Treatment of atrial dysfunction

Abstract

Provided herein are methods, uses, and compositions for treating AF in patients, such as heart failure patients, with low ejection fraction.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 039,438 filed June 15, 2020, and U.S. Provisional Patent Application No. 63 / 042,512 filed June 22, 2020. The disclosures of these priority applications are incorporated herein by reference in their entirety. [Background technology]

[0002] Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting more than 37 million people worldwide. As the global population ages, the prevalence of AF is expected to increase. Individuals with AF are at increased risk of stroke, cognitive decline, cardiovascular events, and death. AF is associated with underlying conditions such as hypertension, coronary heart disease, rheumatic heart disease, heart failure, obesity, diabetes mellitus, and chronic kidney disease. Symptoms may include, but are not limited to, palpitations, tachycardia, shortness of breath, weakness, dizziness, fatigue, chest pain, and confusion.

[0003] AF is defined as a supraventricular tachyarrhythmia with uncoordinated atrial activity leading to ineffective atrial contractions, and can be caused by structural and / or electrical abnormalities of the atria. Electrocardiographic features include irregular RR intervals (if AV conduction is present), absence of distinct repetitive P waves, and irregular atrial activity. Often, episodes become more frequent and longer-lasting over time, and the response to medication decreases. Generally, there are four types of AF (January et al., JACC(2014)64(21):2246-80; Kirchhof et al., Eur Heart J.(2016)37:2893-2962). Paroxysmal AF, also known as intermittent or self-terminating AF, resolves within 7 days of onset, either spontaneously or through intervention. Persistent AF is continuous AF that lasts longer than 7 days and may require pharmacological or electrical cardiovertermination to restore sinus rhythm. Long-term persistent AF is persistent AF that lasts for 12 months or more and may not respond to medication or cardioversion. Persistent (chronic) AF is persistent AF in which the patient and physician jointly decide to discontinue attempts to restore and / or maintain sinus rhythm.

[0004] Atrial fibrillation (AF) affects the function and shape of the left atrial cavity, and vice versa. Over time, AF can lead to decreased left atrial (LA) function (e.g., LA ejection fraction (LAEF)) and atrial remodeling (e.g., fibrosis and / or potentially irreversible increases in LA volume). Furthermore, impaired LA function (e.g., LAEF) is associated with the onset of new-onset atrial fibrillation (Hirose et al., Eur Heart J. (2012) 13(3):243-50) and recurrence of atrial fibrillation after corrective procedures such as ablation. LA enlargement is strongly correlated with AF recurrence after electrical cardiovertization. The LA Dysfunction Index (LAFI), calculated from LAEF, indexed maximum LA volume, and left ventricular outflow tract velocity-time integral, is associated with adverse atrial remodeling and increases the risk of developing incidental AF and / or cardiovascular disease, even in patients with normal left atrial size (Sardana et al., J Am Soc Echocardiogr. (2017) 30(9):904-12). Observational studies have shown that LA parameters are strong independent predictors of cardiovascular outcomes, including AF (Von Jeinsen et al., J Am Soc Echocardiograph. (2019) 33(1):72-81; Schaaf et al., Eur Heart J Cardiovasc Imaging (2017) 18:46-53).

[0005] AF (Atrial Fibrosis) is often accompanied by heart failure. AF occurs in more than half of heart failure patients, while heart failure occurs in more than one-third of AF patients. Heart failure (HF) is a clinical syndrome in which a patient's heart is unable to supply enough blood flow to the body to meet its metabolic needs. In some HF patients, the heart may have difficulty pumping enough blood to support other organs in the body. Other patients may have hardening or rigidity of the myocardium itself, which blocks or reduces blood flow to the heart. These two conditions result in inadequate blood circulation to the body and pulmonary congestion. HF can affect the right side of the heart, the left side, or both sides simultaneously. HF can be either acute (short-term) or chronic (ongoing). When fluid accumulates in various parts of the body, HF may be called congestive HF. Symptoms may include, but are not limited to, excessive fatigue, sudden weight gain, loss of appetite, persistent cough, irregular pulse, chest discomfort, anguina, palpitations, edema (e.g., swelling of the lungs, arms, legs, ankles, face, hands, or abdomen), shortness of breath (difficulty breathing), prominent jugular veins, and decreased exercise tolerance or capacity. AF and HF can cause and exacerbate each other, resulting in a significantly worse prognosis and increased mortality in patients with comorbidity.

[0006] Current treatments for atrial fibrillation (AF) include strategies to control heart rate and sinus rhythm, as well as corrective measures such as surgery (e.g., ablation) and cardioversion to restore sinus rhythm. However, impairments in the function and shape of the LA contribute to AF recurrence after corrective treatment, and currently there are no treatments that directly address both atrial dysfunction and atrial enlargement. Furthermore, patients with concomitant AF and HF have a significantly poor prognosis. There are no effective treatments for the coexistence of AF and HF. In many cases, treatments that have been shown to be effective for AF alone or HF alone have low efficacy (e.g., beta-blockers) and / or have an inadequate safety and tolerability profile (e.g., class I antiarrhythmics) in patients with concomitant HF and AF (Kotecha et al., Eur Heart J(2015)36:3250-7).

[0007] Therefore, there remains a high medical need for new safe, well-tolerated, and effective therapies for improving atrial function in patients with AF, particularly when combined with systolic dysfunction such as reduced left ventricular ejection fraction (e.g., HFrEF). SUMMARY OF THE INVENTION

[0008] The present disclosure provides a method for treating atrial dysfunction in a patient in need of treatment, the method comprising administering to the patient a therapeutically effective amount of Compound I, which is the following structural formula (I):

Chemical formula

[0009] In one aspect, the present disclosure provides a method for treating atrial cardiomyopathy in a patient in need of treatment (e.g., a patient presenting with atrial dysfunction, a patient presenting with atrial fibrillation, etc.), the method comprising administering to the patient a therapeutically effective amount of Compound I.

[0010] In one aspect, the present disclosure provides a method for treating tachyarrhythmia in a patient in need of treatment (e.g., a patient presenting with atrial dysfunction, a patient presenting with atrial fibrillation, etc.), the method comprising administering to the patient a therapeutically effective amount of Compound I.

[0011] In one aspect, the present disclosure provides a method for treating atrial fibrillation in a patient in need of treatment, the method comprising administering to the patient a therapeutically effective amount of Compound I.

[0012] In one aspect, the present disclosure provides a method of reducing the recurrence of atrial fibrillation in a patient in need of treatment, the method comprising administering to the patient a therapeutically effective amount of Compound I. In some embodiments, the recurrence of atrial fibrillation is reduced by 10% or more (e.g., 20%, 30%, 40%, 50% or more, 60%, 70%, 80% or 90%, or more) in the patient.

[0013] In one aspect, the present disclosure provides a method of reducing the burden of atrial fibrillation in a patient in need of treatment, the method comprising administering to the patient a therapeutically effective amount of Compound I. In some embodiments, the burden of atrial fibrillation is reduced by 10% or more (e.g., 20%, 30%, 40%, 50% or more, 60%, 70%, 80% or 90%, or more) in the patient.

[0014] In one aspect, the present disclosure provides a method of shortening the duration of an episode of atrial fibrillation in a patient in need of treatment, the method comprising administering to the patient a therapeutically effective amount of Compound I. In some embodiments, the duration of the episode is shortened by 10% or more (e.g., 20%, 30%, 40%, 50% or more, 60%, 70%, 80% or 90%, or more) in the patient.

[0015] In one aspect, the present disclosure provides a method of reducing the number of episodes of atrial fibrillation during a monitoring period in a patient in need of treatment, the method comprising administering to the patient a therapeutically effective amount of Compound I. In some embodiments, the number of episodes of atrial fibrillation is reduced by 10% or more (e.g., 20%, 30%, 40%, 50% or more, 60%, 70%, 80% or 90%, or more) in the patient.

[0016] In one embodiment, the present disclosure provides a method for maintaining sinus rhythm in a patient requiring treatment, the method comprising administering a therapeutically effective amount of compound I to the patient. In some embodiments, the patient has had atrial tachyarrhythmia for 12 months or less (e.g., 9, 6, or 3 months or less) prior to the administration step. In some embodiments, the atrial tachyarrhythmia is atrial fibrillation.

[0017] In one embodiment, the present disclosure provides a method for restoring sinus rhythm in a patient presenting with atrial tachyarrhythmia, the method comprising administering a therapeutically effective amount of compound I to the patient in combination with a cardiovertermination (e.g., electrical cardiovertermination). In some embodiments, the atrial tachyarrhythmia is atrial fibrillation.

[0018] In one embodiment, the present disclosure provides a method for preventing tachycardia-induced cardiomyopathy in a patient presenting with atrial fibrillation, the method comprising administering a therapeutically effective amount of compound I to the patient. In some embodiments, tachycardia-induced cardiomyopathy is heart failure (e.g., heart failure with reduced ejection fraction (HFrEF)).

[0019] In some embodiments of this method, the patient has left atrial enlargement. In some embodiments, this method includes selecting a patient with left atrial enlargement for treatment with compound I.

[0020] The disclosure also provides a pharmaceutical composition comprising Compound I and a pharmaceutically acceptable excipient; Compound I and a pharmaceutical composition for use in any one of the therapeutic methods described herein; and the use of Compound I for manufacturing a drug for use in any of the therapeutic methods described herein.

[0021] Other features, purposes, and advantages of the present invention will become apparent in the detailed description below. However, it should be understood that the detailed description, while illustrating embodiments and aspects of the present invention, is given only as examples and not as a limitation. Various changes and modifications within the scope of the present invention will become apparent to those skilled in the art from the detailed description. [Brief explanation of the drawing]

[0022] [Figure 1] This is a series of graphs showing the effect of compound I on ex vivo ATP turnover (ATPase) rate in LV and LA porcine myofibrils. Compound I increases ATP metabolism (ATPase) rate in LV and LA porcine myofibrils (Panel A), increases Ca2+ sensitivity in the fibers (Panels B and C; Panel B: LV dilation / pCa curve), and maintains stiffness (Panel D). Panels A-D: Mean + SEM. CTRL, control; LA, left atrium; LV, left ventricle; pCa, Ca2+ sensitivity. [Figure 2] These are a pair of graphs showing the effects of compound I on SET, left atrial function, and shape in vivo in dogs with induced heart failure. Compound I prolonged SET, increased systolic LV function indicators and stroke volume (Panel A), and reduced LA size and improved performance (Panel B). Panels A and B: ±SEM. 5HR, 5 hours post-treatment; LA, atrium; LAEF, left atrial ejection fraction; LAFI, left atrial function index; LV, left ventricle; LVFS, left ventricular diameter shortening percentage; LVSV, left ventricular stroke volume; PRE, pre-administration (i.e., baseline); SET, systolic ejection time. [Figure 3] This is a schematic diagram showing the experimental plan for the effects of compound I on AF-inducing ability and the size and function of the LA in beagle dogs in the presence of phenylephrine. AFIB: Atrial fibrillation. NSR: Normal sinus rhythm. PE: Phenylephrine. [Figure 4] This is a series of graphs showing the effects of compound I on systolic blood pressure (SBP), left atrial minimum volume (LAVolmin), left atrial ejection fraction (LAEF), and duration of atrial fibrillation (AFduration) in dogs treated with the AF-inducing protocol described in Example 3. CPDI: Compound I. PACE: Pace Burst. PE: Phenylephrine. PRE: Prior Treatment. [Figure 5]This is a schematic diagram showing the experimental plan for the effects of dobutamine on AF-inducing ability and LA size and function in beagle dogs in the presence of phenylephrine. AFIB: Atrial fibrillation. NSR: Normal sinus rhythm. PE: Phenylephrine. [Figure 6] The graphs (from left to right) show a comparison of left ventricular ejection fraction (ΔEF) changes between Compound I and dobutamine in dogs treated with the AF-inducing protocol described in Example 3, as well as the effects of dobutamine on left atrial minimum volume (LAVolmin), left atrial ejection fraction (LAEF), and duration of atrial fibrillation (AFduration). CPDI: Compound I. DOB: Dobutamine. PE: Phenylephrine. PRE: Prior treatment [Figure 7A] This is a schematic diagram showing the clinical trial design for treating HFrEF with compound I. BID: twice daily; MAD: multiple dose escalations; SAD: single dose escalation; SRC: Safety Review Committee. [Figure 7B] This is a schematic diagram showing the clinical trial design for treating HFrEF with compound I. BID: twice daily; MAD: multiple dose escalations; SAD: single dose escalation; SRC: Safety Review Committee. [Figure 8] This graph shows the change in LAFI from baseline based on the plasma concentration of compound I. The lines shown are generated using the nonparametric LOESS (locally estimated scatter plot smoothing) method. Detailed description of the invention

[0023] This disclosure provides methods, uses, and compositions relating to the treatment of patients with atrial dysfunction (e.g., AF), including patients with co-occurring atrial dysfunction and systolic dysfunction (impairment of the cardiac contractile function; e.g., decreased left ventricular ejection fraction, e.g., decreased HFrEF).

[0024] Pharmaceutical composition The pharmaceutical composition used in this treatment method contains compound I as the active pharmaceutical ingredient (API). Compound I has the following chemical structure (I): [ka] Compound I refers to compound (R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazole-3-yl)piperidine-1-carboxamide or any pharmaceutically acceptable salt thereof. Compound I is a myosin modulator that increases cross-bridge formation (measured as phosphate release) between actin and myosin in the heart. Cross-bridge formation and separation are critical steps in each cycle of cardiac contraction. Compound I can increase contraction by increasing the number of myosin / actin cross-bridges that reversibly bind to myosin and can participate in the strong binding state of the chemodynamic cycle. However, compound I does not inhibit cross-bridge separation (measured as ADP release) and therefore does not affect other states of the contraction cycle or calcium homeostasis. Compound I partially improves atrial function by improving (e.g., increasing) the contractility of atrial cardiomyocytes (i.e., atrial contractility) without adversely affecting other important attributes of cardiovascular function.

[0025] The pharmaceutical compositions used herein may be provided in oral dosage forms (e.g., liquids, suspensions, emulsions, capsules, or tablets). In some embodiments, particles of compound I are compressed into tablets containing 5, 25, 50, 75, 100, 125, 150, 175, or 200 mg of compound I, respectively. In some embodiments, particles of compound I may be suspended in a suitable liquid such as water, a suspension vehicle, and / or an orally administered flavor syrup.

[0026] Compound I API solids in tablets or oral suspensions may have average particle sizes of, for example, 1–100, 1–50, or 15–50 μm in diameter (e.g., 1–5, 5–10, 1–10, 10–20, or 15–25 μm). In some embodiments, Compound I has an average particle size of 30, 25, 20, 15, 10, or 5 μm or less in diameter. In some embodiments, Compound I API solids have an average particle size of 15–25 μm in diameter with respect to the particle size distribution (PSD) of D50 (i.e., 50% of the particles have a particle size of 15–25 μm in diameter). In certain embodiments, Compound I has an average particle size of 10 μm or less in diameter, e.g., D50 of 10 μm or less (NMT). In certain embodiments, Compound I has an average particle size of 5 μm or less in diameter, e.g., D50 of 5 μm or less (NMT). Particle size analysis is typically performed using the PSD method, which is suitable for determining the particle size of primary particles. Ultrasound may be used to reduce aggregates. The PSD technique used to measure particle size should not itself cause a change in primary particle size. In some embodiments of this disclosure, the PSD method was performed using a Malvern Mastersizer 2000, with and without ultrasound.

[0027] In addition to Compound I API, the pharmaceutical compositions of this disclosure may also contain pharmaceutically acceptable excipients. For example, tablets used herein may contain bulking agents, diluents, binders, flow enhancers, lubricants, and disintegrants. In some embodiments, Compound I tablets contain one or more of microcrystalline cellulose, lactose monohydrate, hypromellose, croscarmellose sodium, and magnesium stearate. The tablets may be coated to facilitate administration.

[0028] Patient group The therapies described herein may be used to treat patients presenting with atrial dysfunction. For example, a patient may present with atrial fibrillation. Abnormal atrial contraction, volume, function, and / or atrial cardiomyopathy may contribute to atrial dysfunction.

[0029] In this specification, a patient may be, for example, 18 years of age or older.

[0030] Left ventricular dysfunction is seen in 20–30% of AF patients. In some cases, patients present with both atrial dysfunction (e.g., atrial fibrillation) and systolic dysfunction (also known as ventricular systolic dysfunction). Systolic dysfunction may include, for example, a reduced left ventricular ejection fraction (e.g., HFrEF). Patients may or may not have received prior treatment for atrial dysfunction and / or systolic dysfunction. The amount of blood pumped by the heart is generally determined by: (a) myocardial contraction (i.e., how well the heart contracts, or its systolic function) and (b) ventricular filling (i.e., how well the heart relaxes and fills with blood, or its diastolic function). Ejection fraction is used to assess the pumping function of the heart; it represents the percentage of blood pumped out of the left ventricle (the main pumping chamber) in a single beat. A normal or retained ejection fraction is 50% or greater. When the heart's contractile function is impaired and the heart exhibits a significant decrease in ejection fraction (i.e., ejection fraction < 50%), this condition is known as reduced ejection fraction heart failure (HFrEF). According to the 2013 American College of Cardiology Foundation / American Heart Association guidelines (Yancy et al., Circulation (2013) 128:e240-327) and the 2019 ACC Expert Consensus Decision Pathway on Risk Assessment, Management, and Clinical Trajectory of Patients Hospitalized With Heart Failure (Hollenberg et al., J Am Coll Cardiol (2019) 74:1966-2011), HFrEF with an ejection fraction ≤ 40% is classified as classic HFrEF, while HFrEF with an ejection fraction of 41-49% is classified as heart failure with intermediate ejection fraction (HFmrEF). In certain embodiments, patients present with both atrial dysfunction (e.g., atrial fibrillation) and diastolic dysfunction. In some cases, patients may present with atrial dysfunction (e.g., atrial fibrillation), systolic dysfunction, and diastolic dysfunction.

[0031] Atrial dysfunctions treated include, but are not limited to, atrial cardiomyopathy (e.g., left atrial myopathy) and atrial arrhythmias such as AF or atrial flutter (e.g., atrial tachyarrhythmias). Atrial dysfunction (e.g., atrial tachyarrhythmias) can be acute or chronic. In certain embodiments, a patient may have had atrial dysfunction (e.g., atrial tachyarrhythmias such as AF) for a period prior to treatment of the present disclosure, such as 9 years, 8 years, 7 years, 6 years, 5 years, 4 years, 3 years, 2 years, 12 months, 9 months, 6 months, 3 months, 1 month, 2 weeks, or 1 week.

[0032] In some embodiments, a patient may have AF, which may be clinically manifest or asymptomatic. When AF cases are caused by a heart valve disorder, they are called valvular AF. AF that is not diagnosed with a heart valve disorder is called non-valvular AF. For example, in some embodiments, non-valvular AF is AF without rheumatic mitral stenosis, mechanical or bioprosthetic heart valves, or mitral valve repair. In terms of timing and duration, the AF being treated may be, for example, paroxysmal, persistent, or long-lasting. In some cases, AF is persistent but not long-lasting AF; that is, it lasts for no more than 12 months. In certain embodiments, a patient's AF load is 1-70%, 2-70%, 3-70%, 1-99%, or 2-99%. Unless otherwise stated, AF load refers to the amount of AF an individual has. In some embodiments, AF load may be quantified as the percentage of time a patient is in AF during the monitoring period. In some embodiments, AF load can be quantified as the duration of the patient's longest AF episode or the number of AF episodes during the monitoring period.

[0033] In some embodiments, the patient further has one or more conditions selected from sleep apnea, hypertension, hyperlipidemia, hyperthyroidism, obesity, diabetes mellitus, impaired glucose tolerance, alcohol use, tobacco use, previous myocardial infarction, chronic obstructive pulmonary disease, heart failure, coronary heart disease, rheumatic heart disease, valvular heart disease, non-valvular heart disease, left ventricular hypertrophy, left ventricular diastolic dysfunction, and renal disease.

[0034] In some embodiments, the patient has a genetic predisposition to AF, such as hereditary cardiomyopathy or channelopathy.

[0035] In some embodiments, the patient has postoperative AF, i.e., AF that develops in the period immediately following surgery (e.g., cardiac surgery).

[0036] In some embodiments, the patient has an implantable device equipped with an atrial lead (e.g., pacemaker, ICD, CRT) or an implantable loop recorder (ILR).

[0037] In some embodiments, the patient has a revised European Heart Rhythm Association (EHRA) symptom score of 1, 2a, 2b, 3, or 4, as defined in Table 1 below. [Table 1]

[0038] In some embodiments, patients have been or are currently being treated with anticoagulants, rate control agents, or rhythm control agents, or have undergone physical interventions such as ablation (e.g., catheter ablation, surgical ablation, etc.), or cardioversion (e.g., electrical cardioversion or pharmacological cardioversion), or any combination thereof, but continue to exhibit AF symptoms. Such symptoms may include, for example, palpitations, tachycardia, fatigue, dizziness, weakness, chest discomfort, decreased exercise capacity, increased urination, shortness of breath, anguina, presyncope, syncope, sleep disturbances, confusion, and psychosocial stress, or any other AF symptoms described herein.

[0039] In certain embodiments, the treatment methods of this disclosure are used to treat patients with atrial dysfunction (e.g., AF such as paroxysmal or persistent AF), the patients having one or a combination of the following: - An implantable device equipped with an atrial lead (pacemaker, ICD, CRT) or an implantable loop recorder (ILR), the device / ILR may have a remote data transmission function; - The recorded AF load is between 2% and 70% (for example, continuously for more than two weeks); -This is a clinical diagnosis of AF (based on electrocardiogram findings) and not due to a temporary condition (such as post-operative symptoms); - No evidence of at least one episode of persistent AF within the last six months (based on medical records, or 12-lead electrocardiogram, or Holter or patch-based AF episodes lasting more than 10 minutes, or previous electrical cardiography), and no evidence of long-term persistent or permanent AF.

[0040] In some embodiments, the patient does not have any one or combination of the following: a) AF load at screening <2% or >70%; b) AF with a reversible etiology (e.g., thyroid disease, alcohol, pulmonary embolism, early postoperative period, acute pericarditis, trauma, etc.); c) Pulmonary hypertension treated with pulmonary vasodilators (e.g., endothelin receptor antagonists, PDE5 inhibitors, etc.); d) Known channel disorders (e.g., long QT syndrome, Brugada syndrome, CPVT, etc.); e) Long-term persistent or permanent atrial fibrillation; f) Atrial fibrillation diagnosed more than 10 years prior to the start of treatment; g) LA diameter>60mm; h) Catheter ablation within six months prior to the start of treatment, or planned or possible catheter ablation during treatment; i) Initiation of a new antiarrhythmic therapy less than one month prior to the start of treatment, or planning to initiate a new antiarrhythmic therapy during treatment; j) The patient has undergone electrocardioversion less than one month prior to the start of treatment; k) NYHA class IV heart failure; l) Symptomatic hypotension or systolic blood pressure <90 mmHg or diastolic blood pressure >95 mmHg; m) Severe aortic valve disease or mitral stenosis, planned or anticipated mitral valve clipping or mitral valve repair during treatment, hypertrophic or infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis, or clinically significant congenital heart disease; n) A major cardiovascular event within 90 days prior to the start of treatment, wherein the cardiovascular event is optionally acute coronary syndrome or stroke; o) A cardiovascular intervention within 90 days prior to the start of treatment, which may optionally be CABG, PCI, or valve repair; p) Implantation of a device within 45 days prior to the start of treatment, the device being optionally a pacemaker or CRT; q) Hospitalization for heart failure or treatment with an IV inotropic agent within 90 days prior to the start of treatment; r) End-stage heart failure; or s) Average life expectancy is less than 6 months.

[0041] If a patient presents with systolic dysfunction in addition to the types of atrial dysfunction described herein (e.g., AF), the systolic dysfunction may be ventricular dysfunction, such as left ventricular dysfunction. Systolic dysfunction may include, for example, reduced left ventricular ejection fraction (LVEF), heart failure (e.g., heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), congestive heart failure, or diastolic heart failure (with reduced systolic reserve)), cardiomyopathy (e.g., ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy (e.g., progressive hypertrophic cardiomyopathy), post-infarction cardiomyopathy, viral cardiomyopathy, toxic cardiomyopathy (optionally, after anthracycline-based anticancer therapy), or metabolic cardiomyopathy (optionally, in combination with enzyme replacement therapy). It may be a syndrome or disorder selected from the group consisting of infiltrative cardiomyopathy (which may also be amyloidosis) and diabetic cardiomyopathy, cardiogenic shock, conditions benefiting from the inotropic effect after cardiac surgery (e.g., ventricular dysfunction due to on-bypass cardiovascular surgery), myocarditis (e.g., viral myocarditis), atherosclerosis, secondary aldosteronism, myocardial infarction, valvular disease (e.g., mitral regurgitation or aortic stenosis), systemic hypertension, pulmonary hypertension or pulmonary artery hypertension, adverse vascular remodeling, pulmonary edema, and respiratory failure.

[0042] The patient may experience systolic heart failure of the left ventricle, right ventricle, or both ventricles. In some embodiments, the patient has right ventricular heart failure. In some embodiments, the patient has pulmonary hypertension (i.e., pulmonary artery hypertension).

[0043] Systolic heart failure may be characterized by a decreased ejection fraction, for example, a decreased left ventricular ejection fraction (e.g., less than approximately 50%, 45%, 40%, or 35%, e.g., LVEF 15–35%, 15–40% (e.g., 15–39%), 15–49%, 20–40%, 20–45%, 20–49%, 40–49%, and 41–49%), and / or increased ventricular end-diastolic pressure and volume.

[0044] In some embodiments, patients have HFrEF (i.e., ejection fraction < 50%). Heart failure with an ejection fraction of 40% or less is classified as classical HFrEF, and heart failure with an ejection fraction of 41–49% is classified as heart failure with intermediate ejection fraction (HFmrEF). Patients may have a left ventricular ejection fraction (LVEF) that is less than 50%, e.g., less than 45%, 40%, 35%, 30%, 25%, 20%, or 15% lower. In certain embodiments, patients have an LVEF of 45% or less (e.g., 20–45%), 40% or less (e.g., 15–40%, 25–40%, 15–39%, or 25–39%), or 35% or less (e.g., 15–35%). HFrEF can be of ischemic or non-ischemic origin and can be chronic or acute.

[0045] In some embodiments, the patient has stable HF, e.g., stable HFrEF. As used herein, a patient who is “stable” with respect to the disease means a patient who has the disease and has not experienced any exacerbations of symptoms that could lead to hospitalization or an emergency visit. For example, a patient with stable HF may have impaired systolic function, but the symptoms of dysfunction can be controlled or stabilized using available therapies.

[0046] In some embodiments, the patient has stable HFrEF (e.g., stable chronic HFrEF of moderate severity) as defined by one or both of the following: (i) LVEF less than 50%; (ii) long-term medication for the treatment of heart failure consistent with current guidelines; this may include at least one of beta-blockers, ACE inhibitors, ARBs, and ARNIs.

[0047] In some embodiments, the patient has paroxysmal or persistent AF with a normal left ventricular ejection fraction (e.g., 50% to less than 60%). In certain embodiments, the patient has heart failure with AF (e.g., paroxysmal or persistent) and a retained ejection fraction (e.g., 50% to less than 60%). In certain embodiments, the patient has AF (e.g., paroxysmal or persistent) and a normal left ventricular ejection fraction without heart failure.

[0048] In some embodiments, the therapies of this disclosure may be used to treat patients presenting with dilated cardiomyopathy (DCM) (e.g., idiopathic DCM or genetic DCM). In certain embodiments, the patient has dilated left or right ventricle, ejection fraction less than 50% (e.g., ≤40%), and no known coronary artery disease. The DCM may be genetic DCM, where the patient has at least one gene mutation in sarcomere contraction or structural proteins known to cause DCM (e.g., myosin heavy chain, titin, or troponin T) (see, e.g., Hershberger et al., Nat Rev Cardiol. (2013) 10(9):531-47 and Rosenbaum et al., Nat Rev Cardiol. (2020) 17(5):286-97). In some embodiments, the gene mutation is located in a gene selected from ABCC9, ACTC1, ACTN2, ANKRD1, BAG3, CRYAB, CSRP3, DES, DMD, DSG2, EYA4, GATAD1, LAMA4, LDB3, LMNA, MYBPC3, MYH6, MYH7, MYPN, PLN, PSEN1, PSEN2, RBM20, SCN5A, SGCD, TAZ, TCAP, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, VCL, or any combination thereof. For example, the gene mutation is located in a gene selected from ACTC1, DES, MYH6, MYH7, TNNC1, TNNI3, TNNT2, TTN, or any combination thereof. In certain embodiments, the gene mutation is located in the MYH7 gene or the TTN gene.

[0049] In some embodiments, patients treated with the therapies described herein have been treated with or are being treated with Enresto® and / or omecamutib, but continue to exhibit symptoms of systolic heart failure. In some embodiments, patients have been treated with or are being treated with an ACE inhibitor or ARB or ARNI in combination with a beta-blocker and optionally an aldosterone antagonist (wherein these agents may be selected, for example, from those described herein), but continue to exhibit symptoms of systolic heart failure.

[0050] In some embodiments, patients treated with the therapies described herein have New York Heart Association (NYHA) class I, II, III, or IV heart failure, as defined in Table 2 below. In certain embodiments, patients have NYHA class II–IV heart failure. [Table 2]

[0051] The therapies of this disclosure may be used to treat patients with AF with or without systolic dysfunction (e.g., reduced left ventricular ejection fraction). In certain embodiments, the therapies of this disclosure may be used to treat patients with AF and reduced left ventricular ejection fraction less than 50% (e.g., HFrEF). For example, the therapy may be used in patients with AF and reduced left ventricular ejection fraction less than 50% (e.g., HFrEF) to maintain sinus rhythm (e.g., normal sinus rhythm) and / or in patients with AF and reduced left ventricular ejection fraction less than 50% (e.g., HFrEF) to reduce the recurrence of atrial fibrillation. In certain embodiments, the patient has paroxysmal or persistent AF. In some cases, the therapy may be used in patients with AF (e.g., paroxysmal or persistent AF) to maintain sinus rhythm (e.g., normal sinus rhythm) and / or in patients with AF (e.g., paroxysmal or persistent AF) to reduce the recurrence of atrial fibrillation.

[0052] In some embodiments, the therapies of the present disclosure may be used to treat patients with atrial insufficiency (e.g., AF) in combination with a reduced left ventricular ejection fraction (e.g., HFrEF) indicating mitral regurgitation. In some embodiments, the mitral regurgitation is chronic. In some embodiments, the mitral regurgitation is acute.

[0053] In certain embodiments, the treatment methods of the present disclosure are used to treat patients having atrial dysfunction (e.g., AF such as paroxysmal or persistent AF) and systolic dysfunction (e.g., reduced left ventricular ejection fraction such as HFrEF), the patients having any one or a combination of the following: - A decrease of less than 50% in LVEF recorded within the past 12 months and at least 30 days thereafter. 1) Hospitalization due to an event that is likely to reduce ejection fraction (e.g., acute coronary syndrome / myocardial infarction, sepsis, etc.); 2) Interventions that are likely to increase EF (e.g., cardiac resynchronization therapy, coronary revascularization); or 3) HF's initial presentation; -HFrEF with concomitant LVEF ≤ 40%, patients are treated with one or a combination of beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and angiotensin receptor neprilysin inhibitors (ARNIs); - At the start of treatment, NT-proBNP ≥ 150 pg / mL or ≥ 100 pg / mL if the patient has a high BMI or is Black; - An implantable device equipped with an atrial lead (pacemaker, ICD, CRT) or an implantable loop recorder (ILR), the device / ILR may have a remote data transmission function; -The recorded AF load is 2-70% (for example, continuously for more than two weeks); and -This is a clinical diagnosis of AF (based on electrocardiogram findings) and not due to a temporary condition (such as post-surgery); and - No evidence of at least one episode of persistent AF within the last six months (based on medical records, or 12-lead electrocardiogram, or Holter or patch-based AF episodes lasting more than 10 minutes, or previous electrical cardiography), and no evidence of long-term persistent or permanent AF. In some embodiments, the patient does not have any one or combination of the following: a) AF load <2% or >70%; b) AF with a reversible etiology (e.g., thyroid disease, alcohol, pulmonary embolism, early postoperative period, acute pericarditis, trauma, etc.); c) Pulmonary hypertension treated with pulmonary vasodilators (e.g., endothelin receptor antagonists, PDE5 inhibitors, etc.); d) Known channel disorders (e.g., long QT syndrome, Brugada syndrome, CPVT, etc.); e) Long-term persistent or permanent atrial fibrillation; f) AF diagnosed more than 10 years before the start of treatment; g) LA diameter>60mm; h) Catheter ablation within six months prior to the start of treatment, or planned or possible catheter ablation during treatment; i) Initiation of a new antiarrhythmic therapy less than one month prior to the start of treatment, or planning to initiate a new antiarrhythmic therapy during treatment; j) The patient has undergone electrocardioversion less than one month prior to the start of treatment; k) NYHA class IV heart failure; l) Symptomatic hypotension or systolic blood pressure <90 mmHg or diastolic blood pressure >95 mmHg; m) Severe aortic valve disease or mitral stenosis, planned or anticipated mitral valve clipping or mitral valve repair during treatment, hypertrophic or infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis, or clinically significant congenital heart disease; n) A major cardiovascular event within 90 days prior to the start of treatment, wherein the cardiovascular event is optionally acute coronary syndrome or stroke; o) A cardiovascular intervention within 90 days prior to the start of treatment, which may optionally be CABG, PCI, or valve repair; p) Implantation of a device within 45 days prior to the start of treatment, the device being optionally a pacemaker or CRT; q) Hospitalization for heart failure or treatment with an IV inotropic agent within 90 days prior to the start of treatment; r) End-stage heart failure; or s) Average life expectancy is less than 6 months.

[0054] In some embodiments, patients treated by the treatment described herein (e.g., patients with atrial dysfunction and / or systolic dysfunction as described herein) have left atrial enlargement (LAE). In certain embodiments, the left atrium is considered enlarged if: - Left atrium diameter (LAD) >4.1 cm in male patients and >3.9 cm in female patients; -LA min Vi is >19 mL / m³ 2 ; -LA max Vi is >41 mL / m³ 2 ; -LAEF is ≤45%; or - Any combination of the above. For example, a patient may have a left atrial diameter (LAD) of 4.1–6.0 cm (male) or 3.9–6.0 cm (female). In some embodiments, a patient may have a left atrial diameter (LAD) of 4.1–5.5 cm (male) or 3.9–5.5 cm (female). In certain embodiments, a patient may have relatively mild left atrial enlargement (e.g., 4.1–4.6 cm (male) or 3.9–4.2 cm (female)). In certain embodiments, a patient may have relatively moderate left atrial enlargement (e.g., 4.7–5.1 cm (male) or 4.3–4.6 cm (female)). In certain embodiments, a patient may have relatively severe left atrial enlargement (e.g., ≥5.2 cm (male) or ≥4.7 cm (female)). In some embodiments, the treatment method includes the step of selecting a patient with LAE for treatment with compound I; this selection may be based, for example, on echocardiography.

[0055] The treatments described herein may include the step of selecting patients having the type of atrial dysfunction described herein (e.g., AF). In some embodiments, patients are further selected as having the type of systolic dysfunction described herein (e.g., reduced left ventricular ejection fraction, such as HFrEF).

[0056] In some embodiments, patients treated by the treatment methods described herein have previously been treated for atrial dysfunction and / or systolic dysfunction, or are currently being treated for standard treatment(s) for the above condition, and have not shown adequate improvement with such treatment.

[0057] In some embodiments, patients treated by the treatment methods described herein have previously received treatment for AF with the therapeutic agents or interventions described herein. In certain embodiments, patients have undergone ablation (e.g., catheter ablation) or cardioversion (e.g., electrical cardioversion), and are therefore post-ablation or post-cardioversion.

[0058] Treatment regimen design The Compound I therapy described herein may treat atrial dysfunction (e.g., AF) in a patient. In certain embodiments, the patient may also have systolic dysfunction, such as reduced left ventricular ejection fraction (e.g., HFrEF). The patient may receive the therapy of this disclosure for at least one month, at least six months, at least twelve months, at least one year, or longer, or until the patient no longer requires treatment.

[0059] In some embodiments of this therapy, compound I is administered in a total daily oral dose of 10 to 700 mg (e.g., 50 to 150 mg). For example, compound I may be administered in a total daily oral dose of 10, 25, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 500, 525, 550, 600, or 700 mg. In another example, compound I may be administered in a total daily oral dose of 50, 100, or 150 mg. In one embodiment, compound I is administered orally in doses of 10 to 175 mg (e.g., 10, 25, 30, 35, 37.5, 40, 45, 50, 55, 60, 62.5, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, or 175 mg) twice daily. For example, compound I may be administered orally in doses of 10 to 75 mg (e.g., 10 mg, 25 mg, 50 mg, or 75 mg) twice daily. In another embodiment, compound I is administered in doses of 25-350 mg QD (once daily) (e.g., 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, It is administered orally in doses of 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, or 350 mg. For example, compound I can be administered orally in 50-150 mg (e.g., 50 mg, 100 mg, or 150 mg) QDs. The interval between BID doses is approximately 10-12 hours, for example, if possible (e.g., morning and evening).

[0060] When used herein, the administration of Compound I or a pharmaceutical composition containing Compound I ("Compound I Drug") includes self-administration by the patient (e.g., oral ingestion by the patient).

[0061] In some embodiments, the patient orally ingests a loading dose of compound I with or without food, then approximately 10–12 hours later, takes a maintenance dose (e.g., the doses described above) with or without food, and then continues with the recommended daily maintenance dose regimen (e.g., morning and evening in the case of a BID regimen) with or without food. The loading dose may be, for example, 1.5 times the maintenance dose in a QD regimen and 2 times the maintenance dose in a BID regimen. In some embodiments, the loading dose is, for example, 50–250 mg of compound I relative to a maintenance dose of 25–75 mg BID or 50–150 mg QD.

[0062] In some embodiments, the absorption of compound I by the patient may be facilitated by food. In some embodiments, the food is high in fat; i.e., more than 50% of the calories in the food come from fat. In some embodiments, when compound I is taken with food (e.g., a high-fat diet), the average particle size of compound IAPI exceeds 15 μm in diameter, and the QD dose exceeds about 200 mg. In some embodiments, the total daily dose of compound I required by the patient when the drug is taken in a food context (e.g., within about 2 hours of food, within about 1.5 hours of food, or within about 1 hour of food) may be less than the total daily dose required by the patient when not taken in a food context. "Within about X hours of food" means about X hours before the start of food intake or after the end of food intake.

[0063] In certain embodiments, tablets or capsules of compound I are taken orally by the patient with food or within about two hours of food (e.g., within about one and a half hours or about one hour of food). In some embodiments, the patient takes the drug orally once a day with a meal. In some embodiments, the patient takes the drug twice a day with meals. For example, the patient may take the drug with breakfast and dinner. In some embodiments, the drug may be taken with a glass of beverage such as water or milk (e.g., whole milk), if desired.

[0064] In some embodiments, the compound IAPI in the drug is micronized to have an average particle size of 10 μm or less in diameter (D50 of 10 μm or less (NMT)) or 5 μm or less in diameter (D50 of 5 μmNMT). In certain embodiments, if the compound I particles in the drug have a D50 of 5 μmNMT or D50 of 10 μmNMT, the drug can be taken orally by the patient twice a day (e.g., every 10-12 hours, or morning and evening), with or without food.

[0065] The dosage used for a particular patient may be adjusted based on the patient's condition and / or patient-specific PK profile. Current studies have shown that the dosages and exposures of the tested drugs are safe and well-tolerated. In some embodiments, compound I may be administered to a patient at doses resulting in plasma concentrations of 1000–8000 ng / mL (e.g., 1000–2000 ng / mL, 1500–3000 ng / mL, 2000–3000 ng / mL, 3000–4000 ng / mL, 3000–4500 ng / mL, 3500–5000 ng / mL, 4000–5000 ng / mL, 5000–6000 ng / mL, 6000–7000 ng / mL, or 7000–8000 ng / mL). In some embodiments, compound I may be administered to a patient at a plasma concentration of less than 2000 ng / mL, 2000–3500 ng / mL, or greater than 3500 ng / mL (e.g., 2000–3500 ng / mL). In some embodiments, compound I may be administered to a patient at a dose such that the plasma concentration of compound I is greater than 1500 ng / mL, 2000, 2250, 2500, 2750, 3000, 3500, 4000, 5000, 6000, or 7000 ng / mL. In some embodiments, the target plasma concentration of compound I is 1000–4000 ng / mL. In certain embodiments, the target plasma concentration of compound I is 1500–3500 ng / mL. In certain embodiments, the target plasma concentration of compound I is 2000–3500 ng / mL. The plasma concentration of compound I can be determined by any method known in the art, such as high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC-MS, e.g., high-performance LC-MS), gas chromatography (GC), or any combination thereof.

[0066] In some embodiments, the treatment described herein includes monitoring the patient for adverse events such as headache, lethargy, chest discomfort, bradycardia, heart block, sinus tachycardia, ventricular tachycardia, palpitations, cardiac arrhythmias, elevated NT-proBNP levels, elevated troponin levels, and myocardial ischemia. If a severe adverse event occurs, the patient may receive treatment for the adverse event and / or discontinue treatment with compound I.

[0067] Combination therapy This disclosure provides both monotherapy and combination therapy of compound I. In combination therapy, the compound I regimen of this disclosure is used in combination with an additional treatment regimen, e.g., guideline-based medical therapy (GDMT), also known as standard-of-care (SOC) therapy, or other treatments useful for treating an associated disease or disorder, for one or more cardiac conditions presented by the patient. The additional therapeutic agent may be administered at or at doses commonly used for that agent, depending on the route, and may be administered concurrently with, sequentially with, or together with compound I.

[0068] In some embodiments, compound I is administered in addition to SOC for atrial dysfunction conditions such as atrial fibrillation, systolic dysfunction conditions such as systolic heart failure and / or reduced left ventricular ejection fraction; or both.

[0069] In certain embodiments, patients presenting with atrial insufficiency (e.g., atrial fibrillation) are given another therapeutic agent to treat the atrial insufficiency in addition to the drug of compound I. In some embodiments, the therapeutic agent is an antithrombotic agent (e.g., an anticoagulant such as a NOAC), a rate control agent, an antiarrhythmic agent (e.g., a class Ia, Ic, or III antiarrhythmic agent), a pharmacological cardioverter, or an RAAS inhibitor. In some embodiments, the drug of compound I is administered to patients who have undergone or are scheduled to undergo a non-pharmacological intervention such as electrical cardiovertermination, left atrial adnexal occlusion (e.g., using a Watchman device) or resection, atrioventricular nodal ablation (e.g., with permanent ventricular pacing), catheter ablation, surgical ablation (e.g., Maze procedure), hybrid catheter and surgical ablation, pulmonary vein ablation, or a permanent pacemaker. Any combination of the above drugs and interventions is also intended.

[0070] In some embodiments, the patient is administered a compound I drug instead of an antiarrhythmic agent. The patient may have received prior treatment with an antiarrhythmic agent and be subsequently replaced with a compound I drug, or the patient may be treated with a compound I drug without prior treatment with an antiarrhythmic agent.

[0071] In some embodiments, patients with atrial insufficiency (e.g., AF) are treated with compound I drugs in addition to ablation (e.g., catheter ablation, surgical ablation, etc.). In certain cases, patients are treated with compound I drugs after ablation (e.g., after catheter ablation).

[0072] In some embodiments, patients with atrial insufficiency (e.g., AF) are treated with an anticoagulant (e.g., NOAC) in combination with a rate control agent (e.g., a beta-blocker, digoxin, and / or amiodarone) in addition to compound I drugs.

[0073] In some embodiments, patients with atrial insufficiency (e.g., AF) are treated with compound I drugs in addition to cardioversion (e.g., electrical cardioversion). In certain cases, patients are treated with compound I drugs after cardioversion (e.g., after electrical cardioversion).

[0074] In some embodiments, patients with atrial insufficiency (e.g., AF) are treated with cardiovertermination (e.g., electrical cardiovertermination) in combination with a compound I drug and an antiarrhythmic drug (e.g., amiodarone, sotalol, or dofetilide).

[0075] In some embodiments, patients with atrial insufficiency (e.g., AF) are treated with ablation (e.g., catheter ablation, surgical ablation, etc.) and antiarrhythmic therapy.

[0076] In certain embodiments, patients presenting with atrial insufficiency (e.g., AF) in addition to systolic insufficiency (e.g., HFrEF, or reduced left ventricular ejection fraction) are given, in addition to compound I drug, optionally, a therapeutic agent for treating atrial insufficiency described herein, another therapeutic agent for treating systolic insufficiency. In some embodiments, the therapeutic agent is a beta-blocker, angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor antagonist (e.g., angiotensin II receptor blocker), angiotensin receptor neprilysin inhibitor (ARNI) (e.g., sacubitril / valsartan), mineralocorticoid receptor antagonist (e.g., aldosterone antagonist), cholesterol-lowering agent (e.g., statin), I fThese include channel inhibitors (e.g., ivabradine), neutral endopeptidase inhibitors (NEPi), positive inotropes, potassium or magnesium, proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors, vasodilators, diuretics (e.g., loop diuretics such as furosemide), RAAS inhibitors, soluble guanylate cyclase (sGC) activators or modifiers (e.g., veliciguat), SGLT2 inhibitors (e.g., dapagliflozin), antiarrhythmic therapies, anticoagulants, antithrombotic agents, antiplatelet agents, or any combination thereof. In certain embodiments, the patient is treated with a compound I drug in addition to an ARNI, a beta-blocker, and / or an MRA. In certain embodiments, the ARNI, beta-blocker, and / or MRA are selected in any combination from those described herein. In certain embodiments, the patient is treated with a compound I drug in addition to an ACE inhibitor and / or an ARB and / or an ARNI, in combination with a beta-blocker and optionally an aldosterone antagonist. In certain embodiments, ACE inhibitors, ARBs, ARNIs, β-blockers, and / or aldosterone antagonists are selected in any combination from those described herein.

[0077] In some embodiments, patients with atrial dysfunction (e.g., AF) and systolic dysfunction (e.g., reduced LVEF such as HFrEF) are treated with catheter ablation in addition to compound I drugs.

[0078] In some embodiments, patients with atrial dysfunction (e.g., AF) and systolic dysfunction (e.g., reduced LVEF such as HFrEF) are treated with compound I drugs in combination with anticoagulants (e.g., NOACs) in combination with rate control agents (e.g., beta-blockers, digoxin, and / or amiodarone).

[0079] In some embodiments, patients with atrial dysfunction (e.g., AF) and systolic dysfunction (e.g., reduced LVEF such as HFrEF) are treated with electrical cardiovertermination in combination with compound I drugs and antiarrhythmic drugs (e.g., amiodarone, sotalol, or dofetilide).

[0080] In some embodiments, patients with atrial dysfunction (e.g., AF) and systolic dysfunction (e.g., reduced LVEF such as HFrEF) are treated with compound I drugs in addition to cardioverters, anticoagulants, diuretics, rate regulators, RAAS antagonists, and rhythm regulators.

[0081] In some embodiments, patients with atrial dysfunction (e.g., AF) and systolic dysfunction (e.g., reduced LVEF such as HFrEF) are treated with compound I drugs in addition to anticoagulants; diuretics; angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and / or mineralocorticoid receptor antagonists.

[0082] In some embodiments, patients with atrial dysfunction (e.g., AF) and systolic dysfunction (e.g., reduced LVEF such as HFrEF) are treated with compound I drugs in addition to ARNIs, such as sacubitril / valsartan (Entresto®) or sodium-glucose cotransporter 2 inhibitors (SGLT2i), such as empaglifozin (e.g., Jardiance®), dapagliflozin (e.g., Farxiga®), canagliflozin (e.g., Invokana®), or sotagliflozin.

[0083] In some embodiments, patients with atrial dysfunction (e.g., AF) and systolic dysfunction (e.g., reduced LVEF such as HFrEF) are treated with compound I drugs in addition to ARNI, beta-blockers, and / or MRAs.

[0084] In some embodiments, patients with atrial dysfunction (e.g., AF) and systolic dysfunction (e.g., reduced LVEF such as HFrEF) are treated with ACE inhibitors and / or ARBs and / or ARNIs in combination with compound I drugs, as well as beta-blockers and optionally aldosterone antagonists.

[0085] In some embodiments, patients with systolic dysfunction (e.g., reduced LVEF such as HFrEF) are treated with ACE inhibitors or ARBs in combination with compound I drugs to prevent new onsets of AF.

[0086] In some embodiments, compound I is administered to patients with atrial dysfunction (e.g., AF) at a higher status of cardiac endocrinology (SOC) for HFrEF complicated with AF (e.g., SOC determined by the CAN-TREAT algorithm) (Kotecha et al., Eur Heart J. (2015) 36:3250-7). The algorithm involves cardiovertermination, anticoagulation therapy (e.g., using vitamin K antagonists such as warfarin or NOACs), normalization of fluid balance (e.g., using diuretics), target initial heart rate <110 bmp (e.g., with beta-blockers or digoxin), regulation of the renin-angiotensin-aldosterone system (e.g., with ACE inhibitors, ARBs, and / or mineralocorticoid receptor antagonists), early intervention for rhythmic control (e.g., using antiarrhythmic agents such as amiodarone and / or dofetilide, cardiovertermination, and / or catheter ablation), treatment of progressive heart failure (e.g., resynchronization therapy), and treatment of other cardiovascular diseases such as ischemia and hypertension.

[0087] Suitable angiotensin-converting enzyme (ACE) inhibitors include, for example, captopril, enalapril, hosinopril, lisinopril, perindopril, quinapril, ramipril, and trandolapril.

[0088] Suitable antiarrhythmic therapies (rhythmia control agents) include, for example, amiodarone, dolonedarone, propafenone, flecainide, dofetilide, ibutilide, quinidine, procainamide, disopyramide, and sotalol. In some embodiments, the antiarrhythmic therapy is of class Ia, Ic, or III.

[0089] Suitable anticoagulants include, for example, warfarin, apixaban, rivaroxaban, edoxaban, and dabigatran. In some embodiments, the anticoagulant is an oral anticoagulant (OAC). In certain embodiments, the OAC may be administered with a vitamin K antagonist. In some embodiments, the anticoagulant is a non-vitamin K oral anticoagulant (NOAC). In some embodiments, the anticoagulant is a vitamin K antagonist (e.g., warfarin, asenocumarol, fenprocum).

[0090] Suitable ARBs include, for example, A-81988, A-81282, BIBR-363, BIBS39, BIBS-222, BMS-180560, BMS-184698, candesartan, candesartan cilexetil, CGP-38560A, CGP-48369, CGP-49870, CGP-63170, CI-996, CV-11194, DA-2079, DE-3489, DMP-811, DuP-167, DuP-532, E-4177, erysartan, EMD-66397, and EMD-7. 3495, Eprosartan, EXP-063, EXP-929, EXP-3174, EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, GA-0056, HN-65021, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, Irbesartan, Isoteoline, KRI-1177, KT3-671, KW-3433, Losartan, LR-B / 057, L-158809, L-158978, L-1592 82, L-159874, L-161177, L-162154, L-163017, L-159689, L-162234, L-162441, L-163007, LR-B / 081, LRB087, LY-285434, LY-302289, LY-315995, LY-235656, LY-301875, ME-3221, Olmesartan, PD-150304, PD-123177, PD-123319, RG-13647, RWJ-38970, RWJ-46458, Salaracin acetate, S- Examples include 8307, S-8308, SC-52458, Supplisartan, Saracin, Salmesin, SL-91.0102, Tasosartan, Telmisartan, UP-269-6, U-96849, U-97018, UP-275-22, WAY-126227, WK-1492.2K, YM-31472, WK-1360, X-6803, Valsartan, XH-148, XR-510, YM-358, ZD-6888, ZD-7155, ZD-8731, and Zolasartan.

[0091] Suitable mineralocorticoid receptor antagonists include, for example, aldosterone inhibitors such as potassium-sparing diuretics. Examples include eplerenone, spironolactone, and canrenone.

[0092] Suitable pharmacological cardioverners include, for example, flecainide, dofetilide, propafenone, amiodarone, ibutilide, and vernacarant.

[0093] Suitable positive inotropes include, for example, digoxin and pimobendan, as well as β-adrenergic receptor agonists such as dobutamine, phosphodiesterase (PDE)-3 inhibitors such as milrinone, and calcium sensitizers such as levocimendan.

[0094] Suitable rate control agents include, for example, beta-blockers, non-dihydropyridine calcium channel blockers (e.g., verapamil, diltiazem), digoxin, digitoxin, digitalis, and amiodarone. Suitable beta-blockers include, for example, bisoprolol, carvedilol, carvedilol CR, atenolol, esmolol, landiolol, nevibolol, propranolol, nadolol, metaprolol tartrate, and sustained-release metoprolol succinate (metoprolol CR / XL).

[0095] Suitable vasodilators include, for example, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, smooth muscle myosin modulators, isosorbide dinitrate, and hydralazine. In cases of atrial insufficiency, calcium channel blockers may be used.

[0096] In some embodiments, compound I is administered in combination with lifestyle changes such as reducing alcohol or caffeine intake, discontinuing smoking, limiting stimulants, achieving or maintaining a healthy weight, physical activity, treating sleep apnea, and / or controlling hypertension and / or blood glucose levels, or any combination thereof.

[0097] If side effects occur, patients may receive treatment for those side effects. For example, a patient experiencing headaches due to treatment with compound I may be treated with analgesics such as ibuprofen and acetaminophen.

[0098] Treatment results The treatments described herein treat and / or improve atrial insufficiency. In some embodiments, the treatments also treat and / or improve systolic insufficiency. As used herein, the terms “treat,” “to treat,” and “treatment” refer to any indication of success in treating or improving symptoms associated with a disease, injury, condition, or dysfunction. These include any objective or subjective parameters such as reduction; remission; relief of symptoms; making the pathology, injury, condition, or symptoms more tolerable to the patient; reducing the frequency or duration of the pathology, injury, condition, or symptoms; or, in some contexts, delaying or preventing the onset of the pathology, injury, condition, or symptoms. Treatment or improvement may be based on any objective or subjective parameters, such as the results of a physical examination. For example, treatment for atrial insufficiency (e.g., AF) may include, but is not limited to, improving atrial myocardial contractility, improving atrial contractility, improving atrial cardiomyopathy, improving atrial arrhythmias (e.g., tachyarrhythmias), reducing AF recurrence, reducing AF burden, preventing AF onset, maintaining sinus rhythm (e.g., after cardioversion), restoring sinus rhythm (e.g., in combination with cardioversion), reducing left atrial volume (e.g., minimum or maximum volume), increasing left atrial ejection rate, increasing left atrial function index, and alleviating or preventing symptoms of atrial insufficiency, one or a combination thereof. Symptoms of atrial insufficiency (e.g., AF) may include, for example, palpitations, tachycardia, fatigue, dizziness, weakness, chest discomfort, decreased exercise capacity, increased urination, shortness of breath, anguina, presyncope, syncope, sleep disturbances, confusion, and psychosocial stress. Treatment for systolic heart failure includes, but is not limited to, any one or a combination of, improving the patient's cardiac function (especially during exercise such as walking or climbing stairs) and alleviating or preventing the symptoms of systolic heart failure. Symptoms of systolic heart failure may include, for example, dyspnea (e.g., orthostatic breathing, paroxysmal nocturnal dyspnea), cough, cardiac asthma, wheezing, hypotension, dizziness, confusion, cold extremities at rest, pulmonary congestion, chronic venous congestion, ankle swelling, peripheral edema or painlessness, nocturnal polyuria, ascites, hepatomegaly, jaundice, coagulation disorders, fatigue, exercise intolerance, jugular venous dilation, rales, peripheral edema, pulmonary vascular redistribution, interstitial edema, pleural effusion, and fluid retention.

[0099] In some embodiments, the therapies of this disclosure reduce AF load and / or AF recurrence in patients (e.g., patients from the population described herein). AF load and / or AF recurrence may be reduced by 10% or more. In some embodiments, AF load and / or AF recurrence may be reduced by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or more, or 100%. In some embodiments, the percentage of time a patient spends in AF during the monitoring period is reduced by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or more, or 100%. In some embodiments, the treatment shortens or reduces the duration of the patient's longest AF episode, or the number of AF episodes during the monitoring period, by, for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or more, or 100%. In some embodiments, the monitoring period may be minutes (e.g., 10, 20, 30, 40, 50 minutes, or more; 10 to 59 minutes), hours (e.g., 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, or more; 1 to 24 hours), days (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days, or more), weeks (e.g., 1 week, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 32 weeks, 40 weeks, or more), or years. For example, the monitoring period may be 24 hours, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, or more.

[0100] In some embodiments, the treatments of the Disclosure maintain sinus rhythm (e.g., normal sinus rhythm) in a patient (e.g., a patient from the population described herein). In certain embodiments, the patient has been or is being treated with cardioversion (e.g., electrical cardioversion). In some embodiments, the treatments of the Disclosure, in combination with cardioversion (e.g., electrical cardioversion), restore sinus rhythm (e.g., normal sinus rhythm) in the patient. In some embodiments, sinus rhythm is maintained for at least 1, 2, 3, 4, 5, 6, or 7 days; at least 1, 2, 3, or 4 weeks; at least 1, 2, 3, 4, 5, 6, 9, or 12 months; at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years; or longer; or until the patient no longer requires treatment.

[0101] In some embodiments, the therapies of the present disclosure reduce or delay the risk of myocardial infarction, ventricular arrhythmias, heart failure, chronic kidney disease, end-stage renal disease, sudden cardiac death, or all-cause mortality in patients.

[0102] In some embodiments, the therapies of the present disclosure improve the quality of life of patients as measured by the 6-Month Walk Test (6-MWT), the Kansas City Cardiomyopathy Questionnaire (KCCQ), the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) scale, and / or the Mayo AF-Specific Symptom Inventory (MAFSI).

[0103] In some embodiments, the therapies of this disclosure may prevent or delay tachycardia-induced cardiomyopathy in patients presenting with atrial fibrillation. In certain embodiments, tachycardia-induced cardiomyopathy is heart failure (e.g., HFrEF).

[0104] In some embodiments, the therapies of this disclosure may prevent or delay incidental AF (the first occurrence of AF) in a patient. Additionally or alternatively, the therapies may prevent or delay recurrence of AF in a patient. In certain embodiments, the patient has systolic dysfunction, such as chronic heart failure (e.g., HFrEF for more than 3 months). In certain embodiments, the patient has left atrial enlargement. In some cases, the patient has both systolic dysfunction and left atrial enlargement.

[0105] In some embodiments, the therapies of this disclosure prevent or delay the progression of AF in a patient. For example, the therapies may prevent or delay the progression of a patient from paroxysmal to persistent AF, or from paroxysmal or persistent AF to long-term persistent or permanent AF. In certain embodiments, the patient has systolic dysfunction, such as chronic heart failure (e.g., HFrEF for more than 3 months). In certain embodiments, the patient has left atrial enlargement. In some cases, the patient has both systolic dysfunction and left atrial enlargement.

[0106] Table 3 below shows the pharmacodynamic (PD) parameters that can be used to measure a patient's atrial function. These PD parameters are routinely used by clinicians and can be measured by standard transthoracic echocardiography. [Table 3]

[0107] In some embodiments, the treatment method of this disclosure includes: - In patients, increase LAEF by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more; -In patients, LA min Reduce Vi by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more; -In patients, LA max Reduce Vi by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more; and / or -In patients, increase LAFI by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more. In certain embodiments, the patient may have left atrial enlargement prior to treatment.

[0108] Current treatments may reduce the risk of cardiovascular death and / or the risk, frequency, or duration of hospitalization / emergency visits in the patient population described herein. Hospitalization and emergency visits may be due to atrial dysfunction, systolic dysfunction, or both, as described herein. In some embodiments, “reducing the risk” of an event means extending the time to the event by at least 10% (e.g., at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more). Risk may be relative or absolute. In some embodiments, the treatment reduces the frequency of hospitalization and emergency visits by at least 10% (e.g., at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%). In some embodiments, this treatment reduces the length of hospital stay by at least 10% (e.g., at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%).

[0109] The advantages of the current treatment method include the following features: The treatment is, (i) Having minimal effect on relaxation (e.g., only a slight increase in systolic ejection time with no discernible effect on diastolic function), calcium homeostasis, or troponin levels (e.g., only a slight increase in troponin); (ii) Does not impair ADP release; (iii) Do not change the cardiac phase distribution; (iv) Has only a slight effect on SET; (v) Not causing drug-related myocardial ischemia (as determined, for example, by clinical symptoms, electrocardiogram, as well as cardiac biomarkers such as troponin, creatine kinase-muscle / brain (CK-MB), cardiac imaging, and coronary angiography); (vi) Does not cause drug-related atrial or ventricular arrhythmias; (vii) Alanine aminotransferase or aspartate aminotransferase, which does not cause drug-induced liver injury as measured by bilirubin; and (viii) The patient's urine, serum, blood, systolic blood pressure, diastolic blood pressure, pulse, body temperature, blood oxygen saturation, or electrocardiogram (ECG) measurements are normal.

[0110] Products and Kits The present invention also provides products such as kits comprising one or more doses of compound I drug and instructions for a patient (for example, for treatment according to the method described herein). The products may also include additional therapeutic agents in the case of combination therapy. Tablets or capsules of compound I can be carded after blister formation, and are manufactured, for example, with 5 to 20 tablets per blister card. Each tablet or capsule may contain 5, 25, 50, 75, or 100 mg of compound I. Such blister cards may or may not further contain loading dose tablets or capsules. The disclosure also includes methods for manufacturing the products.

[0111] Unless otherwise defined herein, scientific and technical terms used in connection with this disclosure shall have meanings generally understood by those skilled in the art. Exemplary methods and materials are described below, and similar or equivalent methods and materials may also be used in the implementation or testing of this disclosure. In case of any conflict, this specification shall prevail, including definitions. In general, the nomenclature and techniques used in connection with cardiology, medicine, medical and pharmaceutical chemistry, and cell biology described herein are well known and commonly used in the art. Enzymatic reactions and purification techniques are generally achieved in the art or are carried out according to the manufacturer's specifications as described herein. Furthermore, unless otherwise required by context, singular terms shall include plural forms and plural terms shall include singular forms. Throughout this specification and its embodiments, the words “have” and “comprise,” or variations such as “has,” “having,” “comprise,” or “comprising,” are understood to mean that they include the integers or groups of integers described, but not exclude other integers or groups of integers. It should also be noted that the term “or” is generally used in its sense to include “and / or,” unless the content explicitly indicates otherwise. The term “about” as used herein refers to a numerical range that is plus or minus 10%, 5%, or 1% of the given number, within the context of a particular usage. Furthermore, the headings provided herein are for convenience only and do not construe as to the scope or meaning of the claimed embodiments.

[0112] All publications and other references mentioned herein are incorporated in their entirety by reference. While multiple documents are cited herein, this citation does not imply that any of these documents constitute part of the common general knowledge in the art.

[0113] The following examples are provided to allow for a more complete understanding of the present invention. These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way. [Examples]

[0114] Example 1: Ex vivo biochemical study of the effect of compound I on left atrial function This example describes a non-clinical study of the effects of compound I on left atrial function.

[0115] Materials and methods ATP turnover rate test The ability of compound I to selectively increase myocardial ATP turnover was evaluated using myofibrils from both the left atrium (LA) and left ventricle (LV) prepared from Yucatan miniature pig hearts, as well as subfragment-1(S1) myosin from cardiac (recombinant) and skeletal muscle (rabbit psoas muscle) and smooth muscle (chicken gizzard). Pig hearts were harvested, the left atrium / ventricle was freshly excised and dissected, frozen in liquid nitrogen, and stored at -80°C. Myofibrils and S1 myosin were prepared as described in Kawas et al., J Biol Chem. (2017) 292 (40:16571-7). Myofibrils from both atrials (n=4 hearts, each repeated twice) and ventricles (n=3 hearts, each repeated twice) were assayed at a constant concentration of 1.0 mg / mL (Ca2 + Sensitivity [pCa] 6.0). Rabbit skeleton (0.2 μM, n=8), chicken gizzard (0.5 μM, n=10), and recombinant human heart (0.5 μM, n=10) S1 myosin were assayed with a constant concentration of actin (14 μM).

[0116] Steady-state ATPase measurements of Compound I at various concentrations (0 - 50 μM, 2% DMSO) were performed using a coupled enzyme system utilizing pyruvate kinase and lactate dehydrogenase. This enzyme system couples the formation of ADP with the oxidation of NADH, resulting in a change in absorbance at 340 nm. The buffer system used in all experiments was 12 mM PIPES, 2 mM MgCl2, and 1 mM dithiothreitol (DTT), pH 6.8 (PM12 buffer). All measurements were performed at 25 °C using a plate reader (SpectraMax; Molecular Devices, LLC, CA, USA), monitoring the change in absorbance over time, and the data were normalized to a scale per second as described in Green et al., Science (2016) 351(6273):617 - 21. Data are presented as mean (standard deviation [SD]) in text and mean ± standard error of the mean (SEM) in numerical form; the half-maximal effective concentration (EC 50 ) values (and 95% confidence interval [CI]) were calculated using a four-parameter fit model (GraphPad Prism, GraphPad Software Inc., CA, USA).

[0117] Myocardial force generation studies Given Ca 2+The ability of compound I to increase myocardial force generation at various concentrations was evaluated using demembranous LA (n=6) and LV (n=6) muscle fibers prepared from three different Yucatan miniature pig hearts. Briefly, as described above, three hearts were harvested, rinsed, and shipped in cold cardiac arrest solution (Custodiol® HTK; Essential Pharmaceuticals, LLC, NC, USA). Upon receipt, LV (papillary) and LA muscle fibers were dissected at 4°C in a highly relaxed solution (100 mM BES, 10 mM EGTA, 6.57 mM gCl2, 10 mM creatine phosphate, 6.22 mM MATP, 41.89 mM KProp, 2.5 μM pepstatin, 1 μM leupeptin, 50 μM PMSF, 5 mM NaN3, pH 7.0). The fiber bundles were cut, defilmed (with a highly relaxed solution containing 1% Triton X-100), fitted with aluminum foil T-clips, and mounted on a mechanical device (Aurora Scientific Inc., ON, Canada). The sarcomere length was set to 2.0 μm. The steady-state isometric tension and stiffness (3% elongation at 250 ms) were determined to be Ca 2+ Measurements were taken with the concentration increased twice (pCa 8.0-4.5, adjusted to maintain a 180 mM ionic strength). The first measurement was performed in the absence of compound I (control, 1% DMSO), and the second measurement was performed in the presence of compound I (3 μM, 1% DMSO). In all cases, the tension values ​​were normalized to the maximum isometric tension of the control (pCa 4.5). Passive and active stiffness were measured using the initial tension response to a short 3% elongation (Ca 2+ The slopes were calculated by measuring the dependent and late slopes, respectively. The data is presented as the mean (SD) in the text and as SEM ± mean in the drawings. 50 The values ​​(and 95% CI) were calculated using a 4-parameter fitted model (GraphPad Prism, GraphPad Software Inc., CA, USA).

[0118] result Compound I increased ATPase activity and calcium sensitivity in LV and LA myofibrils / muscle fibers.

[0119] Compound I increases sarcomere activity (ATPase turnover rate) in both ventricles (maximum activity concentration at half maximum [AC 50 ]:6.0μM;95% confidence interval [CI]:3.7~27.5), and the atrium (AC 50 (3.6 μM; 95% CI: 2.7~5.0) Compound I was associated with a dose-dependent increase in myofibrils, achieving 3.0-fold (±0.3) and 2.3-fold (±0.3) increases (standard deviation [SD] ±) at 50 μM, respectively (Figure 1, Panel A). Compound I activated cardiac (human) S1 myosin (1.4-fold increase in ATPase rate at 3 μM [9]), but not in skeletal muscle or smooth muscle isoforms (data not shown). In defascimated muscle fibers, compound I (3 μM) increased tension-pCa 2+ Shift the relationship to the left (i.e., given Ca 2+ (This generated greater tension at higher concentrations), which in turn altered the Ca in both ventricular fibers without changing the passive stiffness (Figure 1, panel D) or the maximum force generation capacity (data not shown). 2+ Sensitivity (pCa 50 The treatment increased the levels of ([±SD]p<0.05 vs. pre-treatment value) (5.8[±0.04]~6.1[±0.07], Figure 1, panels B and C), and atrial fibers (5.7[±0.05]~5.8[±0.10], Figure 1, panel C).

[0120] In summary, 3 μM of compound I increased ATPase by 56% in the LA and 85% in the LV in porcine myofibrils, shifted calcium sensitivity to the left, increased LV tension by 43% at pCa6.0, and significantly increased calcium sensitivity in both LV and LA porcine myofibrils. These data indicate that compound I increases ATPase activity and calcium sensitivity in both LA and LV, resulting in increased contractile force.

[0121] Example 2: In vivo functional study of the effect of compound I on left atrial function In this example, we evaluate the ability of compound I to improve myocardial performance in vivo in the presence of chronic LV dysfunction / remodeling.

[0122] Materials and methods Seven male beagle dogs underwent a modified series of coronary microembolization protocols to induce chronic LV insufficiency and HF, as determined by both LV remodeling and decreased LV ejection fraction (LVEF) (Geist et al., J Pharmacol Toxicol Methods (2019) 99:106595). A subset of animals (n=5) also received surgical implantation of a wireless telemetry transmitter (TL11M3-D70-PCTP; Data Sciences Int., MN, USA) to provide systemic arterial blood and LV pressure. The microembolization and instrument techniques used have been previously validated (Hartman et al., JACC Basic Transl Sci. (2018) 3(5):625-38).

[0123] The effects of compound I (2-3 mg / kg oral tablets, n=14) on the function and morphology of LV / LA, as well as systemic / ventricular hemodynamics, were investigated by echocardiography in conscious, mildly anesthetized animals (butorphanol 0.25-0.5 mg / kg intravenously) before administration (i.e., baseline) and 5 hours after treatment.

[0124] In these experiments, LV dimensions, LA dimensions (LAd), and aortic dimensions (Aod), as well as LV volume estimates (Simpson and Teichholz methods), were recorded using 2D and 2D-guided M-mode echocardiography (CX50; Philips Medical System, MA, USA) during end-systolic / diastolic periods, in both short-axis (papillary level) and / or apical / parasternal long-axis views. From these measurements, LV stroke volume (LVSV), cardiac output (CO), LV internal diameter shortening percentage (LVFS), LV internal diameter shortening area, LVEF, and LAd / Aod ratio were calculated. LV outflow tract (LVOT) blood flow velocity (via Doppler) was measured, and the LVOT velocity-time integral (LVOT-VTI) was calculated. Furthermore, maximal (end-systolic, LA) max ) and minimum (late expansion, LA min The LA volume of ) was measured using the biplane method. The LA emission rate of both (LAEF = 100 x [LAmax -LA min ] / LA max ) and LA function index (LAFI=[LAEFxLVOT-VTI] / LA max The volume indices were calculated (Thomas et al., Eur J Echocardiogr (2008) 9(3):356-362). Diastolic mitral valve pass-peak velocity (E and A), mitral valve-annular tissue velocity (e', s', and a'), and their ratios in early diastole (E / e') were recorded / used as indicators of diastolic performance. In all cases, atrial and ventricular volume indices were calculated by normalizing against estimated body surface area (0.101 x [body weight [kg] x 2 / 3]), and reported data were derived by averaging at least 3 cardiac cycles. Finally, hemodynamic signals were acquired digitally (1000 Hz) and continuously recorded using a data acquisition / analysis system (IOX; EMKA Technologies). Heart rate (HR), end-systolic and end-diastolic pressures, and peak velocity of pressure rise and fall (dP / dt, respectively) were recorded. max and dP / dt min ), contraction index (dP / dt max (at dP / dt / P), and the time constant of myocardial relaxation (tau 1 / 2 dP / dt min The time to 50% decay was derived from the left ventricular pressure signal. Systolic, diastolic, mean systemic blood pressure, and pulse pressure were derived from the aortic pressure signal. Hemodynamic data were reported as mean values ​​over at least 1 minute (steady state). In vivo data are shown as mean values ​​(SD) in text and as mean ± SEM in figures; the mean difference between pre-treatment and post-treatment values ​​was evaluated by a pre-set significance level of 0.05 using a two-tailed paired t-test (GraphPad Prism, GraphPad Software Inc., CA, USA).

[0125] result In dogs with microembolization-induced heart failure, acute treatment with compound I improved LVEF [±SD]LVEF[±SD](41[5]%~51[6]%; p<0.05), LVFS (19.6[2.7]%~25.6[3.6]%; p<0.05), and peak left ventricular circumferential strain (LVGCS: -13.5[4.4]%~-17.3[4.4]%; p<0.05), resulting in increased LVSV (33.0[5.9]mL vs. 43.6[10.7]mL; p<0.05) (Figure 2, Panel A) and cardiac output (Table 4). Furthermore, compound I prolonged the SET (178

[24] ms vs. 201

[29] ms; p<0.05) (Figure 2, Panel A), but its effect on the derived indices of LV end-diastolic dimension, ventricular volume, or LV volume-pressure was negligible (Table 4). In a subset of dogs instrumented for systemic / LV hemodynamics (via telemetry), compound I had no effect on systemic pressures (±SD), e.g., systolic blood pressure (110

[10] vs. 119

[10] mmHg) or LV end-diastolic blood pressure (18[2]–16[4] mmHg), despite a slight decrease in heart rate (108

[45] –99

[50] bpm; p<0.05).

[0126] Compound I also reduces the LA volume, particularly at the end of diastole (minimum LA volume index) [LA min Vi]: 21.2[8.3] mL / m² 2 Ratio 17.9 [9.0] mL / m² 2 This improves both the LA emission rate (LAEF: 20.4[4.4]% vs. 31.1[6.9]%; p<0.05) and the LA function index (Thomas et al., Eur J Echocardiogr (2008) 9(3):356-62) (LAFI: 7.7[3.3]% vs. 15.2[6.5]%; p<0.05) (Figure 2, Panel B and Table 4). [Table 4-1] [Table 4-2]

[0127] Example 3: In vivo functional study of the effect of compound I on atrial fibrillation induction. This example evaluates the effects of compound I on left atrial function and size and studies its potential effects on altering the substrate of atrial fibrillation.

[0128] Materials and methods The effects of compound I on AF-inducing properties and on LA size and function were investigated by echocardiography (ECHO) and electrocardiogram (ECG) in beagle dogs administered phenylephrine (PE), and compared with the effects of PE alone. The study design is shown in Figure 3.

[0129] Beagle dogs (n=8) were rapidly tested under isoflurane anesthesia. A subset of animals (n=3) had chronically induced left ventricular dysfunction (EF<40%). Animals were assigned to either vehicle or compound I. Anesthesia procedures were performed, a percutaneous introducer was placed in the jugular vein (under strict sterile conditions), and a catheter was inserted into the right atrium or coronary sinus. Once instrumented and stable, the first anesthetic ECHO was performed, and blood was collected for analysis.

[0130] After the initial ECHO and blood sampling, once a stable baseline was achieved, an AF-inducing protocol consisting of 5–10x10 second burst pulses at 33 Hz was administered. After each pulse, the duration of AF was recorded. AF was identified by (1) the presence of an irregular, rapid ventricular response, (2) the absence of a P wave, and (3) the presence of a low-frequency, irregular oscillation (f wave). If AF spontaneously converted to sinus rhythm within 10 minutes, the next pulse was administered. Upon return of regular sinus rhythm, each 10-second burst was segmented to approximately the same duration as the previous AF. If AF was absent, each burst was separated by approximately 10–30 seconds after the completion of the previous burst. If AF persisted for more than 20 minutes, the induction protocol was stopped and the duration of AF was recorded. In any case, if AF did not spontaneously convert before the animal recovered from anesthesia, a medical conversion could be attempted. If consistent atrial fibrillation (AF) does not occur with burst pulses of 5-10x10 seconds at 33 Hz, the right atrium can be stimulated at various frequencies (approximately 10-33 Hz) for longer periods (approximately 10 seconds to 15 minutes).

[0131] Subsequently, PE (0.5–20 μg / kg / min) was administered at a fixed rate. In animals, phenylephrine (PE) caused an increase in systemic / left ventricular pressure (e.g., SBP: 38±7%, 88.6±2.7–122.4±6.9 mmHg, P<0.05) and an increase in left atrial dimension (e.g., LA). min :+28±3%, 22.9±2.0~29.3±2.5mL / m 2 (P<0.05), and short-duration (10-second) right atrial burst pacing episodes induced the production of substrates for AF induction.

[0132] After 5–15 minutes (or sufficient time for steady state), a second anesthetic ECHO was performed. Upon completion, the AF-inducing protocol (as described above) was performed. All observations of AF (visualized via ECG recording), including the duration of AF, were recorded. Subsequently, PE was stopped to restore the hemodynamic effects mediated by PE (i.e., washout). Once sinus rhythm was re-established (using cardioversion if AF persisted beyond 30 minutes), a third anesthetic ECHO was performed. Next, either compound I or vehicle was administered intravenously via a suitable vein. The treatment consisted of a bolus and IV infusion (dosage determined to match the end-systolic pressure or peak LVP, as if PE had been administered alone and targeted to exactly the same dose). After a 10-minute infusion, a fourth anesthetic ECHO was performed. Next, PE infusion (using the same fixation rate as described above) was initiated in combination with compound I or vehicle. During observation of stable hemodynamics (approximately 10 minutes), blood was collected for analysis, and the final ECHO and AF-inducing protocols were performed. After the AF-inducing protocols were successfully completed and the animals returned to normal sinus rhythm, they were allowed to recover.

[0133] result Acute administration of compound I (0.3-0.4 mg / kg IV bolus and 0.3 / 0.4 mg / kg / hr IV infusion) resulted in prolongation of systolic ejection time (SET: +10±3%, P<0.05), increase in left ventricular output (SV: 16±5%, P<0.05), and shortening of the atrial diameter (FS: 13±3%, P<0.05); systemic pressure was maintained under compound I (SBP: 135.7±6.2 mmHg). However, compound I did not affect left atrial size (LAVol min It reduced left atrial size, increased atrial ejection fraction (LAEF), and reduced AF-inducedness (e.g., AF duration) (Figure 4). In summary, compound I significantly reduced AF-inducedness while reducing left atrial size compared to the control condition.

[0134] Example 4: In vivo functional study of the effects of dobutamine on left atrial function and atrial fibrillation induction. This example evaluates the effects of the inotropic agent dobutamine on left atrial function and size, as well as its ability to induce atrial fibrillation.

[0135] Materials and methods The effects of dobutamine on AF-inducing properties and the size and function of the left atrial fibrillation (LA) were investigated by echocardiography (ECHO) and electrocardiogram (ECG) of beagle dogs administered phenylephrine (PE), and compared with the effects of PE alone. Beagle dogs (without left ventricular dysfunction) were evaluated for left atrial function and size, as well as atrial fibrillation-inducing properties, according to the protocol described in Example 3 (test design shown in Figure 5), which allowed for a comparison of the effects of dobutamine with those of compound I shown in Example 3.

[0136] result Dobutamine is an inotropic agent that increases LV contractility through a different mechanism of action than compound I. The effects of dobutamine administration (1-10 μg / kg / hr infusion) were compared with those of compound I as described in Example 3. Both drugs were shown to increase LV contractility (ΔEF; Figure 6, leftmost panel). However, unlike compound I, dobutamine actually prolonged AF duration without shortening it (Figure 6, rightmost panel). These results indicate that compound I's ability to shorten AF duration is due to its unique mechanism and is not a general result of increasing LV contractility.

[0137] Example 5: A randomized, double-blind, placebo-controlled, two-part, adaptive design study on the effects of compound I on left atrial dimension and function in patients with stable HFrEF. This example describes a study to establish the effects of single and multiple escalating oral doses of compound I on left atrial size and function in outpatients with stable heart failure (HFrEF) with reduced ejection fraction. Key eligibility criteria included stable HFrEF of ischemic or non-ischemic origin and treatment with guideline-based medical therapy (initial EF requirements during screening were modified to 20–45%, later revised to 15–35%). Patients with active ischemia or severe or valvular heart disease were excluded.

[0138] Materials and methods Test design In the first part of this two-part study, the single dose escalation (SAD) of compound I was evaluated, and in the second part, the multiple dose escalation (MAD) of compound I was evaluated (Figures 7A and 7B).

[0139] In a clinical trial enrolling patients aged 18–80 years with a clinical diagnosis of stable chronic heart failure with an LVEF of 45% or less (later revised to 35% or less) as determined by echocardiography, treatment consisted of guideline-oriented medical therapy and high-quality echocardiographic imaging. Renal impairment (estimated glomerular filtration rate <30 mL / min / 1.73 m²) 2 Patients were excluded if they had the following conditions: elevated screening cTnI (value >0.15 ng / mL as measured in the central laboratory using the Abbott Architect assay, with the usual upper limit being 0.03 ng / mL), hospitalization for heart failure, acute coronary syndrome in the past 90 days or had received intervention, or untreated severe valvular heart disease. Patients with current or recent atrial fibrillation were also excluded. Detailed inclusion and exclusion criteria are shown below. Selection Criteria 1. Male or female between 18 and 80 years old at the time of screening visit. 2. BMI 18-40 kg / m² 2 3. If the patient has sinus rhythm or stable atrial pacing with a mean resting heart rate (HR) of 50-95 beats / min (bpm) (If the HR measurement before administration on day 1 is 95 bpm or higher, the patient is ineligible for treatment. HR is the average of three measurements taken at 1-minute intervals. A single measurement will not disqualify the patient). 4. Having a stable chronic HFrEF of moderate severity, as defined by all of the following: • For the first three patients in each cohort of the multi-dose trial, the new (higher) daily dose was tested: LVEF of 25–35% was recorded during screening (confirmed by ECHO Central Laboratory). • For other patients in the multi-dose trial cohort (and all patients in the single-dose escalation trial): LVEF of 15-35% was recorded during screening (confirmed by ECHO Central Laboratory). oLVEF must be confirmed in a second screening ECHO, which should be conducted at least 7 days after the first screening ECHO. Both results must meet the selection criteria and be received from the core lab before administration. If the screening window is extended for SRC review, efforts should be made to ensure the second ECHO is close to the scheduled time of randomization. • Chronic drug therapy for the treatment of heart failure in accordance with current guidelines. This involves administering a stable dose for at least two weeks, with no planned changes during the trial. This includes treatment with at least one of the following, unless unacceptable or contraindicated: beta-blockers, angiotensin-converting enzyme (ACE) inhibitors / angiotensin receptor blockers (ARBs) / angiotensin receptor neprilysin inhibitors. Exclusion criteria 1. Inappropriate echocardiographic window 2. Any of the following electrocardiogram abnormalities: (a) QTcF > 480 ms (corrected for friderlicia not attributable to pacing or QRS duration prolongation, mean of 3 screening ECGs) or (b) Type II or higher second-degree atrioventricular block in patients without a pacemaker. 3. Hypersensitivity to Compound I or any component of Compound I preparations. 4. Clinically demonstrated and determined active infection by the principal investigator. 5. A history of any type of malignant tumor within five years prior to screening, excluding the following surgically resected cancers that occurred more than two years prior to screening: cervical cancer in situ, non-melanoma skin cancer, ductal carcinoma in situ, and non-metastatic prostate cancer. 6. A positive serological test for screening for infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV). 7. Liver damage (defined as alanine aminotransferase (ALT) / aspartate aminotransferase (AST) > ULN > 3 times and / or total bilirubin (TBL) > ULN > 2 times) 8. Severe renal failure due to sMDRD (simplified Modification of Diet in Renal Disease equation) (current estimated glomerular filtration rate [eGFR] < 30 mL / min / 1.73 m²) 2 (defined as), 9. Serum potassium <3.5 or >5.5 mEq / L 10. Any persistent out-of-range safety laboratory parameters (chemistry, hematology, urinalysis) deemed clinically important by researchers and medical monitors. 11. A history or finding of any other clinically significant disorder, condition, or disease (including substance abuse) that, in the opinion of the principal investigator, poses a risk to patient safety, interferes with the evaluation, procedure, or completion of the study, or leads to early withdrawal. 12. The patient participated in a clinical trial in which they received any investigational drug (or are currently using an investigational device) within 30 days prior to screening or at least five times the respective elimination half-life (whichever is longer). 13. Except for patients who participated in or were unable to screen for part of this study, previous participants in clinical trials of Compound I may participate in other parts. That is, patients may be enrolled in Part 1 (single dose escalation study) and then in Part 2 (multiple dose study), or in Part 2 (multiple dose study) and then in Part 1 (single dose escalation study). The following are important considerations. • If a patient has an ongoing adverse event (AE), a serious adverse event (SAE), or meets any of the discontinuation criteria, the principal investigator must contact the sponsor before enrolling the patient in the subsequent cohort. Patients require a washout period of at least one week after the completion of a multi-dose trial dose prior to a single-dose escalation trial dose, or after the completion of a single-dose escalation trial dose prior to a multi-dose trial dose. If screening for a multi-dose trial is performed within 12 weeks of the initial single-dose escalation trial, or if screening for a single-dose escalation trial is performed within 12 weeks of the initial multi-dose trial, the patient does not need to be rescreened. The principal investigator must ensure that the patient is clinically stable and that no exclusions have occurred during that time. If more than 12 weeks have passed, or if the patient is clinically unstable, the patient should be rescreened. 14. At screening, symptomatic BP or systolic BP > 170 mmHg or < 90 mmHg, or diastolic BP > 95 mmHg, or HR < 50 bpm. HR and BP are the average of three measurements taken at least one minute apart. 15. Current angina pectoris. 16. Recent (<90 days) acute coronary syndrome. 17. Coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) within the past three months. 18. Recent (<90 days) hospitalization due to heart failure, use of chronic IV inotropic therapy, or other cardiovascular events (e.g., cerebrovascular event). 19. Uncorrected severe valvular heart disease. 20. Based on Central Laboratory's assessment, troponin I (>0.15 ng / mL) levels were elevated at the time of screening. Note: The ULN for the Central Laboratory troponin I assay is 0.03 ng / mL. 21. Presence of an ineligible rhythm that would prevent the study of ECG or echocardiographic evaluation, including: (a) current AF, (b) recent (<2 weeks) persistent AF, or (c) frequent premature contractions. Note: Patients using active cardiac resynchronization therapy (CRT) or a pacemaker (PM) are eligible if initiated at least 2 months prior to the study and there are no plans to change the CRT or PM settings during the study. 22. Average life expectancy < 6 months.

[0140] Part 1 (SAD Cohort) In the single-dose escalation study, single fasted doses of compound I 175–550 mg or placebo were evaluated in a crossover manner in 12 patients across two consecutive cohorts (1 and 2). The interval between single doses was 3 days (later modified to 5 days) to 14 days. In cohort 1, eight patients were enrolled and all received placebo and compound I 175 mg and 350 mg (randomly and blinded) over three periods A–C. Six patients chose to continue for a fourth, optional open-label period D. The compound I doses administered during the open-label period were 350 mg (n=1); 450 mg (divided into two doses; n=1); 525 mg (n=2); and 550 mg (divided into two doses; n=2). Cohort 2 enrolled four patients, all of whom received placebo and compound I 400 mg and 500 mg in a randomized order (effective doses of 400 mg and 500 mg were administered in two divided doses).

[0141] For each treatment period, a pre-administration evaluation and a subsequent single dose were performed on the morning of day 1. Patients underwent continuous pharmacokinetic (PK), pharmacodynamic (PD [transthoracic echocardiography, i.e., TTE]), ECG, and safety laboratory evaluations on day 1 (until evening) and day 2. Patients were discharged on the morning of day 3 and returned to the hospital on day 4 for final PK evaluation and adverse event (AE) evaluation. After all treatment periods were completed, a 7-day follow-up visit was completed at the hospital.

[0142] Part 2 (MAD Cohort) This was a randomized, parallel-group, DB, placebo-controlled, adaptive design, sequentially escalating (oral) multiple-dose trial in patients with stable heart failure. Four MAD cohorts (A, B, C, D) were enrolled (Figure 7B). The SRC reviewed the results of each cohort, determined the dose, and confirmed the initial sample size for subsequent cohorts. Furthermore, the first three patients in each cohort had an LVEF ≥ 25%; the SRC reviewed preliminary safety data from these patients to determine whether to open cohort enrollment to patients with LVEF < 25%.

[0143] In Cohort A, patients received either compound I 75 mg twice daily (BID) or the corresponding placebo after a 2-hour fast, with no food permitted for the following 2 hours. In Cohorts B, C, and D, patients received compound I 50, 75, and 100 mg, respectively, with food (Table 5). [Table 5]

[0144] Patients were hospitalized at the clinical research facility for 11 days and underwent the following three consecutive trial periods: (1) an initial 2-day single-blind placebo trial period (days 1-2); (2) a 7-day randomized (1:3) double-blind treatment period in which placebo or compound I was administered orally twice daily (days 3-9); and (3) a follow-up period for patients discharged from the facility on day 11, followed by a final follow-up visit on day 16. Throughout the 11-day hospitalization period, patients were under continuous monitoring. Patients with implanted ICDs may be permitted not to be hospitalized, but they were required to return to the clinical research facility frequently and be closely monitored under the supervision of medical professionals each time they received double-blind treatment.

[0145] Patients received the drug twice daily (every 12 hours). The drug could be administered within ±2 hours of the scheduled time, as long as the interval between doses was at least 10 hours and no more than 14 hours. The exception to the twice-daily administration was on day 9 (the final dose of the randomized DB investigational drug treatment). On day 9, the morning dose was administered.

[0146] Prior to each medication event, all available safety data from the previous day were reviewed (for non-hospitalized patients, if home care was being utilized, the nurses and facility were in daily contact to ensure safety). DB treatment was administered at approximately the same time each day.

[0147] Compound I was supplied as an oral tablet in blister card form. Placebo tablets were provided and presented in matching form. All clinical trial materials were manufactured, packaged, labeled, and distributed by Sanofi, Inc. (Montpellier, France). Each blister card contained either a 25 mg tablet, a 100 mg tablet, or a placebo tablet. Mixed strength blister cards were not used. Each blister card was labeled in accordance with local regulations to allow each local open-label pharmacist to prepare each dose during the double-blind treatment period. Except for the open-label pharmacists, other site personnel remained blinded to their treatment assignments.

[0148] During the trial, multiple assessments were performed, including: continuous TTE assessment (11–14 TTEs per patient on days 1, 2, 3, 4, 7, 9, 10, and 11); PK sampling (PK samples collected concurrently with each echocardiogram after randomization); ECG (days 2, 3, 4, 7, 9, 10, 11, and 16); troponin (collected concurrently with each ECG after randomization); and safety laboratory assessment. Hospitalized patients received continuous telemetry. Holter monitoring was performed in all patients at baseline (days 1–2) and at the end of the double-blind treatment (days 7–9). Vital signs were collected daily.

[0149] In addition to central assessment, 12-lead ECG, TTE, safety laboratory results, and local troponin assessments were performed by the institution for real-time safety monitoring and patient management. The protocol instructed clinicians to immediately adjust the dose (i.e., administer a lower dose) if the PD effect on TTE was deemed excessive (based on local TTE), for example, if the systolic ejection time prolongation was greater than 75 msec in two consecutive TTEs or greater than >110 msec in one TTE compared to baseline (day 3, pre-administration), or if there was a relative increase of more than 50% in two contractility parameters in two consecutive TTEs. Discontinuation was also required in cases of suspected drug-related coronary ischemia, unexpected serious drug-related adverse events, liver impairment, or clinically significant and persistent changes in vital signs or arrhythmias or HR-corrected QT interval >500 msec using the Fridericia method (QTcF) (not due to pacing or QRS duration prolongation).

[0150] Experimental treatment In Part 1 (SAD), study patients received individual escalating doses (2-3 doses) of compound I and a corresponding single dose of placebo. In Part 2 (MAD), study patients received a single-blind placebo BID on days 1 and 2, followed by DB treatment (placebo or compound I) for 7 days (days 3-9). In cohorts A, B, C, and D, on the morning of day 9, patients received a single dose of placebo or compound I for continuous PK / PD evaluation, and patients in these cohorts received placebo or compound IBID from day 3 to day 8.

[0151] The active pharmaceutical ingredient of Compound I was as described in Example 1 above and was provided as 5 mg, 25 mg, or 100 mg tablets. Placebo tablets were provided as corresponding tablets. The tablets were placed in blister packs and then formed into cards. Each blister card contained either 5 mg only, 25 mg only, 100 mg only, or placebo only. The blister cards were packaged in a "kit box".

[0152] Investigational drug administration, dosing, and schedule The study drug administration consisted of a 5 mg, 25 mg, or 100 mg tablet of compound I, or a corresponding placebo tablet. In Part 1 (SAD), compound I or placebo was administered after an overnight fast (at least 6 hours), while in Part 2 (MAD), compound I was administered after a 2-hour fast (Cohort A) or with food (Cohorts B, C, and D). The dose was taken with a minimum of 240 mL of water, with more water given as needed. The total dose was administered over a maximum of 15 minutes. The administration time used to determine future evaluations was the time the last tablet was taken. The BID regimen was used in the Part 2 (MAD) cohorts.

[0153] In Part 1 (SAD), patients were kept fasting overnight (approximately 6 hours) until 4 hours after administration. Except for water consumed in conjunction with administration, water intake was permitted from approximately 1 hour before administration until approximately 1 hour after administration. If the dose was divided, subjects fasted 6 hours before the first half dose. A low-fat snack could be consumed 2 hours after the first half dose, and fasting continued 2 hours after the second dose.

[0154] In Part 2 (MAD), patients in Cohort A fasted for two hours before and two hours after administration. For example, if the morning dose was administered at 8:00 AM, patients could have a light snack at 6:00 AM and a full breakfast at 10:00 AM. If the afternoon dose was administered at 8:00 PM, patients could have dinner at 6:00 PM and a light snack at 10:00 PM. These times could be adjusted based on national schedules, but the doses were spaced at least 10.5 hours apart. Patients in Cohorts B, C, and D consumed food with each dose.

[0155] Exaggerated pharmacological effects and management of overdose Based on nonclinical pharmacological characteristics, the exaggerated effect of compound I may lead to myocardial ischemia. The duration of the effect follows the PK profile of compound I, T max The half-life is 4–6 hours, approximately 15 hours in healthy volunteers, but slightly longer (20–25 hours) in some patients in Cohort 1 who received compound I. Clinical signs and symptoms such as chest pain, dizziness, sweating, and ECG changes begin to subside within a short period. Any patient with signs and / or symptoms that may be secondary to myocardial ischemia was immediately assessed by a physician for the possibility of myocardial ischemia, and additional electrocardiograms and serial troponin were obtained as part of the assessment, if necessary.

[0156] If signs of myocardial ischemia were present, patients received standard treatment for ischemia, including oxygen and nitrate supplementation, as needed. Compound I may prolong the set-to-stress interval (SET), resulting in a shortened diastolic duration and decreased diastolic ventricular volume; therefore, caution was required when administering agents that increase heart rate (HR). Furthermore, because exaggerated pharmacological effects can increase myocardial oxygen demand, agents that could further increase myocardial oxygen demand should be administered cautiously.

[0157] Patients who received a higher dose than planned were given appropriate support as described above if they experienced exaggerated pharmacological effects.

[0158] Simultaneous therapy During the study, patients continued to take medications for congestive heart failure and other medical conditions at the same doses and approximately the same times as usual, maintaining similar preload and afterload conditions throughout the study to minimize confounding factors for evaluating the effect of compound I. In particular, if patients were treated with diuretics, the timing of diuretic administration for DB treatment was maintained similarly throughout the study. Where applicable, the timing of diuretic administration was collected. If patients were not hospitalized, they were instructed to maintain a consistent timing for daily medication administration, including diuretics where applicable, and to record the administration times.

[0159] All prescription and over-the-counter (OTC) medications were reviewed by the principal investigator. Questions regarding registration or medications were discussed with the medical monitor. OTC medications were administered at a consistent dose throughout the study (at the principal investigator's discretion), not exceeding the amount indicated on the label. All concurrent therapies (prescription or OTC) were recorded. Other investigational therapies were discontinued at least 30 days prior to screening or within 5 half-lives (whichever was longer).

[0160] If a patient had an adverse event (AE) requiring treatment (such as taking acetaminophen or ibuprofen), the drug therapy (including administration time (start / stop), date, dose, and indication) was recorded.

[0161] Test results In the 50 mg BID, compound I achieved steady-state concentrations in the range of 2000 ng / mL to less than 3500 ng / mL. Compound I showed significant LA min A decrease in Vi was observed (-2.1 mL / m2 [p<0.01] and -2.4 mL / m2 [p<0.01] at medium and high concentrations, respectively), an increase in LAEF (+3.3% [p<0.05] and 3.6% [p<0.05] at medium and high concentrations, respectively), and an improvement in LAFI (+6.1 [p<0.01] and +5.8 [p<0.01] at medium and high concentrations, respectively) (Table 6 and Figure 8). [Table 6-1] [Table 6-2]

[0162] overview In patients with HFrEF (mean age 60 years, 25% female, 48% with ischemic heart disease, mean left ventricular ejection fraction 32%), compound I (plasma concentration ≥ 2000 ng / mL) resulted in a reduction in the minimum LA volume index (maximum -2.4 mL / m²) compared to placebo. 2 We obtained an increase in the LA function index (maximum 6.1, p<0.01) and p<0.01. These results are consistent with preclinical findings of direct activation of LA contractility (see Examples 1 and 2).

[0163] Cardiac myosin activator enhances the ATPase activity of myofibrils, and in both myocardial contractility and systole (i.e., SET), Ca 2+-It leads to a dependent increase (Teerlink, Heart Fail Rev. (2009) 14(4):289-98), and all functions are common to compound I, which are now supported by both preclinical and clinical observations. However, compound I is also a selective and direct activator of cardiac actomyosin that does not interfere with the generation of maximum force in ventricular myocardium (Kampourakis et al., J Physiol (2018) 596(1):31-46; Nagy et al., Br J Pharmacol. (2015) 172(18):4506-18; Woody et al., Nat Commun. (2018) 9(1):3838). Furthermore, compound I directly increases force generation in LA fibers, which are known to be composed of inherently weak (alpha)myosin motors (Aksel et al., Cell Rep. (2015) 11(6):910-20), further highlighting myosin's ability to maintain / enhance its intrinsic power generation (power stroke).

[0164] These studies confirm that compound I improved atrial size / function in HFrEF patients.

[0165] Example 6: A randomized, double-blind, parallel-group study on the clinical efficacy and safety of chronic compound I treatment in patients with reduced LVEF and paroxysmal or persistent AF. This example describes the design of a study aimed at establishing the clinical efficacy and safety of chronic treatment with compound I in patients with reduced LVEF (less than 50%) and paroxysmal or persistent AF.

[0166] The primary efficacy objectives of this study include evaluating the effects of compound I on the volume and function of LV and LA as measured by TTE, and evaluating the clinical efficacy of compound I on AF load as continuously measured via an implantable device or ILR.

[0167] The primary safety objective of this study includes evaluating the clinical safety and tolerability of chronic treatment with compound I.

[0168] The secondary objectives of this examination include: - To evaluate the effect of compound I on other TTE parameters (e.g., SET, extension); - To evaluate the effect of compound I on biomarkers (e.g., NT-proBNP, highly sensitive troponin); - To evaluate the clinical efficacy of compound I for AF recurrence; - To evaluate the clinical efficacy of compound I against NYHA; - To evaluate the clinical effects of compound I on patient-reported outcomes (e.g., KCCQ, AFEQT); - To evaluate the pharmacokinetic properties of compound I after chronic treatment; and - To evaluate the PK-PD effect of compound I.

[0169] The exploratory objectives of this study include: - To evaluate the clinical effect of compound I on AF loading as measured via the Zio patch (all patients); - To evaluate the clinical effects of compound I on the day of survival and on the day of discharge; - To evaluate the clinical effect of compound I on outcomes (e.g., cardiovascular death, cardiovascular hospitalization, emergency HF or AF visits); - To evaluate the clinical effect of compound I in a 6-minute walk test (6MWT); and - Evaluate the effect of compound I on the activity level (e.g., using an accelerometer).

[0170] Test design Two cohorts (Cohort 1 and Cohort 2) will be enrolled. A total of approximately 200 patients are planned to be enrolled, but additional cohorts may be added. Of the 200 patients, 100 will have an implantable device or ILR (Cohort 1), and 100 will be in Cohort 2. The expected study duration for each individual patient is up to 8 months, including approximately 2-6 weeks of screening, 6 months (24 weeks) of treatment, and 4 weeks of follow-up.

[0171] Each cohort consists of four parallel groups, each comprising 25 patients, receiving either placebo, compound I at 25 mg BID, compound I at 50 mg BID, or compound I at 75 mg BID.

[0172] Selection Criteria This study will be conducted in patients who meet the following criteria. 1. Male or female between 18 and 85 years of age at the time of screening visit. 2. A decrease in LVEF (less than 50%) has been recorded based on the most recent TTE or screening echocardiogram performed within the past 12 months. -The most recent LVEF in question must not have been performed during an AF episode, and if applicable, it must have been performed at least 30 days after one of the following: 1) Hospitalization due to an event likely to reduce ejection fraction (e.g., acute coronary syndrome / myocardial infarction, sepsis); 2) Interventions that are likely to increase EF (e.g., cardiac resynchronization therapy, coronary revascularization); or 3) First HF presentation, If diagnosed with HFrEF with an LVEF of less than 40%, patients should be treated with GDMT (i.e., standard treatment) including at least one of the following, unless unacceptable or contraindicated: beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and angiotensin receptor neprilysin inhibitors (ARNIs). Such treatments must have been administered at a stable dose for at least three weeks prior to randomization and are not planned to be changed during the trial. 4. NT-proBNP ≥ 150 pg / mL at screening (or > 100 pg / mL in patients with high BMI or Black ancestry) 5. Diagnosis of atrial fibrillation (AF) as defined below: - For Cohort 1 (implantable devices / ILR and paroxysmal atrial fibrillation), patients must meet all of the following criteria: -AF load can be continuously measured. That is, the patient has an implantable device with an atrial lead (pacemaker, ICD, CRT) or an implantable loop recorder (ILR) at the time of screening, or intends to have an ILR implanted during the screening period; and - AF load range at screening (based on device assessment at screening): 2-70%. For patients wishing to receive ILR implantation, eligible AF load is based on the 2wZio patch administered during screening. ILRs will only be implanted after the patient is deemed eligible. Note: The investigation during device / ILR screening must be conducted for a continuous period of more than two weeks. - For Cohort 2 (no implantable device / ILR, paroxysmal or persistent AF), patients must meet all of the following criteria: - AF load cannot be measured continuously, and - The patient has a clinical diagnosis of AF (based on electrocardiogram findings) and is not due to a temporary condition (such as post-surgery); and - The patient has had at least one episode of persistent AF within the 6 months prior to screening (based on medical records, or an episode of AF lasting more than 10 minutes on a 12-lead electrocardiogram, or on Holter or patch monitoring, or based on previous ECV), and has no findings of long-term persistent or permanent AF. 6. Patients in Cohort 1 only: - Implantable devices with atrial leads / ILRs must have remote data transmission capabilities. - The patient is willing and able to send device data from home.

[0173] Exclusion criteria Patients who meet any of the following criteria will be excluded from trial enrollment: AF related: - Patients who are considered for Cohort 1 (i.e., have an implanted device or ILR, or are willing to obtain an ILR), and have an AF load of less than 2% or greater than 70% at screening, -AF has a reversible etiology (thyroid disease, alcohol, pulmonary embolism, early postoperative period, acute pericarditis, trauma, etc.) - The patient has pulmonary hypertension treated with pulmonary vasodilators (endothelin receptor antagonists, PDE5 inhibitors, etc.), - Known channel disorders (e.g., long QT syndrome, Brugada syndrome, or CPVT), - Diagnosed with AF more than 10 years before screening, - Findings of long-term persistent or permanent AF, -AF episodes during screening requiring a change in ECV or antiarrhythmic therapy (Note: One rescreening is permitted), -AF (12-lead electrocardiogram) at randomization, Note: Patients may be randomized a few days after their sinus rhythm returns. -LA diameter (based on the latest TTE) > 60mm, - You have recently (less than 6 months prior to screening) or are planning or may be planning catheter ablation during a trial, -A new antiarrhythmic therapy has been planned and introduced recently (less than one month prior to screening) or during the trial - There is no intention to change the antiarrhythmic drug regimen. - Electrical cardiovertermination (ECV) performed less than one month prior to screening or during screening. -(Optional) The patient is unable to use and record a 6-lead electrocardiogram at home. Related to HF: - Inappropriate echocardiographic window - Class IV NYHA at screening - Symptomatic hypotension or systolic blood pressure <90 mmHg or diastolic blood pressure >95 mmHg at the time of screening; - Severe aortic valve disease or mitral stenosis, planned or anticipated mitral valve clipping or mitral valve repair during an investigation, hypertrophic or infiltrative cardiomyopathy (e.g., amyloidosis), active myocarditis, constrictive pericarditis, or clinically significant congenital heart disease; - Recent (within 90 days prior to screening) major cardiovascular events (e.g., acute coronary syndrome, stroke, etc.), - Recent (within 90 days prior to screening) or planned cardiovascular intervention (including but not limited to CABG, PCI, and valve repair), - Recent (within 45 days prior to screening) or planned device implantations other than ILR implants during screening (pacemakers, CRT, etc.), - Recent (within the last 90 days) hospitalization for heart failure or treatment with IV inotropic agents, - End-stage heart failure, defined as requiring a left ventricular assist device, intra-aortic balloon pump (IABP), or any type of mechanical support, or being awaiting a heart transplant.

[0174] Other exclusion criteria: - Hypersensitivity to Formula I formulation or any component of Formula I formulation, - Determined by the principal investigator, clinically demonstrated active infection, - A history of any type of malignant tumor within five years prior to screening, excluding the following surgically resected cancers that occurred more than two years prior to screening: cervical cancer in situ, non-melanoma skin cancer, ductal carcinoma in situ, and non-metastatic prostate cancer. - Laboratory parameters: - Severe renal failure due to sMDRD (simplified Modification of Diet in Renal Disease equation) (defined as current estimated glomerular filtration rate [eGFR]) <30 mL / min / 1.73 m 2 , - Based on the most recent decision prior to randomization, serum potassium levels are less than 3.5 mEq / L or greater than 5.5 mEq / L (one repeat test is possible), - Based on the most recent decision prior to randomization, AST or ALT > 3x ULN or total bilirubin > 2x ULN (one repeatable lab is possible), - Any (two or more) persistent out-of-range safety laboratory parameters (chemistry, hematology) deemed clinically important by researchers and medical monitors. -A history or finding of other clinically significant impairments, conditions, or diseases (including substance abuse) that, in the opinion of the principal investigator or attending physician, pose a risk to the patient's safety, interfere with the evaluation, procedure, or completion of the study, or lead to early withdrawal. - Average life expectancy is less than 6 months. - The subject participated in a clinical trial in which they received any investigational drug (or were currently using an investigational device) within 30 days prior to screening or at least five times the respective elimination half-life (whichever is longer).

Claims

1. A pharmaceutical composition comprising compound I or a pharmaceutically acceptable salt thereof, for use in treating atrial insufficiency in patients requiring treatment, wherein compound I has structural formula (I): 【Chemistry 1】 A pharmaceutical composition which is (R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazole-3-yl)piperidine-1-carboxamide.

2. A pharmaceutical composition comprising compound I or a pharmaceutically acceptable salt thereof, for use in treating atrial cardiomyopathy in patients requiring treatment, wherein compound I has structural formula (I): 【Chemistry 2】 A pharmaceutical composition which is (R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazole-3-yl)piperidine-1-carboxamide.

3. A pharmaceutical composition comprising compound I or a pharmaceutically acceptable salt thereof, for use in treating atrial tachyarrhythmia in patients requiring treatment, wherein compound I has structural formula (I): 【Transformation 3】 A pharmaceutical composition which is (R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazole-3-yl)piperidine-1-carboxamide.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the patient exhibits atrial fibrillation.

5. A pharmaceutical composition comprising compound I or a pharmaceutically acceptable salt thereof, for use in treating atrial fibrillation in patients requiring treatment, wherein compound I has structural formula (I): 【Chemistry 4】 A pharmaceutical composition which is (R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazole-3-yl)piperidine-1-carboxamide.

6. A pharmaceutical composition comprising compound I or a pharmaceutically acceptable salt thereof, for use in reducing the recurrence of atrial fibrillation in patients requiring treatment, wherein compound I has structural formula (I): 【Transformation 5】 A pharmaceutical composition which is (R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazole-3-yl)piperidine-1-carboxamide.

7. The pharmaceutical composition according to claim 6, wherein the recurrence of atrial fibrillation is reduced by 10% or more.

8. A pharmaceutical composition comprising compound I or a pharmaceutically acceptable salt thereof, used to reduce the atrial fibrillation load in patients requiring treatment, wherein compound I has structural formula (I): 【Transformation 6】 A pharmaceutical composition which is (R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazole-3-yl)piperidine-1-carboxamide.

9. The pharmaceutical composition according to claim 8, wherein the atrial fibrillation load is reduced by 10% or more.

10. A pharmaceutical composition comprising compound I or a pharmaceutically acceptable salt thereof, used to shorten the duration of atrial fibrillation episodes in patients requiring treatment, wherein compound I has structural formula (I): 【Transformation 7】 A pharmaceutical composition which is (R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazole-3-yl)piperidine-1-carboxamide.

11. The pharmaceutical composition according to claim 10, wherein the duration of the episode is shortened by 10% or more.

12. A pharmaceutical composition comprising compound I or a pharmaceutically acceptable salt thereof, used to reduce the number of atrial fibrillation episodes during a monitoring period in patients requiring treatment, wherein compound I has structural formula (I): 【Transformation 8】 A pharmaceutical composition which is (R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazole-3-yl)piperidine-1-carboxamide.

13. The pharmaceutical composition according to claim 12, wherein the number of atrial fibrillation episodes is reduced by 10% or more.

14. A pharmaceutical composition comprising compound I or a pharmaceutically acceptable salt thereof, used to maintain sinus rhythm in patients requiring treatment, wherein compound I has structural formula (I): 【Chemistry 9】 A pharmaceutical composition containing (R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazole-3-yl)piperidine-1-carboxamide.

15. The pharmaceutical composition according to claim 14, wherein the patient has been suffering from atrial tachyarrhythmia for 12 months or less.

16. The pharmaceutical composition according to claim 15, wherein the atrial tachyarrhythmia is atrial fibrillation.

17. A pharmaceutical composition comprising compound I or a pharmaceutically acceptable salt thereof, used in combination with cardiovertermination to restore sinus rhythm in patients presenting with atrial tachyarrhythmia, wherein compound I has structural formula (I): 【Chemistry 10】 A pharmaceutical composition which is (R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazole-3-yl)piperidine-1-carboxamide.

18. The pharmaceutical composition according to claim 17, wherein the cardioversion is an electrical cardioversion.

19. The pharmaceutical composition according to claim 17 or 18, wherein the atrial tachyarrhythmia is atrial fibrillation.

20. A pharmaceutical composition according to any one of claims 1 to 19, wherein the patient also exhibits systolic dysfunction.

21. The pharmaceutical composition according to claim 20, wherein the systolic dysfunction is a syndrome or disorder selected from the group consisting of heart failure, cardiomyopathy, cardiogenic shock, a condition that benefits from inotropic support after cardiac surgery, myocarditis, atherosclerosis, secondary aldosteronism, myocardial infarction, valvular disease, systemic hypertension, pulmonary hypertension or pulmonary artery hypertension, adverse vascular remodeling, pulmonary edema, and respiratory failure.

22. The heart failure is selected from heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), congestive heart failure, and diastolic heart failure (reduced systolic reserve), The cardiomyopathy is selected from ischemic cardiomyopathy, dilated cardiomyopathy, atrial myopathy, left atrial myopathy, progressive hypertrophic cardiomyopathy, post-infarction cardiomyopathy, viral cardiomyopathy, toxic cardiomyopathy, metabolic cardiomyopathy, infiltrative cardiomyopathy, and diabetic cardiomyopathy. The condition that benefits from inotropic support after the aforementioned cardiac surgery is ventricular dysfunction due to on-bypass cardiovascular surgery. The myocarditis is viral myocarditis, and / or The pharmaceutical composition according to claim 21, wherein the valve disease is mitral valve regurgitation or aortic valve stenosis.

23. The pharmaceutical composition according to claim 21, wherein the systolic dysfunction is a decrease in left ventricular ejection fraction (LVEF).

24. A pharmaceutical composition according to any one of claims 1 to 23, wherein the patient also exhibits diastolic dysfunction.

25. The pharmaceutical composition according to any one of claims 1 to 24, wherein the patient has heart failure and has been diagnosed with one of NYHA class II to IV.

26. A pharmaceutical composition according to any one of claims 1 to 25, wherein the patient has HFrEF.

27. The pharmaceutical composition according to claim 26, wherein a patient exhibits atrial fibrillation, and compound I alleviates one or more symptoms of HFrEF, maintains sinus rhythm, reduces recurrence of atrial fibrillation, and / or prevents the onset of atrial fibrillation in the patient.

28. A pharmaceutical composition comprising compound I or a pharmaceutically acceptable salt thereof, for use in preventing tachycardia-induced cardiomyopathy in patients presenting with atrial fibrillation, wherein compound I has structural formula (I): 【Chemistry 11】 A pharmaceutical composition which is (R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazole-3-yl)piperidine-1-carboxamide.

29. The pharmaceutical composition according to claim 28, wherein the tachycardia-induced cardiomyopathy is heart failure.

30. The pharmaceutical composition according to claim 29, wherein the heart failure is heart failure accompanied by a decrease in ejection fraction (HFrEF).

31. The pharmaceutical composition according to any one of claims 1 to 30, wherein the patient has had atrial tachyarrhythmia or atrial fibrillation for a period of 12 months or less prior to the step of administration.

32. A pharmaceutical composition according to any one of claims 1 to 31, wherein the atrial fibrillation is paroxysmal or persistent.

33. A pharmaceutical composition according to any one of claims 1 to 32, wherein the patient has an atrial fibrillation load of 2 to 70%.

34. A pharmaceutical composition according to any one of claims 1 to 33, wherein the patient has postoperative AF.

35. A pharmaceutical composition according to any one of claims 26 to 34, wherein the patient has a left ventricular ejection fraction (LVEF) of less than 50%.

36. A pharmaceutical composition according to any one of claims 1 to 25 or 28 to 34, wherein the patient has a left ventricular ejection fraction (LVEF) of less than 60%.

37. The pharmaceutical composition according to claim 36, wherein the patient has HFpEF.

38. A pharmaceutical composition according to any one of claims 1 to 37, wherein the patient has left atrial enlargement.

39. A pharmaceutical composition according to any one of claims 1 to 38, wherein the patient has atrial myopathy.

40. The pharmaceutical composition according to claim 39, wherein the atrial myopathy is left atrial myopathy.

41. A pharmaceutical composition according to any one of claims 1 to 40, wherein the patient has previously been treated by ablation or cardioversion.

42. The pharmaceutical composition according to claim 41, wherein the ablation is catheter ablation.

43. The pharmaceutical composition according to claim 41, wherein the cardioversion is an electrical cardioversion.

44. The patient said: a) AF load <2% or >70%; b) Atrial fibrillation with a reversible etiology; c) Pulmonary hypertension treated with pulmonary vasodilators; d) It is a known channel disease; e) AF diagnosed more than 10 years before the start of treatment; f) Long-term persistent or permanent atrial fibrillation; g) LA diameter>60mm; h) Catheter ablation within six months prior to the start of treatment, or planned or possible catheter ablation during treatment; i) Initiation of a new antiarrhythmic therapy less than one month prior to the start of treatment, or planning to initiate a new antiarrhythmic therapy during treatment; j) The patient has undergone an electric cardioversion treatment less than one month prior to the start of treatment; k) NYHA Class IV heart failure; l) Symptomatic hypotension or systolic blood pressure <90 mmHg or diastolic blood pressure >95 mmHg; m) Severe aortic valve disease or mitral stenosis, planned or anticipated mitral valve repair during treatment, hypertrophic or infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis, or clinically significant congenital heart disease; n) A major cardiovascular event within 90 days prior to the start of treatment; o) A cardiovascular intervention within 90 days prior to the start of treatment; p) The device is implanted within 45 days prior to the start of treatment; q) Hospitalization due to heart failure or treatment with IV inotropic agents within 90 days prior to the start of treatment; r) End-stage heart failure; or s) Life expectancy of less than 6 months, A pharmaceutical composition according to any one of claims 1 to 43, which does not have any one or combination of the above.

45. A pharmaceutical composition according to any one of claims 1 to 44, wherein the patient is administered compound I in a total daily dose of 10 to 350 mg.

46. The pharmaceutical composition according to any one of claims 1 to 44, wherein the patient is administered compound I in the form of 10 to 175 mg BID, 25 to 325 mg QD, or 25 to 350 mg QD.

47. The pharmaceutical composition according to any one of claims 1 to 44, wherein the patient is administered compound I in a BID of 10 to 75 mg.

48. The pharmaceutical composition according to claim 47, wherein the patient is administered compound I in a BID of 10, 25, 50, or 75 mg.

49. The pharmaceutical composition according to any one of claims 1 to 48, wherein compound I is administered orally to the patient.

50. The pharmaceutical composition according to any one of claims 1 to 49, wherein compound I is administered in a dose such that the plasma concentration of compound I in the patient is 1,000 to 8,000 ng / mL.

51. The pharmaceutical composition according to any one of claims 1 to 50, wherein compound I is ingested by the patient with food, or within two hours, one hour, or 30 minutes after eating food.

52. The pharmaceutical composition according to any one of claims 1 to 51, wherein compound I is provided in a solid form having an average particle size of more than 15 μm, less than 10 μm, 15 μm to 25 μm, 1 μm to 10 μm, or 1 μm to 5 μm.

53. The pharmaceutical composition according to any one of claims 1 to 52, wherein the patient undergoes electrocardioversion before or after the administration step.

54. A pharmaceutical composition according to any one of claims 1 to 53, characterized in that an additional agent is administered to the patient to improve the cardiovascular condition.

55. The pharmaceutical composition according to claim 54, wherein the additional agent is a beta-blocker, an anticoagulant, a vitamin K antagonist, a calcium channel blocker, a diuretic, angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), a mineralocorticoid receptor antagonist, an angiotensin receptor-neprilysin inhibitor (ARNI), an SGLT2 inhibitor, an sGC activator or regulator, an antiarrhythmic therapy, or any combination thereof.

56. A pharmaceutical composition according to any one of claims 1 to 53, characterized by administering an anticoagulant and an antiarrhythmic agent to a patient.

57. A pharmaceutical composition according to any one of claims 1 to 53, characterized by administering an anticoagulant and a rate control agent to a patient.

58. The pharmaceutical composition according to claim 57, wherein the rate control agent is a beta-blocker, digoxin, or amiodarone.

59. A pharmaceutical composition according to any one of claims 1 to 53, characterized by administering to a patient an anticoagulant, a diuretic, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), and / or a mineralocorticoid receptor antagonist.

60. below: a) Reduced risk of emergency outpatient intervention for atrial dysfunction, systolic dysfunction, or both; b) Improvement in quality of life as measured by 6-MWT or KCCQ; c) Improvement of athletic ability; d) Improvement in the patient's NYHA classification; e) Delay in clinical deterioration; f) Reduction of the severity of cardiovascular symptoms; g) Increased left atrial ejection fraction (LAEF); h) Decreased left atrial volume (LA ｍｉｎ VI); and i) Improvement of the left atrial function index (LAFI), A pharmaceutical composition according to any one of claims 1 to 59, which yields any one or a combination of the above.

61. A pharmaceutical composition according to any one of claims 1 to 60, which reduces cardiovascular death or hospitalization.

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