Omecamtiv mecarbil for use in treating heart failure by activating cardiac sarcomere

Abstract

Methods for treating heart failure are described herein. Treatment methods include administering a cardiac sarcomere activator (e.g., omecamtiv mecarbil, or a pharmaceutically acceptable salt and / or hydrate thereof) to a subject in need thereof.

Description

Attorney Docket No. 49892-20222.40METHODS FOR TREATING HEART FAILURE BY ADMINISTERING CARDIAC SARCOMERE ACTIVATORSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit of U.S. Provisional Patent Application No. 63 / 688,806, filed August 29, 2024, and U.S. Provisional Patent Application No. 63 / 722,312, filed November 19, 2024, the disclosures of which are hereby incorporated herein by reference in their entireties.BACKGROUND

[0002] The cardiac sarcomere is the basic unit of muscle contraction in the heart. It is a highly ordered cytoskeletal structure composed of cardiac muscle myosin, actin and a set of regulatory proteins. Small molecule cardiac muscle myosin activators could become promising treatments for acute and chronic heart failure. Cardiac muscle myosin is the cytoskeletal motor protein in the cardiac muscle cell. It is directly responsible for converting chemical energy into the mechanical force, resulting in cardiac muscle contraction.

[0003] Current positive inotropic agents, such as beta-adrenergic receptor agonists or inhibitors of phosphodiesterase activity, increase the concentration of intracellular calcium, thereby increasing cardiac sarcomere contractility. However, the increase in calcium levels increases the velocity of cardiac muscle contraction and shortens systolic ejection time, which has been linked to potentially life-threatening side effects. In contrast, cardiac muscle myosin activators work by a mechanism that directly stimulates the activity of the cardiac muscle myosin motor protein, without increasing the intracellular calcium concentration. They accelerate the rate-limiting step of the myosin enzymatic cycle and shift it in favor of the forceproducing state. Rather than increasing the velocity of cardiac contraction, this mechanism instead lengthens the systolic ejection time, which results in increased cardiac muscle contractility and cardiac output in a potentially more oxygen-efficient manner.

[0004] U.S. Application No. 11 / 155,940 and U.S. Patent No. 7,507,735, herein incorporated by reference, discloses a genus of compounds, including omecamtiv mecarbil (AMG 423, CK- 1827452), having the structure:1MOFO-359714640Attorney Docket No. 49892-20222.40

[0005] Omecamtiv mecarbil is a small molecule cardiac myosin activator, which is a type of myotrope that acts directly on the muscle fiber. Omecamtiv mecarbil, augments cardiac contractility by selectively binding to cardiac myosin increasing the number of force generators (myosin heads) that can bind to the actin filament and undergo a powerstroke once the cardiac cycle starts. In early clinical studies using short-term intravenous administration, omecamtiv mecarbil improved cardiac performance. In patients with chronic heart failure with reduced ejection fraction, treatment with omecamtiv mecarbil for 20 weeks increased left ventricular systolic function, decreased left ventricular systolic and diastolic volumes suggestive of beneficial reverse cardiac remodeling, and reduced natriuretic peptide concentrations and heart rate. In a randomized, placebo-controlled phase 3 clinical trial involving patients with heart failure and a reduced ejection fraction receiving guideline-based pharmacologic and device therapy, those in the omecamtiv mecarbil group had a lower relative risk of a heart-failure event or death from cardiovascular causes than those in the placebo group. This effect was observed without evidence of an increase in the risk of myocardial ischemic events, ventricular arrhythmias, or death from cardiovascular causes or any cause. The lowering of the incidence of the primary outcome was observed across a broad range of both inpatients and outpatients, including those with moderate or severe heart-failure symptoms and a reduced ejection fraction, systolic blood pressure, and renal function.

[0006] Many therapies have been developed that improve cardiovascular outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, none of the currently available drugs directly improve the central defect of HFrEF, reduced systolic function. Moreover, severe impairment of systolic function is often associated with lower blood pressure and greater difficulty tolerating target doses of guideline-directed medical therapies. Myotropes represent a new class of drugs that improve myocardial function by directly augmenting cardiac sarcomere function. The cardiac myosin activator, omecamtiv mecarbil, is the first of this class to be developed and it increases systolic function by selectively facilitating the actin-myosin interaction, increasing contractile force without altering the cardiomyocyte calcium transient.2MOFO-359714640Attorney Docket No. 49892-20222.40

[0007] Despite significant improvements in prognosis with contemporary medical therapy, heart failure with reduced ejection fraction (HFrEF) remains a progressive clinical syndrome and many patients develop worsening over time despite optimal guideline-based treatment. Regardless of terminology, these patients have a high burden of symptoms, recurrent heart failure (HF) hospitalizations, high mortality, and account for a large proportion of the total costs of HF care. As HF progresses, many patients become progressively intolerant of neurohormonal blockade with beta-blockers or renin-angiotensin-aldosterone system (RAAS) modulators due to hypotension or renal dysfunction, limiting their options for medical therapy. Selected patients with advanced HF may be candidates for other therapies such as cardiac transplantation or mechanical cardiac support, but these therapies are costly, highly invasive, and have limited availability. Intravenous inotropic therapy can be used for palliation of symptoms in selected patients but may be associated with increased mortality. Thus, there is a clear unmet need for effective and safe chronic medical therapies for patients with more advanced stages of HF.

[0008] The identification of safe drugs that increase cardiac performance has been a goal of heart failure therapeutics for more than a century, yet those that have been developed have consistently increased the incidence of myocardial ischemia, ventricular arrhythmias, or death due to their mechanism increasing intracellular calcium transients. As a selective cardiac myosin activator, omecamtiv mecarbil has been shown to have no effect on these transients.

[0009] Despite prior developments in this area, there remains a need for additional therapeutics for treating heart failure in patients, in particular, there remains a need for treating heart failure in patients who have severely reduced ejection fraction.BRIEF SUMMARY

[0010] Methods for treating heart failure are described herein. In some aspects, provided is a method of treating heart failure in a patient who exhibits atrial fibrillation or atrial flutter (AFF), has a left ventricular ejection fraction (LVEF) of less than 25% at baseline, and has a pretreatment level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) of at least 3,000 pg / mL, comprising administering to the patient a therapeutically effective amount of omecamtiv mecarbil, or a hydrate, a salt, or a salt of a hydrate thereof.3MOFO-359714640Attorney Docket No. 49892-20222.40

[0011] Also provided is a method of treating heart failure in a patient who has a left ventricular ejection fraction (LVEF) of less than 30% at baseline and a pretreatment level of NT- proBNP of at least 1,000 pg / mL, comprising administering to the patient a therapeutically effective amount of omecamtiv mecarbil, or a hydrate, a salt, or a salt of a hydrate thereof.

[0012] Also provided is a method of preventing or delaying left ventricular assist device (LVAD) implantation and / or cardiac transplantation in a patient, comprising administering to the patient a therapeutically effective amount of omecamtiv mecarbil, or a hydrate, a salt, or a salt of a hydrate thereof.

[0013] Also provided is a method of preventing or delaying new incidence of atrial fibrillation or atrial flutter (AFF) in a patient, comprising administering to the patient a therapeutically effective amount of omecamtiv mecarbil, or a hydrate, a salt, or a salt of a hydrate thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG. 1 shows assigned patient doses of omecamtiv mecarbil to achieve a target plasma concentration of 300 to 750 ng / mL.

[0015] FIG. 2 shows a study protocol for a clinical trial of omecamtiv mecarbil with starting dose of 25 mg twice daily.DETAILED DESCRIPTION

[0016] Described herein are methods of treating heart failure in a patient who exhibits atrial fibrillation or atrial flutter (AFF), has a left ventricular ejection fraction (LVEF) of less than 25% at baseline, and has a pretreatment level of NT-proBNP of at least 3,000 pg / mL, comprising administering to the patient a therapeutically effective amount of omecamtiv mecarbil, or a hydrate, a salt, or a salt of a hydrate thereof. Also provided are methods of treating heart failure in a patient who has a left ventricular ejection fraction (LVEF) of less than 30% at baseline and a pretreatment level of NT-proBNP of at least 1,000 pg / mL, comprising administering to the patient a therapeutically effective amount of omecamtiv mecarbil, or a hydrate, a salt, or a salt of a hydrate thereof. Also provided are methods of preventing or delaying left ventricular assist device (LVAD) implantation and / or cardiac transplantation in a4MOFO-359714640Attorney Docket No. 49892-20222.40 patient, comprising administering to the patient a therapeutically effective amount of omecamtiv mecarbil, or a hydrate, a salt, or a salt of a hydrate thereof. Also provided are methods of preventing or delaying new incidence of atrial fibrillation or atrial flutter (AFF) in a patient, comprising administering to the patient a therapeutically effective amount of omecamtiv mecarbil, or a hydrate, a salt, or a salt of a hydrate thereof.Definitions

[0017] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0018] Reference to “about” a value or parameter herein includes (and describes) that value or parameter per se, and any value or parameter 5% above or 5% below said value or parameter. For example, description to “about X” includes description of “X” and “X + / - 5%”.

[0019] ‘NYHA classification” or “NYHA class” refers to the New York Heart Association functional classification of heart failure symptoms. Descriptions of each of NYHA classes I, II, III, and IV can be found in “Classes of Heart Failure”, American Heart Association, https: / / www.heart.org / en / health-topics / heart-failure / what-is-heart-failure / classes-of-heart- failure, adapted from: 1) Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart Association. Criteria Committee. “Nomenclature and criteria for diagnosis of diseases of the heart and great vessels”. 9th ed. Boston, MA: Lippincott Williams and Wilkins; March 1, 1994; and 2) Criteria Committee, New York Heart Association, Inc. Diseases of the Heart and Blood Vessels. Nomenclature and Criteria for diagnosis, 6th edition Boston, Little, Brown and Co. 1964, p 114. Briefly, NYHA class I indicates that the patient has no limitation of physical activity; ordinary physical activity does not cause undue fatigue, palpitation, dyspnea (shortness of breath). NYHA class II indicates that the patient has slight limitation of physical activity; comfortable at rest; ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of breath). NYHA class III indicates that the patient has marked limitation of physical activity; comfortable at rest; less than ordinary physical activity causes fatigue, palpitation, or dyspnea. NYHA class IV indicates that the patient is unable to carry on any physical activity without discomfort; symptoms of heart failure at rest; if any physical activity is undertaken, discomfort increases.5MOFO-359714640Attorney Docket No. 49892-20222.40

[0020] The term “pharmaceutically acceptable salt” refers to a salt of any of the compounds herein that are known to be non-toxic and are commonly used in the pharmaceutical literature. In some embodiments, the pharmaceutically acceptable salt of a compound retains the biological effectiveness of the compounds described herein and are not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2- hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acid and salicylic acid.Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines including naturally occurring substituted amines; cyclic amines; and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0021] If the compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the compound is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds (see, e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19). Those skilled in the art will recognize various synthetic methodologies that may be used to prepare pharmaceutically acceptable addition salts.

[0022] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal6MOFO-359714640Attorney Docket No. 49892-20222.40 agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

[0023] The terms “patient,” “individual,” and “subject” refer to an animal, such as a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows and humans. In some embodiments, the patient or subject is a human, for example a human that has been or will be the object of treatment, observation or experiment. The compounds, compositions and methods described herein can be useful in both human therapy and veterinary applications.

[0024] ‘Treatment” (and related terms, such as “treat”, “treated”, "treating") includes one or more of: inhibiting a disease or disorder; slowing or arresting the development of clinical symptoms of a disease or disorder; and / or relieving a disease or disorder (i.e., causing relief from or regression of clinical symptoms). The term covers both complete and partial reduction or prevention of the condition or disorder, and complete or partial reduction of clinical symptoms of a disease or disorder. Thus, compounds described and / or disclosed herein may prevent an existing disease or disorder from worsening, assist in the management of the disease or disorder, or reduce or eliminate the disease or disorder.

[0025] Reference to any dose amount of a compound or pharmaceutically acceptable salt thereof described herein (e.g., 25 mg, 37.5 mg, 50 mg, etc. of omecamtiv mecarbil) refers to the amount (e.g., equivalent mass) of said compound without any salt (e.g., omecamtiv mecarbil anhydrous free base).Cardiac Sarcomere Activators (CSA)

[0026] In some embodiments, a CSA induces the activation of by, e.g., sensitizing cardiac myofilaments to Ca2+, activating troponin or tropomyosin, or directly activating the cardiac myosin. In some embodiments, a CSA promotes sarcomere responsiveness to calcium (Ca2+). In some embodiments, the CSA is omecamtiv mecarbil or a pharmaceutically acceptable salt (e.g., omecamtiv mecarbil hydrochloride salt) or a pharmaceutically acceptable hydrate of a pharmaceutically acceptable salt (e.g., omecamtiv mecarbil dihydrochloride hydrate).7MOFO-359714640Attorney Docket No. 49892-20222.40Omecamtiv mecarbil (OM)

[0027] Omecamtiv mecarbil, also known as CK- 1827452 or AMG 423, is a direct activator of cardiac myosin that directly targets the contractile mechanisms of cardiac myocytes intended to enhance efficiency of myocardial contraction in patients suffering from a cardiovascular condition, such as heart failure. The free base of omecamtiv mecarbil is described chemically as methyl 4-(2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-l-carboxylate having the structural formula:

[0028] Omecamtiv mecarbil is disclosed in U.S. Application No. 11 / 155,940 and U.S. Patent No. 7,507,735 titled “Compounds, Compositions and Method”, the entirety of which is incorporated herein by reference. Description of omecamtiv mecarbil and methods of making omecamtiv mecarbil can be found in, e.g., Example 3 column 55 and 56 of the above referenced patent.

[0029] Omecamtiv mecarbil was the subject of several Phase 2 clinical trials, including Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC- HF), which evaluated omecamtiv mecarbil in patients with chronic heart failure and left ventricular systolic dysfunction (see, e.g., NCT01786512). Global Approach to Eowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GAEACTIC- HF), was a Phase 3 global cardiovascular outcomes study, which demonstrated a statistically significant effect of treatment with omecamtiv mecarbil to reduce risk of the primary composite endpoint of cardiovascular death or heart failure events compared to placebo in patients treated with standard of care (see, e.g., NCT02929329). A pharmacokinetic (PK)-guided dosing regimen of omecamtiv mecarbil in the treatment of patients with heart failure is disclosed in U.S. Application No. 16 / 625,958 and U.S. Patent No. 11,576,910 titled “Methods of Treating Heart Failure with Cardiac Sarcomere Activators”, the entirety of which is incorporated herein by reference.

[0030] Omecamtiv mecarbil may be in the form of a salt or a hydrate of a salt, such as omecamtiv mecarbil dihydrochloride hydrate or omecamtiv mecarbil dihydrochloride8MOFO-359714640Attorney Docket No. 49892-20222.40 monohydrate. The molecular formula of omecamtiv mecarbil dihydrochloride hydrate is C20H24FN5O3-2HCI-H2O, with a relative molecular weight of 492.37 g / mol. In some embodiments, omecamtiv mecarbil is in the form of a base (e.g., omecamtiv mecarbil anhydrous free base). In some embodiments, omecamtiv mecarbil is in the form of a salt (e.g., omecamtiv mecarbil hydrochloride salt). In some embodiments, omecamtiv mecarbil is in the form of a salt hydrate (e.g., omecamtiv mecarbil dihydrochloride monohydrate). Omecamtiv mecarbil dihydrochloride salt forms are disclosed in U.S. Patent No. 9,988,354 titled “Salt of Omecamtiv Mecarbil and Process for Preparing Salt”, the entirety of which in incorporated herein by reference. Other salts or crystalline forms of omecamtiv mecarbil are described in, for example, U.S. Patent Publication No. 2021 / 0292271 Al and W02020011626 entitled “Crystalline 2- fluoro-3-nitrotoluene and process for the preparation thereof’ the disclosures of which are incorporated herein by reference in their entireties, W02020014406 entitled “Solid state forms of omecamtiv mecarbil & omecamtiv mecarbil dihcl”, W02021070123 entitled “Solid forms of omecamtiv mecarbil dihydrochloride and processes thereof’, WO2021053175 entitled “Salts of omecamtiv mecarbil and solid forms thereof’, WO2021053189 entitled "Salts of omecamtiv mecarbil and solid forms thereof’, WO2021136477 entitled “Cocrystal of dihydrochloride of compound 1 and preparation method therefor and use thereof', and W02021070124 entitled “Alternate processes for the preparation of omecamtiv mecarbil”.

[0031] A pharmaceutical formulation of omecamtiv mecarbil for oral administration is disclosed in U.S. Patent No. 9,951,015 titled “Heterocyclic Compounds and Their Uses”, the entirety of which is incorporated herein by reference.Patient Subgroups

[0032] Certain types of subjects may receive greater benefit with the treatment methods described herein. In some embodiments, the subject exhibits atrial fibrillation or atrial flutter (AFF), has a left ventricular ejection fraction (LVEF) of less than 25% at baseline, and has a pretreatment level of NT-proBNP of at least 3,000 pg / mL.

[0033] In some embodiments, the subject exhibits a left ventricular ejection fraction (LVEF) of less than 30% at baseline and a pretreatment level of NT-proBNP of at least 1,000 pg / mL. In some embodiments, the subject does not exhibit atrial fibrillation or atrial flutter (AFF). In some embodiments, the subject has a low Left ventricular EF (LVEF), such as about 40% or lower (e.g., about 40%, about 39%, about 38%, about 37%, or about 36%), or about 39% or lower, or9MOFO-359714640Attorney Docket No. 49892-20222.40 about 38% or lower, or about 37% or lower, or about 36% or lower, or about 35% or lower (e.g., about 35%, about 34%, about 33%, about 32%, about 31%), or about 34% or lower, or about 33% or lower, or about 32% or lower, or about 31% or lower, or about 30% or lower, or about29% or lower, or about 28% or lower, or about 27% or lower, or about 26% or lower, or about25% or lower, or about 24% or lower, or about 23% or lower, or about 22% or lower, or about21% or lower, or about 20% or lower. In some embodiments, in conjunction with embodiments above or below, the subject has a LVEF of about 30%, about 29%, about 28%, about 27%, about 26%, about 25%, about 24%, about 23%, about 22%, about 21%, about 20%, about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, or about 10%. In some embodiments, in conjunction with embodiments above or below, the subject has an LVEF of less than 29%, less than 28%, less than 27%, less than 26%, less than 25%, less than 24%, less than 23%, less than 22%, less than 21%, or less than 20% at baseline. In some embodiments, the subject has a LVEF of less than 30% at baseline. In some embodiments, the subject has a LVEF of less than 29% at baseline. In some embodiments, the subject has a LVEF of less than 28% at baseline. In some embodiments, the subject has a LVEF of less than 27% at baseline. In some embodiments, the subject has a LVEF of less than 26% at baseline. In some embodiments, the subject has a LVEF of less than 25% at baseline. In some embodiments, the subject has a LVEF of less than 24% at baseline. In some embodiments, the subject has a LVEF of less than 23% at baseline. In some embodiments, the subject has a LVEF of less than 22% at baseline. In some embodiments, the subject has a LVEF of less than 21% at baseline. In some embodiments, the subject has a LVEF of less than 20% at baseline.

[0034] In some embodiments, the LVEFs described herein are associated with subjects without atrial fibrillation or flutter. In some embodiments, the LVEFs described herein are associated with subjects with atrial fibrillation or flutter. For example, in some embodiments, the subject has a LVEF < 40% without atrial fibrillation or flutter. In some embodiments, the subject has a LVEF < 35% without atrial fibrillation or flutter. In some embodiments, the subject has a LVEF < 30% without atrial fibrillation or flutter. In some embodiments, the subject has a LVEF < 35% with atrial fibrillation or flutter. In some embodiments, the subject has a LVEF < 30% with atrial fibrillation or flutter. In some embodiments, the subject has a LVEF < 25% with atrial fibrillation or flutter. In some embodiments, the subject has a LVEF < 24% with atrial fibrillation or flutter. In some embodiments, the subject has a LVEF < 23% with atrial fibrillation or flutter. In some embodiments, the subject has a LVEF < 22% with atrial10MOFO-359714640Attorney Docket No. 49892-20222.40 fibrillation or flutter. In some embodiments, the subject has a LVEF < 21% with atrial fibrillation or flutter. In some embodiments, the subject has a LVEF < 20% with atrial fibrillation or flutter. In some embodiments, the subject has a LVEF < 19% with atrial fibrillation or flutter. In some embodiments, the subject has a LVEF < 18% with atrial fibrillation or flutter. In some embodiments, the subject has a LVEF < 17% with atrial fibrillation or flutter. In some embodiments, the subject has a LVEF < 16% with atrial fibrillation or flutter. In some embodiments, the subject has a LVEF < 15% with atrial fibrillation or flutter.

[0035] In some embodiments, in conjunction with embodiments above or below, the subject has high NT-proBNP level, such as at least about 1000 pg / mL (e.g., 1000, 1100, 1200, 1300, and 1400), at least about 1500 pg / mL (e.g., 1500, 1600, 1700, 1800, and 1900 pg / mL), at least about 2000 pg / mL (e.g., 2000, 2100, 2200, 2300, and 2400 pg / mL), at least about 2500 pg / mL (e.g., 2500, 2600, 2700, 2800, and 2900 pg / mL), or at least 3000 pg / mL (e.g., 3000, 3500, 4000, 4500, 5000, 5500, 6000, 7000, 8000, 9000, 10,000, 15,000, and 20,000 pg / ml). In some embodiments, the subject has NT-proBNP level of at least about 1000 pg / mL. In some embodiments, the subject has NT-proBNP level of at least about 1500 pg / mL. In some embodiments, the subject has NT-proBNP level of at least about 2000 pg / mL. In some embodiments, the subject has NT-proBNP level of at least about 2500 pg / mL. In some embodiments, the subject has NT-proBNP level of at least about 3000 pg / mL.

[0036] In some embodiments, the NT-proBNP levels described herein are associated with subjects without atrial fibrillation or flutter. In some embodiments, the NT-proBNP levels described herein are associated with subjects with atrial fibrillation or flutter. For example, in some embodiments, the subject has N-terminal pro-B-type natriuretic peptide (NT-proBNP) > 1000 pg / ml without atrial fibrillation or flutter. In some embodiments, the subject has NT- proBNP > 3000 pg / mL with atrial fibrillation or flutter.

[0037] In some embodiments, the LVEFs and NT-proBNP levels described herein are associated with subjects without atrial fibrillation or flutter. In some embodiments, the LVEFs and NT-proBNP levels described herein are associated with subjects with atrial fibrillation or flutter. For example, in some embodiments, the subject has a LVEF < 40% at baseline and a pretreatment level of NT-proBNP of > 1,000 pg / mL without atrial fibrillation or flutter. In some embodiments, the subject has a LVEF < 35% at baseline and a pretreatment level of NT-proBNP11MOFO-359714640Attorney Docket No. 49892-20222.40 of > 1,000 pg / mL without atrial fibrillation or flutter. In some embodiments, the subject has a LVEF < 30% and a pretreatment level of NT-proBNP of > 1,000 pg / mL without atrial fibrillation or flutter. For example, in some embodiments, the subject has a LVEF < 40% at baseline and a pretreatment level of NT-proBNP of > 2,000 pg / mL without atrial fibrillation or flutter. In some embodiments, the subject has a LVEF < 35% at baseline and a pretreatment level of NT-proBNP of > 2,000 pg / mL without atrial fibrillation or flutter. In some embodiments, the subject has a LVEF < 30% and a pretreatment level of NT-proBNP of > 2,000 pg / mL without atrial fibrillation or flutter. In some embodiments, the subject has a LVEF < 35% at baseline and a pretreatment level of NT-proBNP of > 3,000 pg / mL with atrial fibrillation or flutter. In some embodiments, the subject has a LVEF < 30% at baseline and a pretreatment level of NT-proBNP of > 3,000 pg / mL with atrial fibrillation or flutter. In some embodiments, the subject has a LVEF < 25% at baseline and a pretreatment level of NT-proBNP of > 3,000 pg / mL with atrial fibrillation or flutter. In some embodiments, the subject has a LVEF < 35% at baseline and a pretreatment level of NT-proBNP of > 4,000 pg / mL with atrial fibrillation or flutter. In some embodiments, the subject has a LVEF < 30% at baseline and a pretreatment level of NT-proBNP of > 4,000 pg / mL with atrial fibrillation or flutter. In some embodiments, the subject has a LVEF < 25% at baseline and a pretreatment level of NT-proBNP of > 4,000 pg / mL with atrial fibrillation or flutter.

[0038] In some embodiments, in conjunction with embodiments above or below, the subject is taking digoxin. In some embodiments, in conjunction with embodiments above or below, the subject is not taking digoxin.

[0039] In some embodiments, the subject has a systolic blood pressure of less than or equal to 130 mmHg, less than or equal to 120 mmHg, less than or equal to 110 mmHg, less than or equal to 100 mmHg, less than or equal to 90 mmHg, or less than or equal to 80 mmHg. In some embodiments, the subject has a systolic blood pressure of less than or equal to 110 mmHg. In some embodiments, the subject has a systolic blood pressure of less than or equal to 100 mmHg. In some embodiments, the subject has a systolic blood pressure of less than or equal to 90 mmHg. In some embodiments, the subject has a systolic blood pressure of less than or equal to 80 mmHg. In some embodiments, the subject has a systolic blood pressure of less than 130 mmHg, less than 120 mmHg, less than 110 mmHg, less than 100 mmHg, less than 90 mmHg, or less than 80 mmHg. In some embodiments, the subject has a systolic blood pressure of less than 130 mmHg. In some embodiments, the subject has a systolic blood pressure of less than 12012MOFO-359714640Attorney Docket No. 49892-20222.40 mmHg. In some embodiments, the subject has a systolic blood pressure of less than 110 mmHg. In some embodiments, the subject has a systolic blood pressure of less than 100 mmHg. In some embodiments, the subject has a systolic blood pressure of less than 90 mmHg. In some embodiments, the subject has a systolic blood pressure of less than 80 mmHg. In some embodiments, the subject has a systolic blood pressure of more than or equal to 80 mmHg, more than or equal to 90 mmHg, more than or equal to 100 mmHg, more than or equal to 110 mmHg, more than or equal to 120 mmHg, or more than or equal to 130 mmHg. In some embodiments, the subject has a systolic blood pressure of more than or equal to 80 mmHg. In some embodiments, the subject has a systolic blood pressure of more than or equal to 90 mmHg. In some embodiments, the subject has a systolic blood pressure of more than or equal to 100 mmHg. In some embodiments, the subject has a systolic blood pressure of more than or equal to 110 mmHg. In some embodiments, the subject has a systolic blood pressure of more than or equal to 120 mmHg. In some embodiments, the subject has a systolic blood pressure of more than or equal to 130 mmHg. In some embodiments, the subject has a systolic blood pressure of more than 90 mmHg. In some embodiments, the subject has a systolic blood pressure of more than 100 mmHg. In some embodiments, the subject has a systolic blood pressure of more than 110 mmHg. In some embodiments, the subject has a systolic blood pressure of more than 120 mmHg. In some embodiments, the subject has a systolic blood pressure of more than 130 mmHg.

[0040] In some embodiments, the subject has heart failure classified as Class III or IV as determined using the New York Heart Association (NYHA) classification. In some embodiments, the subject has advanced heart failure.

[0041] In some embodiments, the subject is currently hospitalized or has had one or more HF hospitalizations or HF events within 6 months. In some embodiments, the subject has had a HF event within 6 months. In some embodiments, the subject has had a HF event within 3 months. In some embodiments, the subject is currently on a loop diuretic, such as furosemide, bumetanide, torsemide, or ethacrynic acid. In some embodiments, the subject has an LVEF < 30% at baseline, a pretreatment level of NT-proBNP of > 1,000 pg / mL, and has had a HF event within 6 months. In some embodiments, the subject has heart failure classified as Class III or IV as determined using the New York Heart Association (NYHA) classification and has had a HF event within 3 months. An HF event may be a presentation of the patient for an urgent, unscheduled clinic / office / emergency department visit, or hospital admission, with a primary13MOFO-359714640Attorney Docket No. 49892-20222.40 diagnosis of HF, where the patient exhibits new or worsening symptoms of HF on presentation, has objective evidence of new or worsening HF, and receives initiation or intensification of treatment specifically for HF (Hicks 2018).

[0042] In some embodiments, the subject is an inpatient or an outpatient. In some embodiments, the subject is an inpatient. In some embodiments, the subject is an outpatient.Treatment Effect

[0043] In some embodiments, the treatment is effective to prevent or delay the time to a heart failure event, cardiovascular death, left ventricular assist device (LVAD) implantation, cardiac transplantation, or stroke, in the patient. In some embodiments, the treatment is effective to prevent or delay left ventricular assist device (LVAD) implantation and / or cardiac transplantation in the patient. In some embodiments, the treatment is effective to delay the time to a stroke in the patient. In some embodiments, the treatment is effective to prevent or delay a new incidence of atrial fibrillation or atrial flutter (AFF) in the patient.

[0044] In some embodiments, the treatment is effective to prevent or delay in the patient the time to the first event of cardiovascular death or HF event. In some embodiments, the treatment is effective to prevent or delay in the patient the time to all-cause death. In some embodiments, the treatment is effective to prevent or delay in the patient the time to the first event of cardiovascular death or LVAD implantation or cardiac transplantation or stroke.Dosing and Dosing Regimen

[0045] In some embodiments, the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is administered via any suitable route. In some embodiments, the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is administered orally. In some embodiments, in conjunction with other above or below embodiments, the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is administered as a tablet.

[0046] In some embodiments, the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is omecamtiv mecarbil dihydrochloride hydrate. In some embodiments, the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is omecamtiv mecarbil dihydrochloride hydrate Form A. In some embodiments, the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is a solvate.14MOFO-359714640Attorney Docket No. 49892-20222.40

[0047] In some embodiments, the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is administered as a modified release matrix tablet. In some embodiments, in conjunction with other above or below embodiments, the modified release matrix tablets demonstrate a minimal pH-dependent release in-vitro.

[0048] In some embodiments, the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is administered in a dosage of 25 mg twice daily, 37.5 mg twice daily, or 50 mg twice daily. In some embodiments, the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is administered in a dosage of about 20 mg to about 35 mg twice daily. In some embodiments, the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is administered in a dosage of 25 mg twice daily. In some embodiments, the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is administered in a dosage of about 30 mg to about 45 mg twice daily. In some embodiments, the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is administered in a dosage of 37.5 mg twice daily. In some embodiments, the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is administered in a dosage of about 45 mg to about 60 mg twice daily. In some embodiments, the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is administered in a dosage of 50 mg twice daily.

[0049] In some embodiments, the method comprises administering to the subject a first dose level of the CSA of at least about 20 mg twice daily, e.g., 20 mg twice daily, 20.5 mg twice daily, 21 mg twice daily, 21.5 mg twice daily, 22 mg twice daily, 22.5 mg twice daily, 23 mg twice daily, 23.5 mg twice daily, 24 mg twice daily, 24.5 mg twice daily, 25 mg twice daily, 25.5 mg twice daily, 26 mg twice daily, 26.5 mg twice daily, 27 mg twice daily, 27.5 mg twice daily, 28 mg twice daily, 28.5 mg twice daily, 29 mg twice daily, 29.4 mg twice daily, and 30 mg twice daily, and a second dose level of the CSA. In some embodiments, the method comprises administering to the subject a first dose level of the CSA of from about 20 mg twice daily to about 35 mg twice daily, from about 20 mg twice daily to about 30 mg twice daily, or from about 22.5 mg twice daily to about 27.5 mg twice daily, and a second dose level of the CSA. In some embodiments, the first dose level of the CSA is about 25 mg twice daily. In some embodiments, the second dose level of the CSA is the same as the first dose level of the CSA (e.g., about 25 mg twice daily). In some embodiments, the second dose level of the CSA is greater than the first dose level of the CSA (e.g., about 37.5 mg twice daily or about 50 mg twice daily).15MOFO-359714640Attorney Docket No. 49892-20222.40

[0050] In some embodiments, the method comprises: a) administering to the patient an initial dose of the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof of 25 mg twice daily for an initial time period of about 2 weeks, b) administering to the patient a subsequent dose of the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof based on the patient’s plasma concentration of the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof measured at about 2 weeks after the first administration of the initial dose, wherein the subsequent dose of the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is (i) about 25 mg twice daily when the patient’ s plasma concentration of the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is greater than or about 300 ng / mL but less than or about 750 ng / mL, (ii) about 37.5 mg twice daily when the subject’s plasma concentration of the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is greater than or about 200 ng / mL but less than 300 ng / mL, or (iii) about 50 mg twice daily, when the subject’s plasma concentration of the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is less than 200 ng / mL.

[0051] In some embodiments, the treatment comprises administering to the subject a first dose level of the CSA of at least about 20 mg twice daily (e.g., 25 mg twice daily) for an initial period of time. In some embodiments, the initial period of time is at least about 2 weeks, e.g., 2 weeks, 2.5 weeks, 3 weeks, 3.5 weeks, 4 weeks, 4.5 weeks, 5 weeks, 5.5 weeks, and 6 weeks. In some embodiments, the initial period of time is 2 to 6 weeks, 2 to 5 weeks, 2 to 4 weeks, 3 to 6 weeks, 3 to 5 weeks, 3 to 4 weeks, 4 to 5 weeks, or 4 to 6 weeks. In some embodiments, the initial period of time is about 4 weeks. In some embodiments, the initial period of time is about2 weeks.

[0052] In some embodiments, the treatment further comprises administering to the subject a second dose level of the CSA for a second period of time based on the subject’s plasma concentration of the CSA determined after administration of the first dose level of the CSA has started. In some embodiments, the second period of time is at least about 2 weeks, e.g., 2 weeks, 2.5 weeks, 3 weeks, 3.5 weeks, 4 weeks, 4.5 weeks, 5 weeks, 5.5 weeks, and 6 weeks. In some embodiments, the initial period of time is 2 to 6 weeks, 2 to 5 weeks, 2 to 4 weeks, 3 to 6 weeks,3 to 5 weeks, 3 to 4 weeks, 4 to 5 weeks, 4 to 6 weeks, or for as long as treatment is recommended or efficacious.Combination Therapy16MOFO-359714640Attorney Docket No. 49892-20222.40

[0053] In some embodiments, in conjunction with embodiments above or below, the disclosed methods can comprise administering one or more additional therapeutics suitable for treating / ameliorating one or more cardiovascular conditions. In some embodiments, in conjunction with embodiments above or below, the disclosed methods comprise administering to the patient a therapeutically effective amount of an angiotensin-converting enzyme (ACE) inhibitor. In some embodiments, in conjunction with embodiments above or below, the disclosed methods comprise administering to the patient a therapeutically effective amount of a mineralocorticoid receptor antagonist (MRA).

[0054] In some cases, the ACE inhibitor comprises one or more agents selected from benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril.

[0055] In some cases, the MRA comprises one or more agents selected from spironolactone, eplerenone, canrenoic acid, canrenone, and drosprienone.EXAMPLES

[0056] The application may be better understood by reference to the following non-limiting examples, which are provided as exemplary embodiments of the application. The following examples are presented in order to more fully illustrate embodiments and should in no way be construed, however, as limiting the broad scope of the application. While certain embodiments of the present application have been shown and described herein, it will be obvious that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the spirit and scope of the invention. It should be understood that various alternatives to the embodiments described herein may be employed in practicing the methods described herein.

[0057] The following abbreviations are used in the Examples: ACEi refers to angiotensinconverting enzyme inhibitor; ARB refers to angiotensin receptor blocker; ARNi refers to angiotensin receptor-neprilysin inhibitor; BB refers to beta blocker; CRT refers to cardiac resynchronization therapy; ED refers to emergency department; EF refers to ejection fraction; eGFR refers to estimated glomerular filtration rate; HF refers to heart failure; HFrEF refers to heart failure and reduced ejection fraction; hsTn refers to high- sensitivity troponin I; ICD refers to implantable cardioverter-defibrillator; KCCQ refers to Kansas City Cardiomyopathy17MOFO-359714640Attorney Docket No. 49892-20222.40Questionnaire; LVEF refers to left ventricular ejection fraction; MAGGIC refers to MetaAnalysis Global Group in Chronic HF; MRA refers to mineralocorticoid receptor antagonist; NEJM refers to The New England Journal of Medicine; NT-proBNP refers to N-terminal pro-B- type natriuretic peptide; NYHA refers to New York Heart Association; SBP refers to systolic blood pressure; SGLT2 refers to sodium-glucose co-transporter 2; and WOCBP refers to a woman of childbearing potential.

[0058] The endpoints of studies and event definitions were based on ACC / AHA standards for endpoint definitions in cardiovascular clinical trials as described in Hicks et al. 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials, J Am Coll Cardiol 2018;71:1021-34.Example 1 - Clinical TrialPatient Eligibility

[0059] Patient eligibility requirements include the following criteria for inclusion. Participants must be aged > 18 years and < 85 years. Patients must have a history of chronic HFrEF, defined as requiring treatment for HF for a minimum of 3 months prior to randomization. Patients must be on oral loop diuretics at time of screening. Patients without atrial fibrillation or flutter must have a Left Ventricular EF (LVEF) < 30%. Patients with atrial fibrillation or flutter must have a LVEF < 25%. LVEF must be confirmed by an EF measurement (e.g. local echocardiogram, core laboratory echocardiogram, cardiac magnetic resonance imaging, or other) performed within 6 months prior to screening, and at least 3 months after acute coronary syndrome (ACS), cardiac surgery, valve procedures, any coronary revascularization, and / or cardiac resynchronization therapy (CRT). Patients must be currently hospitalized or have > 1 HF event within 6 months prior to screening. Patients must be established on standard of care (SoC) therapies consistent with physician discretion and regional clinical practice guidelines. Patients with atrial fibrillation or flutter at randomization will be capped at 15% of study participants. Patients must have a systolic blood pressure of < 130 mmHg and a diastolic blood pressure < 90 mmHg. Patients must have B-type natriuretic peptide (BNP) > 300 pg / ml or N-terminal pro-BNP (NT-proBNP) > 1000 pg / ml (for subjects with atrial fibrillation, the cut off levels are: BNP > 900 pg / mL or NT-proBNP > 3000 pg / mL at screening). A female patient is eligible to participate if she is not pregnant, breastfeeding, or planning to18MOFO-359714640Attorney Docket No. 49892-20222.40 donate eggs, and is not a WOCBP or is a WOCBP using a highly effective or acceptable method of contraception.

[0060] Patient eligibility requirements also include the following criteria for exclusion from the study. Patients with ACS, cardiac surgery, valve surgery, any coronary revascularization, and / or CRT within 3 months of randomization are excluded. Patients with atrial fibrillation or flutter on digoxin are excluded from the study. Patients admitted to long term care facility or hospice are excluded from the study. Patients with a projected survival of < 12 months due to non-cardiovascular causes based on clinical judgement are excluded from the study. Patients receiving intravenous inotropes or intravenous vasopressors < 3 days prior to randomization are excluded from the study. Patients receiving mechanical hemodynamic support or mechanical ventilation < 7 days prior to randomization are excluded from the study. Patients receiving intravenous diuretics, intravenous vasodilators, or supplemental oxygen therapy < 12 hours prior to randomization are excluded from the study. Patients with an estimated glomerular filtration rate (eGFR) < 20 mL / min / 1.73m2 or receiving dialysis at screening are excluded from the study. Patients with previous solid organ transplant or intent to transplant (on transplant list) are excluded from the study. Patients receiving treatment in another investigational device or drug study or are within 30 days (or 5 half-lives for drugs, whichever is longer) of ending such investigational treatment are excluded from the study. Patients having previously received omecamtiv mecarbil are excluded from the study. Patients unable to swallow the investigational product are excluded from the study. Patients with a history or evidence of any other clinically significant disorder, condition, or disease (except those outlined previously) that, in the opinion of the investigator, if consulted, would pose a risk to patient safety or interfere with the study evaluation, procedures, or completion are excluded from the study. Patients with a current pregnancy or planned pregnancy during the study period, or planned breastfeeding during treatment or within 5 days after the end of treatment are excluded from the study. Patients with an inability to provide informed consent or to comply with study schedule are excluded from the study.Study Procedures

[0061] A randomized, placebo-controlled, double-blind, parallel group, multicenter, phase 3 study in outpatient and inpatient adults with symptomatic HFrEF and severely reduced LVEF (defined by LVEF < 30%, NT-proBNP > 1,000 pg / mL, and a heart failure event within the19MOFO-359714640Attorney Docket No. 49892-20222.40 preceding 6 months) is performed. The study is event-driven and concludes when approximately 850 primary composite events (cardiovascular death, first HF event, LVAD implantation, cardiac transplantation, or stroke) have occurred. The trial will be conducted at large, multicenter integrated health delivery networks in the United States, Canada, and Europe.

[0062] Using the electronic health record (EHR) participants are screened for eligibility criteria at clinical sites associated with large integrated healthcare delivery networks. Eligible participants sign electronic informed consent forms, after which they enter a screening period either in the inpatient or outpatient setting. At screening, all subjects should be established for at least 30 days on standard of care therapies for HFrEF consistent with regional clinical practice guidelines. Eligibility is confirmed via a local echocardiogram performed within 6 months of screening.

[0063] Approximately 1,800 screened subjects who meet all eligibility criteria are enrolled and randomized in a 1:1 ratio to omecamtiv mecarbil or placebo. Randomization is stratified by the presence of AFF at screening and the randomization setting (currently hospitalized for HF or recently and not currently hospitalized for HF). The results are blinded to investigators. To evaluate medication tolerance and adherence prior to randomization, a run-in phase is conducted as follows: all participants are started on 25 mg twice daily. After two weeks, a pre-dose omecamtiv mecarbil plasma level is tested. Based on the results of this test, participants with an omecamtiv mecarbil level below the quantifiable limit of 85 ng / mL or < 750 ng / mL after two weeks of dosing are excluded from the study. The remaining participants are then to be randomized 1:1 to either placebo or their personalized dose of omecamtiv mecarbil (25 mg, 37.5 mg, or 50 mg) to achieve a target plasma concentration of 300 to 750 ng / mL, shown in FIG. 1. (Abbreviations for FIG. 1: BID, twice daily; OM, omecamtiv mecarbil; PK, pharmacokinetic.) The investigational product is an omecamtiv mecarbil oral modified-release tablet in 25, 37.5, and 50 mg doses. A new supply of investigational product (IP) is administered to all subjects (OM and placebo) at the beginning of the run-in period, randomization, week 2, and all in- person visits, regardless of randomized treatment cohort to maintain the blind. All participants and investigators are unaware of the dispensed dose. Post-randomization assessments are performed at weeks 2, 12, 24, 36, 48, and every 12 weeks thereafter, alternating remote and in- person visits, and the end of the study (remote). Endpoint adjudication occurs via the EHR by the local investigator with additional central adjudication of all events. A summary of the clinical trial design is provided in the FIG. 2. (Footnote for FIG. 2:aAfter the 2-week run-in,20MOFO-359714640Attorney Docket No. 49892-20222.40 patients with undetectable omecamtiv mecarbil levels (< 85 ng / mL) or levels > 750 ng / mL, intolerance, or documented non-adherence will be excluded and will not be eligible for randomization. Abbreviations for FIG. 2: AFF, atrial fibrillation or flutter; HF, heart failure; KCCQ, Kansas City Cardiomyopathy Questionnaire; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal prohormone of B-type natriuretic peptide; OM, omecamtiv mecarbil; PK, pharmacokinetic.)

[0064] The administration of omecamtiv mecarbil or placebo will be temporarily suspended if the patient has clinical signs or symptoms consistent with acute myocardial infarction or ischemia, followed by omecamtiv mecarbil testing.Study Outcomes

[0065] The primary outcome is a composite of the time to a heart failure event, cardiovascular death, left ventricular assist device (LVAD) implantation, cardiac transplantation, or stroke, whichever occurs first. A heart failure event is defined as an urgent clinic visit, emergency department visit or hospitalization for subjectively and objectively worsening heart failure leading to treatment intensification beyond changed oral diuretic therapy.

[0066] Secondary outcomes are: the time to the first HF hospitalization; the time to the first event of cardiovascular death or HF event; the time to all-cause death, the time to the first event of cardiovascular death or LVAD implantation or cardiac transplantation or stroke (to evaluate the effect of omecamtiv mecarbil compared with placebo on irreversible morbidity / mortality related to HFrEF), the time to the first event of the primary composite endpoint components in a subgroup of patients with severe heart failure (LVEF < 30%, NYHA class 3-4, HF event within the last 3 months); the time to the first event of the following components: cardiovascular (CV) death, LVAD implantation / cardiac transplantation, and stroke; and the time to CV mortality.

[0067] Exploratory outcomes are: the time to first and recurrent HF hospitalizations; the change from screening to week 24 in NT-proBNP; an incidence of new AFF; the frequency of initiation of chronic inotrope therapy, LVAD implantation, or cardiac transplantation; the change in KCCQ total summary score (TSS) from randomization to week 24 in patients with a score of < 80 at randomization; changes in health status measured by EQ-5D-5L and cost of care; and the time to all-cause mortality.Safety21MOFO-359714640Attorney Docket No. 49892-20222.40

[0068] Safety endpoints include: incidence of reported major adverse cardiac events (CV death, non-fatal stroke, non-fatal myocardial infarction, unstable angina hospitalization, HF hospitalization); and incidence of any adverse events leading to IP discontinuation, serious adverse events (SAEs), and adverse events of special interest (AESIs).

[0069] The safety and tolerability profile of omecamtiv mecarbil is evaluated in comparison with a placebo in patients with HFrEF. Participant incidence of reported major adverse cardiac events, including cardiovascular death, cardiac arrest, non-fatal stroke, non-fatal myocardial infarction, unstable angina hospitalization, and heart failure hospitalization is reported. Participant incidence of any adverse events (AE) leading to drug discontinuation, serious adverse events (SAEs), and adverse events of special interest (AESIs) is reported.

[0070] A Bayesian Cox proportional hazards model determines the treatment effectiveness for the primary composite endpoint and key secondary endpoints. The primary analysis of the primary composite endpoint uses a likelihood ratio test from a Cox model and stratified by randomization setting and presence of AFF at screening. The primary analysis occurs after approximately 850 primary endpoint events have occurred and interim analyses are conducted when 425 (50%) and 638 (75%) events have occurred. The primary composite endpoint events include cardiovascular death, HF event, LVAD implantation / cardiac transplantation, or stroke. The secondary endpoints are assessed using the same Cox model as the primary composite endpoint. The change in NT-proBNP levels from screening and KCCQ from randomization to week 24 are assessed using a mixed model fit within each randomization setting containing their baseline values, baseline estimated glomerular filtration rate (eGFR), presence of AFF at screening, visit number, treatment group, and treatment-by-visit. A subgroup analysis will consider these subgroups: LVEF < 25% vs > 25%, LVEF median, AFF vs no AFF, inpatient vs outpatient, systolic blood pressure < 100 mmHg vs > 100 mmHg, NYHA class 2 vs class 3 and 4, and NT- proBNP median.

[0071] For the exploratory endpoints, the change in KCCQ total summary score from randomization to week 24 is assessed using a mixed model fit within each randomization setting containing the baseline KCCQ value, baseline eGFR, and AFF at screening, visit, treatment, and treatment-by-visit. The NT-proBNP value is determined by the exponentiation of the change from screening in log-transformed values from a mixed model within each randomization setting containing the log baseline NT-proBNP value, AFF at screening, baseline eGFR, scheduled22MOFO-359714640Attorney Docket No. 49892-20222.40 visit, trial group, and interaction of the trial group with the scheduled visit. The between-group difference of NT-proBNP will be the geometric mean ratio. The times to first and recurrent hospitalizations will be analyzed using a semiparametric joint frailty model with all-cause mortality as a terminal event as described previously (Liu et al. 2004). The time to new AFF will be analyzed using the same Cox model as the primary composite endpoint.

[0072] All deaths, potential primary endpoint events, and major cardiac ischemic events (myocardial infarction, unstable angina, hospitalization, and coronary revascularization) will be centrally adjudicated.23MOFO-359714640

Claims

Attorney Docket No. 49892-20222.40CLAIMSWhat is claimed is:

1. A method of treating heart failure in a patient who exhibits atrial fibrillation or atrial flutter (AFF), has a left ventricular ejection fraction (LVEF) of less than 25% at baseline, and has a pretreatment level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) of at least 3,000 pg / mL, comprising administering to the patient a therapeutically effective amount of omecamtiv mecarbil, or a hydrate, a salt, or a salt of a hydrate thereof.

2. A method of treating heart failure in a patient who has a left ventricular ejection fraction (LVEF) of less than 30% at baseline and a pretreatment level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) of at least 1,000 pg / mL, comprising administering to the patient a therapeutically effective amount of omecamtiv mecarbil, or a hydrate, a salt, or a salt of a hydrate thereof.

3. The method of claim 2, wherein the patient does not exhibit atrial fibrillation or atrial flutter (AFF).

4. The method of claim 2 or 3, wherein the patient has an LVEF of less than 29%, less than 28%, less than 27%, less than 26%, less than 25%, less than 24%, less than 23%, less than 22%, less than 21%, or less than 20% at baseline.

5. The method of any one of claims 2-4, wherein the patient has a pretreatment level of NT- proBNP of at least 1,500 pg / mL, at least 2,000 pg / mL, or at least 2,500 pg / mL.

6. The method of any one of claims 1-5, wherein the patient is not receiving digoxin.

7. The method of any one of claims 2-5, wherein the patient is receiving digoxin.

8. The method of any one of claims 1-7, wherein the patient has a systolic blood pressure of < 100 mmHg.

9. The method of any one of claims 1-8, wherein the patient has heart failure classified as Class III or IV as determined using the New York Heart Association (NYHA) classification.

10. The method of any one of claims 1-9, wherein the patient has advanced heart failure.24MOFO-359714640Attorney Docket No. 49892-20222.4011. The method of any one of claims 1-10, wherein the patient has had at least one heart failure hospitalization within 6 months prior to the treatment.

12. The method of any one of claims 1-11, wherein the patient is an inpatient.

13. The method of any one of claims 1-11, wherein the patient is an outpatient.

14. The method of any one of claims 1-13, wherein the treatment is effective to prevent or delay left ventricular assist device (LVAD) implantation and / or cardiac transplantation in the patient.

15. The method of any one of claims 1-13, wherein the treatment is effective to prevent or delay new incidence of atrial fibrillation or atrial flutter (AFF).

16. A method of preventing or delaying left ventricular assist device (LVAD) implantation and / or cardiac transplantation in a patient, comprising administering to the patient a therapeutically effective amount of omecamtiv mecarbil, or a hydrate, a salt, or a salt of a hydrate thereof.

17. A method of preventing or delaying new incidence of atrial fibrillation or atrial flutter (AFF) in a patient, comprising administering to the patient a therapeutically effective amount of omecamtiv mecarbil, or a hydrate, a salt, or a salt of a hydrate thereof.

18. The method of claim 16, wherein the patient i) exhibits atrial fibrillation or atrial flutter (AFF); ii) has a left ventricular ejection fraction (LVEF) of less than 25% at baseline; and iii) has a pretreatment level of NT-proBNP of at least 3,000 pg / mL.

19. The method of claim 16 or 17, wherein the patient has a left ventricular ejection fraction (LVEF) of less than 30% at baseline and pretreatment level of NT-proBNP of at least 1,000 pg / mL.

20. The method of any one of claims 1-19, wherein the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is administered orally.

21. The method of any one of claims 1-20, wherein the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is administered as a tablet.25MOFO-359714640Attorney Docket No. 49892-20222.4022. The method of any one of claims 1-21, wherein the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is omecamtiv mecarbil dihydrochloride hydrate.

23. The method of any one of claims 1-18, wherein the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is administered as a modified release matrix tablet.

24. The method of any one of claims 1-23, wherein the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is administered in a dosage of 25 mg twice daily, 37.5 mg twice daily, or 50 mg twice daily.

25. The method of any one of claims 1-24, wherein the method comprises: a. administering to the patient an initial dose of the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof of 25 mg twice daily for an initial time period of about 2 weeks, b. administering to the patient a subsequent dose of the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof based on the patient’s plasma concentration of the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof measured at about 2 weeks after the first administration of the initial dose, wherein the subsequent dose of the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is (i) about 25 mg twice daily when the patient’s plasma concentration of the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is greater than or about 300 ng / mL but less than or about 750 ng / mL, (ii) about 37.5 mg twice daily when the subject’s plasma concentration of the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is greater than or about 200 ng / mL but less than 300 ng / mL, or (iii) about 50 mg twice daily , when the subject’s plasma concentration of the omecamtiv mecarbil, or the hydrate, salt, or salt of the hydrate thereof is less than 200 ng / mL.26MOFO-359714640

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