0746] (ii) Efficacy: dose response

[0747] The primary efficacy outcome was to assess the dose response of the combination of new clinical ischemic stroke during the treatment period and new hidden cerebral infarction detected by MRI at Day 90 in the modified ITT population (those participants with clinical ischemic stroke or who underwent MRI at Day 90). Although the incidence of the combined outcome was numerically lower at the 50 mg and 100 mg twice daily doses, there was no clear trend in the dose-response (placebo 16.6%, 25 mg once daily 16.2%, 25 mg twice daily 18.5%, 50 mg twice daily 14.1%, 100 mg twice daily 14.7%, 200 mg twice daily 16.4%, % is incidence, n / N %). However, except for 200 mg twice daily, all doses of milvexian numerically reduced the incidence of clinical ischemic stroke (excluding hidden cerebral infarction) in the ITT population, with doses of 25 to 100 mg twice daily showing approximately 30% relative risk reduction (RRR) relative to placebo (placebo 5.5%, 25 mg once daily 4.6%, 25 mg twice daily 3.8%, 50 mg twice daily 4.0%, 100 mg twice daily 3.5%, 200 mg twice daily 7.7%). Similar trends were observed within 21 days (the expected treatment period with DAPT).

[0748] In the AXIOMATIC-TKR study, a 25 mg twice daily dose of milvexian showed similar efficacy to enoxaparin with a favorable safety profile. In the AXIOMATIC-SSP study, a 25 mg twice daily dose of milvexian was numerically superior to placebo in preventing clinical ischemic stroke (HR 0.69, 95% CI 0.36 to 1.30), but no further improvement in efficacy was observed at higher doses.

[0749] The primary endpoint was numerically lower at the 50 mg and 100 mg BD doses, but there was no dose-response trend. Milvexian numerically reduced the incidence of clinical ischemic stroke events (acute IS and excluding hidden cerebral infarction) in the ITT population at all milvexian doses except 200 mg twice daily (see Table 7 below). Milvexian doses of 25 mg BID to 100 mg BID were effective in reducing clinical ischemic stroke in patients following ischemic stroke or TIA, and these doses showed an approximately 30% relative risk reduction (RRR) in the treatment group for the occurrence of ischemic stroke relative to the placebo group (see Table 7 below). Figure 4 ).

[0750]

[0751] Includes clinical events up to day 21

[0752] (1) Wald 95% CI within the group

[0753] (2) Use Ward's confidence limits to construct the 95% CI of the RR

[0754] Program source: BMS_GBS\CV010\OZA75318\Biostatistics\Production\Tables\CSR\rt-ef-clinstk.sas

[0755] (iii) Efficacy: Bleeding risk

[0756] The primary safety (bleeding) outcomes were BARC type 3 and 5 bleeding as shown in Table 8. No fatal bleeding occurred in any treatment group. In addition, no intracranial hemorrhage occurred with milvexian. The incidence (n / N%) of bleeding endpoints was low (0.6% to 1.6%) and there were no fatal bleeding. The incidence (%) of major bleeding (BARC type 3 and 5) was the same as placebo (0.6%) for both 25 mg QD and BID doses of milvexian, while a modest increase in the incidence of bleeding was observed in the milvexian 50 mg BD group. (See Figure 3 ).

[0757] The incidence (n / N%) of major bleeding (BARC 3 and 5, primary safety endpoint) was low overall (placebo 0.6%, 25 mg once daily 0.6%, 25 mg twice daily 0.6%, 50 mg twice daily 1.5%, 100 mg twice daily 1.6%, 200 mg twice daily 1.5%), and there were no fatal bleeding. The incidence of major bleeding was similar to placebo for the 25 mg once daily and twice daily doses of milvexian, while a modest increase was observed in the milvexian dose groups of 50 mg twice daily and above (see Table 8).

[0758]

[0759] (1) Clopper Pearson Exact CI within the group

[0760] (2) Exact confidence limits were used to construct 95% CIs for risk differences and RRs.

[0761] Bleeding events related to treatment-emergent AEs or asymptomatic ICH detected by MRI at day 90 were included.

[0762] Program source: BMS_GBS\CV010\OZA75318\Biostatistics\Production\Tables\CSR\rt-bl-maja.sas

[0763] Table 9. BARC Type of Bleeding (All Treated Participants):

[0764]

[0765]

[0766] Hgb, hemoglobin; HT, hemorrhagic transformation; CABG, coronary artery bypass grafting.

[0767] As shown in Table 9 above, milvexian has a similar incidence of intracranial hemorrhage to placebo. Although all patients received background antiplatelet therapy, no fatal bleeding was observed and severe bleeding (e.g., symptomatic intracranial hemorrhage) was not increased with milvexian relative to placebo. Symptomatic intracranial hemorrhage events occurred in the study in placebo (n=2; 0.3); milvexian 50 mg BID (n=3, 0.9%); and milvexian 200 mg BID (n=1, 0.3%). No intracranial hemorrhage events occurred in the milvexian dose groups of 25mg QD, 25mg BID, and 100mg BID. No dose-response was observed for this type of bleeding. Overall, no fatal bleeding occurred and there was no increase in ICH (BARC-3c), which is the most harmful bleeding to patients. In addition, BARC-3 bleeding did not increase in the 25mg QD and 25mg BID study groups.

[0768] "Despite advances in secondary prevention, early stroke recurrence following an ischemic stroke or transient ischemic attack (TIA) remains a significant risk. Anticoagulants are not currently used when patients have non-cardioembolic ischemic stroke due to bleeding concerns, and these data suggest that milvexian may provide additional benefit to stroke patients in clinical practice."

[0769] The overall AE and SAE profile of milvexian appeared similar to that of placebo, except for the 200 mg twice daily dose.

[0770] Milvexian represents an antithrombotic therapy with a favorable bleeding and tolerability profile, which provides a treatment option for patients who are currently untreated or poorly treated due to bleeding concerns.

[0771] (iv) Efficacy: Secondary endpoints

[0772] Event rate of the combination of new ischemic nonfatal stroke, nonfatal myocardial infarction, or all-cause death.

[0773] Location, number, and volume of new FLAIR+DWI lesions.

[0774] The National Institutes of Health Stroke Scale (NIHSS), modified Reye's Scale (mRS), Montreal Cognitive Assessment (MoCA), and Digit Symbol Transformation Test (a subtest of WAIS-IV) were collected at baseline (at randomization of NIHSS), at days 21 and 90, and at the time of a new stroke event. The MoCA and DSST (a subset of WAIS-IV) were read by a third-party central laboratory blinded to treatment.

[0775] Descriptive statistics and corresponding changes from baseline for the National Institutes of Health Stroke Scale (NIHSS), modified Reye's Scale (mRS), Montreal Cognitive Assessment (MoCA), and Digit Symbol Transformation Test (a subtest of the WAIS-IV) were summarized by treatment group, as applicable.

[0776] Baseline characteristics

[0777] Overall, the majority of index events (75.7%) were ischemic strokes with an NIHSS ≤ 5 in approximately 96% of randomized subjects.

[0778] Baseline disease characteristics were balanced between treatment groups, with the exception of the 200 mg BID group (4.7%), where NIHSS scores of 6 to 7 were higher than in the other groups (range: 2.1% to 4.0%). The NIHSS score was increased to 7 only with the latest protocol (version 06) to broaden the study population. Randomization to the 200 mg BID group will not occur until safety data for this population is collected and subsequent DMC assessments may be performed due to safety precautions. In the same protocol amendment, the NIHSS score inclusion criteria were increased from ≤5 to ≤7. Therefore, due to the staggered opening of the treatment groups, more subjects with NIHSS scores of 6 or 7 were assigned to the highest dose group.

[0779] Baseline stroke imaging assessments (MRI) were performed in nearly all (99.6%; 1668 / 1675) subjects randomized to milvexian and nearly all placebo subjects (99.4%; 687 / 691). At Day 90, study MRI was performed in 90.7% (1520 / 1675) of all subjects randomized to milvexian and 89.6% (619 / 691) of placebo subjects. Overall, approximately 4.5% of Day 90 MRIs were obtained within the designated window of 106 days, with double-blind treatment limited to 96 days.

[0780] Baseline MRI features for treatment are summarized below:

[0781] 24.7% of subjects in the placebo group versus 23.0% in the combined milvexian group had no detectable recent ischemic lesions on DWI sequences, which is consistent with the proportion of TIA patients randomized in the study.

[0782] 7.9% of subjects in the placebo group versus 9.3% of subjects in the combined milvexian group had lacunar infarcts detected by MRI.

[0783] The median number of new ischemic lesions at baseline was 2.0 in all study treatment groups.

[0784] The median volume of the latest ischemic lesion at baseline was 1.6 mL and 1.4 mL for placebo and all milvexian treatment groups, respectively (Table 14.2.5).

[0785] One quarter of the subjects (25.0%) had chronic ischemic infarction.

[0786] Signs of chronic bleeding were present in 27.4% of the subjects.

[0787] Microbleeds (≤10 mm) occurred in one quarter of the subjects (25.8%), and major bleeding >10 mm occurred in 0.9% to 2.7% of the subjects.

[0788] White matter abnormalities were detected in 93.7% of all treatment groups.

[0789] The above MRI characteristics were well balanced between the placebo and milvexian treatment groups.

[0790] New composite of ischemic stroke, myocardial infarction, and all-cause mortality

[0791] The combined incidence of new ischemic stroke, MI, and all-cause death was lower with milvexian at dose levels ranging from 25 mg QD to 100 mg BID compared to placebo. See Table 10 below. The relative risk of this combined event ranged from 0.78 to 0.85 for milvexian at 25 mg QD to 100 mg BID compared to placebo, but there was no clear dose-response trend.

[0792] In contrast, the milvexian 200 mg BID dose group had a numerically higher incidence of this combined endpoint than placebo (9.4% vs. 6.1%, respectively; relative risk: 1.55), as well as higher rates of ischemic stroke (7.7% vs. 5.5%, respectively), myocardial infarction (0.9% vs. 0.3%, respectively), and all-cause mortality (1.1% vs. 0.7%, respectively).

[0793] Table 10. Descriptive Summary of Combined Event Rates of New Ischemic Stroke, MI, and All-cause Death—All Randomized Subjects

[0794]

[0795] Note: Clinical events and deaths were included up to Day 90. With the implementation of Amendment 05, subjects were randomized to the 50 mg QD (N=22) and 100 mg QD (N=18) treatment groups.

[0796] (1) 95% CI within the group

[0797] (2) Use Ward's confidence limits to construct the 95% CI of the RR

[0798] Location, number, and volume of new FLAIR+DWI lesions

[0799] About the quantitative and vascular area information of sudden infarction detected by MRI at the 90th day is summarized in the following table 11 and table 12.At baseline, the latest ischemic lesions are detected and quantified using DWI sequence.Sudden infarction (defined as new imaging lesions compared with baseline MRI, which may be relevant to symptomatic ischemic stroke or essentially recessive) is detected on FLAIR sequence at the 90th day, and is classified as DWI positive or DWI negative based on whether it can also be detected on DWI sequence.The DWI positive lesions at the 90th day are likely to be relevant to the infarction occurring in the late follow-up period (approximately from the 30th day to the 90th day), while the DWI negative lesions are more likely to be relevant to early infarction (occurring at approximately the 30th day).Also the vascular area of ​​sudden infarction is assessed at the 90th day.

[0800] The key results are as follows:

[0801] The incidence of incident infarctions detected by MRI at day 90 was numerically lower with milvexian than with placebo at dose levels of 50 BID to 200 BID, with no apparent dose response.

[0802] Most of the sudden infarcts on MRI were single lesions, and less than 3% of the subjects in the different treatment groups had multiple sudden infarcts with no apparent relationship to drug administration.

[0803] The mean volume of the incident infarct with milvexian was small (0.9 to 3.0 mL) and numerically lower than placebo at all dose levels except the 25 mg BID group.

[0804] Among subjects with incident infarction detected by MRI at day 90, the proportion of DWI-positive lesions was higher (range: 8.7% to 12.6%) than that of DWI-negative lesions (range: 3.3% to 6.0%).

[0805] The mean volume of DWI-positive incident infarcts was numerically lower with milvexian than with placebo at all dose levels. The mean volume of DWI-negative incident infarcts was numerically lower with milvexian than with placebo at dose levels of 25QD and 50BID to 200BID.

[0806] Many precipitous infarcts are located in the neovascular area that is the index stroke. The most common neovascular site for precipitous infarcts is the middle cerebral artery (MCA).

[0807] Table 11. Descriptive Summary of Number and Volume of Incident Infarcts at Day 90 - All Randomized Subjects with Evaluable MRI

[0808]

[0809]

[0810] Note: The number and volume of incident infarctions considered are only for patients with incident infarction.With the implementation of Amendment 05, subjects were randomized to the 50 mg QD (N=22) and 100 mg QD (N=18) treatment groups.

[0811] Table 12. Descriptive Summary of Vascular Territories with Incident Infarction at Day 90 Compared with Baseline—All Randomized Subjects with Evaluable MRI

[0812]

[0813]

[0814] Note: With the implementation of Amendment 05, subjects were randomized to the 50 mg QD (N=22) and 100 mg QD (N=18) treatment groups.

[0815] NIHSS, mRS, MoCA, and DSST

[0816] For functional outcome measures, milvexian-treated subjects had lower NIHSS and mRS scores at the time of a new stroke event compared with placebo.

[0817] For cognitive outcome measures, MoCA and DSST scores showed overall improvements after baseline in the different treatment groups including placebo.

[0818] Descriptive summaries of mRS and NIHSS are shown in Tables 13 and 14, respectively. MoCA and DSST were also assessed. In all four measures, the mean change results from baseline at Day 21 and Day 90 assessments were similar across all analyzed milvexian dose levels (except for the 50 and 100 mg QD groups, which were not large enough for comparison) and placebo. In all treatment groups, including placebo, there was an overall improvement in stroke severity (NIHSS) and cognitive function (DSST and MoCA) scores among subjects assessed at Day 21 and Day 90:

[0819] The median NIHSS and mRS scores at the time of a new stroke event were numerically lower in the milvexian group compared with placebo.

[0820] Regardless of treatment assignment, all subjects showed overall improvements in cognitive measures over the course of the study:

[0821] The mean MoCA score of 22 points at baseline increased by an average of 2 points across all groups through days 21 and 90.

[0822] Mean DSST scores from baseline of 31 to 37 points across all groups increased by an average of 5 to 7 points from baseline through Day 21 and increased by an additional 1 to 2 points through Day 90. Improvement in this DSST measure did not appear to be treatment or dose dependent.

[0823] Table 13. Descriptive Summary of Subjects' mRS at First Recurrent Stroke - All Randomized Subjects

[0824]

[0825]

[0826] Note: Recurrent stroke includes ischemic stroke and unexplained stroke.With the implementation of Amendment 05, subjects were randomized to 50 mg QD (N=22) and 100 mg QD (N=18) treatment groups.

[0827] Table 14. Descriptive Summary of NIHSS at First Recurrent Stroke—All Randomized Subjects

[0828]

[0829] Note: Recurrent stroke includes ischemic stroke and unexplained stroke.With the implementation of Amendment 05, subjects were randomized to 50 mg QD (N=22) and 100 mg QD (N=18) treatment groups.

[0830] (v) Efficacy: Pharmacodynamics

[0831] One objective of the study was to evaluate the dose-response of milvexian on pharmacodynamic (PD) biomarkers, with endpoints being % change from baseline in aPTT and factor XI coagulation activity during treatment, measured using descriptive statistics and corresponding percentage change from baseline.

[0832] A portion of the ITT population that included subjects with at least one PD endpoint (1995 subjects total) was evaluated after the first dose of milvexian. The percentage change (%) from baseline in aPTT and factor XI coagulation activity was summarized by treatment group and nominal time point. In addition, exposure-response relationship (ER) analysis was performed using data collected from all treated subjects (2334 subjects total) to explore the relationship between milvexian exposure and the percentage change (%) from baseline in aPTT and factor XI coagulation activity. A dose-dependent increase in aPTT and a dose-dependent decrease in factor XI coagulation activity were observed in the milvexian treatment group.

[0833] Summary statistics of the activated partial thromboplastin time (aPTT) and percent change from baseline for the pharmacodynamic population are shown in Table 15 below:

[0834]

[0835]

[0836] The following FXI coagulation activities were observed in this study:

[0837]

[0838]

[0839] Nominal time points were used for PD biomarker data analysis. For post-baseline time points, N represents subjects with baseline and post-baseline values ​​for that time point. Values ​​greater than the upper limit of quantitation were set as the upper limit of summary statistics. Baseline = non-missing results with a collection date less than or equal to the date of the first active dose of study drug in each treatment group at the time point "baseline-pre-dose". With the implementation of Amendment 05, subjects were randomized to 50 mg QD (N=22) and 100 mg QD (N=18) treatment groups.

[0840] Example 2. Bioavailability Study and Results of 25 mg and 100 mg Film-Coated DC Tablets versus 25 mg and 100 mg SDP Oral Capsules in Healthy Participants

[0841] The first Phase 1 trial is an open-label, randomized, crossover study evaluating relative oral bioavailability, pharmacokinetics, and food effects following a single dose (for Parts 1, 3, and 4) or multiple doses (for Part 2). Part 1 of this first Phase 1 study will evaluate the relative bioavailability and food effects of a single dose of 200 mg of milvexian administered as a film-coated DC tablet compared to 100 mg comparator SDP oral capsules under fasting and fed conditions. Part 2 of this first Phase 1 study will characterize the pharmacokinetics (PK) of multiple doses of milvexian administered twice daily for 5 days at 200 mg of milvexian in the form of a film-coated DC tablet and either 25 mg or 200 mg of comparator SDP oral capsules. 100 mg and 25 mg capsule formulations (see Table 17 below) are described in WO 2020210629, wherein the capsules contain MCC and anhydrous lactose DC in a weight ratio of binder (MCC) to filler (anhydrous lactose) of 1:1. The composition and physical properties of the 25 mg and 100 mg film-coated DC tablets are provided in Table A above.

[0842] Blood samples were drawn at predetermined time points after drug administration as specified in the clinical study protocol. The concentrations of the samples were measured using a validated analytical method (liquid chromatography tandem mass spectrometry). TM (Version 8.1, Pharsight, A Certara TM Company, LP, Princeton, NJ, USA) software derives the pharmacokinetic parameters (e.g., Cmax, AUC, etc.) of each subject from the time-concentration curve by non-compartmental methods. last and AUC ∞ ).

[0843]

[0844]

[0845] *SDP was prepared according to the composition and method described in WO 2020210629

[0846] The treatment regimens for Part 1 and Part 2 are summarized in Table 18 below.

[0847]

[0848] *DC: Direct Compression

[0849] **RC: Roller Pressed Granulation

[0850] For the 200 mg dose, the absolute bioavailability of the 100 mg SDP capsule comparative formulation was 52% under fasting conditions and 72% under fed conditions.

[0851] In the single dose administration regimen of Part 1, at a 200 mg dose, the 100 mg film-coated DC tablets showed about 9.0% to about 11% improvement compared to the oral SDP capsules. The 100 mg film-coated DC* oral tablets had a lower food effect. To achieve better patient compliance, it is preferred that milvexian be administered with or without meals. Pharmaceutical formulations with less food effect provide better patient compliance.

[0852] In the multiple dose BID administration regimen of Part 2, 2×100 mg film-coated DC tablets showed approximately 5% to 7% lower bioavailability compared to 2×100 mg SDP oral capsules. 25 mg film-coated DC tablets (DC tablets) showed approximately 11% to 13% lower bioavailability compared to 25 mg SDP oral capsules (see FIG. 8A to FIG. 8D , milvexian dosing profile over time after BID administration).

[0853] In the second Phase 1 trial, Part 1 was an open-label, randomized, 3-way crossover study in healthy participants to evaluate the relative oral bioavailability, pharmacokinetics, and food effects of a single oral dose of 200 mg of milvexian in the form of 2×100 mg SDPDC tablets compared to 200 mg of 2×100 mg SDP granule capsules under fasting conditions, and to evaluate the effect of food on the bioavailability of milvexian after a single dose of 200 mg of milvexian in the form of 2×100 mg SDP DC tablets. Part 2 was an open-label, randomized, 2-way crossover study in healthy participants to evaluate the PK and relative bioavailability of a single oral dose of 50 mg of milvexian in the form of 2×25 mg SDP tablets compared to 50 mg of milvexian in the form of 2×25 mg SDP granule capsules under fasting conditions in healthy participants.

[0854] PK (AUC) of 2 × 100 mg and 1 × 25 mg SDP DC tablets and 25 mg and 100 mg SDP granule capsule formulations generated in two Phase 1 studies under fed and fasting conditions inf and C max ) data, the results demonstrated that the tablets exhibited less inter-participant PK variability in healthy participants compared with the capsules.

[0855] Results of clinical studies demonstrated that, for tablets with similar dissolution rates, the AUC of 2 × 100 mg film-coated DC* oral tablets was significantly higher than that of 2 × 100 mg granule capsule formulations. ∞ (Also called AUC inf ) met the bioequivalence criteria.

Claims

1. A method of preventing ischemic stroke or reducing the risk of ischemic stroke in a human patient who has or has had ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising: milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg once daily or in an amount of 12.5 mg to 200 mg twice daily; and standard of care; wherein the regimen is effective to prevent ischemic stroke in the human patient.

2. A regimen for use in preventing ischemic stroke or reducing the risk of ischemic stroke in a human patient who has or has had ischemic stroke or transient ischemic attack, the regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg once daily or in an amount of 12.5 mg to 200 mg twice daily; and standard of care; wherein the regimen is effective in reducing the risk of ischemic stroke in the human patient relative to a placebo taken together with the standard of care.

3. A method of treating a human patient who has or has had an ischemic stroke or transient ischemic attack, comprising administering to the human patient a regimen comprising: milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg once daily or 12.5 mg to 200 mg twice daily, and standard of care; wherein the regimen is effective to reduce the risk of ischemic stroke in the human patient, and wherein the human patient does not experience an ischemic stroke during the duration of the regimen.

4. A regimen for use in treating a human patient who has or has had ischemic stroke or transient ischemic attack, comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg once daily or 12.5 mg to 200 mg twice daily, and standard of care; wherein the use comprises administering the regimen to the human patient, and wherein the regimen is effective to reduce the risk of ischemic stroke in the human patient, and wherein the human patient does not experience an ischemic stroke during the duration of the regimen.

5. A method of treating a patient population, wherein the patients have or have had an ischemic stroke or transient ischemic attack, the method comprising administering to the patients in the population a regimen comprising: milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg once daily or in an amount of 12.5 mg to 200 mg twice daily; and standard of care; wherein within 90 days of initiation of the regimen, the percentage of patients in the population experiencing an ischemic stroke is less than 10%.

6. A regimen for use in treating a patient population comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg once daily or in an amount of 12.5 mg to 200 mg twice daily; and standard of care; wherein the patient suffers from or has suffered from ischemic stroke or transient ischemic attack, wherein the use comprises administering the regimen to patients in the population, and wherein within 90 days of initiation of the regimen, the percentage of patients in the population experiencing ischemic stroke is less than 10%.

7. The method according to any one of claims 1, 3 or 5, or the regimen for use according to any one of claims 2, 4 or 6, wherein the standard of care comprises antiplatelet therapy.

8. The method or regimen of claim 7, wherein the antiplatelet therapy comprises a single antiplatelet therapy.

9. The method or regimen according to claim 8, wherein the single antiplatelet therapy is aspirin, preferably wherein aspirin is administered in an amount of 75 to 100 mg per day.

10. The method or regimen of claim 8, wherein the single antiplatelet therapy is a P2Y12 inhibitor, preferably clopidogrel, ticagrelor, ticlopidine, cangrelor or prasugrel, or clopidogrel administered in an amount of 75 mg per day, or ticlopidine administered in an amount of 250 to 500 mg per day.

11. The method or regimen of claim 7, wherein the antiplatelet therapy comprises dual antiplatelet therapy.

12. The method or regimen of claim 11, wherein the dual antiplatelet therapy is aspirin and a P2Y12 inhibitor, preferably wherein the aspirin is administered in an amount of 75 to 100 mg per day, and preferably wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, ticlopidine, cangrelor or prasugrel, or clopidogrel administered in an amount of 75 mg per day.

13. The method or regimen of claim 7, wherein the antiplatelet therapy comprises Aggrenox, a combination of aspirin and dipyridamole (persantine).

14. The method or regimen of any one of claims 1 to 13, wherein the milvexian is administered in an amount selected from the group consisting of 25 mg once a day, 25 mg twice a day, 50 mg twice a day, 100 mg twice a day, 200 mg twice a day, and less than 200 mg twice a day.

15. The method or regimen according to claim 14, wherein the milvexian is administered in an amount of 25 mg twice daily.

16. The method or regimen of any one of claims 1 to 15, wherein the risk of ischemic stroke is reduced compared to the placebo administered in conjunction with standard of care, preferably wherein the risk of ischemic stroke is reduced compared to the placebo administered in conjunction with antiplatelet therapy.

17. The method or regimen of claim 16, wherein the risk of ischemic stroke when the regimen is administered divided by the risk of ischemic stroke when a placebo is administered along with the standard of care (ie, the relative risk) is from about 0.6 to about 0.

9.

18. The method or regimen of claim 16, wherein the relative risk reduction is from about 10% to about 40%.

19. The method according to any one of the preceding claims, wherein the risk of ischemic stroke is reduced in a dose-dependent manner with the amount of milvexian administered.

20. The method according to any one of claims 1 to 19, wherein the relative risk of bleeding according to the Bleeding Academic Research Consortium (BARC) type 3 and type 5 criteria does not exceed 3 compared to placebo together with the standard of care, preferably compared to placebo together with antiplatelet therapy.

21. The method according to any one of claims 1 to 20, wherein the relative risk of bleeding according to the Bleeding Academic Research Consortium (BARC) type 2 criteria does not exceed 2.6 compared to placebo together with the standard of care, preferably compared to placebo together with antiplatelet therapy.

22. The method according to any one of claims 1 to 21, wherein the relative risk of bleeding according to ISTH criteria (major bleeding or clinically relevant non-major bleeding (CRNM)) does not exceed 3 compared to placebo together with the standard of care, preferably compared to placebo together with antiplatelet therapy.

23. The method or regimen of any one of claims 1 to 22, wherein the human patient does not experience bleeding according to the Bleeding Academic Research Consortium (BARC) type 3 and type 5 criteria.

24. The method or regimen of any one of claims 1 to 23, wherein administration of the regimen results in a dose-dependent decrease in the patient's FXI coagulation activity relative to baseline.

25. The method or regimen according to any one of claims 1 to 24, wherein administration of the regimen results in a decrease in the patient's FXI coagulation activity from about 7% to about 43% relative to baseline, preferably from about 7% to about 20% relative to baseline.

26. The method or regimen of any one of claims 1 to 25, wherein administration of the regimen results in a dose-dependent prolongation of activated partial thromboplastin time (aPTT) relative to baseline.

27. The method or regimen according to any one of claims 1 to 26, wherein the administration of the regimen results in an activated partial thromboplastin time (aPTT) being prolonged by about 27% to about 115% relative to baseline, preferably in the range of about 27% to 64% relative to baseline.

28. The method or regimen of any one of claims 1 to 27, wherein the administration does not result in a statistically significant increase in major bleeding complications.

29. The method or regimen according to any one of claims 1 to 28, wherein the milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered in the form of a pharmaceutical composition, wherein the pharmaceutical composition is a solid oral pharmaceutical composition, preferably wherein the solid oral pharmaceutical composition is a tablet, or wherein the tablet is an immediate release tablet.

30. The method or regimen of claim 29, wherein the tablet has a disintegration time in water of less than 20 seconds.

31. The method of any one of claims 1 to 30, wherein the administration results in a milvexian plasma half-life in the range of about 13 hours to about 16 hours during repeated dosing.

32. The method of any one of claims 1 to 31, wherein the administration is such that the milvexian plasma concentration reaches steady state in about 3 to 6 days.

33. The method of any one of claims 1 to 32, wherein the milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered regardless of the timing of food intake.

34. A method of reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg twice daily and (ii) single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT), wherein the method achieves a relative risk of ischemic stroke of about 0.6 to about 0.9 relative to placebo administration.

35. A method of reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg twice daily and (ii) single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT), wherein the method achieves a relative risk reduction of ischemic stroke of about 10% to about 40% relative to placebo administration.

36. The method of claim 35, wherein the method achieves a relative risk reduction of ischemic stroke of about 28% to about 32% relative to placebo administration.

37. The method of claim 35, wherein the method achieves a relative risk reduction of ischemic stroke of about 30%.

38. The method of any one of claims 34 to 37, wherein the method further achieves at least one of the following safety outcomes: (i) no fatal bleeding events comparable to placebo administration; (ii) no intracranial hemorrhage events comparable to placebo administration; or (iii) an incidence of major bleeding (BARC types 3 and 5) comparable to placebo administration.

39. milvexian for use in a method of reducing the risk of ischemic stroke in a human patient who has or has had ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg twice daily and (ii) single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT), wherein the method achieves a relative risk of ischemic stroke of about 0.6 to about 0.9 relative to placebo administration.

40. milvexian for use in a method of reducing the risk of ischemic stroke in a human patient who has or has had ischemic stroke or transient ischemic attack, the method comprising administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) administered in an amount of 25 mg twice daily and (ii) single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT), wherein the method achieves a relative risk reduction of ischemic stroke of about 10% to about 40% relative to placebo administration.

41. Milvexian for use according to claim 40, wherein the method achieves a relative risk reduction of ischemic stroke of about 10% to about 40% relative to placebo administration.

42. Milvexian for use according to claim 40, wherein the method achieves a relative risk reduction of ischemic stroke of about 28% to about 32% relative to placebo administration.

43. milvexian for use according to any one of claims 39 to 42, wherein the method further achieves at least one of the following safety outcomes: (i) no fatal bleeding events comparable to placebo administration; (ii) no intracranial bleeding events comparable to placebo administration; or (iii) an incidence of major bleeding (BARC type 3 and type 5) comparable to placebo administration.

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