Use of Milvexian to Treat or Prevent Ischemic Stroke

Abstract

Factor XIa inhibitors having therapeutic properties useful in methods for treating or preventing ischemic stroke.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 63 / 370,031, filed August 1, 2022; U.S. Provisional Application No. 63 / 401,361, filed August 26, 2022; U.S. Provisional Application No. 63 / 379,848, filed October 17, 2022; and U.S. Provisional Application No. 63 / 498,945, filed April 28, 2023. The disclosures of each of the foregoing applications are incorporated herein by reference in their entirety.

[0002] Technical Field The present disclosure relates to the use of milvexian to treat or prevent ischemic stroke while maintaining hemostasis in patients with acute ischemic stroke or transient ischemic attack (TIA). [Background technology]

[0003] Ischemic stroke is a devastating and common condition. Data from the Global Burden of Disease study estimated the global prevalence of ischemic stroke to be 77 million in 2019, with the highest age-adjusted incidence rates in Southeast / East / Central Asia, Central / Eastern Europe, North Africa, and the Middle East. Across Europe, stroke accounts for more than 1 in 10 all-cause deaths each year and 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 over the age of 20 self-report having had a stroke, and an additional 3.4 million U.S. adults are projected 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 a leading cause of mortality worldwide in patients with coronary, peripheral, or cerebrovascular atherosclerosis.

[0004] Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by lipid deposition in the subendothelial space, endothelial dysfunction leading to calcium accumulation, and subsequent leukocyte infiltration and smooth muscle proliferation. Vascular injury, such as that occurring during erosion or rupture of atherosclerotic lesions, triggers blood coagulation to maintain hemostasis (protection against blood loss). This results in thrombus formation and acute coronary syndrome (ACS). Atherothrombosis results from the formation of a thrombus on a ruptured or eroded atherosclerotic plaque and manifests clinically as myocardial infarction (MI), peripheral artery disease (PAD), or ischemic stroke (not due to embolization from the heart).

[0005] The relationship between coagulation and atherothrombosis has been demonstrated in numerous animal and clinical studies (Ngo et al., Pharmacological targeting of coagulation factor XI mitigates the development of experimental atherosclerosis in low-density lipoprotein receptor-deficient mice, J Thromb Haemost. 2021;19:1001-1017). Numerous coagulation components are present in human atherosclerotic lesions, strongly indicating a role for coagulation activity during early plaque progression. Furthermore, thrombin, tissue factor pathway inhibitor, coagulation factor VIII (F), and activated FXa (FXa) have all been shown to contribute to plaque progression in mice. Components of the intrinsic pathway, such as factor XII (FXII) and, more recently, factor XI (FXI), have also been shown to play a role in atherogenesis through unknown mechanisms in ApoE- / - mice.

[0006] The etiology of ischemic stroke results from either a thrombotic or embolic event that causes reduced blood flow to the brain. In a thrombotic event, blood flow to the brain is obstructed in a blood vessel due to dysfunction within the vessel itself secondary to atherosclerotic disease, arterial dissection, fibromuscular dysplasia, or an inflammatory condition. In an embolic event, debris from another part of the body blocks blood flow through the affected vessel. The etiology of stroke affects both prognosis and outcome (Ntaios G. Embolic Stroke of Undetermined Source: JACC Review Topic of the Week. J Am Coll Cardiol. 2020 Jan 28;75(3):333-340; Pierik et al., Distribution of Cardioembolic Stroke: A Cohort Study. Cerebrovasc Dis. 2020;49(1):97-104).

[0007] A key component in the pathophysiology of cerebrovascular ischemic stroke events is activated platelets (Field et al., Antiplatelet Therapy for Secondary Prevention of Stroke, Stroke, 4th Ed., Vancouver, 2015, Chapter 61, pp. 992-1013). Correspondingly, antiplatelet therapy is essential in the prevention of such events. After a first ischemic stroke, the risk of recurrent ischemic stroke is high (Tsao et al., see above). The current standard of care for secondary prevention of cerebrovascular events after non-cardioembolic ischemic stroke or TIA is single-agent antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT) with patient-level risk factor modification through increased 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 procedures directed by these guidelines, the residual risk of recurrent stroke remains high even when patients are treated with a combination of aspirin and clopidogrel (see Field et al., supra), and intensification of antiplatelet therapy and prolongation of treatment are limited by the increased risk of blood loss.

[0008] Researchers have tested various strategies to achieve better efficacy in patients, for example, using more potent or longer-duration antiplatelet therapy or a combination of antiplatelet and anticoagulant therapy. However, the long-term use of DAPT is not supported by evidence from randomized trials. The MATCH trial, which started up to 3 months after ischemic stroke and compared clopidogrel and aspirin versus clopidogrel alone as long-term treatment, showed no efficacy benefit over 18 months of treatment. The CHARISMA trial, which started any time up to 5 years after ischemic stroke or TIA and compared clopidogrel and aspirin versus aspirin alone for long-term treatment, showed no overall efficacy benefit over a median follow-up of 28 months.

[0009] The risk of recurrent stroke represents a significant and persistent 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).

[0010] Activated coagulation factor XI (FXIa) is a key serine protease involved in amplifying thrombin generation. Increased thrombin levels pose a risk of thrombosis. Inhibition of FXIa reduces thrombin generation and prevents thrombosis while maintaining normal hemostasis. FXIa contributes relatively modestly to hemostasis but is involved in the growth and stabilization of thrombi (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 in individuals born with FXI deficiency suggest that FXI(a) inhibition is a promising strategy for secondary stroke prevention (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).

[0011] Analysis of genetically determined FXI has shown that 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). Patients with congenital FXI deficiency (hemophilia C) have been shown to have a lower risk of stroke and venous thromboembolism (Gailani et al., Factor XI as a therapeutic target. Arterioscler Thromb Vasc Biol. 2016;36(7):1316-1322; Peyvandi, et al; European Network of Rare Bleeding Disorders Group. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders. J Thromb Haemost. 2012 Apr;10(4):615-621).Studies of deep vein thrombosis prophylaxis have demonstrated reduced venographically defined thrombosis and favorable blood loss profiles with reduced FXI levels or inhibition of FXIa (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). The potential for therapeutic efficacy with low risk of blood loss makes FXI and FXIa promising targets for secondary prevention of stroke.

[0012] The high human and economic costs of thromboembolic events highlight the need for newer and better therapeutic options for the management of thrombotic disorders. Developing agents with potent antithrombotic effects but minimal risk of blood loss presents a challenge, as this requires a fine balancing act in regulating the hemostatic process. Dual pathway inhibition with antiplatelet therapy and anticoagulants is another strategy to potentially improve efficacy in patients after recent ischemic stroke or TIA. Although data from the WARSS trial showed no benefit for the use of anticoagulation with warfarin versus antiplatelet therapy with aspirin alone, exploratory outcomes in the COMPASS trial in subjects with stable atherosclerotic vascular disease demonstrated that a dual-pathway mechanism using antiplatelet therapy and anticoagulants improved efficacy by reducing the risk of further ischemic stroke, which is more prone to massive blood loss (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, novel therapeutic options, such as oral formulations of FXIa inhibitors, are needed to prevent recurrent adverse vascular events in patients who have or have had ischemic stroke or transient ischemic attack (TIA).

[0013] Milvexian (BMS-986177 / JNJ-70033093) is a direct-acting, high-affinity inhibitor of human coagulation factor XIa (Dilger et al. Discovery of milvexian, a high-affinity, orally bioavailable inhibitor of factor XIa in clinical studies for antithrombotic therapy. J Med Chem 2022;65(3):1770-85). Milvexian is a compound represented by formula (I): [ka] It is a macrocyclic compound having the structure:

[0014] Milvexian has the 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 1 It is also known by the name H-3-aza-1(4,2)-pyridina-2(5,4)-pyrazolacyclonaphan-4-one.

[0015] Milvexian and methods for preparing milvexian are described in U.S. Patent No. 9,453,018, the entire contents of which are incorporated herein by reference. Solvates, crystalline forms, and amorphous forms of milvexian are also known in the art. See, for example, International Publication Nos. 2021207659 and 2022081473. Amorphous solid dispersion compositions of milvexian in one or more polymers are described in International Publication No. 2020210629, the entire contents of which are incorporated herein by reference.

[0016] The Milvexian clinical program included 4,114 participants exposed to the study intervention (Milvexian, placebo, or comparator). Of these, 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 severe blood loss were assessed as adverse drug reactions in the Milvexian clinical development program: gastrointestinal blood loss, procedural bleeding, blood loss due to 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).

[0017] Several other small molecule FXIa inhibitors have been investigated in several human trials for the secondary prevention of ischemic stroke in patients with or who have had an ischemic stroke or transient ischemic attack (TIA). For example, the PACIFIC-Stroke Phase II trial evaluated the safety and efficacy of three doses of asundexan (10 mg, 20 mg, or 50 mg once daily for 26 to 52 weeks) when added to standard-of-care antiplatelet therapy in patients after acute noncardioembolic ischemic stroke. Compared with placebo, asundexan added to antiplatelet therapy did not reduce the composite of covert brain infarction or ischemic stroke, nor did it increase the composite of major blood loss or clinically important non-major blood loss. (Shoamanesh et al., Factor XIa inhibition with asundexian after acute non-cardioembolic ischemic stroke (PACIFIC-Stroke): an international, randomized, double-blind, placebo-controlled, phase 2b trial, Lancet, Vol. 400, Issue 10357, pp. 997-1007, DOI: https: / / doi.org / 10.1016 / S0140-6736(22)01588-4). However, the PACIFIC-AMI and PACIFIC stroke trials did not have the statistical power to test the clinical efficacy of a 50 mg dose of asundexan administered once daily to reduce thrombotic events, such as ischemic vascular events, in patients after an acute heart attack or acute non-cardioembolic ischemic stroke, particularly due to its ability to reduce FXIa activity in the blood.

[0018] Small molecule FXIa inhibitors have been investigated in several human trials. 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). The PACIFIC-AF phase II trial evaluated the safety of Asundexian (20 mg, 50 mg QD, 12 weeks) compared with apixaban in patients with atrial fibrillation (Piccinini, JP; et al., Safety of the Oral Factor XIa Inhibitor Asundexian Compared with Apixaban in Patients with Atrial Fibrillation (PACIFIC-AF): a Multicenter, Randomized, Double-blind, Double-dummy, Dose-finding Phase 2 Study. Lancet, 2022, 399, 1383-1390). Summary of the Invention [Problem to be solved by the invention]

[0019] Therefore, vascular and thromboembolic diseases remain a leading cause of death and disability worldwide. Despite major advances in thrombus treatment, anticoagulant therapy is limited by residual blood loss and high thrombus risk for many patients. [Means for solving the problem]

[0020] (summary) The present disclosure provides a treatment regimen comprising the oral preparation of milvexian or its pharmaceutically acceptable salt or solvate, the potent and highly selective FXIa inhibitor as described above for the targeted regulation of coagulation through the inhibition of the contact pathway that inhibits activated factor XIa (FXIa), and one or more antiplatelet therapies for treating and preventing thrombus formation and embolism, thereby reducing the risk of adverse cerebrovascular events such as recurrent ischemic stroke in patients who have or have had ischemic stroke or transient ischemic attack (TIA), and maintaining hemostasis while reducing thrombin generation as a result of FXIa inhibition associated with the inhibition of platelet activation.Compared to antiplatelet therapy alone, the treatment regimen described herein provides a more favorable balance between the risk of ischemia and blood loss.

[0021] The present disclosure generally relates to methods for treating or preventing ischemic stroke in patients who have or have had an ischemic stroke or transient ischemic attack (TIA). More specifically, the present disclosure relates to the use of milvexian (or a pharmaceutically acceptable salt or solvate thereof) to reduce the risk of ischemic stroke in patients who have or have had an ischemic stroke or TIA, without a clinically significant increase in the risk of blood loss compared to placebo.

[0022] In a first aspect, the present disclosure provides a method for administering an amount of Milvexian (or its pharmaceutically acceptable salt or solvate) and DAPT to patients in an experimental group who have or have had ischemic stroke or TIA in a randomized, double-blind clinical trial, which effectively reduces the risk of ischemic stroke in the patient, and the risk in the experimental group is numerically reduced compared to the risk reduction caused by administering placebo and DAPT to patients in a placebo-controlled reference group.In some embodiments of the first aspect, a pharmaceutical composition comprising 25 mg, 50 mg, 100 mg or 200 mg of Milvexian (or its pharmaceutically acceptable salt or solvate) and a pharmaceutically acceptable carrier is administered twice a day in the experimental group. 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 once daily to the experimental group. In some embodiments of the first aspect, a pharmaceutical composition comprising 25 mg to 200 mg of Milvexian (or a pharmaceutically acceptable salt or solvate thereof) and a pharmaceutically acceptable carrier is administered twice daily to the experimental group.

[0023] In some aspects, the disclosure provides a method for preventing ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack, 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 daily, or in an amount of 25 mg to 200 mg twice daily, wherein milvexian (or a pharmaceutically acceptable salt or solvate thereof) is added in addition to standard of care.

[0024] In another aspect, the disclosure provides a method of reducing the risk of ischemic stroke in a human patient having or having had an ischemic stroke or transient ischemic attack, 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 daily or in an amount of 20 mg to 200 mg twice daily, wherein milvexian (or a pharmaceutically acceptable salt or solvate thereof) is added in addition to standard of care.

[0025] In some aspects, the disclosure provides a method for preventing ischemic stroke in a human patient who is having or has had an ischemic stroke or a transient ischemic attack, comprising administering to the human patient a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) 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 who is having or has had an ischemic stroke or a transient ischemic attack, compared to standard of care alone.

[0026] In some aspects, the disclosure provides a method of reducing the risk of ischemic stroke in a human patient who is having 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) in an amount of 25 mg once daily or in an amount of 25-200 mg twice daily and standard of care, wherein the regimen is effective in reducing the risk of ischemic stroke in the human patient who is having or has had an ischemic stroke or transient ischemic attack, compared to standard of care alone.

[0027] In some aspects, the disclosure provides a method of treating a human patient having or who has had an ischemic stroke or a transient ischemic attack, comprising administering to the human patient a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) 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 having or who has had an ischemic stroke or a transient ischemic attack, and wherein the human patient does not suffer from an ischemic stroke during the duration of the regimen.

[0028] In another aspect, the disclosure provides a method of treating a patient population, wherein patients in the population have or have had an ischemic stroke or transient ischemic attack, comprising administering to patients in the population a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) 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 an ischemic stroke within 90 days of starting the regimen is less than 5%.

[0029] In another aspect, the disclosure provides milvexian for use in a method for preventing 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) in an amount of 25 mg once daily, or in an amount of 25 mg to 200 mg twice daily; and standard of care.

[0030] In another aspect, the present disclosure provides milvexian (or a pharmaceutically acceptable salt or solvate thereof) for use in the prevention of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack, wherein the milvexian is administered in a regimen comprising once daily in an amount of 25 mg, or twice daily in an amount of 25 mg to 200 mg, along with standard of care.

[0031] In another aspect, the disclosure provides a composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) for use in a method for preventing 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 in conjunction with standard of care.

[0032] In another aspect, the disclosure provides milvexian (or a pharmaceutically acceptable salt or solvate thereof) for use in a method for reducing the risk of ischemic stroke in a human patient who is having or has had an ischemic stroke or a transient ischemic attack, the method comprising administering to the human patient a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) once daily in an amount of 25 mg, or twice daily in an amount of 25 mg to 200 mg, and standard of care; wherein the regimen is effective in reducing the risk of ischemic stroke in the human patient who is having or has had an ischemic stroke or a transient ischemic attack, compared to standard of care alone.

[0033] In another aspect, the present disclosure provides milvexian (or a pharmaceutically acceptable salt or solvate thereof) for use in reducing the risk of ischemic stroke in a human patient who is having or has had an ischemic stroke or a transient ischemic attack, wherein the milvexian is administered in a regimen comprising once daily in an amount of 25 mg, or twice daily in an amount of 25 mg to 200 mg, together with standard of care; wherein the regimen is effective in reducing the risk of ischemic stroke in a human patient who is having or has had an ischemic stroke or a transient ischemic attack, compared to standard of care alone.

[0034] In another aspect, the disclosure provides a composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) for use in a method for reducing the risk of ischemic stroke in a human patient who is having or has had an ischemic stroke or a transient ischemic attack, the composition being 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, together with standard of care, wherein the regimen is effective in reducing the risk of ischemic stroke in the human patient who is having or has had an ischemic stroke or a transient ischemic attack, compared to standard of care alone.

[0035] In another aspect, the disclosure provides milvexian (or a pharmaceutically acceptable salt or solvate thereof) for use in a method of treating a human patient who is having or has had an ischemic stroke or transient ischemic attack, comprising administering to the human patient a regimen comprising 25 mg once daily or 25 mg to 200 mg twice daily of milvexian (or a pharmaceutically acceptable salt or solvate thereof) and standard of care, wherein the human patient does not suffer from an ischemic stroke during the duration of the regimen.

[0036] In another aspect, the present disclosure provides milvexian (or a pharmaceutically acceptable salt or solvate thereof) for use in the treatment of a human patient who is having or has had an ischemic stroke or transient ischemic attack, wherein the milvexian is administered in a regimen comprising once daily in an amount of 25 mg or twice daily in an amount of 25 mg to 200 mg, along with standard of care, and wherein the human patient does not suffer from an ischemic stroke during the duration of the regimen.

[0037] In another aspect, the disclosure 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 who 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, along with standard of care, wherein the human patient does not suffer from an ischemic stroke during the duration of the regimen.

[0038] In another aspect, the disclosure provides milvexian (or a pharmaceutically acceptable salt or solvate thereof) for use in a method of treating a patient population, wherein patients in the population have or have had an ischemic stroke or transient ischemic attack, comprising administering to patients in the population a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) once daily in an amount of 25 mg, or twice daily in an amount of 25 mg to 200 mg, and standard of care; wherein the percentage of patients in the population who experience an ischemic stroke within 90 days of starting the regimen is less than 5%.

[0039] In another aspect, the present disclosure provides milvexian (or a pharmaceutically acceptable salt or solvate thereof) for use in the treatment of a human patient who is having or has had an ischemic stroke or transient ischemic attack, wherein the milvexian is administered in a regimen comprising once daily in an amount of 25 mg or twice daily in an amount of 25 mg to 200 mg, along with standard of care, wherein the percentage of patients in the population who experience an ischemic stroke within 90 days of starting the regimen is less than 5%.

[0040] In another aspect, the disclosure 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 who 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 in conjunction with standard of care, wherein the percentage of patients in the population who experience an ischemic stroke within 90 days of starting the regimen is less than 5%. [Brief explanation of the drawings]

[0041] [Figure 1] Figure 1 shows the coagulation pathway. Description: 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. [Figure 2]Figure 2 shows the AXIOMATIC-SSP study design described in Example 1. Legend: BID, twice daily; MRI, magnetic resonance imaging; QD, once daily; SOC, standard of care; PD, pharmacodynamics; PK, pharmacokinetics; LD, loading dose. *Within 48 hours of the index event and prior to randomization. †300 mg clopidogrel LD + 100 mg aspirin. ‡600 mg clopidogrel LD permitted. §Within 72 hours of the index event and up to 24 hours after randomization; if MRI is performed after randomization, clinical neuroimaging is recommended for eligibility assessment (to minimize protocol deviations if imaging results are negative). ¶Compared to the first or second dose of study drug. ||The 200 mg BID cohort will be added after 450 participants from the low dose have completed the 21-day visit. [Figure 3] Figure 3 shows the incidence of ischemic stroke and major blood loss by group in the clinical trial described in Example 1. Figure 3 illustrates that Milvexian numerically reduced the incidence of clinical ischemic stroke in patients with a history of ischemic stroke or high-risk TIA in all treatment groups at all doses except 200 mg BID. Doses from 25 to 100 mg BID showed a similar relative risk reduction (RRR) of approximately 30% for ischemic stroke compared to placebo, with a similar trend observed within 21 days (the intended treatment period for DAPT). Figure 3 also illustrates that the incidence of major blood loss (BARC types 3 and 5) for the 25 mg QD and BID doses of Milvexian was the same as placebo (0.6%). [Figure 4]Figure 4 illustrates a Kaplan-Meier plot of time to ischemic stroke and pending stroke for 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 illustrates the time from randomization to the first occurrence of any ischemic stroke event for pooled doses of Milvexian. The vertical line indicates the time point for evident clinical benefit (approximately 10 days, early evident benefit) for participants treated with Milvexian versus placebo. The reduction in the incidence of ischemic stroke events occurred relatively early after treatment initiation. The benefit conferred by Milvexian was maintained throughout the entire treatment period (e.g., 90 days) compared to placebo. [Figure 5] FIG. 5 illustrates a Kaplan-Meier plot of the time course of symptomatic ischemic stroke in the intention-to-treat population in the placebo, 25 mg QD, 25 mg BID, 50 mg BID, 100 mg BID, and 200 mg BID dose groups. [Figure 6] FIG. 6 illustrates the incidence (%, 95% CI) of symptomatic ischemic stroke and BARC type 3c blood loss in the placebo, 25 mg QD, 25 mg BID, 50 mg BID, 100 mg BID, and 200 mg BID dose groups. [Figure 7] Figure 7 illustrates the incidence (%, 95% CI) of the composite of symptomatic 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 all doses of Milvexian except 200 mg BID had lower rates of recurrent symptomatic ischemic stroke and TIA. Doses of 25 mg QD to 100 mg BID numerically reduced symptomatic ischemic stroke and TIA by 27% to 40% compared to placebo (within-group Wald 95% CI; 95% CIs for RRs are constructed using Wald confidence limits; clinical events are included up to day 90). [Figure 8A]8A shows the plasma concentration of Milvexian on Day 1 as a function of time after BID administration (2 x 100 mg) of a film-coated direct compression tablet of the present disclosure compared to the plasma concentration of Milvexian on Day 1 as a function of time after BID administration (2 x 100 mg) of a capsule containing Milvexian. See Example 2. [Figure 8B] 8B shows the plasma concentration of Milvexian on Day 5 as a function of time after BID administration (2 x 100 mg) of a film-coated direct compression tablet of the present disclosure compared to the plasma concentration of Milvexian on Day 5 as a function of time after BID administration (2 x 100 mg) of a capsule containing Milvexian. See Example 2. [Figure 8C] 8C shows the plasma concentration of Milvexian on Day 1 as a function of time after BID administration (1 x 25 mg) of a film-coated direct compression tablet of the present disclosure compared to the plasma concentration of Milvexian on Day 1 as a function of time after BID administration (1 x 25 mg) of a capsule containing Milvexian. See Example 2. [Figure 8D] 8D shows the plasma concentration of Milvexian on Day 5 as a function of time after BID administration (1×25 mg) of a film-coated direct compression tablet of the present disclosure compared to the plasma concentration of Milvexian on Day 5 as a function of time after BID administration (1×25 mg) of a capsule containing Milvexian. See Example 2. [Figure 9] Figure 9 shows the benefit-risk profile of milvexian in the Phase II AXIOMATIC-SSP trial. See Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0042] As used herein, "preventing" refers to reducing the risk of occurrence. In some embodiments, preventing encompasses eliminating the risk of occurrence (i.e., reducing the risk of occurrence to zero). Thus, "prevention" includes prophylactic treatments that aim to reduce the probability of occurrence of a clinical condition. In some embodiments, for any of the methods described herein, "preventing" encompasses reducing the recurrence of ischemic stroke or TIA.

[0043] In some embodiments, "preventing" is synonymous with "reducing the risk" or "reducing the incidence" of adverse cerebrovascular events (e.g., non-cardioembolic ischemic stroke). Reducing the risk or reducing the incidence means that there is a numerically and / or statistically significant reduction or decline in the incidence of adverse cerebrovascular events of at least 1% or more. Preferably, this reduction is 2% or more, 3% or more, 4% or more, 5% or more, 6% or more, 7% or more, 10% or more, 20% or more, 26% or more, 34% or more, 50% or more, 64% or more, or 74% or more. These reductions include confidence intervals of greater than or equal to 50%, greater than or equal to 75%, greater than or equal to 80%, greater than or equal to 90%, greater than or equal to 95%, greater than or equal to 98%, and greater than or equal to 99%, with confidence intervals of greater than or equal to 95% being preferred.

[0044] Within the scope of this disclosure, "prophylactic treatment" refers to the protective treatment of a condition by administering a therapeutically effective amount of Milvexian or a pharmaceutically acceptable salt or solvate thereof to a patient to reduce and / or minimize the risk of the condition and / or reduce the risk of recurrence. Patients may be selected for prophylactic treatment based on factors known to increase the risk of suffering from a clinical condition compared to the general population. For prophylactic treatment, the patient may or may not have a clinical condition. "Prophylactic treatment" treatment can be divided into (a) primary prophylactic treatment and (b) secondary prophylactic treatment. Primary prophylactic treatment is defined as treatment to reduce or minimize the risk of a condition in patients who have not yet exhibited a clinical condition, and secondary prophylactic treatment is defined as minimizing or reducing the risk of recurrence or a second occurrence of the same or similar clinical condition.

[0045] As used herein, the term "treating" refers to ameliorating the signs or symptoms of a disease or condition in a patient and / or preventing a disease or condition in a patient. As used herein, unless otherwise specified, terms such as "treating," "treatment," and the like include the management and care of a patient for the purpose of combating a disease, condition, or disorder, and include the administration of milvexian to prevent the onset of symptoms or complications, alleviate symptoms or complications, or eradicate the disease, condition, or disorder. Thus, "treating" or "treatment" encompasses the treatment of a disease state in a human, and includes (a) inhibiting the disease state, i.e., halting its progression, and / or (b) alleviating the disease state, i.e., causing reversal of the pathology.

[0046] As used herein, the term "patient population" refers to a particular group of individual patients suffering from an indication, for example, a group of patients in a particular treatment group of a clinical trial.

[0047] As used herein, a "risk factor" is a demographic factor that influences the underlying risk of an event independently of any drug treatment.

[0048] As used herein, the term "cerebrovascular accident" or "cerebrovascular disease" refers to a neurological problem resulting from an interruption in blood flow to the brain, resulting in damage or death of brain cells due to lack of oxygen. In some embodiments, cerebrovascular disease includes transient ischemic attack. In some embodiments, cerebrovascular disease includes stroke. How a stroke or transient ischemic attack affects the body depends on the exact location in the brain where the blood supply is interrupted.

[0049] As used herein, the term "stroke" (also called a cerebrovascular event) refers to an acute episode of neurological dysfunction resulting from a lack of blood flow and insufficient oxygen to the brain, resulting in the death of brain tissue (cerebral infarction). Strokes can be either ischemic or hemorrhagic. In an ischemic stroke, blood supply to a portion of the brain is cut off because a blood clot blocks a blood vessel, either due to a localized thrombus in an abnormal artery (atherosclerosis) or an embolus that forms upstream and travels through the bloodstream. In a hemorrhagic stroke, a blood vessel ruptures, disrupting normal blood flow and allowing blood to leak into and destroy an area of the brain. Most strokes begin suddenly and progress rapidly, causing brain damage within minutes (complete stroke). Rarely, a stroke continues to worsen over hours to days as the area of dying brain tissue steadily expands (progressive stroke). Ischemic stroke may be lacunar or non-lacunar in nature.If ischemic stroke is caused by arterial occlusion due to an embolism possibly resulting from a blood clot formed in the heart or one of its valves, the ischemic stroke may be a cardioembolic ischemic stroke.In some embodiments, the ischemic stroke is a non-cardioembolic ischemic stroke.In some embodiments, the terms "ischemic stroke" and "symptomatic ischemic stroke" may be used interchangeably.

[0050] In some embodiments, ischemic stroke refers to neurological deficits resulting from acute non-lacunar cerebral infarction detected by neuroimaging (CT or MRI) and associated with clinical symptoms.

[0051] In some embodiments, the ischemic stroke is further characterized by a National Institutes of Health Stroke Score (NIHSS) of ≦7.

[0052] In another embodiment, the ischemic stroke is further characterized by a National Institutes of Health Stroke Score (NIHSS) of 8-15.

[0053] In other embodiments, the ischemic stroke is further characterized by a National Institutes of Health Stroke Score (NIHSS) of ≦15.

[0054] In other embodiments, the ischemic stroke is further characterized by evidence of atherosclerotic plaque in the involved intracranial or carotid arteries, ulceration or thrombus in the feeding arteries, documented by imaging (Doppler ultrasound, CTA, MRA, catheter angiography).

[0055] 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 (mRS) of ≦3, ≦4, ≦5, or ≦6.

[0056] As used herein, the term "transient ischemic attack (TIA)" (also known as mini-stroke) refers to a temporary period of focal neurological symptoms similar to those in a stroke. A TIA does not cause lasting damage. A TIA is caused by a temporary reduction in blood supply to a part of the brain, which can last for several minutes. Similar to an ischemic stroke, a TIA occurs when a blood clot or debris reduces or blocks blood flow to a part of the nervous system (e.g., high-risk TIA).

[0057] In some embodiments, the TIA may be a "high-risk transient ischemic attack," which is the onset of acute neurological deficits due in part to focal cerebral ischemia by history or examination, accompanied by complete resolution of the deficit and no evidence of cerebral infarction on neuroimaging (CT or MRI).

[0058] In some embodiments, high-risk transient ischemic attack is further characterized by an ABCD2 score of ≧6 or is characterized by motor symptoms. See Rothwell PM, et al. A simple score (ABCD) to identify individuals at high early risk of stroke after transient ischemic attack. Lancet. 2005 Jul 2-8;366(9479):29-36.

[0059] In other embodiments, high-risk transient ischemic attacks are further characterized by evidence of atherosclerotic plaque in the involved intracranial or carotid arteries, ulceration or thrombus in the feeding arteries, documented by imaging (Doppler ultrasound, CTA, MRA, catheter angiography).

[0060] As used herein, " pharmaceutically acceptable salts " refers to derivatives that compounds are modified by forming their acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups, such as amines; and alkali or organic salts of acidic groups, such as carboxylic acids. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of parent compounds formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; as well as 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, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid. Pharmaceutically acceptable salts of milbexian can be synthesized using conventional chemical methods. Generally, such salts can be prepared by reacting milbexian with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, Pa. (1990), the disclosure of which is incorporated herein by reference.

[0061] As used herein, the term "standard of care" refers to a treatment regimen that is generally accepted by medical professionals as appropriate for a particular type of disease (e.g., stroke) and is widely used by medical professionals. The current standard of care for secondary prevention of recurrent cerebrovascular events after non-cardioembolic ischemic stroke or TIA is SAPT or DAPT, which involves modifying patient-level risk factors through increased physical activity and smoking cessation, as well as 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 short-term (21–90 days) DAPT with ASA and clopidogrel, followed by early initiation of antiplatelet therapy (ideally within 12–24 hours and at least 7 days of symptom onset) in patients with a recent mild (NIHSS score ≤3) noncardioembolic ischemic stroke or high-risk TIA (ABCD2 score ≥4) (Kleindorfer 2021). 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 as defined in the guidelines, 30-day DAPT with ticagrelor and ASA may be considered (Kleindorfer 2021). The ESO guidelines recommend 21 days of DAPT with ASA and clopidogrel followed by SAPT in mild non-cardioembolic ischemic stroke (NIHSS score ≤ 3) or high-risk TIA (ABCD2 score ≥ 4), or 30 days of DAPT with ASA and ticagrelor followed by SAPT in patients with mild to moderate non-cardioembolic ischemic stroke (NIHSS score ≤ 5) or high-risk TIA (ABCD2 score ≥ 6 or other high-risk characteristics) (Dawson 2021).In some embodiments, the standard of care for stroke is that commonly followed by clinicians for the treatment of ischemic stroke in human patients who have had a recent (within 0-48 hours) ischemic stroke or transient ischemic attack. See, e.g., AHA / ASA Guidelines, i.e., 2021 Guideline for the Prevention of Stroke in Patients With 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.

[0062] As used herein, the term "placebo medication" or "placebo" refers to standard of care as defined above. In some embodiments, "placebo medication" or "placebo" refers to an antiplatelet administration regimen including dual antiplatelet therapy (DAPT) or single antiplatelet therapy (SAPT). In some embodiments, "placebo medication" or "placebo" refers to DAPT including 75 mg of clopidogrel and 100 mg of aspirin (see Figure 2). In some aspects, a placebo is also referred to as a "control."

[0063] As used herein, "safe" means that the regimen provides a net clinical benefit, as determined by a regulatory agency, such that the reduced risk for ischemic stroke (or cardiovascular death or myocardial infarction) in humans compared to antiplatelet therapy alone outweighs the increased risk of adverse events, e.g., severe blood loss.

[0064] As used herein, "effective" means that the regimen provides a reduced risk and treatment for ischemic stroke (or cardiovascular death or myocardial infarction) when compared to antiplatelet therapy alone.

[0065] As used herein, the term "clinically proven" means that the safety and / or effectiveness of the regimen is demonstrated by clinical investigation, e.g., at least one clinical trial.

[0066] The absolute risk reduction (ARR) is the percentage of patients in the control group (i.e., not receiving the regimen) who had a poor outcome minus the percentage of patients in the treatment group (i.e., receiving the regimen) who had a poor outcome. For example, if the incidence in the control group is 20% (i.e., 20% of patients in the control group experience a poor outcome) and the incidence in the treatment group is 12% (i.e., 12% of patients experience a poor outcome), the absolute risk reduction (ARR) is 8% (i.e., 20% - 12%).

[0067] "Relative risk" (RR) is the rate of poor outcomes (e.g., suffering from an ischemic stroke) in the treatment group (i.e., the group receiving the regimen) divided by the rate of poor outcomes in the control group (i.e., the group not receiving the regimen). For example, if 20% of patients in the control group experience a poor outcome and 12% of patients in the treatment group experience a poor outcome, then RR = 0.12 / 0.20 = 0.6. Thus, an RR less than 1 represents a reduced risk.

[0068] As used herein, the term "relative risk reduction" (RRR) refers to how much a regimen reduces the risk of a poor outcome compared to a control group that did not receive the regimen. For example, if 20% of patients in the control group experience a poor outcome and 12% of patients in the treatment group experience a poor outcome, then RRR = (1 - RR) * 100%=[1-(0.12 / 0.20)] * 100%=0.4 * 100% = 40%. Therefore, an RRR greater than 0% represents a reduction in risk.

[0069] As used herein, the term "dose-dependent" means that the risk of occurrence is inversely proportional to the amount of Milvexian administered.

[0070] As used herein, the term "duration of a regimen" refers to the time during which a patient is administered a regimen.

[0071] As used herein, "Bleeding Academic Research Consortium (BARC) Type 3 criteria" refers to: a. overt blood loss and a decrease in hemoglobin of 3 to <5 g / dL (where the decrease in hemoglobin is associated with blood loss); transfusion with overt blood loss; b. overt blood loss and a decrease in hemoglobin of ≥ 5 g / dL (where the decrease in hemoglobin is associated with blood loss); cardiac tamponade; blood loss requiring surgical intervention for management; blood loss requiring IV vasoactive agents; or c. intracranial hemorrhage confirmed by autopsy, imaging, or lumbar puncture; intraocular hemorrhage compromising vision. See, e.g., Roxana Mehran, et al. Standardized Bleeding Definitions for Cardiovascular Clinical Trials, Circulation. 2011;123:2736-2747.

[0072] As used herein, "Bleeding Academic Research Consortium (BARC) Type 5 criteria" are: a. likely fatal blood loss; or b. definitely fatal blood loss (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.

[0073] As used herein, a "Bleeding Academic Research Consortium (BARC) Type 2 criterion" is: any clinically evident sign of bleeding that is "potentially actionable" and requires diagnostic testing, hospitalization, or treatment by a medical professional. See, e.g., Roxana Mehran, et al. Standardized Bleeding Definitions for Cardiovascular Clinical Trials, Circulation. 2011;123:2736-2747.

[0074] As used herein, the "ISTH criteria (major blood loss or clinically significant non-major blood loss (CRNM) criteria)" are as follows: ISTH massive blood loss in non-surgical patients has the following manifestations: i. fatal blood loss, and / or ii. Blood loss in critical areas or organs, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular areas with compartment syndrome; and / or iii. Hemoglobin level 20gL -1 (1.24 mmol L -1 ) or greater decrease or blood loss resulting in the transfusion of two or more units of whole blood or red blood cells is defined as having ISTH CRNM blood loss does not meet the criteria for the ISTH definition of major blood loss but meets the following criteria: i. Requiring medical intervention by a medical professional ii. Leading to hospitalization or an escalation in the level of care iii. Facilitate in-person (i.e., not solely by telephone or electronic communication) assessments Any signs or symptoms of bleeding (e.g., blood loss greater than would be expected for the clinical situation, including blood loss found by imaging alone) that meet at least one of the following criteria:

[0075] Use of approximation terms such as "approximately" or "about" when referring to, for example, an amount, a time period, a degree of effect, etc., will be understood to mean a number that may be within 5% (greater or less), or within 7.5% (greater or less), or within 10% (greater or less), or within 12.5% (greater or less), or within 15% (greater or less), or within 17.5% (greater or less), or within 20% (greater or less) of the specified number.

[0076] It is understood that the use of the term "equivalent" when referring to, for example, amount, time, degree of effect, etc., can mean a number within 0% (greater or less), or within 0.5% (greater or less); or within 1.0% (greater or less); or within 2.0% (greater or less); or within 3.0% (greater or less); or within 4.0% (greater or less); or within 5.0% (greater or less). In some embodiments, "equivalent" refers to a degree of effect measured by a number that is within 0% (greater or less) of a specific number; for example, the incidence (%) of major blood loss (BARC types 3 and 5) for Milvexian 25 mg QD and BID doses was the same as that of placebo (0.6%). In some embodiments, "equivalent" means not statistically different. Statistics can be interpreted with a two-sided significance of 0.05, and all confidence intervals are calculated at a two-sided confidence level of 95%.

[0077] As used herein, the term "intent-to-treat population" (ITT population) refers to (i) all randomized participants who were randomized to treatment, regardless of whether they received study drug. For the primary efficacy endpoint analysis, the population includes all randomized participants who had a primary endpoint event (new ischemic stroke during the study period or new hidden cerebral infarction detected by MRI at 90 days); or (ii) an evaluable MRI image at 90 days. All other efficacy analyses are performed on the ITT population during the double-blind treatment period. This population is analyzed according to the treatment assigned at randomization. All treated participants include all participants who received at least one dose of study drug. This is the primary population used in safety analyses, which are analyzed according to the treatment assigned at randomization.

[0078] As used herein, the term "patient who has or has had an ischemic stroke or transient ischemic attack" or "patients who have or have had an ischemic stroke or transient ischemic attack" refers to patients who have an ischemic stroke or transient ischemic attack before starting a treatment regimen including Milvexian (or a pharmaceutically acceptable salt or solvate thereof).

[0079] As used herein, the term "activated partial thromboplastin time (aPTT)" refers to the measurement of the intrinsic and terminal coagulation pathways of the coagulation cascade. It indicates the time, in seconds, for plasma to clot after the addition of phospholipids, intrinsic pathway activators, and calcium. The name "activated partial thromboplastin time" comes from the unique format of the test, in which only the phospholipid concentration (as opposed to the phospholipid and surfactant concentrations) was controlled, while the name "partial thromboplastin" was applied to phospholipid preparations at the time that accelerated clotting but did not correct the long clotting time of hemophilic plasma. The term "partial" refers to the presence of phospholipid but not tissue factor. Normal and reference ranges vary depending on the reagent and instrument combination, particularly the phospholipid composition.

[0080] In some embodiments, aPTT is measured as follows: plasma samples are incubated with Actin FS aPTT assay reagent, which contains a standard amount of phospholipids and a contact activator (ellagic acid) that activates the intrinsic coagulation pathway. After a 3-minute incubation, calcium chloride is added to initiate clotting, and the formation of a fibrin clot is measured optically. The time to clot formation (measured in seconds) is reported as the activated partial thromboplastin time (aPTT).

[0081] As used herein, "Factor XI clotting activity" is determined using a one-stage aPTT-based clotting time assay. Serial dilutions of normal pooled plasma are mixed with FXI-depleted plasma, and clotting times are measured according to standard aPTT protocols to establish a reference range. Subject test plasma is treated identically and compared to the reference plasma.

[0082] In some embodiments, factor XI clotting activity is measured as follows: Factor XI (FXI) activity is measured using a modified activated partial thromboplastin time (aPTT) on a Siemens BCS® XP analyzer using Actin FS (Siemens Healthcare). A six-point calibration curve (approximately 5-150%) was generated using a secondary calibrator (standard human plasma, Siemens Healthcare Diagnostics Inc.) with known concentrations of human FXI assigned by the manufacturer. An approximately 100% reference standard was diluted in saline on the BCS® XP analyzer to generate preselected calibration levels of FXI. The calibration curve was plotted with percent (%) FXI activity on the x-axis and clotting time in seconds on the y-axis. A log / lin regression curve fit was used. The sample to be tested was mixed with FXI-depleted plasma (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 to clot formation (measured optically) is compared to the time on a calibration curve. Samples are tested at a base dilution (1:10) prepared in saline with BCS® XP.

[0083] In some aspects, the disclosed methods are directed to preventing ischemic stroke in adult patients after acute ischemic stroke or high-risk transient ischemic attack. In other aspects, the disclosed methods are directed 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 "has or has had" and "have or have had."

[0084] In another aspect, the methods of the present disclosure are directed to the prevention of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack.

[0085] In some aspects, the methods of the present disclosure are directed to reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack.

[0086] In some aspects, the present disclosure provides methods of treating a human patient having or who has had an ischemic stroke or transient ischemic attack.

[0087] In another aspect, the disclosure provides a method of treating a patient population, wherein the patients have or have had an ischemic stroke or transient ischemic attack.

[0088] The methods of the present disclosure are performed on a human patient. In some embodiments, the human patient is female. In other embodiments, the human patient is male.

[0089] In some embodiments, the human patient is at least 40 years old.

[0090] In other embodiments, the human patient is at least 50 years of age.

[0091] In other embodiments, the human patient is at least 60 years of age.

[0092] In other embodiments, the human patient is at least 70 years of age.

[0093] In some aspects of the methods of the present disclosure, the patient is administered a regimen comprising Milvexian or a pharmaceutically acceptable salt or solvate thereof.

[0094] In some embodiments, the regimen comprises milvexian.

[0095] In some embodiments, the milvexian in the regimen comprises a solvate of milvexian.

[0096] In other embodiments, the regimen comprises a pharmaceutically acceptable salt of Milvexian.

[0097] In an embodiment of the method of the present disclosure, in which the regimen includes a solvate or pharmaceutically acceptable salt of Milvexian, the specified amount is based on Milvexian. That is, the amount of solvate or pharmaceutically acceptable salt in the regimen contains a specified amount of Milvexian. For example, a regimen including 50 mg of Milvexian (or a pharmaceutically acceptable salt or solvate thereof) refers to a regimen including either 50 mg of Milvexian or an amount of a pharmaceutically acceptable salt or solvate of Milvexian equivalent to 50 mg of Milvexian.

[0098] In some embodiments, the methods of the disclosure include administering to a human patient (or patients in a patient population) a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 12.5 mg to 200 mg twice daily and standard of care.

[0099] In some embodiments, the methods of the disclosure include administering to a human patient (or patients in a patient population) a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 25 mg once daily or 25-200 mg twice daily and standard of care.

[0100] In some embodiments, the regimen includes milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 12.5 mg twice daily and standard of care.

[0101] In some embodiments, the regimen includes milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 25 mg once daily and standard of care.

[0102] In some embodiments, the regimen includes milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 25 mg twice daily and standard of care, where the standard of care allows for a loading dose of an antiplatelet agent.

[0103] In other embodiments, the regimen includes milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 12.5 mg to 200 mg twice daily and standard of care. Thus, in some embodiments, the regimen includes, 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 twice daily in one of the following doses: 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg or 200mg, and standard of care.

[0104] In other embodiments, the regimen includes milvexian (or a pharmaceutically acceptable salt or solvate thereof) twice daily in an amount of 25 mg to 200 mg and standard of care. Thus, in some embodiments, the regimen includes milvexian (or a pharmaceutically acceptable salt or solvate thereof) twice daily 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, and standard of care.

[0105] In other embodiments, the regimen includes milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 12.5 mg to less than 200 mg twice daily and standard of care. Thus, in some embodiments, the regimen includes, 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 , 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg or 190mg twice daily, and standard of care.

[0106] In other embodiments, the regimen includes milvexian (or a pharmaceutically acceptable salt or solvate thereof) twice daily in an amount of 25 mg to less than 200 mg and standard of care. Thus, in some embodiments, the regimen includes milvexian (or a pharmaceutically acceptable salt or solvate thereof) twice daily 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, and standard of care.

[0107] In some embodiments of the disclosed methods, Milvexian is administered in an amount of 25 mg once daily.

[0108] In some embodiments of the disclosed methods, Milvexian is administered in an amount of 12.5 mg twice daily.

[0109] In some embodiments of the disclosed methods, Milvexian is administered in an amount of 25 mg twice daily.

[0110] In some embodiments of the disclosed methods, Milvexian is administered in an amount of 50 mg twice daily.

[0111] In some embodiments of the disclosed methods, Milvexian is administered in an amount of 100 mg twice daily.

[0112] In some embodiments of the disclosed methods, Milvexian is administered in an amount of 200 mg twice daily.

[0113] In some embodiments of the disclosed methods, Milvexian is administered in an amount of less than 200 mg twice daily.

[0114] In some aspects, the present disclosure is directed to a method of preventing or reducing the risk of ischemic stroke in a human patient having or having had an ischemic stroke or transient ischemic attack, comprising administering to the human patient (i) a pharmaceutical composition comprising Milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 25 mg twice daily, and (ii) a regimen comprising single-agent antiplatelet therapy (SAPT) or dual-agent antiplatelet therapy (DAPT).

[0115] In another aspect, the present disclosure is directed to milvexian for use in preventing or reducing the risk of ischemic stroke in a human patient who has previously had an ischemic stroke or transient ischemic attack, wherein the milvexian is administered in an amount of 25 mg twice daily in conjunction with single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT).

[0116] In some aspects, the regimen used in the disclosed methods comprises a standard of care.

[0117] In some embodiments, the standard of care includes antiplatelet therapy.

[0118] In some embodiments of any of the methods disclosed herein, an individualized standard of care, antiplatelet therapy (DAPT or SAPT) and a specific P2Y12 inhibitor (clopidogrel, ticagrelor, ticlopidine, cangrelor or prasugrel) are administered to the patient.

[0119] In some embodiments of any of the methods disclosed herein, the standard of care includes clopidogrel and aspirin for 21 days, followed by clopidogrel alone or aspirin alone from day 22 to day 90.

[0120] In some embodiments of any of the methods disclosed herein, the standard of care includes clopidogrel and aspirin for 90 days, or aspirin alone for 90 days.

[0121] In some embodiments of any of the methods disclosed herein, the standard of care includes clopidogrel and aspirin for 90 days.

[0122] In some embodiments of any of the methods disclosed herein, the standard of care includes ticagrelor alone for 90 days or aspirin alone for 90 days.

[0123] In some embodiments of any of the methods disclosed herein, the standard of care includes ticagrelor alone for 90 days.

[0124] In some embodiments of any of the methods disclosed herein, the standard of care includes ticagrelor and aspirin for 30 days.

[0125] In some embodiments of any of the methods disclosed herein, the antiplatelet therapy comprises a selective inhibitor of phosphodiesterase type 3 (PDE3), which inhibits clot formation by increasing cAMP. In some embodiments, the selective PDE3 inhibitor is cilostazol.

[0126] In some embodiments of any of the methods disclosed herein, the antiplatelet therapy comprises a dual nucleoside transport and PDE3 inhibitor that inhibits clot formation. In some embodiments, the dual nucleoside transport and PDE3 inhibitor is dipyridamole.

[0127] In some embodiments of any of the methods disclosed herein, the antiplatelet therapy comprises cilostazol or dipyridamole alone. In some embodiments of any of the methods disclosed herein, the antiplatelet therapy comprises cilostazol or a P2Y12 inhibitor. In some embodiments of any of the methods disclosed herein, the antiplatelet therapy comprises cilostazol or clopidogrel alone.

[0128] In some embodiments, the standard of care comprises single agent antiplatelet therapy (SAPT).

[0129] In some embodiments, the standard of care comprises dual antiplatelet therapy (DAPT).

[0130] In some embodiments, the standard of care includes dual antiplatelet therapy (DAPT) for 21 days followed by single antiplatelet therapy (SAPT).

[0131] In some aspects, the regimen used in the disclosed methods comprises milvexian and antiplatelet therapy.

[0132] In some embodiments, the antiplatelet therapy comprises single agent antiplatelet therapy.

[0133] In some embodiments, the single agent antiplatelet therapy is aspirin.

[0134] In some embodiments of single agent antiplatelet therapy, aspirin is administered in an amount of 50-150 mg daily, 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 daily.

[0135] In some embodiments of single agent antiplatelet therapy, aspirin is administered in an amount of 75-100 mg daily, for example, one of: 75 mg, 80 mg, 81 mg, 85 mg, 90 mg, 95 mg, or 100 mg daily.

[0136] In some embodiments of the single agent antiplatelet therapy, aspirin is administered in an amount of 75 mg daily.

[0137] In some embodiments of the mono-antiplatelet therapy, aspirin is administered in an amount of 81 mg daily.

[0138] In some embodiments of the single agent antiplatelet therapy, aspirin is administered in an amount of 100 mg daily.

[0139] In other embodiments, the single agent antiplatelet therapy is a P2Y12 inhibitor.

[0140] In some embodiments of the single agent antiplatelet therapy, the P2Y12 inhibitor is clopidogrel, ticagrelor, ticlopidine, cangrelor, or prasugrel.

[0141] In some embodiments of the single agent antiplatelet therapy, the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel.

[0142] In some embodiments of the single agent antiplatelet therapy, the P2Y12 inhibitor is clopidogrel.

[0143] In some embodiments of single agent antiplatelet therapy, clopidogrel is administered in an amount of 75 mg to 600 mg daily, for example, one of: 75 mg, 150 mg, 225 mg, 300 mg, 375 mg, 450 mg, 525 mg, or 600 mg daily.

[0144] In some embodiments of the single agent antiplatelet therapy, the P2Y12 inhibitor is ticagrelor.

[0145] In some embodiments of the single agent antiplatelet therapy, the P2Y12 inhibitor is ticlopidine.

[0146] In some embodiments of the single agent antiplatelet therapy, the P2Y12 inhibitor is cangrelor.

[0147] In some embodiments, the single agent antiplatelet therapy is ticlopidine.

[0148] In some embodiments, ticlopidine is administered in an amount of 250-500 mg daily, for example, 150 mg or 500 mg daily.

[0149] In other embodiments of the disclosed methods, the antiplatelet therapy comprises dual antiplatelet therapy.

[0150] In some embodiments, the dual antiplatelet therapy is aspirin and ticlopidine.

[0151] In some embodiments, the dual antiplatelet therapy is aspirin and a P2Y12 inhibitor.

[0152] In some embodiments of dual antiplatelet therapy, aspirin is administered in an amount of 50-150 mg daily, 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 daily.

[0153] In some embodiments of dual antiplatelet therapy, aspirin is administered in an amount of 75-100 mg daily, for example, one of: 75 mg, 80 mg, 81 mg, 85 mg, 90 mg, 95 mg, or 100 mg daily.

[0154] In some embodiments of dual antiplatelet therapy, aspirin is administered in an amount of 75 mg daily.

[0155] In some embodiments of the dual antiplatelet therapy, aspirin is administered in an amount of 81 mg daily.

[0156] In some embodiments of the dual antiplatelet therapy, aspirin is administered in an amount of 100 mg daily.

[0157] In some embodiments of the dual antiplatelet therapy, the P2Y12 inhibitor is clopidogrel, ticagrelor, ticlopidine, cangrelor, or prasugrel.

[0158] In some embodiments of the dual antiplatelet therapy, the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel.

[0159] In some embodiments of the dual antiplatelet therapy, the P2Y12 inhibitor is clopidogrel.

[0160] In some embodiments of dual antiplatelet therapy, clopidogrel is administered in an amount of 75 mg to 600 mg daily, for example, one of: 75 mg, 150 mg, 225 mg, 300 mg, 375 mg, 450 mg, 525 mg, or 600 mg daily.

[0161] In some embodiments of dual antiplatelet therapy, clopidogrel is administered as a loading dose.

[0162] In some embodiments, the loading dose is between 300-600 mg daily.

[0163] In some embodiments of the dual antiplatelet therapy, clopidogrel is administered in an amount of 75 mg daily.

[0164] In some embodiments of the dual antiplatelet therapy, clopidogrel is administered in an amount of 150 mg daily.

[0165] In some embodiments of the dual antiplatelet therapy, clopidogrel is administered in an amount of 225 mg daily.

[0166] In some embodiments of the dual antiplatelet therapy, clopidogrel is administered in an amount of 300 mg daily.

[0167] In some embodiments of the dual antiplatelet therapy, clopidogrel is administered in an amount of 375 mg daily.

[0168] In some embodiments of the dual antiplatelet therapy, clopidogrel is administered in an amount of 450 mg daily.

[0169] In some embodiments of the dual antiplatelet therapy, clopidogrel is administered in an amount of 525 mg daily.

[0170] In some embodiments of the dual antiplatelet therapy, clopidogrel is administered in an amount of 600 mg daily.

[0171] In some embodiments, the antiplatelet therapy includes Aggrenox, a combination of aspirin and dipyridamole (Persantin).

[0172] In some embodiments, the antiplatelet therapy comprises a combination of single-agent antiplatelet therapy and dual-agent antiplatelet therapy.

[0173] In some embodiments of the disclosed methods, the dual antiplatelet therapy is administered for a maximum of 21 consecutive days, and the single antiplatelet therapy is administered thereafter.

[0174] In another aspect, the regimen used in the methods of the present disclosure is effective in preventing ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack.

[0175] In another aspect, the regimens used in the methods of the present disclosure are effective in reducing the risk of ischemic stroke in human patients who have or have had an ischemic stroke or transient ischemic attack.

[0176] In another aspect, the regimens used in the methods of the present disclosure are safe and effective in preventing ischemic stroke in human patients who have or have had an ischemic stroke or transient ischemic attack.

[0177] In another aspect, the regimens used in the methods of the present disclosure are 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.

[0178] In another aspect, the regimens used in the methods of the present disclosure have been clinically proven safe and effective in preventing ischemic stroke in human patients who have or have had an ischemic stroke or transient ischemic attack.

[0179] In another aspect, the regimens used in the methods of the present disclosure have been clinically proven 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.

[0180] In some embodiments of the disclosed methods, the risk of ischemic stroke is reduced by the regimen compared to administration of a placebo with standard of care.

[0181] In some embodiments of the disclosed methods, the relative risk of ischemic stroke with the regimen 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 0.65, 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 0.7 to 0.65, about 0.7 to 0.65, about 0.7 to 0.7 0.6, about 0.65 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.

[0182] In some embodiments of the disclosed methods, the relative risk reduction of ischemic stroke with the regimen is about 10-40%, e.g., about 10-15%, about 15-20%, about 15-25%, about 15-30%, about 15-35%, about 20-25%, about 20-30%, about 20-35%, about 20-40%, about 25-30%, about 25-35%, about 25-40%, about 30-35%, about 30-40%, about 35-35%, about 35 ... 40%, about 35-40%, or one of 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% or about 40%.

[0183] In some embodiments of the disclosed methods, the absolute risk reduction of ischemic stroke with the regimen is about 1-10%, e.g., about 1-2%, about 1-3%, about 1-4%, about 1-5%, about 1-6%, about 1-7%, about 1-8%, about 1-9%, about 2-3%, about 2-4%, about 2-5%, about 2-6%, about 2-7%, about 2-8%, about 2-9%, about 2-10%, about 3-4%, about 3-5%, about 3-6%, about 3-7%, about 3-8%, about 3-8%, about 3-9%, about 4-10 ... about 9%, about 3-10%, about 4-5%, about 4-6%, about 4-7%, about 4-8%, about 4-9%, about 4-10%, about 5-6%, about 5-7%, about 5-8%, about 5-9%, about 5-10%, about 6-7%, about 6-8%, about 6-9%, about 6-10%, about 7-8%, about 7-9%, about 7-10%, about 8-9%, about 8-10% or about 9-10%, or one of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10%.

[0184] In some embodiments of the disclosed methods, the risk of ischemic stroke is reduced by the regimen compared to administration of a placebo with antiplatelet therapy.

[0185] In some embodiments of the disclosed methods, the relative risk of ischemic stroke with the regimen compared to placebo 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 0.7 to 0.65 ... 0.6, about 0.65 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.

[0186] In some embodiments of the disclosed methods, the relative risk reduction of ischemic stroke with the regimen compared to placebo with antiplatelet therapy is about 10-40%, e.g., about 10-15%, about 15-20%, about 15-25%, about 15-30%, about 15-35%, about 20-25%, about 20-30%, about 20-35%, about 20-40%, about 25-30%, about 25-35%, about 25-40%, about 30-35%, about 30-40%, about 35-35%, about 35 ... 40%, about 35-40%, or one of 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% or about 40%.

[0187] In some embodiments of the disclosed methods, the absolute risk reduction of ischemic stroke with the regimen compared to placebo with antiplatelet therapy is about 1-10%, e.g., about 1-2%, about 1-3%, about 1-4%, about 1-5%, about 1-6%, about 1-7%, about 1-8%, about 1-9%, about 2-3%, about 2-4%, about 2-5%, about 2-6%, about 2-7%, about 2-8%, about 2-9%, about 2-10%, about 3-4%, about 3-5%, about 3-6%, about 3-7%, about 3-8%, about 3-9%, about 3-10%, about 4-5%, about 4-6%, about 4-7%, about 4-8%, about 4-9%, about 4-10%, about 5-6%, about 5-7%, about 5-8%, about 5-9%, about 5-10%, about 6-7%, about 6-8%, about 6-9%, about 6-10%, about 7-8%, about 7-9%, about 7-10%, about 8-9%, about 8-10% or about 9-10%, or one of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10%.

[0188] In some embodiments of the disclosed methods, the amount of Milvexian administered reduces the risk of ischemic stroke in a dose-dependent manner.

[0189] In some aspects of the disclosed methods, the human patient administered the regimen does not suffer an ischemic stroke during the duration of the regimen.

[0190] In some embodiments, the regimen is between 4 weeks and 52 weeks in duration, e.g., 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.

[0191] 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.

[0192] In some embodiments, the regimen is administered chronically, i.e., the duration of the regimen is for the rest of the patient's life.

[0193] 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.

[0194] In some embodiments of the disclosed methods in which the regimen is administered to a patient population, the percentage of patients in the population who experience an ischemic stroke within 90 days of initiating the regimen is about 10% or less, e.g., 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. or less, about 8.8% 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, 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.

[0195] In some embodiments of the disclosed methods, the relative risk of blood loss by Bleeding Academic Research Consortium (BARC) Type 3 or Type 5 criteria with the regimen is 3 or less, for example, one or less 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, compared to a placebo with standard of care.

[0196] In some embodiments of the disclosed methods, the relative risk of blood loss by Bleeding Academic Research Consortium (BARC) type 3 or 5 criteria with the regimen is 3 or less, for example, 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 or less, compared to placebo with antiplatelet therapy.

[0197] In some embodiments of the disclosed methods, the relative risk of severe blood loss according to Bleeding Academic Research Consortium (BARC) type 3 or 5 criteria is independent of the amount of Milvexian administered.

[0198] In other embodiments of the disclosed methods, the human patient does not experience severe blood loss according to Bleeding Academic Research Consortium (BARC) type 3 and 5 criteria.

[0199] In some embodiments of the disclosed methods, the relative risk of bleeding by Bleeding Academic Research Consortium (BARC) Type 2 criteria with the regimen is 2.6 or less, for example, 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 or less, compared to placebo with standard of care.

[0200] In some embodiments of the disclosed methods, the relative risk of blood loss by Bleeding Academic Research Consortium (BARC) Type 2 criteria with the regimen is 2.6 or less, for example, 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 or less, compared to placebo with antiplatelet therapy.

[0201] In some embodiments of the disclosed methods, the relative risk of blood loss according to the Bleeding Academic Research Consortium (BARC) Type 2 criteria is independent of the amount of Milvexian administered.

[0202] In other embodiments of the disclosed methods, the human patient does not experience Bleeding Academic Research Consortium (BARC) Type 2 blood loss.

[0203] In some embodiments of the methods of the present disclosure, the relative risk of blood loss according to ISTH criteria (major blood loss or clinically significant non-major blood loss (CRNM)) with the regimen is 3 or less, for example, one or less 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, compared to placebo with standard of care.

[0204] In some embodiments of the disclosed methods, the relative risk of blood loss according to the ISTH criteria (major blood loss or clinically significant non-major blood loss (CRNM)) with the regimen is 3 or less, for example, one or less 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, compared to placebo with antiplatelet therapy.

[0205] In some embodiments of the disclosed methods in which the regimen is administered to a patient population, the patient receives a Bleeding Academic Research The percentage of patients in the population who experience severe blood loss according to the British Association for Clinical Research Consortium (BARC) Type 3 or 5 criteria is about 2% or less, e.g., 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.

[0206] In some embodiments of the disclosed methods, in which the regimen is administered to a patient population, the percentage of patients in the population who experience blood loss according to 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 2.2% or less, about 2.1% or less, about 2% or less. less than, 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.

[0207] In some embodiments of the disclosed methods in which the regimen is administered to a patient population, the percentage of patients in the population who experience blood loss according to ISTH criteria (major blood loss or clinically significant non-major blood loss (CRNM)) criteria within 90 days is about 5% or less, e.g., 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. 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 3.0% 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 It is one of 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.

[0208] In some embodiments of the disclosed methods, administration of the regimen reduces FXI clotting activity in the patient.

[0209] In some embodiments, factor XI (FXI) activity is measured using a modified activated partial thromboplastin time (aPTT) on a Siemens BCS® XP analyzer using Actin FS (Siemens Healthcare). A six-point calibration curve (approximately 5-150%) was generated using secondary calibrator samples (standard human plasma, Siemens Healthcare Diagnostics Inc.) with known concentrations of human FXI assigned by the manufacturer. Approximately 100% reference standards were diluted in saline on the BCS® XP analyzer to generate preselected calibration levels of FXI. The calibration curve was plotted with percent (%) FXI activity on the x-axis and clotting time in seconds on the y-axis. A log / lin regression curve fit was used. The sample to be tested was mixed with FXI-depleted plasma (containing less than 1% FXI and at least 75% of all other factors) to normalize all other factors. APTT reagent (Actin FS) was added, and the mixture was incubated. After incubation, calcium chloride is added to the mixture and the time to clot formation (measured optically) is compared to the time on a calibration curve. Samples are tested at a base dilution (1:10) prepared by BCS® XP in saline.

[0210] In some embodiments of the disclosed methods, administration of the regimen dose-dependently reduces FXI clotting activity in the patient relative to baseline.

[0211] In some embodiments of the disclosed methods, administration of the regimen reduces FXI clotting activity in the patient by about 7% to about 70% relative to baseline.

[0212] In other embodiments, in the methods of the present disclosure, administration of the regimen reduces FXI clotting activity in the patient by about 7% to about 43% relative to baseline.

[0213] In other embodiments, in the methods of the present disclosure, administration of the regimen reduces FXI clotting activity in the patient by about 7% to about 20% relative to baseline.

[0214] In some embodiments, in the methods of the disclosure, administration of the regimen increases a patient's FXI clotting activity 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%, 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 100%, about 101%, about 102%, about 1 The concentration of HCl is reduced by 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%.

[0215] In some embodiments, in the methods of the disclosure, administration of the regimen reduces FXI clotting activity in a patient 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% relative to baseline.

[0216] In other embodiments, in the methods of the present disclosure, administration of the regimen reduces the patient's FXI clotting activity 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% relative to baseline.

[0217] In other embodiments, in the methods of the disclosure, administration of the regimen reduces FXI clotting activity in the patient by the amount shown in Table 16 in Example 1.

[0218] 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.

[0219] In some embodiments of the disclosed methods, administration of the regimen results in a prolongation of activated partial thromboplastin time (aPTT) ranging from about 27% to about 115% relative to baseline.

[0220] In some embodiments of the disclosed methods, administration of the regimen results in an improvement of about 27% to about 115% relative to baseline, such as, for example, 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%, approximately 44%, approximately 45%, approximately 46%, approximately 47%, approximately 48%, approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55%, approximately 56%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, Approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 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.

[0221] In some embodiments of the disclosed methods, administration of the regimen results in a prolongation of activated partial thromboplastin time (aPTT) ranging from about 27% to about 64% relative to baseline.

[0222] In some embodiments of the disclosed methods, 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, 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 a patient's aPTT prior to any administration of the regimen.

[0223] In some embodiments of the disclosed methods, administration of the regimen results in an increase in activated partial thromboplastin time (aPTT) by the amount shown in Table 15 in Example 1.

[0224] In some embodiments, aPTT is determined as follows: plasma samples are incubated with a standard amount of phospholipids and the contact activator (ellagic acid) Actin FS aPTT assay reagent, which activates the intrinsic coagulation pathway. After a 3-minute incubation, calcium chloride is added to initiate clotting, and the formation of a fibrin clot is measured optically. The time to clot formation (measured in seconds) is reported as the activated partial thromboplastin time (aPTT).

[0225] In some aspects of the methods of the present disclosure, the pharmaceutical composition comprising Milvexian (or a pharmaceutically acceptable salt or solvate thereof) is a solid oral pharmaceutical composition.

[0226] In some embodiments, the dose of Milvexian or a pharmaceutically acceptable salt thereof administered may be formulated as an immediate release formulation.

[0227] In some embodiments, the administered dose of Milvexian may be formulated as an immediate release capsule formulation.

[0228] In some embodiments, the administered dose of Milvexian may be formulated as an amorphous solid dispersion composition of Milvexian in one or more polymers.

[0229] In some embodiments, the polymer in the amorphous solid dispersion is hypromellose acetate succinate (HPMCAS).

[0230] In some embodiments, the amorphous solid dispersion composition of milvexian in one or more polymers is prepared by spray drying.

[0231] In some embodiments, the amorphous solid dispersion composition of milvexian in one or more polymers comprises milvexian molecularly dispersed in one or more polymers.

[0232] In some embodiments of the disclosed methods, the solid oral pharmaceutical composition comprises a spray-dried amorphous solid dispersion (SDP) consisting essentially of milvexian free form and a pH-dependent enteric-soluble polymer.

[0233] In some embodiments, the SDP is a spray-dried amorphous solid dispersion prepared by the compositions and methods described in WO 2020210629. The SDP consists essentially of Milvexian free form and hypromellose acetate succinate (HPMCAS-MG) in a weight ratio of 3:1 (Milbexian:HPMCAS-MG).

[0234] In some embodiments of the disclosed methods, the SDP comprises milvexian free form and a pH-dependent enteric-soluble polymer in a weight ratio of 3:1 (milvexian:polymer).

[0235] In some embodiments of the disclosed methods, the pH-dependent enteric-soluble polymer is cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose ES grade (HPMC ES), hydroxypropyl methylcellulose acetate succinate (HPMC-AS) LF, LG, MF, MG or HF grades, such as Aqoat®, polyvinyl acetate phthalate (PVAP), such as Sureteric® and Opadry®, and shellac resins, such as SSB® Aquagold, or polyvinylpyrrolidone (PVP).

[0236] In some embodiments of the disclosed methods, the pH-dependent enteric-soluble polymer is hydroxypropylmethylcellulose-AS MG.

[0237] In some embodiments of the methods of the present disclosure, the solid oral pharmaceutical composition further comprises a binder, such as microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), or a combination thereof.

[0238] In some embodiments of the methods of the present disclosure, the solid oral pharmaceutical composition further comprises a filler, for example, lactose monohydrate.

[0239] In some embodiments of the methods of the present disclosure, the solid oral pharmaceutical composition further comprises a disintegrant.

[0240] In some embodiments of the methods of the present disclosure, the solid oral pharmaceutical composition further comprises a lubricant.

[0241] In some embodiments of the disclosed methods, the solid oral pharmaceutical composition is a tablet.

[0242] In some embodiments of the disclosed methods, the solid oral pharmaceutical composition is an immediate release tablet.

[0243] In some embodiments of the disclosed methods, the solid oral pharmaceutical composition is a direct compression tablet.

[0244] In some embodiments of the disclosed methods, the solid oral pharmaceutical composition is a roller-compressed tablet.

[0245] In some embodiments of the methods of the present disclosure, the solid oral pharmaceutical composition is a film-coated tablet.

[0246] In some embodiments of the disclosed methods, the film coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol-polyvinyl alcohol graft copolymer, and talc.

[0247] In some embodiments of the methods of the present disclosure, the film coating comprises a polyethylene glycol-polyvinyl alcohol graft copolymer.

[0248] In some embodiments, the film coating comprises Opadry.

[0249] In some embodiments, the film coating comprises polyvinyl alcohol, iron oxide, macrogol (PEG) polyvinyl alcohol graft copolymer, and talc.

[0250] In some embodiments, the film coating comprises a film coating material comprising OpadryQX 321A220063 Yellow, polyvinyl alcohol, iron oxide, macrogol (PEG) polyvinyl alcohol graft copolymer, and talc.

[0251] In some embodiments, the solid oral pharmaceutical composition is a tablet having the composition and / or characteristics shown in Table A: TIFF2025525915000003.tif123160

[0252] In some embodiments, where the solid pharmaceutical composition is a tablet, the tablet has a disintegration time in water of less than 20 seconds.

[0253] In other embodiments, where the solid pharmaceutical composition is a tablet, the tablet has a disintegration time in water of less than 15 seconds.

[0254] In other embodiments, where the solid pharmaceutical composition is a tablet, the tablet has a disintegration time in water of less than 10 seconds.

[0255] In some embodiments of the methods of the present disclosure, the solid pharmaceutical composition is a capsule.

[0256] In some aspects of the methods of the present disclosure, the human patient administered a pharmaceutical composition comprising Milvexian (or a pharmaceutically acceptable salt or solvate thereof) is unable to swallow a tablet dosage form.

[0257] In some embodiments of the disclosed methods, the solid oral pharmaceutical composition is dispersed in an aqueous medium to form an aqueous dispersion for administration.

[0258] In some embodiments of the disclosed methods, the solid oral pharmaceutical composition is a tablet that disperses in an aqueous medium to form an aqueous dispersion for administration.

[0259] 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.

[0260] In those embodiments in which the solid oral pharmaceutical composition is dispersed in an aqueous medium to form an aqueous dispersion, the aqueous medium is water, saline, phosphate buffer, vegetable juice, or fruit juice, including, for example, applesauce.

[0261] In those embodiments in which the solid oral pharmaceutical composition is a tablet dispersed in an aqueous medium to form an aqueous dispersion, the aqueous medium is water, saline, phosphate buffer, vegetable juice, or fruit juice, including, for example, applesauce.

[0262] In some embodiments of the disclosed methods, in which the solid oral pharmaceutical composition is dispersed in an aqueous medium to form an aqueous dispersion for administration, the aqueous dispersion is administered to a human patient via a nasogastric tube or a spoon.

[0263] In some embodiments of the disclosed methods, where the solid oral pharmaceutical composition is a tablet that disperses 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.

[0264] 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 Milvexian plasma half-life ranging from 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 Milvexian plasma half-life ranging from about 13 hours to about 16 hours between repeated doses. 1 / 2 ) as used herein refers to the formula t 1 / 2 =log e 2 / λz, where λz is the apparent terminal elimination rate constant 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 range of about 8 hours to about 16 hours. In some embodiments, the half-life (t 1 / 2 ) has an average value range of about 11 hours to about 16 hours. In a preferred embodiment, the half-life (t 1 / 2 ) has an average range of about 13 hours to about 16 hours.

[0265] In some embodiments of the disclosed methods, administration of a pharmaceutical composition comprising milvexin (or a pharmaceutically acceptable salt or solvate thereof) to a human patient results in a plasma concentration of milvexin that reaches steady state in about 3 to 6 days. As used herein, the term "steady state" refers to steady state plasma concentrations as defined by regulatory authorities such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

[0266] 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 plasma concentration of milvexian that reaches a steady state in about 3 days.

[0267] 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 plasma concentration of milvexian that reaches a steady state in about 4 days.

[0268] 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 plasma concentration of milvexian that reaches a steady state in about 5 days.

[0269] 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 plasma concentration of milvexian that reaches a steady state in about 6 days.

[0270] 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.

[0271] In some embodiments, the regimen used in the method of the present disclosure can be administered by using separate dosage forms for milvexian and antiplatelet therapy, or by using a combined dosage form containing both milvexian and antiplatelet therapy.These dosage forms further comprise pharmaceutically acceptable excipients.When a combined dosage form is used in a method in which milvexian is administered twice a day, the present invention includes using a combined dosage form for one of the daily administrations, and using a dosage form containing milvexian and no antiplatelet therapy as the second dosage form in the daily regimen.The present invention also includes using a combined dosage form containing antiplatelet therapy and milvexian for both twice a day administrations.

[0272] "Combination" for the purposes of the present invention means not only dosage forms containing all components (so-called fixed-dose combinations), and combination packs or kits which may contain the components separated from one another in packaging together with instructions for use according to one of the methods for treating or reducing the risk of a disorder or injury disclosed herein, but also components in which the components are administered simultaneously or sequentially, as long as they are employed for the prophylaxis and / or treatment of the same disease. The combinations of the present invention may also be used in the preparation of medicaments.

[0273] The individual active ingredients of the combination are known in the art and may be employed in dosages that are sub-therapeutically effective when used alone, without the other elements of the claimed combination.

[0274] Formulations of Milvexian are described in U.S. Pat. No. 9,453,018, WO 2021207659, WO 2022081473, and WO 2020210629, which are incorporated herein by reference in their entireties. Combination dosage forms including both Milvexian and antiplatelet therapy can be made following these examples of formulations of Milvexian, well-known formulations of antiplatelet therapy, and the understanding of one of ordinary skill in the art of pharmaceutical formulation.

[0275] The methods disclosed herein can be used in combination with additional cardiovascular medication(s). For example, the methods and combinations involving milvexian and antiplatelet therapy disclosed herein can be used with one or more of the following additional cardiovascular medications: (1) Angiotensin-converting enzyme (ACE) inhibitors, such as benazepril (Lotensin®), captopril (Capote®), enalapril (Vasotec®), fosinopril (Monopril®), lisinopril (Prinivil®, Zestril®), moexipril. (Univasc®), perindopril (Aceon®), quinapril (Accupril®), ramipril (Altace®), and trandolapril (Mavik®); (2) angiotensin II (AII) receptor antagonists, such as embusartan, losartan (Cozaar®), valsartan (Diovan®), irbesartan (Avapro®), candesartan (Atacand®), eprosartan (Teveten®) and telmisartan (Micardis®); (3) statins, such as atorvastatin (Lipitor®), rosuvastatin (Crestor®), and simvastatin (Zocor® and FloLipid®); (4) nicotinic acid, such as lovastatin (Advicor®), (5) cholesterol absorption inhibitors, such as ezetimibe / simvastatin (Vytorin®); and (6) beta-adrenergic blockers, such as acebutolol (Sectral®), atenolol (Tenormin®), betaxolol (Kerlone®), bisoprolol / hydrochlorothiazide (Ziac®), bisoprolol (Zebeta®), metoprolol (Lopressor®, Toprol® XL), nadolol (Corgard®), propranolol (Inderal®), and sotalol (Betapace®).

[0276] All conventional modes of administration are suitable for administering the regimens of the present disclosure, preferably orally, lingually, sublingually, bucally, rectally, topically, or parenterally (i.e., avoiding the intestinal tract, i.e., intravenously, intracardially, intradermally, subcutaneously, transdermally, intraperitoneally, or intramuscularly), preferably orally, for both milvexian and antiplatelet therapy.

[0277] In some aspects, the present disclosure provides milvexian (or a pharmaceutically acceptable salt or solvate thereof) for use in the methods disclosed herein.

[0278] In another aspect, the present disclosure provides a composition comprising Milvexian (or a pharmaceutically acceptable salt or solvate thereof) for use in the methods disclosed herein.

[0279] The present invention includes pharmaceutical products or dosage forms that contain milvexian, an antiplatelet therapy, or both milvexian and an antiplatelet therapy, in addition to non-toxic, inert, pharmaceutically suitable excipients and / or carriers. Also included are processes for producing these pharmaceutical products. These pharmaceutical products may further contain, in addition to milvexian, an antiplatelet therapy, or both milvexian and an antiplatelet therapy, an active pharmaceutical ingredient, such as a cardiovascular drug, as discussed herein, for use with the combinations and methods of use of the present invention.

[0280] As used herein, the term "dosage form" refers to a physical manifestation containing Milvexian and one or more pharmaceutically acceptable excipients that delivers a dose of Milvexian to a patient. In some embodiments, the amount of Milvexian in the dosage form is preferably 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 of a tablet, pill, capsule, powder, granule, sterile parenteral solution, or suspension; for oral, parenteral, intranasal, or sublingual administration. In some embodiments, the pharmaceutical product is prepared by the compositions and methods described in International Publication No. WO2020210629.

[0281] As used herein, the term "pharmaceutical product" refers to a dosage form containing Milvexian administered multiple times per day to a patient in an amount that results in about a 27% to about a 36% reduction in the incidence of 90-day clinical ischemic stroke events in the patient compared to a placebo group.

[0282] In some embodiments, the pharmaceutical product is a dosage form containing milvexian administered multiple times per day to a patient in an amount that results in a relative risk reduction of about 27% to about 36% in the occurrence of clinical ischemic stroke over a 90-day period compared to a placebo group with standard of care.

[0283] In some embodiments, the pharmaceutical product is a dosage form containing milvexin administered multiple times per day to a patient in an amount that results in a relative risk reduction of about 27% to about 36% in the occurrence of clinical ischemic stroke over a 90-day period compared to a placebo group with antiplatelet therapy.

[0284] In some embodiments, the amount of milvexian in the dosage form is less than about 20 mg to 200 mg.

[0285] In some embodiments, the amount of milvexian in the dosage form is less than about 25 mg to 200 mg.

[0286] In some embodiments, the amount of Milvexian in the dosage form is from about 25 mg to about 100 mg.

[0287] In some embodiments, the amount of Milvexian in the dosage form is from about 25 mg to about 50 mg.

[0288] In some embodiments, the amount of Milvexian in the dosage form is from about 75 mg to about 100 mg.

[0289] In some embodiments, the amount of Milvexian in the dosage form is about 20 mg.

[0290] In some embodiments, the amount of Milvexian in the dosage form is about 25 mg.

[0291] In some embodiments, the amount of Milvexian in the dosage form is about 50 mg.

[0292] In some embodiments, the amount of Milvexian in the dosage form is about 75 mg.

[0293] In some embodiments, the amount of Milvexian in the dosage form is about 100 mg.

[0294] In some embodiments, the amount of Milvexian in the dosage form is about 125 mg.

[0295] In some embodiments, the amount of Milvexian in the dosage form is about 150 mg.

[0296] In some embodiments, the amount of Milvexian in the dosage form is about 175 mg.

[0297] In some embodiments, the dosage form is administered twice daily to a patient at risk for clinical ischemic stroke.

[0298] In one embodiment, the present disclosure provides a twice-daily pharmaceutical product administered to a patient who has or has had an ischemic stroke or transient ischemic attack.

[0299] In some embodiments, for any of the pharmaceutical products described herein, the amount of milvexian in the pharmaceutical product in each administration ranges from about 25 mg to about 100 mg.

[0300] In some embodiments, for any of the pharmaceutical products described herein, the amount of milvexian in the pharmaceutical product in each administration is about 25 mg.

[0301] In some embodiments, for any of the pharmaceutical products described herein, the pharmaceutical product causes about a 30% relative risk reduction (RRR) in the occurrence of a clinical ischemic stroke event in patients relative to a placebo group, without an increase in blood loss.

[0302] In one embodiment, the disclosure provides a method for preventing adverse cerebrovascular or cardiovascular events in a human patient with atherosclerosis, comprising 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 combinations thereof; wherein the pharmaceutical composition is administered twice daily.

[0303] In some embodiments, the antiplatelet therapy is a P2Y12 inhibitor.

[0304] In some embodiments, the P2Y12 inhibitor is clopidogrel, ticagrelor, ticlopidine, cangrelor, or prasugrel.

[0305] In some embodiments, the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel.

[0306] In some embodiments, the antiplatelet therapy is aspirin.

[0307] In some embodiments, the human patient is treated with aspirin and clopidogrel combination therapy on days 1-21, followed by at least 90 days of aspirin monotherapy.

[0308] In some embodiments, the patient is treated with aspirin and / or clopidogrel without adjusting the milvexian dose.

[0309] In some embodiments, the adverse cerebrovascular or cardiovascular event comprises one or more of a stroke, a heart attack, or death.

[0310] In some embodiments, the adverse cerebrovascular or cardiovascular event occurs in an organ selected from the heart, brain, limbs, blood supply system, or blood vessels.

[0311] In some embodiments, the adverse cerebrovascular or 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.

[0312] In some embodiments, the adverse cerebrovascular event or adverse cardiovascular event comprises one or more major adverse limb events (MAVE) selected from the group consisting of MACE; major adverse limb events (MALE), including one or more selected from acute limb ischemia, chronic limb ischemia, or major amputation; symptomatic venous thromboembolic events, and combinations thereof.

[0313] In some embodiments, the adverse cerebrovascular or cardiovascular event is selected from the group consisting of arrhythmogenic cardiomyopathy (ACM), non-fatal myocardial infarction, ischemic stroke, and combinations thereof.

[0314] In some embodiments, the adverse cerebrovascular or cardiovascular event comprises cardiovascular mortality.

[0315] In some embodiments, the adverse cerebrovascular or cardiovascular event comprises arrhythmogenic cardiomyopathy (ACM).

[0316] In one embodiment, this disclosure provides a method for preventing adverse cardiovascular events in a human patient diagnosed with atherosclerosis, comprising administering to the human patient: (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) a regimen comprising an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and combinations thereof.

[0317] In some embodiments, the pharmaceutical composition is administered twice daily;

[0318] In some embodiments, the adverse cardiovascular event is one or more selected from the group consisting of all-cause mortality (ACM); cardiovascular (CV) mortality; myocardial infarction (MI); unstable angina (UA); "all stroke" or "any stroke" (ischemic, hemorrhagic, or of unknown cause); ischemic stroke; acute limb ischemia (ALI); major vessel (non-traumatic) lower limb amputation; symptomatic venous thromboembolism (VTE: (pulmonary embolism (PE), deep vein thrombosis (DVT)); ischemia-driven coronary revascularization; stent thrombosis; hospitalization for any reason classified as (1) planned or unplanned, (2) arterial or venous thrombotic event, or neither; and transient ischemic attack (TIA).

[0319] In some embodiments, administration of the regimen results in at least a 25% relative risk reduction (RRR) in the occurrence of symptomatic venous thromboembolism (VTE; pulmonary embolism (PE), deep vein thrombosis (DVT)) in patients without increased blood loss compared to a placebo group.

[0320] In some embodiments, the adverse cardiovascular event is one or more of CV death, MI, or ischemic stroke.

[0321] Provided is a method for reducing the incidence of one or more adverse thrombotic events selected from new ischemic stroke, MI, or all-cause mortality in a human patient diagnosed with atherosclerosis, comprising administering to the human patient: (i) a pharmaceutical composition comprising 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) a regimen comprising an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and combinations thereof; wherein the pharmaceutical composition is administered twice daily.

[0322] In some embodiments, administration of the regimen results in a relative risk of 0.85 or less versus placebo.

[0323] Provided is a method for preventing ischemic stroke in a human patient diagnosed with atherosclerosis, comprising administering to the human patient: (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) a regimen comprising an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and combinations thereof; wherein the pharmaceutical composition is administered twice daily.

[0324] In some embodiments, administration of the regimen results in at least a 25% relative risk reduction (RRR) in the occurrence of a clinical ischemic stroke event in patients relative to a placebo group, without an increase in blood loss.

[0325] In some embodiments, the clinical benefit of the regimen in reducing the incidence of clinical ischemic stroke is maintained throughout the 90-day treatment period.

[0326] In some embodiments, administration of the regimen reduces FXI clotting activity in the patient by about 7% to about 20% relative to baseline.

[0327] In some embodiments, administration of the regimen results in a prolongation of activated partial thromboplastin time (aPTT) ranging from about 27% to about 64% relative to baseline.

[0328] In some embodiments, administration does not result in a statistically significant increase in major blood loss complications.

[0329] 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 tablet has a disintegration time in water of less than 20 seconds.

[0330] In some embodiments, administration results in a milvexin plasma half-life ranging from about 13 hours to about 16 hours. In some embodiments, administration results in a milvexin plasma half-life ranging from about 13 hours to about 16 hours between repeat doses.

[0331] In some embodiments, administration results in a milvexin plasma concentration that reaches steady state in about 3 to 6 days.

[0332] In some embodiments, a pharmaceutical composition comprising Milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered without regard to the timing of food intake.

[0333] In some embodiments, the human patient is unable to swallow a tablet dosage form.

[0334] 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 a spoon. In some embodiments, the pharmaceutical composition is orally administered as an aqueous dispersion by dispersing the oral tablet in the aqueous medium for less than 1 minute.

[0335] In some embodiments of any of the pharmaceutical products described herein, the clinical benefit of the pharmaceutical product in reducing the incidence of clinical ischemic stroke is maintained throughout the 90-day treatment period.

[0336] The present disclosure is also directed to the following aspects: Embodiment 1. A method of preventing ischemic stroke in a human patient having or having 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) once daily in an amount of 25 mg, or twice daily in an amount of 12.5 mg to 200 mg, and standard of care; wherein the regimen is effective in preventing ischemic stroke in the human patient. Embodiment 2. A method of reducing the risk of ischemic stroke in a human patient who is having 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) in an amount of 25 mg once daily, or in an amount of 12.5 mg to 200 mg twice daily; and a standard of care; wherein the regimen is effective in reducing the risk of ischemic stroke in the human patient relative to a placebo with the standard of care. Embodiment 3. The method of embodiment 1 or embodiment 2, wherein the standard of care comprises antiplatelet therapy. Embodiment 4 The method of embodiment 3, wherein the antiplatelet therapy comprises single agent antiplatelet therapy. Embodiment 5 The method of embodiment 4, wherein the single agent antiplatelet therapy is aspirin. Embodiment 6 The method of embodiment 5, wherein the aspirin is administered in an amount of 75-100 mg daily. Embodiment 7 The method of embodiment 6, wherein the aspirin is administered daily in an amount of 75 mg. Embodiment 8 The method of embodiment 6, wherein the aspirin is administered daily in an amount of 81 mg. Embodiment 9 The method of embodiment 6, wherein the aspirin is administered daily in an amount of 100 mg. Embodiment 10 The method of embodiment 4, wherein the single agent antiplatelet therapy is a P2Y12 inhibitor. Embodiment 11 The method of embodiment 10, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel. Embodiment 12 The method of embodiment 11, wherein the P2Y12 inhibitor is clopidogrel. Embodiment 13 The method of embodiment 12, wherein clopidogrel is administered in an amount of 75 mg daily. Embodiment 14 The method of embodiment 4, wherein the single agent antiplatelet therapy is ticlopidine. Embodiment 15. The method of embodiment 14, wherein the ticlopidine is administered in an amount of 250-500 mg daily. Embodiment 16 The method of embodiment 3, wherein the antiplatelet therapy comprises dual antiplatelet therapy. Embodiment 17 The method of embodiment 16, wherein the dual antiplatelet therapy is aspirin and a P2Y12 inhibitor. Embodiment 18 The method of embodiment 17, wherein the aspirin is administered in an amount of 75 to 100 mg daily. Embodiment 19 The method of embodiment 18, wherein the aspirin is administered daily in an amount of 75 mg. Embodiment 20 The method of embodiment 18, wherein the aspirin is administered daily in an amount of 81 mg. Embodiment 21 The method of embodiment 18, wherein the aspirin is administered daily in an amount of 100 mg. Embodiment 22 The method of any of embodiments 17 to 21, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel. Embodiment 23 The method of embodiment 22, wherein the P2Y12 inhibitor is clopidogrel. Embodiment 24 The method of embodiment 23, wherein clopidogrel is administered daily in an amount of 75 mg. Embodiment 25 The method of embodiment 3, wherein the antiplatelet therapy comprises Aggrenox, a combination of aspirin and dipyridamole (persantin). Embodiment 26 The method of any one of embodiments 1 to 25, wherein Milvexian is administered once daily in an amount of 25 mg. Embodiment 27 The method of any one of embodiments 1 to 25, wherein Milvexian is administered in an amount of 25 mg twice daily. Embodiment 28 The method of any one of embodiments 1 to 25, wherein Milvexian is administered in an amount of 50 mg twice daily. Embodiment 29 The method of any one of embodiments 1 to 25, wherein Milvexian is administered in an amount of 100 mg twice daily. Embodiment 30 The method of any one of embodiments 1 to 25, wherein milvexian is administered in an amount of 200 mg twice daily. Embodiment 31 The method of any one of embodiments 1 to 25, wherein Milvexian is administered in an amount of less than 200 mg twice daily. Embodiment 32 The method of any one of embodiments 1 to 31, wherein the risk of ischemic stroke is reduced as compared to administration of a placebo with standard of care. Embodiment 33 The method of any one of embodiments 1 to 32, wherein the risk of ischemic stroke is reduced as compared to administration of a placebo with antiplatelet therapy. Embodiment 34. The method of embodiment 32 or embodiment 33, wherein the relative risk is about 0.9 to 0.6. Embodiment 35. The method of embodiment 32 or embodiment 33, wherein the relative risk reduction is about 10 to 40%. Embodiment 36 The method of any one of the preceding embodiments, wherein the risk of ischemic stroke is reduced in a dose-dependent manner with the amount of Milvexian administered. Embodiment 37. A method for preventing ischemic stroke in a human patient who is having 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) in an amount of 25 mg twice daily; and standard of care; wherein the regimen is effective in preventing ischemic stroke in the human patient. Embodiment 38. A method of reducing the risk of ischemic stroke in a human patient who is having 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) 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 a placebo with standard of care. Embodiment 39. The method of any one of embodiments 1 to 38, wherein the relative risk of blood loss according to Bleeding Academic Research Consortium (BARC) Type 3 and Type 5 criteria is 3 or less compared to placebo with standard of care. Embodiment 40. The method of any one of embodiments 1 to 39, wherein the relative risk of blood loss according to Bleeding Academic Research Consortium (BARC) Type 3 and Type 5 criteria is 3 or less compared to placebo with antiplatelet therapy. Embodiment 41. The method of any one of embodiments 1 to 40, wherein the risk of severe blood loss according to Bleeding Academic Research Consortium (BARC) Type 3 and Type 5 criteria is independent of the amount of Milvexian administered. Embodiment 42. The method of any one of embodiments 1 to 41, wherein the relative risk of blood loss according to Bleeding Academic Research Consortium (BARC) Type 2 criteria is 2.6 or less compared to placebo with standard of care. Embodiment 43. The method of any one of embodiments 1 to 42, wherein the relative risk of blood loss according to Bleeding Academic Research Consortium (BARC) Type 2 criteria is 2.6 or less compared to placebo with antiplatelet therapy. Embodiment 44. The method of any one of embodiments 1 to 43, wherein the risk of blood loss according to the Bleeding Academic Research Consortium (BARC) Type 2 criteria is independent of the amount of milvexian administered. Embodiment 45. The method of any one of embodiments 1 to 44, wherein the relative risk of blood loss according to ISTH criteria (major blood loss or clinically significant non-major blood loss (CRNM)) is 3 or less compared to placebo with standard of care. Embodiment 46. The method of any one of embodiments 1 to 45, wherein the relative risk of blood loss according to ISTH criteria (major blood loss or clinically significant non-major blood loss (CRNM)) compared to placebo with antiplatelet therapy is 3 or less. Embodiment 47. A method of treating a human patient having or having 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) 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, and the human patient does not suffer from an ischemic stroke during the duration of the regimen. Embodiment 48. A method of treating a human patient having or having 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) 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, and wherein the human patient does not suffer from an ischemic stroke during the duration of the regimen. Embodiment 49. The method of embodiment 47 or embodiment 48, wherein the standard of care comprises antiplatelet therapy. Embodiment 50. The method of embodiment 49, wherein the antiplatelet therapy comprises single-agent antiplatelet therapy. Embodiment 51 The method of embodiment 50, wherein the single agent antiplatelet therapy is aspirin. Embodiment 52. The method of embodiment 51, wherein the aspirin is administered daily in an amount of 75 to 100 mg. Embodiment 53 The method of embodiment 51, wherein the aspirin is administered daily in an amount of 75 mg. Embodiment 54 The method of embodiment 51, wherein the aspirin is administered daily in an amount of 81 mg. Embodiment 55 The method of embodiment 51, wherein the aspirin is administered daily in an amount of 100 mg. Embodiment 56 The method of embodiment 50, wherein the single agent antiplatelet therapy is a P2Y12 inhibitor. Embodiment 57 The method of embodiment 56, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel. Embodiment 58 The method of embodiment 57, wherein the P2Y12 inhibitor is clopidogrel. Embodiment 59 The method of embodiment 58, wherein clopidogrel is administered daily in an amount of 75 mg. Embodiment 60 The method of embodiment 50, wherein the single agent antiplatelet therapy is ticlopidine. Embodiment 61 The method of embodiment 60, wherein ticlopidine is administered in an amount of 250 to 500 mg daily. Embodiment 62 The method of embodiment 49, wherein the antiplatelet therapy comprises dual antiplatelet therapy. Embodiment 63 The method of embodiment 62, wherein the dual antiplatelet therapy is aspirin and a P2Y12 inhibitor. Embodiment 64 The method of embodiment 63, wherein the aspirin is administered daily in an amount of 75 to 100 mg. Embodiment 65 The method of embodiment 64, wherein the aspirin is administered daily in an amount of 75 mg. Embodiment 66 The method of embodiment 64, wherein the aspirin is administered daily in an amount of 81 mg. Embodiment 67 The method of embodiment 64, wherein the aspirin is administered daily in an amount of 100 mg. Embodiment 68 The method of any of embodiments 63 to 67, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel. Embodiment 69 The method of embodiment 68, wherein the P2Y12 inhibitor is clopidogrel. Embodiment 70 The method of embodiment 69, wherein clopidogrel is administered daily in an amount of 75 mg. Embodiment 71 The method of embodiment 49, wherein the antiplatelet therapy comprises Aggrenox, a combination of aspirin and dipyridamole (persantin). Embodiment 72 The method of any one of embodiments 47 or 49-71, wherein Milvexian is administered once daily in an amount of 25 mg. Embodiment 73. The method of any one of embodiments 47 to 71, wherein Milvexian is administered in an amount of 25 mg twice daily. Embodiment 74 The method of any one of embodiments 47 or 49-71, wherein Milvexian is administered in an amount of 50 mg twice daily. Embodiment 75. The method of any one of embodiments 47 or 49-71, wherein Milvexian is administered in an amount of 100 mg twice daily. Embodiment 76 The method of any one of embodiments 47 or 49-71, wherein Milvexian is administered twice daily in an amount of less than 200 mg. Embodiment 77 The method of any one of embodiments 47 or 49-71, wherein Milvexian is administered in an amount of 200 mg twice daily. Embodiment 78. The method of any one of embodiments 47 to 77, wherein the regimen is administered for at least 12 weeks. Embodiment 79. The method of any one of embodiments 47 to 77, wherein the regimen is administered for at least 24 weeks. Embodiment 80. The method of any one of embodiments 47 to 77, wherein the regimen is administered for at least 36 weeks. Embodiment 81 The method of any one of embodiments 47 to 77, wherein the regimen is administered for at least 48 weeks. Embodiment 82. The method of any one of embodiments 47 to 81, wherein the relative risk of blood loss according to Bleeding Academic Research Consortium (BARC) Type 3 and Type 5 criteria is 3 or less compared to placebo with standard of care. Embodiment 83. The method of any one of embodiments 47 to 81, wherein the relative risk of blood loss according to Bleeding Academic Research Consortium (BARC) Type 3 and Type 5 criteria is 3 or less compared to placebo with antiplatelet therapy. Embodiment 84. The method of any one of embodiments 47 to 81, wherein the risk of severe blood loss according to Bleeding Academic Research Consortium (BARC) Type 3 and Type 5 criteria is independent of the amount of Milvexian administered. Embodiment 85. The method of any one of embodiments 47 to 84, wherein the relative risk of blood loss according to the Bleeding Academic Research Consortium (BARC) Type 2 criteria is 2.6 or less compared to placebo with standard of care. Embodiment 86. The method of any one of embodiments 47 to 85, wherein the relative risk of blood loss according to Bleeding Academic Research Consortium (BARC) Type 2 criteria is 2.6 or less compared to placebo with antiplatelet therapy. Embodiment 87. The method of any one of embodiments 47 to 86, wherein the risk of blood loss according to the Bleeding Academic Research Consortium (BARC) Type 2 criteria is independent of the amount of milvexian administered. Embodiment 88. The method of any one of embodiments 47 to 87, wherein the relative risk of blood loss according to ISTH criteria (major blood loss or clinically significant non-major blood loss (CRNM)) is 3 or less compared to placebo with standard of care. Embodiment 89. The method of any one of embodiments 47 to 88, wherein the relative risk of blood loss according to ISTH criteria (major blood loss or clinically significant non-major blood loss (CRNM)) compared to placebo with antiplatelet therapy is 3 or less. Embodiment 90. The method of any one of embodiments 47 to 88, wherein the human patient does not experience blood loss according to Bleeding Academic Research Consortium (BARC) Type 3 and Type 5 criteria. Embodiment 91. A method of treating a patient population, wherein patients in the population have or have had an ischemic stroke or transient ischemic attack, comprising administering to patients in the population a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) 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 starting the regimen is less than 10%. Embodiment 92. A method of treating a patient population, wherein the patients have or have had an ischemic stroke or transient ischemic attack, comprising administering to patients in the population a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 25 mg twice daily; and standard of care; wherein the percentage of patients in the population who experience an ischemic stroke within 90 days of starting the regimen is less than 10%. Embodiment 93. The method of embodiment 91 or embodiment 92, wherein the percentage of patients in the population who experience an ischemic stroke within 90 days of starting the regimen is less than 4%. Embodiment 94. The method of any one of embodiments 91 to 93, wherein the standard of care comprises antiplatelet therapy. Embodiment 95. The method of embodiment 94, wherein the antiplatelet therapy is a single-agent antiplatelet therapy. Embodiment 96 The method of embodiment 95, wherein the single agent antiplatelet therapy is aspirin. Embodiment 97. The method of embodiment 96, wherein aspirin is administered daily in an amount of 75 to 100 mg. Embodiment 98. The method of embodiment 97, wherein aspirin is administered daily in an amount of 75 mg. Embodiment 99. The method of embodiment 97, wherein aspirin is administered daily in an amount of 81 mg. Embodiment 100. The method of embodiment 97, wherein the aspirin is administered daily in an amount of 100 mg. Embodiment 101. The method of embodiment 95, wherein the single agent antiplatelet therapy is a P2Y12 inhibitor. Embodiment 102 The method of embodiment 101, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel. Embodiment 103 The method of embodiment 102, wherein the P2Y12 inhibitor is clopidogrel. Embodiment 104 The method of embodiment 103, wherein clopidogrel is administered daily in an amount of 75 mg. Embodiment 105 The method of embodiment 95, wherein the single agent antiplatelet therapy is ticlopidine. Embodiment 106 The method of embodiment 105, wherein ticlopidine is administered daily in an amount of 250 to 500 mg. Embodiment 107. The method of embodiment 94, wherein the antiplatelet therapy is dual antiplatelet therapy. Embodiment 108. The method of embodiment 107, wherein the dual antiplatelet therapy is aspirin and a P2Y12 inhibitor. Embodiment 109. The method of embodiment 108, wherein the aspirin is administered daily in an amount of 75 to 100 mg. Embodiment 110. The method of embodiment 109, wherein the aspirin is administered daily in an amount of 75 mg. Embodiment 111 The method of embodiment 109, wherein the aspirin is administered daily in an amount of 81 mg. Embodiment 112 The method of embodiment 109, wherein the aspirin is administered daily in an amount of 100 mg. Embodiment 113 The method of any of embodiments 108 to 112, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel. Embodiment 114 The method of embodiment 113, wherein the P2Y12 inhibitor is clopidogrel. Embodiment 115 The method of embodiment 114, wherein clopidogrel is administered daily in an amount of 75 mg. Embodiment 116 The method of embodiment 94, wherein the antiplatelet therapy comprises Aggrenox, i.e., a combination of aspirin and dipyridamole (persantin). Embodiment 117. The method of any one of embodiments 91 or 93-116, wherein Milvexian is administered once daily in an amount of 25 mg. Embodiment 118. The method of any one of embodiments 91 to 116, wherein Milvexian is administered in an amount of 25 mg twice daily. Embodiment 119. The method of any one of embodiments 91 or 93 to 116, wherein Milvexian is administered in an amount of 50 mg twice daily. Embodiment 120. The method of any one of embodiments 91 or 93-116, wherein Milvexian is administered in an amount of 100 mg twice daily. Embodiment 121 The method of any one of embodiments 91 or 93-116, wherein Milvexian is administered twice daily in an amount of less than 200 mg. Embodiment 122. The method of any one of embodiments 91 or 93-116, wherein Milvexian is administered in an amount of 200 mg twice daily. Embodiment 123. The method of any one of embodiments 91-122, wherein the percentage of patients in the population experiencing severe blood loss according to Bleeding Academic Research Consortium (BARC) type 3 or 5 criteria within 90 days is about 2% or less. Embodiment 124. The method of any one of embodiments 91-122, wherein the percentage of patients in the population experiencing blood loss according to Bleeding Academic Research Consortium (BARC) Type 2 criteria within 90 days is about 3.5% or less. Embodiment 125. The method of any one of embodiments 91-122, wherein the percentage of patients in the population experiencing blood loss according to ISTH criteria (major blood loss or clinically significant non-major blood loss (CRNM) criteria) within 90 days is about 5% or less. Embodiment 126. A method for preventing acute ischemic stroke or ischemic stroke following a high-risk transient ischemic attack in an adult patient, comprising administering to the adult patient a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 25 mg once daily or in an amount of 12.5 mg to 200 mg twice daily. Embodiment 127. A method for reducing the risk of ischemic stroke following acute ischemic stroke or a high-risk transient ischemic attack in an adult patient, comprising administering to the adult patient a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 25 mg once daily or in an amount of 12.5 mg to 200 mg twice daily. Embodiment 128. A method for preventing acute ischemic stroke or ischemic stroke following a high-risk transient ischemic attack in an adult patient, comprising administering to the adult patient a regimen comprising Milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 25 mg twice daily. Embodiment 129. A method for reducing the risk of acute ischemic stroke or ischemic stroke following a high-risk transient ischemic attack in an adult patient, comprising administering to the adult patient a regimen comprising Milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 25 mg twice daily. Embodiment 130. The method of any one of embodiments 126 to 129, further comprising administering a standard of care to the adult patient. Embodiment 131. The method of embodiment 130, wherein the standard of care comprises antiplatelet therapy. Embodiment 132. The method of embodiment 131, wherein the antiplatelet therapy comprises single-agent antiplatelet therapy. Embodiment 133 The method of embodiment 132, wherein the single agent antiplatelet therapy is aspirin. Embodiment 134. The method of embodiment 133, wherein the aspirin is administered daily in an amount of 75 to 100 mg. Embodiment 135 The method of embodiment 134, wherein the aspirin is administered daily in an amount of 75 mg. Embodiment 136 The method of embodiment 134, wherein the aspirin is administered daily in an amount of 81 mg. Embodiment 137 The method of embodiment 134, wherein the aspirin is administered daily in an amount of 100 mg. Embodiment 138 The method of embodiment 132, wherein the single agent antiplatelet therapy is a P2Y12 inhibitor. Embodiment 139 The method of embodiment 138, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel. Embodiment 140 The method of embodiment 139, wherein the P2Y12 inhibitor is clopidogrel. Embodiment 141 The method of embodiment 140, wherein clopidogrel is administered daily in an amount of 75 mg. Embodiment 142 The method of embodiment 132, wherein the single agent antiplatelet therapy is ticlopidine. Embodiment 143. The method of embodiment 142, wherein ticlopidine is administered in an amount of 250 to 500 mg daily. Embodiment 144. The method of embodiment 131, wherein the antiplatelet therapy comprises dual antiplatelet therapy. Embodiment 145. The method of embodiment 144, wherein the dual antiplatelet therapy is aspirin and a P2Y12 inhibitor. Embodiment 146. The method of embodiment 145, wherein aspirin is administered daily in an amount of 75 to 100 mg. Embodiment 147. The method of embodiment 146, wherein the aspirin is administered daily in an amount of 75 mg. Embodiment 148. The method of embodiment 146, wherein the aspirin is administered daily in an amount of 81 mg. Embodiment 149. The method of embodiment 146, wherein the aspirin is administered daily in an amount of 100 mg. Embodiment 150 The method of any of embodiments 145 to 149, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel. Embodiment 151 The method of embodiment 150, wherein the P2Y12 inhibitor is clopidogrel. Embodiment 152 The method of embodiment 151, wherein clopidogrel is administered daily in an amount of 75 mg. Embodiment 153 The method of embodiment 131, wherein the antiplatelet therapy comprises Aggrenox, i.e., a combination of aspirin and dipyridamole (persantin). Embodiment 154. The method of any one of embodiments 126, 127, or 130-153, wherein Milvexian is administered once daily in an amount of 25 mg. Embodiment 155. The method of any one of embodiments 126 to 153, wherein Milvexian is administered in an amount of 25 mg twice daily. Embodiment 156. The method of any one of embodiments 126, 127, or 130-153, wherein Milvexian is administered in an amount of 50 mg twice daily. Embodiment 157. The method of any one of embodiments 126, 127, or 130-153, wherein Milvexian is administered in an amount of 100 mg twice daily. Embodiment 158. The method of any one of embodiments 126, 127, or 130-153, wherein Milvexian is administered in an amount of 200 mg twice daily. Embodiment 159. The method of any one of embodiments 126, 127, or 130-153, wherein Milvexian is administered twice daily in an amount of less than 200 mg. Embodiment 160. The method of any one of embodiments 126 to 159, wherein the risk of ischemic stroke is reduced compared to administration of a placebo with standard of care. Embodiment 161 The method of any one of embodiments 126 to 160, wherein the risk of ischemic stroke is reduced compared to administration of a placebo with antiplatelet therapy. Embodiment 162. The method of embodiment 160 or embodiment 161, wherein the relative risk is about 0.9 to 0.6. Embodiment 163. The method of embodiment 160 or embodiment 161, wherein the relative risk reduction is about 10 to 40%. Embodiment 164. The method of any one of embodiments 126 to 163, wherein the risk of ischemic stroke is reduced in a dose-dependent manner with the amount of milvexian administered. Embodiment 165. The method of any one of embodiments 126 to 164, wherein the relative risk of blood loss according to Bleeding Academic Research Consortium (BARC) Type 3 and Type 5 criteria is 3 or less compared to placebo with standard of care. Embodiment 166. The method of any one of embodiments 126 to 165, wherein the relative risk of blood loss according to Bleeding Academic Research Consortium (BARC) Type 3 and Type 5 criteria is 3 or less compared to placebo with antiplatelet therapy. Embodiment 167. The method of any one of embodiments 126 to 166, wherein the risk of severe blood loss according to Bleeding Academic Research Consortium (BARC) Type 3 and Type 5 criteria is independent of the amount of Milvexian administered. Embodiment 168. The method of any one of embodiments 126 to 167, wherein the relative risk of blood loss according to the Bleeding Academic Research Consortium (BARC) Type 2 criteria is 2.6 or less compared to placebo with standard of care. Embodiment 169. The method of any one of embodiments 126 to 167, wherein the relative risk of blood loss according to Bleeding Academic Research Consortium (BARC) Type 2 criteria is 2.6 or less compared to placebo with antiplatelet therapy. Embodiment 170. The method of any one of embodiments 126 to 169, wherein the risk of blood loss according to the Bleeding Academic Research Consortium (BARC) Type 2 criteria is independent of the amount of milvexian administered. Embodiment 171. The method of any one of embodiments 126 to 170, wherein the relative risk of blood loss according to ISTH criteria (major blood loss or clinically significant non-major blood loss (CRNM)) is 3 or less compared to placebo with standard of care. Embodiment 172. The method of any one of embodiments 126 to 171, wherein the relative risk of blood loss according to ISTH criteria (major blood loss or clinically significant non-major blood loss (CRNM)) is 3 or less compared to placebo with antiplatelet therapy. Aspect 173. A pharmaceutical product administered twice daily to patients who have or have had an ischemic stroke or transient ischemic attack. Embodiment 174. The pharmaceutical product of embodiment 173, wherein the amount of Milvexian in each administration ranges from about 25 mg to about 100 mg. Embodiment 175. The pharmaceutical product of embodiment 174, wherein the amount of Milvexian in each administration is about 25 mg. Embodiment 176. The pharmaceutical product of any one of embodiments 173 to 175, wherein the pharmaceutical product causes a relative risk reduction (RRR) of about 30% in the occurrence of a clinical ischemic stroke event in the patient relative to a placebo group, without an increase in blood loss. Embodiment 177. The pharmaceutical product of any one of embodiments 173 to 176, wherein the clinical benefit of the pharmaceutical product in reducing the incidence of clinical ischemic stroke is maintained throughout the 90-day treatment period. Embodiment 178 The method of any one of embodiments 1 to 172, wherein administration of the regimen reduces FXI clotting activity in the patient by about 7% to about 20% relative to baseline. Embodiment 179. The method of any one of embodiments 1 to 172 or 178, wherein administration of the regimen results in a prolongation of activated partial thromboplastin time (aPTT) ranging from about 27% to about 64% relative to baseline. Embodiment 180. The method of any one of embodiments 1-172 or 178-179, wherein the administration does not result in a statistically significant increase in major blood loss complications. Embodiment 181 The method of any one of embodiments 1 to 172 or 178 to 180, wherein Milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered in a pharmaceutical composition that is a solid oral pharmaceutical composition. Embodiment 182. The method of embodiment 181, wherein the solid oral pharmaceutical composition is a tablet. Embodiment 183. The method of embodiment 182, wherein the tablet is an immediate-release tablet. Embodiment 184. The method of embodiment 182 or embodiment 183, wherein the tablet has a disintegration time in water of less than 20 seconds. Embodiment 185. The method of any one of embodiments 1 to 172 or 178 to 184, wherein the administration results in a milvexian plasma half-life ranging from about 13 hours to about 16 hours. Embodiment 186 The method of any one of embodiments 1 to 172 or 178 to 185, wherein the administration results in a milvexin plasma concentration that reaches a steady state in about 3 to 6 days. Embodiment 187. The method of any one of embodiments 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. Embodiment 188. The method of any one of embodiments 1-172 or 178-187, wherein the human patient is unable to swallow the tablet dosage form. Embodiment 189. The method of any one of embodiments 182 to 188, wherein the tablet is dispersed in an aqueous medium to form an aqueous dispersion. Embodiment 190. The method of embodiment 189, wherein the aqueous medium is water, saline, phosphate buffer, vegetable juice, or fruit juice, including, for example, applesauce. Embodiment 191 The method of embodiment 189 or embodiment 190, wherein the aqueous dispersion is administered to the human patient via a nasogastric tube or a spoon. Embodiment 192 The method of any one of embodiments 182 to 191, wherein Milvexian is orally administered as an aqueous dispersion by dispersing an oral tablet in an aqueous medium for less than 1 minute. Embodiment 193. A method for preventing or reducing the risk of ischemic stroke in a human patient who is having or has had an ischemic stroke or transient ischemic attack, comprising administering to the human patient (i) a pharmaceutical composition comprising Milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 25 mg twice daily, and (ii) a regimen comprising single-agent antiplatelet therapy (SAPT) or dual-agent antiplatelet therapy (DAPT), wherein the method achieves at least one of the following efficacy outcomes: (i) a relative risk for ischemic stroke of about 0.6 to about 0.9 compared to placebo dosing; (ii) a numerical reduction in the absolute risk of ischemic stroke relative to placebo dosing; (iii) a Kaplan-Meier ratio (Kaplan-Meier ratio) for ischemic stroke compared to placebo dosing. (iv) a numerical reduction in the percentage of patients with ischemia relative to placebo medication; or (v) achieving a relative risk reduction for ischemic stroke of about 10% to about 40% compared to placebo medication. Embodiment 194. A method for preventing or reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack, comprising administering to the human patient (i) a pharmaceutical composition comprising Milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 25 mg twice daily, and (ii) a regimen comprising single-agent antiplatelet therapy (SAPT) or dual-agent antiplatelet therapy (DAPT), preferably achieving a relative risk for ischemic stroke of about 0.6 to about 0.9 compared to placebo dosing. Embodiment 195. A method for reducing the risk of ischemic stroke in a human patient who is having or has had an ischemic stroke or transient ischemic attack, comprising administering to the human patient (i) a pharmaceutical composition comprising Milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 25 mg twice daily, and (ii) a regimen comprising single-agent antiplatelet therapy (SAPT) or dual-agent antiplatelet therapy (DAPT), preferably achieving a relative risk reduction for ischemic stroke of about 10% to about 40% compared to placebo dosing. Embodiment 196. The method of embodiment 195, achieving a relative risk reduction for ischemic stroke of about 28% to about 32% compared to placebo administration. Embodiment 197. The method of embodiment 195, achieving a relative risk reduction for ischemic stroke of about 30% compared to placebo administration. Embodiment 198. The method of any one of embodiments 193 to 196, further achieving at least one of the following safety outcomes: (i) no fatal blood loss events, equivalent to placebo dosing; (ii) no intracranial hemorrhage events, equivalent to placebo dosing; or (iii) an incidence of major blood loss (BARC types 3 and 5) equivalent to placebo dosing. Embodiment 199. The method of any one of embodiments 193 to 198, wherein administration of the regimen causes a reduction in FXI clotting activity in the patient of about 7% to about 20% relative to baseline. Embodiment 200. The method of any one of embodiments 193-198, wherein administration of the regimen causes a prolongation of activated partial thromboplastin time (aPTT) in the patient relative to baseline ranging from about 27% to about 64%. Embodiment 201. The method of any one of embodiments 193 to 196, wherein Milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered in a pharmaceutical composition that is a solid oral pharmaceutical composition. Embodiment 202. The method of embodiment 201, wherein the solid oral pharmaceutical composition is a tablet. Embodiment 203. The method of embodiment 202, wherein the tablet is an immediate-release tablet. Embodiment 204. The method of embodiment 202 or embodiment 203, wherein the tablet has a disintegration time in water of less than 20 seconds. Embodiment 205. The method of any one of embodiments 193-198 or embodiments 201-204, wherein the administration results in a milvexian plasma half-life between repeat doses ranging from about 13 hours to about 16 hours. Embodiment 206. The method of any one of embodiments 193 to 198 or embodiments 201 to 205, wherein the administration results in a milvexin plasma concentration that reaches a steady state in about 3 to 6 days. Embodiment 207. The method of any one of embodiments 193-196 or embodiments 201-205, wherein Milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered without regard to the timing of food intake. Embodiment 208. The method of any one of embodiments 193-198 or embodiments 201-206, wherein the patient is unable to swallow the tablet dosage form. Embodiment 209. The method of any one of embodiments 193 to 198, wherein the tablet is dispersed in an aqueous medium to form an aqueous dispersion. Embodiment 210 The method of embodiment 209, wherein the aqueous medium is water, saline, phosphate buffer, vegetable juice, or fruit juice, including, for example, applesauce. Embodiment 211 The method of embodiment 209 or embodiment 210, wherein the aqueous dispersion is administered to the human patient via a nasogastric tube or a spoon. Embodiment 212 The method of any one of embodiments 209 to 211, wherein Milvexian is orally administered as an aqueous dispersion by dispersing the oral tablet in an aqueous medium for less than 60 seconds. Embodiment 213. Milvexian for use in 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 (i) a pharmaceutical composition comprising Milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 25 mg twice daily, and (ii) a regimen comprising single-agent antiplatelet therapy (SAPT) or dual-agent antiplatelet therapy (DAPT), wherein the method comprises administering to the human patient: ... Milvexian for use in a method that achieves at least one of: (i) a relative risk for ischemic stroke of about 0.6 to about 0.9 compared to placebo medication; (ii) a numerical reduction in the absolute risk of ischemic stroke compared to placebo medication; (iii) a numerical reduction in the Kaplan-Meier rate for ischemic stroke compared to placebo medication; (iv) a numerical reduction in the percentage of patients with ischemia compared to placebo medication; or (v) a relative risk reduction for ischemic stroke of about 10% to about 40% compared to placebo medication. Embodiment 214. Milvexian for use in a method for reducing the risk of ischemic stroke in a human patient who is having or has had an ischemic stroke or transient ischemic attack, the method comprising administering to the human patient (i) a pharmaceutical composition comprising Milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 25 mg twice daily, and (ii) a regimen comprising single-agent antiplatelet therapy (SAPT) or dual-agent antiplatelet therapy (DAPT), preferably wherein the method achieves a relative risk for ischemic stroke of about 0.6 to about 0.9 compared to placebo dosing. Embodiment 215. Milvexian for use in a method for reducing the risk of ischemic stroke in a human patient who is having or has had an ischemic stroke or transient ischemic attack, the method comprising administering to the human patient (i) a pharmaceutical composition comprising Milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 25 mg twice daily, and (ii) a regimen comprising single-agent antiplatelet therapy (SAPT) or dual-agent antiplatelet therapy (DAPT), preferably wherein the method achieves a relative risk reduction for ischemic stroke of about 10% to about 40% compared to placebo dosing. Embodiment 216. Milvexian for use according to embodiment 215, wherein the method achieves a relative risk reduction for ischemic stroke of about 10% to about 40% compared to placebo administration. Embodiment 217. Milvexian for use according to embodiment 215, wherein the method achieves a relative risk reduction for ischemic stroke of about 28% to about 32% compared to placebo administration. Embodiment 218. Milvexian for use according to any one of embodiments 213 to 217, wherein the method further achieves at least one of the following safety outcomes: (i) no fatal blood loss events, equivalent to placebo dosing; (ii) no intracranial blood loss events, equivalent to placebo dosing; or (iii) an incidence of major blood loss (BARC types 3 and 5) equivalent to placebo dosing. Embodiment 219. Milvexian for use according to any one of embodiments 213 to 217, wherein administration of the regimen causes a reduction in FXI clotting activity in the patient of about 7% to about 20% relative to baseline. Embodiment 220. Milvexian for use according to any one of embodiments 213 to 217, wherein administration of the regimen causes a prolongation of activated partial thromboplastin time (aPTT) in the patient relative to baseline ranging from about 27% to about 64%. Embodiment 221. Milvexian for use according to any one of embodiments 213 to 217, wherein Milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered in a pharmaceutical composition that is a solid oral pharmaceutical composition. Embodiment 222. Milvexian for use according to embodiment 221, wherein the solid oral pharmaceutical composition is a tablet. Embodiment 223. The method of embodiment 202, wherein the tablet is an immediate-release tablet. Embodiment 224. The method of embodiment 202 or embodiment 203, wherein the tablet has a disintegration time in water of less than 20 seconds. Embodiment 225. The method of any one of embodiments 213-217 or embodiments 221-224, wherein the administration results in a milvexian plasma half-life between repeat doses ranging from about 13 hours to about 16 hours. Embodiment 226 The method of any one of embodiments 213 to 217 or embodiments 221 to 225, wherein the administration results in a milvexin plasma concentration that reaches a steady state in about 3 to 6 days. Embodiment 227 The method of any one of embodiments 213-217 or embodiments 221-226, wherein Milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered without regard to the timing of food intake. Embodiment 228. The method of any one of embodiments 213-217 or embodiments 221-227, wherein the patient is unable to swallow the tablet dosage form. Embodiment 229. The method of any one of embodiments 213-217, wherein the tablet is dispersed in an aqueous medium to form an aqueous dispersion. Embodiment 230. The method of embodiment 229, wherein the aqueous medium is water, saline, phosphate buffer, vegetable juice, or fruit juice, including, for example, applesauce. Embodiment 231 The method of embodiment 229 or embodiment 230, wherein the aqueous dispersion is administered to the human patient via a nasogastric tube or a spoon. Embodiment 232 The method of any one of embodiments 229 to 231, wherein Milvexian is orally administered as an aqueous dispersion by dispersing the oral tablet in an aqueous medium for less than 60 seconds. Embodiment 233. The method of any one of embodiments 193 to 232, wherein the antiplatelet therapy is a single-agent antiplatelet therapy. Embodiment 234. The method of embodiment 233, wherein the single agent antiplatelet therapy is aspirin. Embodiment 235. The method of embodiment 234, wherein aspirin is administered daily in an amount of 75 to 100 mg. Embodiment 236 The method of embodiment 235, wherein the aspirin is administered daily in an amount of 75 mg. Embodiment 237 The method of embodiment 235, wherein the aspirin is administered daily in an amount of 81 mg. Embodiment 238 The method of embodiment 235, wherein the aspirin is administered daily in an amount of 100 mg. Embodiment 239. The method of any one of embodiments 193 to 232, wherein the single agent antiplatelet therapy is a P2Y12 inhibitor. Embodiment 240 The method of embodiment 239, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel. Embodiment 241 The method of embodiment 240, wherein the P2Y12 inhibitor is clopidogrel. Embodiment 242 The method of embodiment 242, wherein clopidogrel is administered daily in an amount of 75 mg. Embodiment 243 The method of any one of embodiments 193 to 232, wherein the single agent antiplatelet therapy is ticlopidine. Embodiment 244. The method of embodiment 243, wherein ticlopidine is administered daily in an amount of 250 to 500 mg. Embodiment 245. The method of any one of embodiments 193 to 232, wherein the antiplatelet therapy is dual antiplatelet therapy. Embodiment 246. The method of embodiment 245, wherein the dual antiplatelet therapy is aspirin and a P2Y12 inhibitor. Embodiment 247. The method of embodiment 246, wherein aspirin is administered daily in an amount of 75 to 100 mg. Embodiment 248. The method of embodiment 247, wherein the aspirin is administered daily in an amount of 75 mg. Embodiment 249. The method of embodiment 247, wherein the aspirin is administered daily in an amount of 81 mg. Embodiment 250 The method of embodiment 247, wherein the aspirin is administered daily in an amount of 100 mg. Embodiment 251 The method of any of embodiments 245 to 250, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel. Embodiment 252 The method of embodiment 251, wherein the P2Y12 inhibitor is clopidogrel. Embodiment 253 The method of embodiment 252, wherein clopidogrel is administered daily in an amount of 75 mg. Embodiment 254 The method of any one of embodiments 193 to 232, wherein the antiplatelet therapy comprises Aggrenox, i.e., a combination of aspirin and dipyridamole (persantin). Embodiment 255. The method of any one of embodiments 193 to 254, wherein the pharmaceutical composition is a tablet having the composition and / or characteristics set forth in Table A. Embodiment 256. The method of embodiment 255, wherein the tablet comprises a spray-dried amorphous solid dispersion (SDP). Embodiment 257. The method of embodiment 255, wherein the tablet comprises about 22.0% w / w of spray-dried amorphous solid dispersion (SDP) based on the total weight of the tablet. Embodiment 258. The method of embodiment 255, wherein the tablet comprises about 43.0% w / w silicified microcrystalline cellulose, based on the total weight of the tablet. Embodiment 259. The method of embodiment 255, wherein the tablet comprises about 22.0% w / w of SDP and about 43.0% w / w of silicified microcrystalline cellulose, based on the total weight of the tablet. Embodiment 260. The method of any one of embodiments 255 to 259, wherein the SDP consists essentially of Milvexian free form and hypromellose acetate succinate MC grade (HPMCAS-MG) in a weight ratio of 3:1 (Milvexian:HPMCAS-MG). Embodiment 261. The method of embodiment 255, wherein the tablet consists essentially of 25 mg of milveixian, HPMCAS-MG, silicified microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate. Embodiment 262 The method of embodiment 261, wherein the tablet further comprises a film coating comprising polyvinyl alcohol, iron oxide, macrogol (PEG) polyvinyl alcohol graft copolymer, and talc. Embodiment 263. A method for preventing or reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack, comprising administering to the human patient (i) a pharmaceutical composition comprising Milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 25 mg twice daily, and (ii) a regimen comprising single-agent antiplatelet therapy (SAPT) or dual-agent antiplatelet therapy (DAPT), wherein the method is characterized by one of the following efficacy outcomes: (i) placebo administration or ... (ii) a numerical reduction in the absolute risk of ischemic stroke relative to placebo medication; (iii) a numerical reduction in the Kaplan-Meier rate for ischemic stroke relative to placebo medication; (iv) a numerical reduction in the percentage of patients with ischemia relative to placebo medication; or (v) a relative risk reduction for ischemic stroke of about 10% to about 40% relative to placebo medication. Embodiment 264. A method for preventing or reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack, comprising administering to the human patient (i) a pharmaceutical composition comprising Milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 25 mg twice daily, and (ii) a regimen comprising single-agent antiplatelet therapy (SAPT) or dual-agent antiplatelet therapy (DAPT), wherein the method achieves a relative risk for ischemic stroke of about 0.6 to about 0.9 compared to placebo dosing. Embodiment 265. A method for reducing the risk of ischemic stroke in a human patient who is having or has had an ischemic stroke or transient ischemic attack, comprising administering to the human patient (i) a pharmaceutical composition comprising Milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 25 mg twice daily, and (ii) a regimen comprising single-agent antiplatelet therapy (SAPT) or dual-agent antiplatelet therapy (DAPT), wherein the method achieves a relative risk reduction for ischemic stroke of about 10% to about 40% compared to placebo administration. Embodiment 266 The method of embodiment 265, achieving a relative risk reduction for ischemic stroke of about 28% to about 32% compared to placebo administration. Embodiment 267 The method of embodiment 265, achieving a relative risk reduction for ischemic stroke of about 30% compared to placebo administration. Embodiment 268. The method of any one of embodiments 263-266, further achieving at least one of the following safety outcomes: (i) no fatal blood loss events, equivalent to placebo dosing; (ii) no intracranial blood loss events, equivalent to placebo dosing; or (iii) an incidence of major blood loss (BARC types 3 and 5) equivalent to placebo dosing. Embodiment 269 The method of any one of embodiments 263 to 268, wherein administration of the regimen causes a reduction in FXI clotting activity in the patient of about 7% to about 20% relative to baseline. Embodiment 270 The method of any one of embodiments 263-268, wherein administration of the regimen causes a prolongation of activated partial thromboplastin time (aPTT) in the patient relative to baseline ranging from about 27% to about 64%. Embodiment 271 The method of any one of embodiments 263 to 266, wherein Milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered in a pharmaceutical composition that is a solid oral pharmaceutical composition. Embodiment 272. The method of embodiment 271, wherein the solid oral pharmaceutical composition is a tablet. Embodiment 273. The method of embodiment 272, wherein the tablet is an immediate-release tablet. Embodiment 274. The method of embodiment 272 or embodiment 273, wherein the tablet has a disintegration time in water of less than 20 seconds. Embodiment 275. The method of any one of embodiments 263-268 or embodiments 271-274, wherein the administration results in a milvexian plasma half-life between repeat doses ranging from about 13 hours to about 16 hours. Embodiment 276 The method of any one of embodiments 263 to 268 or embodiments 271 to 275, wherein the administration results in a milvexin plasma concentration that reaches a steady state in about 3 to 6 days. Embodiment 277 The method of any one of embodiments 263-266 or embodiments 271-275, wherein Milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered without regard to the timing of food intake. Embodiment 278. The method of any one of embodiments 263-268 or embodiments 271-276, wherein the patient is unable to swallow the tablet dosage form. Embodiment 279 The method of any one of embodiments 263 to 268, wherein the tablet is dispersed in an aqueous medium to form an aqueous dispersion. Embodiment 280. The method of embodiment 279, wherein the aqueous medium is water, saline, phosphate buffer, vegetable juice, or fruit juice, including, for example, applesauce. Embodiment 281 The method of embodiment 279 or embodiment 280, wherein the aqueous dispersion is administered to the human patient via a nasogastric tube or a spoon. Embodiment 282 The method of any one of embodiments 279 to 281, wherein Milvexian is orally administered as an aqueous dispersion by dispersing the oral tablet in an aqueous medium for less than 60 seconds. Embodiment 283. Milvexian for use in a method for reducing the risk of ischemic stroke in a human patient who is having or has had an ischemic stroke or transient ischemic attack, the method comprising administering to the human patient (i) a pharmaceutical composition comprising Milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 25 mg twice daily, and (ii) a regimen comprising single-agent antiplatelet therapy (SAPT) or dual-agent antiplatelet therapy (DAPT), wherein the method achieves one of the following efficacy outcomes: A method that achieves at least one of: (i) a relative risk for ischemic stroke of about 0.6 to about 0.9 compared to placebo medication; (ii) a numerical reduction in the absolute risk of ischemic stroke compared to placebo medication; (iii) a numerical reduction in the Kaplan-Meier rate for ischemic stroke compared to placebo medication; (iv) a numerical reduction in the percentage of patients with ischemia compared to placebo medication; or (v) a relative risk reduction for ischemic stroke of about 10% to about 40% compared to placebo medication. Embodiment 284. Milvexian for use in a method for reducing the risk of ischemic stroke in a human patient who is having or has had an ischemic stroke or transient ischemic attack, the method comprising administering to the human patient (i) a pharmaceutical composition comprising Milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 25 mg twice daily, and (ii) a regimen comprising single-agent antiplatelet therapy (SAPT) or dual-agent antiplatelet therapy (DAPT), wherein the method achieves a relative risk for ischemic stroke of about 0.6 to about 0.9 compared to placebo dosing. Embodiment 285. Milvexian for use in a method for reducing the risk of ischemic stroke in a human patient who is having or has had an ischemic stroke or transient ischemic attack, the method comprising administering to the human patient (i) a pharmaceutical composition comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 25 mg twice daily, and (ii) a regimen comprising single-agent antiplatelet therapy (SAPT) or dual-agent antiplatelet therapy (DAPT), wherein the method achieves a relative risk reduction for ischemic stroke of about 10% to about 40% compared to placebo dosing. Embodiment 286. Milvexian for use according to embodiment 285, wherein the method achieves a relative risk reduction for ischemic stroke of about 10% to about 40% compared to placebo administration. Embodiment 287. Milvexian for use according to embodiment 285, wherein the method achieves a relative risk reduction for ischemic stroke of about 28% to about 32% compared to placebo administration. Embodiment 288. Milvexian for use according to any one of embodiments 283 to 287, wherein the method further achieves at least one of the following safety outcomes: (i) no fatal blood loss events, equivalent to placebo dosing; (ii) no intracranial blood loss events, equivalent to placebo dosing; or (iii) an incidence of major blood loss (BARC types 3 and 5) equivalent to placebo dosing. Embodiment 289. Milvexian for use according to any one of embodiments 283 to 287, wherein administration of the regimen causes a reduction in FXI clotting activity in the patient of about 7% to about 20% relative to baseline. Embodiment 290. Milvexian for use according to any one of embodiments 283 to 287, wherein administration of the regimen causes a prolongation of activated partial thromboplastin time (aPTT) in the patient relative to baseline ranging from about 27% to about 64%. Embodiment 291. Milvexian for use according to any one of embodiments 283 to 287, wherein the Milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered in a pharmaceutical composition that is a solid oral pharmaceutical composition. Embodiment 292. Milvexian for use according to embodiment 291, wherein the solid oral pharmaceutical composition is a tablet. Embodiment 293 The method of embodiment 272, wherein the tablet is an immediate-release tablet. Embodiment 294. The method of embodiment 272 or embodiment 273, wherein the tablet has a disintegration time in water of less than 20 seconds. Embodiment 295. The method of any one of embodiments 283-287 or embodiments 291-294, wherein the administration results in a milvexian plasma half-life between repeat doses ranging from about 13 hours to about 16 hours. Embodiment 296 The method of any one of embodiments 283 to 287 or embodiments 291 to 295, wherein the administration results in a milvexin plasma concentration that reaches a steady state in about 3 to 6 days. Embodiment 297 The method of any one of embodiments 283 to 287 or embodiments 291 to 296, wherein Milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered without regard to the timing of food intake. Embodiment 298. The method of any one of embodiments 283-287 or embodiments 291-297, wherein the patient is unable to swallow the tablet dosage form. Embodiment 299. The method of any one of embodiments 283 to 287, wherein the tablet is dispersed in an aqueous medium to form an aqueous dispersion. Embodiment 300. The method of embodiment 299, wherein the aqueous medium is water, saline, phosphate buffer, vegetable juice, or fruit juice, including, for example, applesauce. Embodiment 301 The method of embodiment 299 or embodiment 300, wherein the aqueous dispersion is administered to the human patient via a nasogastric tube or a spoon. Embodiment 302 The method of any one of embodiments 299-301, wherein Milvexian is orally administered as an aqueous dispersion by dispersing the oral tablet in an aqueous medium for less than 60 seconds. Embodiment 303. The method of any one of embodiments 263 to 302, wherein the antiplatelet therapy is a single-agent antiplatelet therapy. Embodiment 304. The method of embodiment 303, wherein the single agent antiplatelet therapy is aspirin. Embodiment 305. The method of embodiment 304, wherein the aspirin is administered daily in an amount of 75 to 100 mg. Embodiment 306 The method of embodiment 305, wherein the aspirin is administered daily in an amount of 75 mg. Embodiment 307 The method of embodiment 305, wherein the aspirin is administered daily in an amount of 81 mg. Embodiment 308 The method of embodiment 305, wherein the aspirin is administered daily in an amount of 100 mg. Embodiment 309. The method of any one of embodiments 263 to 302, wherein the single agent antiplatelet therapy is a P2Y12 inhibitor. Embodiment 310 The method of embodiment 309, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel. Embodiment 311 The method of embodiment 310, wherein the P2Y12 inhibitor is clopidogrel. Embodiment 312 The method of embodiment 312, wherein clopidogrel is administered daily in an amount of 75 mg. Embodiment 313 The method of any one of embodiments 263 to 302, wherein the single agent antiplatelet therapy is ticlopidine. Embodiment 314 The method of embodiment 313, wherein the ticlopidine is administered daily in an amount of 250 to 500 mg. Embodiment 315. The method of any one of embodiments 263 to 302, wherein the antiplatelet therapy is dual antiplatelet therapy. Embodiment 316. The method of embodiment 315, wherein the dual antiplatelet therapy is aspirin and a P2Y12 inhibitor. Embodiment 317. The method of embodiment 316, wherein the aspirin is administered daily in an amount of 75 to 100 mg. Embodiment 318. The method of embodiment 317, wherein the aspirin is administered daily in an amount of 75 mg. Embodiment 319. The method of embodiment 317, wherein the aspirin is administered daily in an amount of 81 mg. Embodiment 320. The method of embodiment 317, wherein the aspirin is administered daily in an amount of 100 mg. Embodiment 321 The method of any of embodiments 315-320, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel. Embodiment 322 The method of embodiment 311, wherein the P2Y12 inhibitor is clopidogrel. Embodiment 323 The method of embodiment 312, wherein clopidogrel is administered daily in an amount of 75 mg. Embodiment 324 The method of any one of embodiments 263 to 302, wherein the antiplatelet therapy comprises Aggrenox, i.e., a combination of aspirin and dipyridamole (persantin). Embodiment 325. The method of any one of embodiments 263 to 314, wherein the pharmaceutical composition is a tablet having the composition and / or characteristics set forth in Table A. Embodiment 326. The method of embodiment 325, wherein the tablet comprises a spray-dried amorphous solid dispersion (SDP). Embodiment 327. The method of embodiment 325, wherein the tablet comprises about 22.0% w / w of spray-dried amorphous solid dispersion (SDP) based on the total weight of the tablet. Embodiment 328. The method of embodiment 325, wherein the tablet comprises about 43.0% w / w silicified microcrystalline cellulose, based on the total weight of the tablet. Embodiment 329. The method of embodiment 325, wherein the tablet comprises about 22.0% w / w of SDP and about 43.0% w / w of silicified microcrystalline cellulose, based on the total weight of the tablet. Embodiment 330. The method of any one of embodiments 325 to 329, wherein the SDP consists essentially of Milvexian free form and hypromellose acetate succinate MC grade (HPMCAS-MG) in a weight ratio of 3:1 (Milbexian:HPMCAS-MG). Embodiment 331. The method of embodiment 325, wherein the tablet consists essentially of 25 mg of milveixian, HPMCAS-MG, silicified microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate. Embodiment 332. The method of embodiment 331, wherein the tablet further comprises a film coating comprising polyvinyl alcohol, iron oxide, macrogol (PEG) polyvinyl alcohol graft copolymer, and talc.

[0337] 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.

[0338] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference herein. [Example]

[0339] Example 1. Thrombotic Treatment with Factor XIa Inhibition to Optimize the Management of Acute Thromboembolic Events for Secondary Stroke Prevention (AXIOMATIC-SSP) The AXIOMATIC-SSP trial 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 strokes in patients receiving aspirin and clopidogrel after acute ischemic stroke or high-risk TIA. The primary objective is to determine the dose-response relationship of milvexian in participants with acute ischemic stroke or TIA who are being treated with aspirin and clopidogrel. A key secondary objective is to assess the rate of major blood loss in this population compared with placebo. Study population

[0340] The main inclusion criteria for patient participation are listed in Table 1 . [Table 1]

[0341] Individuals aged ≥40 years who had a history of ischemic stroke or high-risk TIA were recruited and randomized within 48 hours of symptom onset. Eligible stroke was defined as a symptomatic, nonlacunar, 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 (score range: 0–42, with higher scores representing greater stroke severity). Petechial hemorrhagic changes in the index infarct and microbleeds were acceptable. Eligible TIA was defined as the acute onset of neurological deficits contributing to cerebral ischemia, accompanied by complete resolution of disability, absence of cerebral infarction on neuroimaging, an ABCD2 score of ≥6 (score range: 0–7, with higher scores indicating a higher risk of stroke), or 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 visible intracranial or extracranial atherosclerotic plaque of any degree, but not complete occlusion on imaging, and a premorbid modified Rankin score (mRS) ≤ 3.

[0342] Exclusion criteria for patient participation are summarized in Table 2 . [Table 2]

[0343] Potential participants were excluded if they had evidence of large-vessel dissection, intracranial tumor (other than meningioma), or arteriovenous malformation that could explain their symptoms. Also excluded were those with a history of bleeding in the brain or spinal cord and those with conditions that, in the investigator's opinion, would contraindicate anticoagulation therapy. Requirements for dual antiplatelet therapy or planned use of anticoagulants for more than 21 days, with the exception of heparin or low-molecular-weight heparin to maintain patency of indwelling catheters, were exclusionary factors. Known SARS-CoV-2 infection within the four weeks prior to screening was also an exclusionary factor.

[0344] Study Procedures and Visits Following informed consent, participants were randomized to receive either Milvexian or matching placebo plus open-label, uncoated aspirin 100 mg and clopidogrel (loading dose 300–600 mg, followed by 75 mg daily). Clopidogrel was administered for 21 days, with concurrent aspirin and Milvexian or matching placebo continued through day 90 (see Figure 2). Randomization was initially to a 25 mg QD dose and 25 mg, 50 mg, and 100 mg BID doses, as well as 200 mg BID Milvexian after review of safety and efficacy data by an independent DMC. Despite the delayed initiation of randomization to the 200 mg BID dose, the trial aimed to achieve a 2:1 randomization between placebo and each Milvexian dose by the end of enrollment.

[0345] Milvexian dosing was initiated within 6 hours of the baseline scan. If a baseline MRI could not be performed within 48 hours of symptom onset, it could be obtained after randomization, but up to 72 hours after symptom onset. Study visits occurred on days 21 and 90, with a telephone contact on day 60. In approximately 450 patients, central laboratory tests were also obtained on day 60. An end-of-study MRI brain scan was obtained on day 90 and with a telephone contact on day 97. NIHSS, Montreal Cognitive Assessment (MoCA), and Digit Symbol Substitution Test (DSST) were collected at visits on days 1, 21, and 90, and after any new clinical stroke.

[0346] Study objectives and evaluation items The primary efficacy outcome was a composite of ischemic stroke events during the treatment period or new, hidden cerebral infarctions detected by comparing MRI scans at 90 days with baseline. All images were read independently by two blinded neuroradiologists, and discrepancies were resolved by consensus. A new infarction was defined as a new lesion consistent with an ischemic infarction on the 90-day MRI on diffusion-weighted imaging (DWI) or fluid-attenuated inversion recovery (FLAIR) sequences. Clinical overt stroke was determined by the site investigator according to a standardized definition. Briefly, to qualify as an outcome event, a clinical diagnosis of stroke required a sustained increase in the NIHSS score of ≥ 3 points unexplained by other factors, such as infection, or was confirmed as a new infarction by imaging. A hidden cerebral infarction was defined as a small ischemic brain lesion detected on MRI scans at 90 days in the absence of a symptomatic ischemic stroke event.

[0347] The secondary endpoint of major blood loss was determined by the occurrence of types 3 and 5 blood loss 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 included the volume and number of new infarcts detected by MRI imaging and the rate of any type of clinical blood loss with Milvexian compared with placebo. Blood loss was further assessed using the International Society on Thrombosis and Haemostasis (ISTH) and PLATElet Inhibition and Patient Outcomes (PLATO) criteria. Central laboratory samples were used to determine the dose-response relationship with PD markers and the PK of Milvexian.

[0348] Statistical Considerations Sample size calculations for the primary endpoint were performed using simulations with the Dose-Finding package in the R statistical analysis software to detect dose-response effects using generalized multiple comparisons and modeling (gMCP-Mod). Bornkamp B, Pinheiro J, Bretz F. R: dose-finding package, version 0.9-16. Comprehensive R archive network. Vienna, Australia: The R Foundation; 2018; CRAN.R-project. Comprehensive R archive network. Vienna, Australia: The R Foundation. A 2500-patient clinical trial simulation was performed, assuming a true incidence of 15% for placebo, a plateau-shaped dose-response relationship with a maximum relative risk reduction vs. placebo of 32% for Milvexian 100 or 200 mg BID, and the addition of 25 mg QD as the minimum dose to the prescribed BID dosing 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. The candidate model is E max The models included logistic, exponential, and exponential models.

[0349] 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 groups in a 2:1:1:1:1:1:1 ratio would provide approximately 80% power to demonstrate a dose-response relationship, with a type I error of 0.049. A sample size of approximately 2350 participants was targeted, allowing for up to 10% of participants missing images at 90 days.

[0350] All randomized participants will be included in the analysis of the primary endpoint if they have either a symptomatic ischemic stroke event by day 90 or an evaluable MRI at the day 90 visit. Due to the COVID-19 pandemic, MRIs from all day 90 visits will be included in the primary analysis, regardless of timing. All other efficacy analyses will be conducted on the randomized (intent-to-treat, ITT) population up to day 90.

[0351] If a dose-response relationship exists, fitted estimates of the incidence of the primary endpoint are calculated using the weighted average of the fitted models in each of the treatment groups, with weights determined from the Akaike Information Criterion (AIC) for each model. The observed incidence of the primary endpoint is summarized by treatment group using the fitted model from the gMCP-Mod procedure. gMCP-Mod incorporates the rate of events at each dose level and then uses a logit scale during the remainder of the gMCP-Mod procedure.

[0352] The population for the primary efficacy endpoint analysis included all randomized participants with either (i) a primary endpoint event (new ischemic stroke during the study period or new occult cerebral infarction detected by MRI at 90 days) or (ii) an evaluable MRI image at 90 days.

[0353] The population for the safety analysis includes all participants who received at least one dose of study drug. This is the primary population used in the safety analysis and is analyzed according to treatment assigned at randomization.

[0354] To assess the robustness of the primary efficacy analysis, further sensitivity analyses will be performed using the following methods. Sensitivity analyses will repeat the primary analyses but include MRIs obtained up to day 106. The primary analysis was repeated using all randomized participants, and participants without a 90-day MRI and without any events were counted as event-free (Analysis #1) or as having an event (Analysis #2). If ≥ 5% of participants have protocol deviations that meet predefined criteria and have the potential to affect the interpretation of the primary safety or efficacy endpoint analysis, the primary analysis will be repeated excluding participants with such protocol deviations.

[0355] 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, previous ischemic stroke or TIA, hypertension, thrombolysis / thrombectomy, previous antiplatelet therapy, and previous statin therapy.

[0356] For other events, incidence rates within each treatment group and associated relative risk reductions between each Milvexian group and placebo are shown. NIHSS, mRS, MoCA, and DSST (subtests of the WAIS-IV) are summarized at baseline, days 21 and 90, and at the time of new stroke events.

[0357] All safety data analyses were performed in participants treated with ≥1 dose of double-blind drug. The proportion of participants with major blood loss events (BARC types 3 and 5) and criteria defined by BARC, ISTH, and PLATO will be summarized by treatment group. Additional summaries will include characteristics of cerebral microbleeds, hemorrhagic transformation of ischemic stroke, and asymptomatic intracranial blood loss. Adverse events and laboratory data, as well as PK and PD data, will be summarized. result

[0358] (i) Participants The Phase II AXIOMATIC-SSP trial randomized 2,366 participants aged ≥40 years with a nonlacunar, noncardioembolic ischemic stroke (NIHSS score ≤7) or high-risk TIA within 48 hours of the onset of signs or symptoms. The trial was conducted at 367 sites in 27 countries. Eligible participants were randomized to receive one of five double-blind doses of milvexin (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo. A 16-fold dose range (25 mg to 400 mg total daily dose) of milvexin was compared with placebo on a background of aspirin and clopidogrel (DAPT) for 21 days, followed by 69 days of aspirin monotherapy (see Figure 2).

[0359] All participants received 21 days of background treatment with open-label ASA and clopidogrel, followed by open-label ASA from days 22 to 90. All 2366 randomized subjects were included in the intention-to-treat (ITT) analysis set. As shown in Table 3, 859 (36.3%) participants were female, and 1884 (79.6%) participants were white. The mean (SD) age of participants was 69.8 (10.9). As shown in Table 6, of the 2366 subjects in the ITT analysis set, 1675 (74.7%) received at least one dose of study drug and were therefore included 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, 1,252 (74.7%) participants completed study treatment, and 423 (25.3%) participants discontinued study treatment prematurely. Demographic and baseline characteristics were balanced between groups. Patients were well-treated with other therapies for glycemic and cardiovascular risk management (see Tables 1 and 2). Baseline characteristics were balanced in the Milvexian compared with placebo groups and were directly comparable, as shown in Tables 3 and 5 below. Participant baseline characteristics are summarized in Tables 3-6 below. [Table 3] [Table 4-1] [Table 4-2] [Table 5] [Table 6]

[0360] (ii) Efficacy: dose response The primary efficacy outcome was to assess the dose response for the composite of new clinical ischemic stroke during treatment and new hidden cerebral infarction detected by MRI at day 90 in the modified intention-to-treat population (participants with either clinical ischemic stroke or MRI at day 90). The incidence of the composite outcome was numerically low with the 50 mg and 100 mg twice-daily doses, with no clear trend in 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% (% are incidence, n / N%)). However, Milvexian significantly reduced the rate of clinical ischemic stroke (excluding hidden cerebral infarction) in the intention-to-treat population at all doses except 200 mg twice daily, with doses of 25 to 100 mg twice daily demonstrating a relative risk reduction (RRR) of approximately 30% versus 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 intended treatment period for DAPT.

[0361] In the AXIOMATIC-TKR trial, Milvexian at a dose of 25 mg twice daily demonstrated efficacy equivalent to enoxaparin with a favorable safety profile. In the AXIOMATIC-SSP trial, Milvexian at a dose of 25 mg twice daily was numerically better than placebo for preventing clinical ischemic stroke (HR 0.69, 95% CI 0.36^1.30), with no further improvement in efficacy observed at higher doses.

[0362] The primary endpoint was numerically lower at the 50 mg and 100 mg BD doses, but no dose-response trend was present. Milvexian numerically reduced the incidence of clinical ischemic stroke events (acute IS, excluding hidden cerebral infarction) in the ITT population at all doses except 200 mg twice daily (see Table 7). Milvexian was effective in reducing clinical ischemic stroke in patients with ischemic stroke or post-TIA at doses of 25 mg to 100 mg twice daily; these doses demonstrated a relative risk reduction (RRR) of approximately 30% for ischemic strokes in the treatment group versus the placebo group (see Figure 4). [Table 7]

[0363] (iii) Efficacy: Risk of blood loss The primary safety (blood loss) outcome was BARC type 3 and 5 blood loss, which is shown in Table 8. There were no fatal blood loss events in any treatment group. Furthermore, there were no intracranial hemorrhage events with Milvexian. The incidence of bleeding endpoints (n / N%) was low (0.6%-1.6%), and there were no fatal blood loss events. The incidence of major blood loss (BARC type 3 and 5) for the 25 mg QD and BID doses of Milvexian was similar to placebo (0.6%), while a moderate increase in blood loss rate was observed in the 50 mg BD group. (See Figure 3.) The incidence (n / N%) of major blood loss (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%), with no fatal blood loss. Rates of major blood loss for the 25 mg once-daily and twice-daily doses of Milvexian were similar to placebo, although a moderate increase was observed in the 50 mg twice-daily or higher dose groups (see Table 8). [Table 8] [Table 9]

[0364] As illustrated above in Table 9, Milvexian had a similar rate of intracranial blood loss to placebo. Despite all patients receiving background antiplatelet therapy, no increase in fatal or severe blood loss (e.g., symptomatic intracranial hemorrhage) was observed with Milvexian compared to placebo. Symptomatic intracranial blood loss events during the study occurred with placebo (n=2; 0.3); Milvexian 50 mg BID (n=3, 0.9%); and Milvexian 200 mg BID (n=1, 0.3%). There were no intracranial blood loss events in the 25 mg QD, 25 mg BID, and 100 mg BID Milvexian dose groups. No dose-response for this type of blood loss was observed. Overall, there was no fatal blood loss or increase in ICH (BARC-3c), the most harmful type of blood loss for patients. In addition, there was no increase in BARC-3 blood loss in the 25 mg QD and 25 mg BID study groups.

[0365] Early stroke recurrence after ischemic stroke or transient ischemic attack (TIA) remains a significant risk despite advances in secondary prevention. Due to concerns about blood loss, anticoagulants are not currently used when patients suffer from non-cardioembolic ischemic stroke. These data suggest that Milvexian may provide additional benefit to stroke patients in clinical practice.

[0366] The overall AE and SAE profile for Milvexian appears to be similar to placebo, with the exception of the 200 mg twice daily dose.

[0367] Milvexian represents a thrombotic therapy with a favorable blood loss and tolerability profile, offering a treatment option for patients currently untreated or undertreated due to blood loss concerns.

[0368] (iv) Efficacy: Secondary endpoint Rate of composite events of new nonfatal ischemic stroke, nonfatal myocardial infarction, or all-cause death.

[0369] Location, number, and volume of new FLAIR+DWI lesions.

[0370] The National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), Montreal Cognitive Assessment (MoCA), and Digit Symbol Substitution Test (a subtest of the WAIS-IV) were collected at baseline (at randomization for the NIHSS), days 21 and 90, and at the time of any new stroke event. The MoCA and DSST (a subtest of the WAIS-IV) were read by a third-party central laboratory blinded to the study.

[0371] Descriptive statistics and corresponding changes from baseline (where applicable) assessed by the National Institutes of Health Stroke Score (NIHSS), modified Rankin Scale (mRS), Montreal Cognitive Assessment (MoCA), and Digit Symbol Substitution Test (a subtest of the WAIS-IV) were summarized by treatment group. Baseline characteristics

[0372] Overall, most index events (75.7%) were ischemic strokes, and approximately 96% of randomized subjects had an NIHSS ≦5.

[0373] Baseline disease characteristics were balanced between treatment groups, with the exception of a higher NIHSS score of 6 to 7 in the 200 mg BID group (4.7%) than in the other groups (range: 2.1% to 4.0%). In the latest protocol (version 06) for expanding the study population, the NIHSS score only increased to 7. Randomization to the 200 mg BID group was not performed until safety data were collected in this group, so that subsequent DMC assessments could be performed as a safety precaution. In the same protocol revision, the inclusion criterion for NIHSS score was increased from <5 to <7. Therefore, due to the staggered opening of this treatment group, a larger number of subjects with an NIHSS score of 6 or 7 were assigned to the highest dose group.

[0374] Baseline stroke imaging assessments (MRIs) were performed in nearly all (99.6%; 1668 / 1675) subjects randomized to Milvexian and nearly all (99.4%; 687 / 691) placebo subjects. At day 90, MRI studies were performed in 90.7% (1520 / 1675) of all subjects randomized to Milvexian and 89.6% (619 / 691) placebo subjects. Overall, approximately 4.5% of day 90 MRIs were obtained outside the specified 106-day window, limiting double-blind treatment to 96 days.

[0375] Baseline MRI characteristics by procedure are summarized below:

[0376] 24.7% of subjects in the placebo group vs. 23.0% in the Milvexian combination group had no recent ischemic lesions detectable on DWI sequences, consistent with the proportion of TIA patients randomized in the trial.

[0377] 7.9% of subjects in the placebo group vs. 9.3% in the Milvexian combination group had lacunar infarctions detected by MRI.

[0378] The median number of recent ischemic lesions at baseline was 2.0 across all study treatment groups.

[0379] The median recent ischemic lesion volume at baseline was 1.6 mL and 1.4 mL for placebo and all Milvexian treatment groups, respectively (Table 14.2.5).

[0380] One-quarter of subjects (25.0%) had chronic ischemic infarction.

[0381] There was evidence of chronic bleeding in 27.4% of subjects.

[0382] One-quarter of subjects (25.8%) had microbleeds (≤10 mm), and 0.9% to 2.7% of subjects had macrobleeds >10 mm.

[0383] White matter abnormalities were detected in 93.7% of all treatment groups.

[0384] The above MRI characteristics were well balanced between the placebo and milvexian-treated groups. Composite of new ischemic stroke, myocardial infarction, and all-cause mortality

[0385] The composite event rate of new ischemic stroke, MI, and all-cause death was lower with Milvexian at dose levels from 25 mg QD to 100 mg BID than with placebo (see Table 10 below). The relative risk of this composite event with Milvexian compared to placebo ranged from 0.78 to 0.85 across the range of 25 mg QD to 100 mg BID, with no clear dose-response trend.

[0386] In contrast, the Milvexian 200 mg BID dose group had a numerically higher rate of this composite endpoint than placebo (9.4% and 6.1%, respectively; relative risk: 1.55), and a higher incidence of ischemic stroke (7.7 and 5.5%, respectively), myocardial infarction (0.9% and 0.3%, respectively), and all-cause mortality (1.1% and 0.7%, respectively). [Table 10]

[0387] Location, number and volume of new FLAIR+ DWI lesions Quantification and vascular territory information for MRI-detected infarct events at 90 days are summarized in Tables 11 and 12 below. At baseline, recent ischemic lesions were detected and quantified using DWI sequences. Infarct events (defined as new imaging lesions compared with baseline MRI that were associated with symptomatic ischemic stroke or were occult in nature) were detected with FLAIR sequences at 90 days and classified as DWI-positive or DWI-negative based on whether they could also be detected with DWI sequences. DWI-positive lesions at 90 days are likely associated with infarcts occurring later during follow-up (approximately days 30-90), while DWI-negative lesions are more likely associated with infections occurring earlier (by approximately day 30). The vascular territory of infarct events was also assessed at 90 days. The main results are as follows:

[0388] The rate of MRI-detected infarct events at 90 days was numerically lower with milvexian than with placebo at dose levels from 50 BID to 200 BID, with no clear dose response.

[0389] The majority of infarct events were single lesions on MRI, and less than 3% of subjects had multiple infarct events across the different treatment groups, with no apparent relationship to medication.

[0390] The mean volume of infarct events was small (0.9–3.0 mL) and numerically lower than placebo for Milvexian at all dose levels except the 25 mg BID group.

[0391] Among subjects with MRI-detected infarct events at 90 days, there was a higher proportion of DWI-positive lesions (range: 8.7%-12.6%) than DWI-negative lesions (range: 3.3%-6.0%).

[0392] The mean volume of DWI-positive infarct events was numerically lower with Milvexian than with placebo at all dose levels.The mean volume of DWI-negative infarct events was numerically lower with Milvexian than with placebo at dose levels of 25 QD and 50 to 200 BID.

[0393] Some infarct events were located in the new vascular territory as the index stroke. The most common new vascular territory for infarct events was the middle cerebral artery (MCA). [Table 11-1] [Table 11-2] [Table 11-3] [Table 12]

[0394] NIHSS, mRS, MoCA and DSST For functional outcome measures, NIHSS and mRS scores at the time of new stroke events were lower in subjects treated with milvexian compared with placebo.

[0395] For cognitive outcome measures, MoCA and DSST scores showed overall improvement after baseline across the different treatment groups, including placebo.

[0396] Descriptive summaries for the mRS and NIHSS are shown in Tables 13 and 14, respectively. MoCA and DSST were also assessed. For all four scales, the main changes from baseline results for the 21-day and 90-day assessments were similar across all analyzed Milvexian dose levels (except the 50 and 100 mg QD groups, which were not large enough for comparison), and also for placebo. Across all treatment groups, including placebo, there was an overall improvement in scores for stroke severity (NIHSS) and cognitive function (DSST and MoCA) in subjects for the 21-day and 90-day assessments:

[0397] Median scores for the NIHSS and mRS at the time of new stroke events were numerically lower in the milvexian group compared with placebo.

[0398] All subjects, regardless of treatment assignment, showed overall improvement in cognitive measures over the course of the study:

[0399] The mean MoCA score of 22 points at baseline increased by an average of 2 points by days 21 and 90 in all groups.

[0400] The mean DSST score of 31 to 37 points across all groups at baseline increased by an average of 5 to 7 points from baseline to Day 21 and by a further 1 to 2 points by Day 90. This improvement in the DSST scale did not appear to be treatment or dose-dependent. [Table 13] [Table 14]

[0401] (v) Efficacy: Pharmacodynamics One objective of the study was to evaluate the dose-response of Milvexian on pharmacodynamic (PD) biomarkers, with endpoints being the % change from baseline in aPTT and factor XI clotting activity during treatment, measured using descriptive statistics and the corresponding % change from baseline.

[0402] A subgroup of the ITT population, including subjects with at least one PD endpoint (a total of 1995 subjects), was evaluated after the first dose of Milvexian. Percent (%) changes from baseline in aPTT and factor XI clotting activity are summarized by treatment group and nominal time point. Additionally, an exposure-response (ER) analysis was performed to examine the relationship of Milvexian exposure to percent (%) changes from baseline in aPTT and factor XI clotting activity using data collected from all treated subjects (a total of 2334 subjects). A dose-dependent increase in aPTT and a dose-dependent decrease in factor XI clotting activity were observed in the Milvexian-treated group.

[0403] Summary statistics for activated partial thromboplastin time (aPTT) and percent change from baseline for the pharmacodynamic population are presented below in Table 15. [Table 15]

[0404] The FXI clotting activities observed in this study were as follows: [Table 16]

[0405] Example 2. Bioavailability Study and Results of 25 mg and 100 mg Film-Coated DC Tablets Versus 25 mg and 100 mg Comparative SDP Oral Capsules in Healthy Participants The initial Phase 1 study is an open-label, randomized, crossover study to evaluate the relative oral bioavailability, pharmacokinetics, and food effect after single doses (Parts 1, 3, and 4) and multiple doses (Part 2). Part 1 of this initial Phase 1 study is designed to evaluate the relative bioavailability and food effect of a single dose of 200 mg Milvexian administered as a film-coated DC tablet compared with a 100 mg comparison SDP oral capsule under fasted and fed conditions. Part 2 of this initial Phase 1 study is designed to characterize the pharmacokinetics (PK) of 200 mg Milvexian administered as a film-coated DC tablet and multiple doses of Milvexian administered as 25 mg or 200 mg comparison SDP oral capsules administered twice daily for 5 days. The 100 mg and 25 mg capsule formulations (see Table 17 below) are described in WO2020210629, where the capsules contain MCC and lactose anhydrous DC in a 1:1 binder (MCC) to filler (lactose anhydrous) weight ratio. The composition and physical properties for the 25 mg and 100 mg film-coated DC tablets are shown in Table A above.

[0406] Blood samples were collected at predetermined time points after drug administration as specified in the clinical trial protocol. Sample concentrations were measured using a validated analytical method (liquid chromatography with tandem mass spectrometry). Individual subject pharmacokinetic parameters (e.g., Cmax, AUClast and AUC ∞ ) are derived from the time-concentration profiles by non-compartmental methods using Phoenix™ WinNonlin® (version 8.1, Pharsight, A Certara™ Company, LP, Princeton, NJ, USA) software. [Table 17]

[0407] The treatment regimens for Part 1 and Part 2 are summarized in Table 18 below. [Table 18]

[0408] The absolute bioavailability for the 100 mg SDP capsule comparator formulation is 52% under fasted conditions and 72% under fed conditions for the 200 mg dose.

[0409] In part 1 of the single-dose administration regimen, the 100 mg film-coated DC tablets demonstrated approximately 9.0% to 11% improvement compared to the 200 mg oral SDP capsules. * Oral tablets have a lower food effect. To achieve better patient compliance, it is preferable to administer Milvexian with or without food. Drug formulations with a small food effect result in better patient compliance.

[0410] In part 2 of the multiple-dose BID dosing regimen, the 2 x 100 mg film-coated DC tablets exhibited approximately 5-7% lower bioavailability when compared to the 2 x 100 mg SDP oral capsules. The 25 mg film-coated DC tablets (DC tablets) exhibited approximately 11-13% lower bioavailability when compared to the 25 mg SDP oral capsules (see Figures 8A-8D for Milvexian dosing curves as a function of time after BID administration).

[0411] In this Phase 2 study, Part 1 was an open-label, randomized, three-way crossover study in healthy participants to evaluate the relative oral bioavailability, pharmacokinetics, and food effect of a single oral dose of 200 mg Milvexian as 2 x 100 mg SDP DC tablets compared with 200 mg 2 x 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 Milvexian as 2 x 100 mg SDP DC tablets. Part 2 was an open-label, randomized, two-way crossover study in healthy participants to evaluate the PK and relative bioavailability of a single oral dose of 50 mg Milvexian as 2 x 25 mg SDP tablets compared with 50 mg Milvexian as 2 x 25 mg SDP granule capsules under fasting conditions in healthy participants.

[0412] PK (AUC) data generated under two Phase 1 studies under fed and fasted conditions for 2 x 100 mg and 1 x 25 mg SDP DC tablet and 25 mg and 100 mg SDP granule capsule formulations. inf and C max ) In a pooled analysis of the data, results demonstrated that in healthy participants, tablets showed less inter-participant PK variability than capsules.

[0413] Clinical trial results show that for tablets with similar dissolution rates, 2 x 100 mg film-coated DC * AUC of oral coated tablets ∞ (AUC inf (also known as ) demonstrated that bioequivalence criteria were met for a 2 x 100 mg granule capsule formulation.

Claims

1. 1. A method for preventing or reducing the risk of ischemic stroke in a human patient having or having 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) 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.

2. A regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) 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 a human patient compared to a placebo with standard of care, and for use in preventing or reducing the risk of ischemic stroke in a human patient who has or has had an ischemic stroke or transient ischemic attack.

3. A method of treating a human patient having or who 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) once daily in an amount of 25 mg or twice daily in an amount of 12.5 mg to 200 mg and standard of care; wherein the regimen is effective in reducing the risk of ischemic stroke in the human patient, and the human patient does not suffer from an ischemic stroke during the duration of the regimen.

4. A regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) once daily in an amount of 25 mg, or twice daily in an amount of 12.5 mg to 200 mg, and standard of care for use in treating a human patient who is having or has had an ischemic stroke or transient ischemic attack, wherein said use comprises administering the regimen to the human patient, wherein the regimen is effective in reducing the risk of ischemic stroke in the human patient, and wherein the human patient does not suffer from an ischemic stroke during the duration of the regimen.

5. 1. A method of treating a patient population in which the patients have or have had an ischemic stroke or transient ischemic attack, comprising administering to patients in the population a regimen comprising milvexian (or a pharmaceutically acceptable salt or solvate thereof) 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 starting the regimen is less than 10%.

6. 1. A regimen comprising: milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 25 mg once daily or in an amount of 12.5 mg to 200 mg twice daily for use in treating a patient population in which the patients have or have had an ischemic stroke or transient ischemic attack; and standard of care, said use comprising administering the regimen to patients in the population, wherein the percentage of patients in the population who experience an ischemic stroke within 90 days of starting the regimen is less than 10%.

7. 10. The method of any one of claims 1, 3 or 5 or the regimen for use of any one of claims 2, 4 or 6, wherein the standard of care comprises antiplatelet therapy.

8. 8. The method or regimen of claim 7, wherein the antiplatelet therapy comprises single-agent antiplatelet therapy.

9. 9. The method or regimen of claim 8, wherein the single agent antiplatelet therapy is aspirin, preferably aspirin administered in an amount of 75-100 mg daily.

10. 9. The method or regimen of claim 8, wherein the mono-antiplatelet therapy is a P2Y12 inhibitor, preferably clopidogrel, ticagrelor, ticlopidine, cangrelor or prasugrel, or clopidogrel administered daily in an amount of 75 mg, or ticlopidine administered daily in an amount of 250-500 mg.

11. 8. The method or regimen of claim 7, wherein the antiplatelet therapy comprises dual antiplatelet therapy.

12. 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 75-100 mg daily, and preferably wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, ticlopidine, cangrelor or prasugrel, or clopidogrel administered in an amount of 75 mg daily.

13. 8. The method or regimen of claim 7, wherein the antiplatelet therapy comprises Aggrenox (i.e., a combination of aspirin and dipyridamole (persantin)).

14. 14. The method or regimen of any one of claims 1 to 13, wherein Milvexian is administered in an amount selected from the group consisting of 25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, 200 mg twice daily, and less than 200 mg twice daily.

15. 15. The method or regimen of claim 14, wherein Milvexian is administered in an amount of 25 mg twice daily.

16. 16. The method or regimen of any one of claims 1 to 15, wherein the risk of ischemic stroke is reduced compared to administration of a placebo with standard of care, preferably the risk of ischemic stroke is reduced compared to administration of a placebo with antiplatelet therapy.

17. 17. The method or regimen of claim 16, wherein the risk of ischemic stroke when receiving the regimen divided by the risk of ischemic stroke when receiving a placebo with standard of care (i.e., the relative risk) is about 0.6 to about 0.

9.

18. 17. The method or regimen of claim 16, wherein the relative risk reduction is from about 10 to about 40%.

19. 10. The method of 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. 20. The method of any one of claims 1 to 19, wherein the relative risk of blood loss according to Bleeding Academic Research Consortium (BARC) Type 3 and Type 5 criteria is 3 or less compared to placebo with standard of care, preferably compared to placebo with antiplatelet therapy.

21. 21. The method of any one of claims 1 to 20, wherein the relative risk of blood loss according to Bleeding Academic Research Consortium (BARC) Type 2 criteria is 2.6 or less compared to placebo with standard of care, preferably compared to placebo with antiplatelet therapy.

22. 22. The method of any one of claims 1 to 21, wherein the relative risk of blood loss according to ISTH criteria (major blood loss or clinically significant non-major blood loss (CRNM)) is less than or equal to 3 compared to placebo with standard of care, preferably compared to placebo with antiplatelet therapy.

23. 23. The method or regimen of any one of claims 1 to 22, wherein the human patient does not experience blood loss according to Bleeding Academic Research Consortium (BARC) Type 3 and Type 5 criteria.

24. 24. The method or regimen of any one of claims 1 to 23, wherein administration of the regimen results in a dose-dependent reduction in FXI clotting activity in the patient relative to baseline.

25. 25. The method or regimen of any one of claims 1 to 24, wherein administration of the regimen reduces the patient's FXI clotting activity by about 7% to about 43% relative to baseline, preferably by about 7% to about 20% relative to baseline.

26. 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. 27. The method or regimen of any one of claims 1 to 26, wherein administration of the regimen results in an increase in activated partial thromboplastin time (aPTT) ranging from about 27% to about 115% relative to baseline, preferably from about 27% to 64% relative to baseline.

28. 28. The method or regimen of any one of claims 1 to 27, wherein administration does not result in a statistically significant increase in major blood loss complications.

29. 29. The method or regimen of any one of claims 1 to 28, wherein Milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered in a pharmaceutical composition that is a solid oral pharmaceutical composition, preferably the solid oral pharmaceutical composition is a tablet, or the tablet is an immediate-release tablet.

30. 30. The method or regimen of claim 29, wherein the tablet has a disintegration time in water of less than 20 seconds.

31. 31. The method of any one of claims 1 to 30, wherein the administration results in a milvexian plasma half-life ranging from about 13 hours to about 16 hours between repeat doses.

32. 32. The method of any one of claims 1 to 31, wherein administration results in a milvexian plasma concentration that reaches a steady state in about 3 to 6 days.

33. The method according to any one of claims 1 to 32, wherein Milvexian (or a pharmaceutically acceptable salt or solvate thereof) is administered without taking into consideration the timing of food intake.

34. 1. A method for reducing the risk of ischemic stroke in a human patient who is having or has had an ischemic stroke or transient ischemic attack, comprising administering to the human patient (i) a pharmaceutical composition comprising Milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 25 mg twice daily, and (ii) a regimen comprising single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT), wherein the method achieves a relative risk for ischemic stroke of about 0.6 to about 0.9 compared to placebo administration.

35. 1. A method for reducing the risk of ischemic stroke in a human patient who is having or has had an ischemic stroke or transient ischemic attack, comprising administering to the human patient (i) a pharmaceutical composition comprising Milvexian (or a pharmaceutically acceptable salt or solvate thereof) in an amount of 25 mg twice daily, and (ii) a regimen comprising single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT), wherein the method achieves a relative risk reduction for ischemic stroke of about 10% to about 40% compared to placebo administration.

36. 36. The method of claim 35, which achieves a relative risk reduction for ischemic stroke of about 28% to about 32% compared to placebo administration.

37. 36. The method of claim 35, achieving a relative risk reduction for ischemic stroke of about 30%.

38. 38. The method of any one of claims 34-37, further achieving at least one of the following safety outcomes: (i) no fatal blood loss events, equivalent to placebo dosing; (ii) no intracranial blood loss events, equivalent to placebo dosing; or (iii) an incidence of major blood loss (BARC types 3 and 5) equivalent to placebo dosing.

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

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

41. 41. Milvexian for use according to claim 40, wherein the method achieves a relative risk reduction for ischemic stroke of about 10% to about 40% compared to placebo administration.

42. 41. Milvexian for use according to claim 40, wherein the method achieves a relative risk reduction for ischemic stroke of about 28% to about 32% compared 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 blood loss events, equivalent to placebo dosing; (ii) no intracranial blood loss events, equivalent to placebo dosing; or (iii) an incidence of major blood loss (BARC types 3 and 5) equivalent to placebo dosing.

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