Method for treating cardiac failure by cardiac sarcomere activator

Abstract

To provide a method for treating a subject having cardiac failure.SOLUTION: A method includes administering an initial dose of cardiac sarcomere activator (CSA) to a subject for a first period, and subsequently, administering a dose of CSA based on the plasma concentration of CSA in the subject at the end of the first period to the subject.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS The benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 62 / 527,983, filed June 30, 2017, is hereby claimed, the disclosure of which is incorporated herein by reference. [Background technology]

[0002] Heart failure (HF) is a clinical syndrome defined by an imbalance between cardiac function and the body's metabolic demands. It is the final pathway for many diseases affecting the heart (Hilfiker-Kleiner et al., 2006). HF affects more than 26 million people worldwide, with more than 3.5 million new cases diagnosed each year. Prevalence has been shown to increase with age (Lopez-Sendon, 2011), suggesting that the incidence of HF may increase as people age. In the United States (US), more than 5 million people, or nearly 2.0% of the population, have HF (Go et al., 2013). In Europe, it is estimated that at least 15 million people have HF (Dickstein et al., 2008). HF is usually further classified as either "reduced" or "preserved" ejection fraction. The 1-year mortality rate for patients with heart failure with reduced ejection fraction (HFrEF) in Western developed countries is typically 10%–25% per year; however, depending on the severity of HF, this rate can range from as low as 5% per year in patients with stable New York Heart Association (NYHA) class I–II disease to as high as 75% per year in patients with NYHA class III–IV disease (Mozaffarian et al., 2007; Bhatia et al., 2006; Levy et al., 2006; Solomon et al., 2004). The burden of HF can also be seen in data from recurrent hospitalizations. Medicare data and data from privately insured patients indicate that 12%–27% of patients hospitalized with HF are readmitted within 30 days of their hospital stay, with overall mortality reaching 12% over the same period (Jencks et al., 2009; McIlvennan et al., 2014).

[0003] HF is most commonly caused by coronary artery disease (CAD); other causes include hypertensive heart disease, valvular heart disease, and idiopathic causes (Ambrosy et al., 2014). In an effort to preserve cardiac output and organ perfusion, HF progresses through stages involving compensatory mechanisms characterized by increased sympathetic tone, peripheral vasoconstriction, and activation of various neurohormonal pathways. These adaptive properties provide short-term relief but may be impaired by prolonged or prolonged activation. Patients experience dyspnea, fatigue, and fluid retention, ultimately developing pulmonary congestion and peripheral edema. The goals of treatment are to improve symptoms, prolong survival, and reduce rehospitalization (Yancy et al., 2013; Ponikowski et al., 2016). Although several pharmacological and non-pharmacological interventions, including angiotensin-converting enzyme inhibitors (ACEs), beta-blockers, aldosterone antagonists, coronary revascularization, and biventricular pacing (Jessup and Brozena, 2003; Krum and Teerlink, 2011), have been shown to reduce hospitalization and improve mortality in HF, mortality and morbidity remain high, as noted above. Additionally, these available treatments, which act on compensatory mechanisms (e.g., sodium retention, arterial and venous constriction, neuroendocrine activation, and increased heart rate), often fail to control symptoms or restore quality of life.

[0004] Although reduced left ventricular ejection fraction (LVEF) is a central factor in HF, there are no safe medical therapies that directly improve cardiac function at the myocardial segment level in HF patients. The compensatory mechanisms described above are deployed to preserve cardiac output and organ perfusion in scenarios of impaired myocardial contractility. Attempts to improve cardiac contractility in chronic HF patients via chronic stimulation of adrenergic receptor pathways (e.g., dobutamine or ibopamine) or phosphodiesterase inhibitors (i.e., milrinone) have been successful (Tacon et al., 2012). Both agents have significant safety liabilities due to their mechanism of action. Increased intracellular calcium can improve contractility, albeit at the expense of increased tissue oxygen consumption and arrhythmias. The addition of long-term oral milrinone to SoC in patients with severe chronic HFrEF has been associated with increased mortality and morbidity (Packer et al., 1991). Oral ibopamine, a dopamine receptor agonist (DA-1 and DA-2), also failed to demonstrate clinical benefit when added to SoC in outpatients with HFrEF (Hampton et al, 1997). [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Hilfiker-Kleiner et al., 2006 [Non-patent document 2] Lopez-Sendon, 2011 [Non-patent document 3] Go et al., 2013 [Non-patent document 4] Dickstein et al., 2008 [Non-patent document 5] Mozaffarian et al., 2007 [Non-patent document 6] Bhatia et al., 2006 [Non-Patent Document 7] Levy et al., 2006 [Non-patent document 8] Solomon et al., 2004 [Non-Patent Document 9] Jencks et al., 2009 [Non-Patent Document 10] McIlvennan et al., 2014 [Non-Patent Document 11] Ambrosy et al., 2014 [Non-Patent Document 12] Yancy et al., 2013 [Non-Patent Document 13] Ponikowski et al., 2016 [Non-Patent Document 14] Jessup and Brozena, 2003 [Non-Patent Document 15] Krum and Teerlink, 2011 [Non-Patent Document 16] Tacon et al., 2012 [Non-Patent Document 17] Packer et al., 1991 [Non-Patent Document 18] Hampton et al., 1997 Summary of the Invention [Problem to be solved by the invention]

[0006] Thus, there remains a need for safe and effective methods of treating the etiology of HF, including HFrEF. [Means for solving the problem]

[0007] Provided herein are therapeutic methods that include administering a cardiac segment activating agent (CSA) at an initial dose, e.g., a starting dose, for an initial period of time, and subsequently administering the CSA at a dose determined based on the subject's plasma concentration during or at the end of the initial period. In exemplary embodiments, the therapeutic methods of the present disclosure provide a method for treating a subject with CSA. In exemplary embodiments, the therapeutic methods of the present disclosure provide a method for individualizing treatment of a subject with CSA. In exemplary embodiments, the therapeutic methods of the present disclosure provide a safe and improved method for treating subjects with heart failure, e.g., HFrEF, that maximizes effective exposure in each individual subject while avoiding overexposure to CSA.

[0008] Accordingly, the present disclosure provides a method of treating a subject with heart failure. In an exemplary embodiment, the method includes (a) administering an initial dose of a cardiac segment activator (CSA) to the subject over an initial period of time, and (b) subsequently administering doses of CSA to the subject based on the subject's plasma concentration of CSA during or at the end of the initial period of time. In an exemplary embodiment, the initial dose is a minimum effective dose (MED) of CSA. In an exemplary embodiment, CSA has reached a steady state in the subject by the end of the initial period of time or by the time the plasma concentration of CSA is determined. In an exemplary embodiment, the method includes subsequently administering doses of CSA to the subject based on the subject's steady-state plasma concentration of CSA. In an exemplary embodiment, the doses subsequently administered to the subject are one of two options: either the same as the initial dose or greater than the initial dose. In alternative or additional exemplary embodiments, the dose administered to the subject subsequently is one of three options: (i) the same as the initial dose, (ii) greater than the initial dose but less than the maximum dose, or (iii) the maximum dose. In exemplary embodiments, when the subject's plasma concentration of CSA exceeds a threshold concentration, the dose administered subsequently is the same as the initial dose. In exemplary cases, the threshold concentration is about 1.0 to about 1.5 times the minimum value of the target concentration range. In exemplary embodiments, when the subject's plasma concentration of CSA is less than the threshold, the dose administered subsequently is greater than the initial dose. In exemplary cases, the threshold concentration is about 1.0 to about 1.5 times the minimum value of the target concentration range.

[0009] In an exemplary embodiment, a method for treating a subject with HF includes (a) administering an initial dose of CSA to the subject over an initial period of time, and (b) subsequently administering doses of CSA to the subject based on the subject's plasma concentration of CSA during or at the end of the initial period. In an exemplary embodiment, when the subject's plasma concentration of CSA is equal to or greater than the minimum value of the target concentration range, the subsequently administered dose is the same as the initial dose. In an exemplary embodiment, when the subject's plasma concentration of CSA is less than the minimum value of the target concentration range, the subsequently administered dose is greater than the initial dose. In an exemplary embodiment, when the subject's plasma concentration of CSA is greater than or about 1.5 times the minimum value of the target concentration range, the subsequently administered dose is the same as the initial dose. In an exemplary embodiment, when the subject's plasma concentration of CSA is less than 1.5 times the minimum value of the target concentration range but greater than or about the minimum value of the target concentration range, the subsequently administered dose is greater than the initial dose but less than the maximum dose. In an exemplary embodiment, when the subject's plasma concentration of CSA is below the minimum of the target concentration range, the subsequently administered dose is the maximum dose.

[0010] Methods for determining a treatment regimen for a subject are also provided. In exemplary embodiments, the method includes (a) administering a minimum effective dose (MED) dose of CSA to the subject over an initial period of time, wherein the CSA reaches a steady state in the subject during or by the end of the initial period, and (b) determining the subject's plasma concentration of CSA at the end of the initial period. In exemplary embodiments, the treatment regimen after the initial period includes a dose of CSA that is either the same as or greater than the initial dose. In exemplary embodiments, when the subject's plasma concentration of CSA is above a threshold concentration, in exemplary cases about 1.0 to about 1.5 times the minimum of the target concentration range, the treatment regimen after the initial period includes a dose of CSA that is the same as the initial dose. In exemplary embodiments, when the subject's plasma concentration of CSA is below a threshold concentration, in exemplary cases about 1.0 to about 1.5 times the minimum of the target concentration range, the treatment regimen after the initial period includes a dose of CSA that is greater than the initial dose. In alternative or additional exemplary embodiments, the treatment regimen after the initial period includes a dose that is one of three options: the subsequently administered dose is (i) the same as the initial dose, (ii) greater than the initial dose but less than the maximum dose, or (iii) the maximum dose. In exemplary embodiments, the treatment regimen after the initial period includes a dose of CSA that is (i) essentially the same as the initial dose when the plasma concentration of CSA is greater than or about 1.5 times the minimum of the target concentration range, (ii) greater than the initial dose but less than the maximum dose when the subject's plasma concentration of CSA is greater than or about the minimum of the target concentration range but less than about 1.5 times the minimum of the target concentration range, or (iii) the maximum dose when the plasma concentration of CSA is less than the minimum of the target concentration range. [Brief explanation of the drawings]

[0011] [Figure 1] 1 is a description of the study design and treatment regimen of the study described in Example 1. [Figure 2] 1 is a representation of the clinical trial profile described in Example 3. [Figure 3]3A is a set of graphs showing least squares mean (SE) changes from baseline to week 20 in efficacy endpoints. FIG. 3A is a graph of change in systolic ejection time. FIG. 3B is a graph of change in stroke volume. FIG. 3C is a graph of change in LVESD. FIG. 3D is a graph of change in LVEDD. FIG. 3E is a graph of change in heart rate. FIG. 3F is a graph of change in NT-proBNP. P values ​​are for comparison with placebo. LVESD = left ventricular end-systolic diameter; LVEDD = left ventricular end-diastolic diameter; NT-proBNP = N-terminal brain natriuretic peptide; PK = pharmacokinetics. [Figure 4] 1 is a graph showing the change from baseline in maximum cardiac troponin I concentration versus maximum omecamtib mecarbil plasma concentration. Each point represents one patient (n=429). The linear regression line for the change in maximum troponin I concentration, calculated as (0.000066 × maximum omecamtib mecarbil concentration) + 0.023, shows very poor correlation with maximum omecamtib mecarbil plasma concentration (r2=0.017). DETAILED DESCRIPTION OF THE INVENTION

[0012] Treatment method Presented herein is data supporting a treatment method that includes administering CSA at an initial dose, e.g., a pre-administration starting dose, for an initial period, and subsequently administering CSA at a dose determined based on the subject's plasma concentration of CSA during or at the end of the initial period. In exemplary embodiments, the disclosed treatment method provides a way to treat a subject with CSA. In exemplary embodiments, the disclosed treatment method provides a safe way to treat a subject with heart failure, e.g., HFrEF, and avoid overexposure to CSA.

[0013] Thus, the present disclosure provides a method of treating a subject with heart failure. In an exemplary embodiment, the method includes (a) administering an initial dose of CSA to the subject over an initial period of time, and (b) subsequently administering doses of CSA to the subject based on the subject's plasma concentration of CSA at the end of the initial period of time. In an exemplary embodiment, the initial dose is a minimum effective dose (MED) of CSA. In an exemplary embodiment, CSA has reached a steady state in the subject by the end of the initial period of time or by the time the plasma concentration of CSA is determined. In an exemplary embodiment, the dose subsequently administered to the subject is one of two options: the subsequently administered dose is either the same as the initial dose or exceeds the initial dose. In alternative or additional exemplary embodiments, the dose subsequently administered to the subject is one of three options: the subsequently administered dose is (i) the same as the initial dose, (ii) exceeds the initial dose but below the maximum dose, or (iii) is the maximum dose. In exemplary embodiments, when the subject's plasma concentration of CSA is above the threshold concentration, illustratively about 1.0 to about 1.5 times the minimum of the target concentration range, the subsequently administered dose is the same as the initial dose. In exemplary embodiments, when the subject's plasma concentration of CSA is below the threshold concentration, illustratively about 1.0 to about 1.5 times the minimum of the target concentration range, the subsequently administered dose is greater than the initial dose.

[0014] In an exemplary embodiment, a method for treating a subject with HF includes (a) administering an initial dose of CSA to the subject over an initial period of time, and (b) subsequently administering doses of CSA to the subject based on the subject's plasma concentration of CSA during or at the end of the initial period, wherein the initial dose is the MED of CSA, and CSA has reached a steady state in the subject by the end of the initial period or by the time the CSA concentration is determined. In an exemplary embodiment, when the subject's plasma concentration is above or near the threshold concentration, subsequently administered doses are the same as the initial dose. In an exemplary embodiment, when the subject's plasma concentration is below the threshold concentration, subsequently administered doses are greater than the initial dose. In an exemplary embodiment, the threshold concentration is about 1.0 to about 1.5 times the minimum of the target concentration range. In an exemplary embodiment, the threshold concentration is about 1.0 times the minimum of the target concentration range. In exemplary embodiments, the subsequent dose is (i) the same as the initial dose when the subject's plasma concentration is greater than or approximately equal to the first threshold concentration; (ii) the subsequent dose is greater than the initial dose but less than the maximum dose when the subject's plasma concentration is less than the first threshold concentration but greater than or approximately equal to the second threshold concentration; or (iii) the subsequent dose is the maximum dose when the subject's plasma concentration is less than the second threshold concentration.In exemplary embodiments, the first threshold concentration is about 1.5 times the minimum value of the target concentration range.In exemplary embodiments, the second threshold concentration is the minimum value of the target concentration range.

[0015] In an exemplary embodiment, when the subject's plasma concentration is greater than or about 1.5 times the minimum value of the target concentration range, the subsequent dose is the same as the first dose. In an exemplary embodiment, when the subject's plasma concentration is less than 1.5 times the minimum value of the target concentration range but greater than or about the minimum value of the target concentration range, the subsequent dose is greater than the first dose but less than the maximum dose. In an exemplary embodiment, when the subject's plasma concentration is less than the minimum value of the target concentration range, the subsequent dose is the maximum dose.

[0016] heart failure The therapeutic methods of the present disclosure are methods for treating heart failure (HF). HF is defined as the inability of the heart to supply sufficient blood flow to meet the body's needs. Heart failure can be classified according to the New York Heart Association (NYHA) classification system for heart failure, summarized in the table below.

[0017] [Table 1]

[0018] Heart failure can be systolic heart failure (also known as systolic dysfunction), which is heart failure caused by or characterized by systolic dysfunction. Simply put, systolic dysfunction is a condition in which the heart's pumping function or contraction (i.e., systole) is weakened. The left ventricle loses its ability to contract normally, and therefore the heart cannot pump with sufficient force to push enough blood into the circulation. Systolic dysfunction can be characterized by a reduced or decreased ejection fraction, for example, an ejection fraction less than about 45%, and increased ventricular end-diastolic pressure and volume. Thus, in some cases, systolic heart failure is referred to as heart failure with reduced ejection fraction (HFrEF). In exemplary cases, systolic dysfunction is characterized by a left ventricular ejection fraction of about 40% or less. In some embodiments, the strength of ventricular contraction, as measured by the amount of blood pumped per minute, is weakened and insufficient to eject sufficient blood during each heartbeat, resulting in low cardiac output. Systolic heart failure can result from ischemic heart disease, or alternatively, can result from non-ischemic cardiac causes.

[0019] HFrEF may be a chronic condition and may also be referred to as chronic heart failure (CHF). In an exemplary embodiment, the subject has heart failure for more than 4 weeks while receiving standard of care (SOC) for HF. Alternatively, heart failure may be an acute condition, i.e., acute heart failure. In an exemplary embodiment, the subject has heart failure for less than 4 weeks while receiving standard of care (SOC) for HF.

[0020] Signs and symptoms of heart failure include dyspnea (e.g., orthopnea, paroxysmal nocturnal dyspnea), cough, cardiac asthma, wheezing, dizziness, confusion, cold extremities at rest, pulmonary congestion, chronic venous congestion, ankle swelling, peripheral or generalized edema, nocturia, ascites, hepatomegaly, jaundice, coagulopathy, fatigue, reduced exercise capacity, jugular vein distention, pulmonary rales, peripheral edema, pulmonary vascular redistribution, interstitial edema, pleural effusion, fluid retention, or a combination thereof. Other signs and symptoms of HF include compensatory mechanisms characterized by increased sympathetic tone, peripheral vasoconstriction, activation of various neurohormonal pathways, sodium retention, arterial and venous constriction, neuroendocrine activation, and elevated heart rate.

[0021] For purposes herein, the disclosed methods of treating a subject with heart failure include methods of treating a subject with any of the HF types described herein, e.g., HFrEF, CHF. The term "treat" and related words do not necessarily mean 100% or complete treatment. Rather, there are various degrees of treatment that those skilled in the art will recognize as having potential benefit or therapeutic effect. In this regard, the disclosed methods of treating a subject with HF can provide any amount or level of treatment. Furthermore, the treatment provided by the disclosed methods can include treatment of one or more conditions or symptoms or signs of the HF being treated. The treatment provided by the disclosed methods can also include slowing the progression of HF. For example, the methods can treat HF ​​by increasing the ejection fraction, increasing the strength of ventricular contractions, increasing cardiac output or blood flow to the circulation, etc.

[0022] subject In some embodiments of the present disclosure, the subject is a mammal, including, but not limited to, mammals of the order Rodentia, such as mice and hamsters, and mammals of the order Lagomorpha, such as rabbits; mammals of the order Carnivora, including Felidae (cats) and Canidae (dogs); mammals of the order Artiodactyla, including Bovidae (cows) and Porcinae (pigs), or Perissodactyla, including Equidae (horses). In some aspects, the mammal is a mammal of the order Primates, Ceboids, or Simoids (monkeys), or Anthropoids (humans and apes). In some aspects, the mammal is a human.

[0023] In exemplary embodiments, the human is male or female, e.g., male or female, aged 18 years or older. In exemplary embodiments, the subject has a confirmed diagnosis of HF, e.g., systolic heart failure, HFrEF, or CHF. In exemplary embodiments, the subject has a history of chronic heart failure or chronic HF. In exemplary embodiments, the subject requires HF treatment for at least 30 days before receiving treatment with CSA. In exemplary embodiments, the subject has been hospitalized with HF as the primary cause of hospitalization within one year before receiving CSA treatment. In exemplary embodiments, the subject has NYHA class II, class III, or class IV heart failure. In exemplary cases, the subject has a left ventricular ejection fraction of about 35% or less. In exemplary embodiments, the subject has a B-type natriuretic peptide (BNP) level greater than or about 125 pg / mL or an NT-proBNP level greater than or about 400 pg / mL. In an exemplary embodiment, the subject is receiving an angiotensin receptor-neprilysin inhibitor (ARNi) and has an NT-proBNP level greater than or about 400 pg / mL. In an exemplary case, the subject has atrial fibrillation and has a BNP level greater than or about 375 pg / mL or an NT-proBNP level greater than or about 1200 pg / mL. In an exemplary embodiment, the subject meets one or more or all of the inclusion criteria outlined in Example 2. In an exemplary embodiment, the subject meets one or more or all of the exclusion criteria outlined in Example 2. In an exemplary embodiment, the subject requires CSA. In an exemplary embodiment, the subject has a symptomatic chronic serious illness that has recently required acute treatment (e.g., a recent hospitalization or emergency room (ER) stay) and has biomarker evidence (e.g., BNP) of progressive disease.

[0024] In exemplary embodiments, the human is a male or female under the age of 18. In exemplary embodiments, the human is 6 years of age or older and under the age of 18.

[0025] Myocardial segment activator The methods disclosed herein include administering a cardiac muscle fiber activator. As used herein, the term "cardiomyosensory fiber activator" or "CSA" refers to a compound that activates cardiac muscle fibers, e.g., Ca. 2+ CSA refers to an agent that induces activation of cardiac myocytes by sensitizing them to troponin or tropomyosin, or that directly activates cardiac myosin. In an exemplary case, CSA refers to an agent that induces activation of cardiac myocytes by sensitizing them to calcium (Ca 2+ For example, CSAs that enhance sarcomeric responsiveness to calcium include levosimendan or pimobendan. In exemplary embodiments, the CSA is an agent that has an additional effect on myofilaments, such as SR-33805, an HNO donor, or CXL-1020.

[0026] In exemplary embodiments, CSA directly interacts with myosin and / or stabilizes the pre-power stroke structure of myosin, which promotes its transition to an actin-bound state. In exemplary embodiments, CSA is an activator of cardiac myosin. In an exemplary case, the activator of cardiac myosin is omecamtiv mecarbil. In exemplary embodiments, CSA targets one or more of myosin, actin, troponin, and tropomyosin. In exemplary embodiments, CSA activates one or more of myosin, actin, troponin, and tropomyosin.

[0027] Omecamtivmecarbil (OM) In an exemplary embodiment, the method comprises administering omecamtiv mecarbil (OM) or a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing. The molecular formula of the free base of OM is: 20 H 24 FN5O3, the chemical structure of which is shown below: [ka]

[0028] References to "omecamtiv mecarbil" or "OM" are understood and described to refer to and describe any form of OM, including the free base, any pharmaceutically acceptable salts thereof, any solvates of any of the foregoing, and mixtures thereof in any ratio. In one embodiment, OM is administered to a subject as the free base. In some embodiments, OM is administered to a subject as a hydrochloride salt, such as the dihydrochloride salt. In some embodiments, OM is administered to a subject as a hydrate. In some embodiments, OM is administered to a subject as a hydrate salt. In some embodiments, OM is administered to a subject as the dihydrochloride salt hydrate.

[0029] OM (also known as AMG 423, CK-1827452) is a novel small molecule classified as a cardiac myosin activator that increases cardiac contractile force by selectively and directly activating the enzymatic domain of cardiac myosin heavy chain, a force-generating motor protein in cardiac myocytes, without increasing intracellular calcium (Teerlink et al., 2011; Malik et al., 2011). OM increases left ventricular systolic ejection time (SET) without altering the velocity of contraction (dP / dt) or increasing heart rate. Furthermore, left ventricular filling pressure, left atrial pressure, and overall peripheral vascular resistance are reduced, providing evidence that prolonging SET and improving systolic function can favorably influence hemodynamics leading to HF symptoms. The beneficial effects of OM were achieved without significant effects on myocardial oxygen uptake, blood pressure, or coronary blood flow (Shen et al., 2010; Malik et al., 2011).

[0030] The completed omecamtiv mecarbir clinical program includes ten Phase 1 studies, four Phase 2a studies in subjects with chronic heart failure, one Phase 2b study in subjects with acute heart failure (AHF), and one Phase 2 study in subjects with chronic stable heart failure. In these studies, the efficacy, safety, tolerability, PK, and PD of omecamtiv mecarbir were evaluated by intravenous (IV) infusion for up to 72 hours and oral administration for up to 20 weeks.

[0031] To date, 1097 subjects have received at least one dose of omecamtiv mecarbil treatment across 16 trials, including 278 healthy volunteers in a Phase 1 trial, 147 subjects with HF in a Phase 2a trial, 303 subjects with AHF in a Phase 2b trial (IV formulation), and 369 subjects with chronic HF in a Phase 2b trial (modified-release [MR] formulation).

[0032] There are two ongoing clinical trials: a Phase 2b, double-blind, randomized, placebo-controlled study to evaluate the safety, PK, and efficacy of omecamtiv mecarbil in Japanese subjects with chronic heart failure with reduced ejection fraction (HFrEF) and a Phase 3, double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety of omecamtiv mecarbil on mortality and morbidity in subjects with HFrEF.

[0033] The recently completed Phase 2b study in subjects with chronic HF (COSMIC-HF) represents the most comprehensive and relevant clinical data set to support a Phase 3 outcome study. COSMIC-HF was designed to evaluate the MR formulation of omecamtiv mecarbil in subjects with chronic HFrEF and was conducted in two phases: 1) a dose-escalation phase designed to select an oral MR formulation and dose of omecamtiv mecarbil for further evaluation in a subsequent expansion phase; and 2) an expansion phase during which the PK, PD, safety, and tolerability of the selected MR formulation and dose in subjects with chronic HF and left ventricular systolic dysfunction were evaluated over a 20-week treatment period.

[0034] Clinical trials for OM are described, for example, in Teerlink et al., 2011; and Cleland et al., 2011, each of which is incorporated by reference in its entirety.

[0035] Dosage As used herein, the term "dose" refers to a measured amount of a therapeutic agent taken at one time. For purposes of the present disclosure, the amount or dose of CSA administered to a subject should be sufficient to produce, e.g., a therapeutic response in the subject or animal over an appropriate period of time. For example, the dose of CSA should be sufficient to treat HF ​​as described herein for a period of about 1-4 minutes, 1-4 hours, or 1-4 weeks or more, e.g., 5-20 weeks or more, from the time of administration. In certain embodiments, the period will be even longer. The dose can be determined by the efficacy of the particular CSA and the condition of the animal (e.g., human) as well as the body weight of the animal (e.g., human) being treated.

[0036] Many assays for determining the dose to be administered are known in the art.For the present specification, the starting dose to be administered to a mammal can be determined by using an assay that includes comparing the degree to which HF is treated when a given dose of CSA is administered to a mammal between sets of mammals, each set being given a different dose of CSA.The degree to which HF is treated when a certain dose is administered can be explained, for example, by the degree to which ejection fraction increases through the action of CSA in a mouse model of HFrEF.Methods for measuring ejection fraction are known in the art.See the examples described herein.

[0037] Dosages may also be determined based on the existence, nature, and extent of any adverse side effects that may accompany the administration of a particular CSA. Typically, the attending physician will determine the dosage to treat each individual patient, taking into account a variety of factors, such as age, weight, general health, diet, sex, the therapeutic agent being administered, the route of administration, existing clinical data, package inserts, and the severity of the condition being treated.

[0038] Initial dose and initial duration In the methods of the present disclosure, an initial dose of CSA is administered to a subject. In an exemplary embodiment, the initial dose is the minimum effective dose (MED) of CSA. As used herein, a "minimum effective dose" or "MED" is the minimum dose of CSA that produces a measurable change in cardiac function, determined, for example, across an entire population of subjects, and that is statistically significantly greater than the response produced by a placebo. In an exemplary embodiment, the MED is the minimum value of the therapeutic range of CSA. The therapeutic range of a drug, also known as the therapeutic range, is the range of drug dosages that can effectively treat a disease without toxic effects. In an exemplary embodiment, the initial dose is the minimum dose at which evidence of efficacy is detectable. In an exemplary embodiment, the initial dose is the MED determined in a clinical trial with human subjects, and the MED is the minimum dose at which evidence of efficacy is detectable in more than about 50% of the subjects participating in the clinical trial. In exemplary embodiments, the initial dose is the MED determined in a clinical trial with human subjects, where the MED is the smallest dose at which evidence of efficacy is detectable in more than about 60%, more than about 70%, more than about 80%, more than about 90%, or more than about 95% of the subjects participating in the clinical trial.

[0039] In an exemplary embodiment, an initial dose of CSA is administered to a subject over an initial period. In an exemplary embodiment, the initial dose of CSA is repeatedly administered to a subject during the initial period. In an exemplary embodiment, the initial dose of CSA is repeatedly administered to a subject during the initial period, each initial dose being the same amount of CSA. In an exemplary embodiment, the CSA reaches a steady state in the subject by the end of the initial period or earlier during the initial period. "Steady state" refers to when the overall intake of the drug is in dynamic equilibrium with its elimination. In an exemplary embodiment, the initial period is at least 3 days, at least 4 days, at least 5 days, at least 6 days, or at least about 1 week. In an exemplary embodiment, the initial period is greater than about 1 week, e.g., about 1.5 weeks, about 2 weeks, about 3 weeks, about 4 weeks, or about 1 month. In an exemplary embodiment, the initial period is greater than 1 month, e.g., about 1.5 months, about 2 months, or about 3 months or longer. In an exemplary embodiment, the initial period is at least about 1 week or at least about 2 weeks. In exemplary embodiments, the initial period is from about 1 week to about 3 weeks or about 2 weeks.

[0040] In an exemplary embodiment, the initial dose of CSA is about 20 mg to about 30 mg or about 22.5 mg to about 27.5 mg. For example, the initial dose is about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, or about 30 mg. In an exemplary embodiment, the initial dose is about 25 mg. In an exemplary embodiment, the initial dose, for example, 25 mg, is taken twice daily. In an exemplary embodiment, the initial dose is orally administered to the subject. In an exemplary embodiment, the CSA is OM.

[0041] In exemplary embodiments, the CSA is OM, and the initial dose is 25 mg of OM.In exemplary embodiments, the method comprises administering to the subject an initial dose of 25 mg of OM via oral administration.In exemplary embodiments, the method comprises administering to the subject an initial dose of 25 mg of OM twice a day.In exemplary cases, the initial period is at least about 2 weeks.In exemplary embodiments, the method comprises administering to the subject about 25 mg of OM twice a day via oral administration for at least about 2 weeks.

[0042] Later dose In an exemplary embodiment of the disclosed method, a dose of CSA is administered to the subject after an initial period, the dose being based on the subject's plasma concentration of CSA during or at the end of the initial period. In an exemplary embodiment, the dose administered after the initial period depends on the plasma concentration of CSA, which decreases relative to a target concentration range for CSA. As used herein, the term "target concentration range" is synonymous with the "therapeutic range" referred to in Korean J Intern Med 24(1):1-10(2009) and refers to the range of plasma concentrations of a drug within which a therapeutic response can be expected.

[0043] In an exemplary embodiment, the dose administered to the subject subsequently is one of two options: the dose administered subsequently is either the same as the initial dose or greater than the initial dose. In alternative or additional exemplary embodiments, the dose administered to the subject subsequently is one of three options: the dose administered subsequently is (i) approximately the same as the initial dose, (ii) greater than the initial dose but less than the maximum dose, or (iii) the maximum dose. In yet other embodiments, the dose administered to the subject subsequently is one of four or more options: the dose administered subsequently is (i) approximately the same as the initial dose, (ii) one of two or more unequal doses, each greater than the initial dose but less than the maximum dose, or (iii) the maximum dose. In an exemplary embodiment, when the subject's plasma concentration of CSA exceeds a threshold concentration, the dose administered subsequently is the same as the initial dose. In exemplary cases, the threshold concentration is about 1.0 to about 1.5 (e.g., about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5) times the minimum of the target concentration range. In exemplary embodiments, when the subject's plasma concentration is below the threshold, subsequent doses are administered that exceed the initial dose.

[0044] In an exemplary embodiment, the maximum dose is the maximum of the therapeutic range of CSA. The therapeutic range of a drug, also known as the therapeutic window, is the range of drug dosages that can effectively treat a disease without toxic effects. In an exemplary embodiment, the maximum dose is the maximum tolerated dose (MTD). In an exemplary embodiment, the maximum dose is the MTD determined in a human clinical trial, where the MTD is the maximum dose tolerated by more than about 50% of the subjects participating in the clinical trial. In an exemplary embodiment, the maximum dose is the MTD determined in a human clinical trial, where the MTD is the maximum dose tolerated by more than about 60%, more than about 70%, more than about 80%, more than about 90%, or more than about 95% of the subjects participating in the clinical trial.

[0045] In exemplary embodiments, when the subject's plasma concentration of CSA is above or about the threshold concentration, the subsequently administered dose is the same as the initial dose. In exemplary embodiments, when the subject's plasma concentration of CSA is below the threshold concentration, the subsequently administered dose is greater than the initial dose. In exemplary embodiments, the threshold concentration is about 1.0 to about 1.5 (e.g., about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5) times the minimum value of the target concentration range. In exemplary embodiments, the threshold concentration is the minimum value of the target concentration range. In exemplary embodiments, when the subject's plasma concentration of CSA is above or about the minimum value of the target concentration range, the subsequently administered dose is about the same as the initial dose, and when the subject's plasma concentration of CSA is below the minimum value of the target concentration range, the subsequently administered dose is greater than the initial dose.

[0046] In an exemplary embodiment, the subsequent dose of CSA is based on the subject's plasma concentration of CSA relative to a first threshold and a second threshold. In an exemplary embodiment, the first threshold concentration is about 1.5 times the minimum value of the target concentration range, and the second threshold concentration is the minimum value of the target concentration range. In an exemplary embodiment, the subsequent dose is (i) the same as the initial dose when the subject's plasma concentration of CSA is above or at about the first threshold concentration, (ii) above the initial dose but below the maximum dose when the subject's plasma concentration of CSA is below the first threshold concentration but above or at about the second threshold concentration, or (iii) the maximum dose when the subject's plasma concentration of CSA is below the second threshold concentration.

[0047] In an exemplary embodiment, the minimum value of the target concentration range is 200 ng / mL, so that when the subject's CSA plasma concentration is greater than or about 300 ng / mL, the subsequently administered dose is the same as the initial dose. In an exemplary embodiment, when the subject's CSA plasma concentration is less than 300 ng / mL but greater than or about 200 ng / mL, the subsequently administered dose is greater than the initial dose but less than the maximum dose. In an exemplary embodiment, when the subject's CSA plasma concentration is less than 200 ng / mL, the subsequently administered dose is the maximum dose. In an exemplary embodiment, the maximum dose is about twice the initial dose, and the dose greater than but less than the maximum dose is 1.5 times the initial dose. In an exemplary embodiment, the initial dose is about 20 mg to about 30 mg, optionally about 25 mg. In an exemplary embodiment, the maximum dose is about 45 mg to about 55 mg, optionally about 50 mg. In an exemplary embodiment, the dose above the initial dose but below the maximum dose is about 35 mg to about 40 mg, optionally about 37.5 mg.

[0048] In an exemplary embodiment, the initial dose is about 20 mg to about 30 mg, and the dose administered after the initial period is (a) about 45 mg to about 75 mg when the plasma concentration of CSA during or at the end of that period is less than the minimum of the target concentration range, (b) about 30 mg and less than about 45 mg when the plasma concentration of CSA during or at the end of that period is greater than the minimum of the target concentration range or about the minimum of the target concentration range, but less than about 1.5 times the minimum of the target concentration range, or (c) about the same as the initial dose when the plasma concentration of CSA during or at the end of that period is, for example, greater than the minimum of the target concentration or about about 1.5 times the minimum of the target concentration. In an exemplary embodiment, when the plasma concentration of CSA during or at the end of that period is less than the minimum of the target concentration range, subsequent doses are about 45 mg to about 55 mg, optionally about 50 mg. In an exemplary embodiment, when the plasma concentration of CSA during or at the end of the period is equal to or greater than the minimum value of the target concentration range, but less than 1.5 times the minimum value of the target concentration range, subsequent doses are from about 35 mg to about 40 mg, optionally about 37.5 mg.

[0049] In an exemplary embodiment, the target concentration range of CSA is about 200 ng / mL to about 1200 ng / mL, optionally about 200 ng / mL to about 1000 ng / mL. In an exemplary embodiment, the target concentration range is about 200 ng / mL to about 1000 ng / mL, the initial dose is about 25 mg, the maximum dose is about 50 mg, and doses less than the maximum dose but greater than the initial dose are about 37.5 mg. In an exemplary embodiment, when the plasma concentration of CSA is greater than or about 300 ng / mL, subsequent doses are about 25 mg, when the plasma concentration of CSA is less than about 200 ng / mL, subsequent doses are about 50 mg, and when the plasma concentration of CSA is greater than or about 200 ng / mL but less than 300 ng / mL, subsequent doses are 37.5 mg. In an exemplary embodiment, the CSA is OM, and optionally, the OM is administered to the subject via oral administration twice daily.

[0050] In an exemplary embodiment, the treatment method comprises administering only one initial dose and / or only one subsequent dose. In an alternative embodiment, the method comprises administering two or more initial doses and / or two or more subsequent doses. In an exemplary aspect, the method comprises repeatedly administering the initial dose during an initial period, each initial dose being the same amount, e.g., about 25 mg. In an exemplary aspect, the method comprises administering the initial dose to the subject daily, twice daily, three times daily, four times daily, or more than once daily for the duration of the initial period, optionally for at least or about two weeks. In an exemplary aspect, the method comprises administering the initial dose to the subject weekly, twice weekly, three times weekly, four times weekly, five times weekly, or more than once daily for the duration of the initial period, optionally for at least or about two months. In an exemplary embodiment, the method includes repeatedly administering subsequent doses after an initial period, each subsequent dose being the same amount, e.g., about 25 mg, about 37.5 mg, about 50 mg, provided that the subsequent doses are based on the subject's plasma concentration of CSA during or at the end of the initial period. In an exemplary embodiment, the dose of CSA is repeatedly administered to the subject for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, or more, after the initial period. In an exemplary embodiment, the method includes administering the subsequent doses to the subject daily, twice daily, three times daily, four times daily, or more than once a day. In an exemplary embodiment, the method includes administering the subsequent doses to the subject weekly, twice weekly, three times weekly, four times weekly, five times weekly, or more than once a week. In an exemplary embodiment, the frequency with which the initial dose is administered during the initial period is the same as the frequency with which the subsequent doses are administered after the initial period. In exemplary embodiments, subsequent doses are administered twice daily for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks or more. In exemplary embodiments, subsequent doses are administered via oral administration.

[0051] In an exemplary embodiment, the CSA is OM, and subsequent doses of OM are administered to the subject twice daily via oral administration, with each subsequent dose being about 50 mg when the plasma concentration of OM is less than about 200 ng / mL, each subsequent dose being about 37.5 mg when the plasma concentration of OM is greater than or equal to about 200 ng / mL but less than 300 ng / mL, and each subsequent dose being about 25 mg when the plasma concentration of OM is greater than or equal to about 300 ng / mL but less than 1000 ng / mL.

[0052] Formulations, routes of administration and regimens In exemplary embodiments, CSA is present in the pharmaceutical composition at a purity level suitable for administration to a patient. In some embodiments, the CSA has a purity level of at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% and a pharmaceutically acceptable diluent, carrier, or excipient. In some embodiments, the pharmaceutical composition comprises CSA at a concentration of at least A, where A is about 10 mg, about 15 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, or more. In some embodiments, the pharmaceutical composition comprises CSA at a concentration of up to B, where B is about 100 mg, about 75 mg, about 50 mg, or 25 mg. In some embodiments, the composition may contain CSA in a concentration range of A to B mg / ml, e.g., from about 0.001 mg to about 100.0 mg. In exemplary embodiments, the pharmaceutical composition comprises CSA at a concentration of 25 mg, 37.5 mg, or 50 mg.

[0053] Depending on the route of administration, the particular CSA for use, and other factors, the pharmaceutical composition may contain additional pharmaceutically acceptable ingredients, including, for example, acidifying agents, additives, adsorbents, aerosol propellants, gas scavengers, alkalizing agents, anti-caking agents, anticoagulants, antimicrobial preservatives, antioxidants, preservatives, bases, binders, buffering agents, chelating agents, coating agents, colorants, desiccants, surfactants, diluents, disinfectants, disintegrants, dispersants, solubility enhancers, dyes, emollients, emulsifiers, Included are emulsion stabilizers, fillers, film-forming agents, flavor enhancers, flavorings, glidants, gelling agents, granulating agents, wetting agents, lubricants, mucoadhesives, ointment bases, ointments, oily vehicles, organic bases, tablet bases, pigments, plasticizers, abrasives, preservatives, sequestering agents, skin penetration agents, solubilizers, solvents, stabilizers, suppository bases, surface CSAs, surfactants, suspending agents, sweeteners, therapeutic agents, thickeners, tonicity agents, toxic agents, viscosity enhancing agents, water absorption agents, water-miscible co-solvents, water softeners or humectants.

[0054] Thus, in some embodiments, the pharmaceutical composition comprises any one or combination of the following ingredients: gum arabic, acesulfame potassium, acetyl tributyl citrate, acetyl triethyl citrate, agar, albumin, alcohol, dehydrated alcohol, denatured alcohol, diluted alcohol, arachidonic acid, alginic acid, aliphatic polyester, alumina, aluminum hydroxide, aluminum stearate, amylopectin, α-amylose, ascorbic acid, ascorbyl palmitate, aspartame, bacteriostatic water for injection, bentonite, bentonite magma, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, benzyl benzoate, bronopol, butylhydroxyanisole, butylhydroxytoluene, butylparaben, sodium butylparaben, calcium alginate, calcium ascorbate, calcium carbonate, calcium cyclamate, calcium hydrogen phosphate anhydrous, calcium hydrogen phosphate dehydrate, tricalcium phosphate, calcium propionate, calcium silicate, calcium sorbate, calcium stearate, calcium sulfate, calcium sulfate semi-solid. Hydrate, canola oil, carbomer, carbon dioxide, calcium carboxymethylcellulose, sodium carboxymethylcellulose, beta-carotene, carrageenan, castor oil, hydrogenated castor oil, cationic emulsifying wax, cellulose acetate, cellulose acetate phthalate, ethyl cellulose, microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, sodium carboxymethylcellulose, cetostearyl alcohol, cetrimide, cetyl alcohol, chlorhexidine, chlorobutanol, chlorocresol, cholesterol, chlorhexidine acetate, Chlorhexidine gluconate, chlorhexidine hydrochloride, chlorodifluoroethane (HCFC), chlorodifluoromethane, chlorofluorocarbons (CFC) chlorophenoxyethanol, chloroxylenol, corn syrup solids, anhydrous citric acid, citric acid monohydrate, cocoa butter, coloring agent, corn oil, cottonseed oil, cresol, m-cresol, o-cresol, p-cresol, croscarmellose sodium, crospovidone, cyclamic acid, cyclodextrin, dextrates, dextrin, dextrose, dextrose anhydrous,Diazolidinyl urea, dibutyl phthalate, dibutyl sebacate, diethanolamine, diethyl phthalate, difluoroethane (HFC), dimethyl-β-cyclodextrin, cyclodextrin-type compounds such as Captisol®, dimethyl ether, dimethyl phthalate, edetate dipotassium, edetate disodium, disodium hydrogen phosphate, docusate calcium, docusate potassium, docusate sodium, dodecyl gallate, dodecyltrimethylammonium bromide, edetate calcium disodium, edetic acid, eglumin, Ethyl alcohol, ethyl cellulose, ethyl gallate, ethyl laurate, ethyl maltol, ethyl oleate, ethylparaben, potassium ethylparaben, sodium ethylparaben, ethyl vanillin, fructose, fructose liquid, ground fructose, fructose spirogen-free, powdered fructose, fumaric acid, gelatin, glucose, liquid glucose, saturated vegetable fatty acid glyceride mixture, glycerin, glyceryl behenate, glyceryl monooleate, glyceryl monostearate, self-emulsifying glyceryl monostearate, palmitoyl palmitate Glyceryl stearate, glycine, glycol, glycofurol, guar gum, heptafluoropropane (HFC), hexadecyltrimethylammonium bromide, isomerized liquid sugar, human serum albumin, hydrocarbons (HC), dilute hydrochloric acid, hydrogenated vegetable oil, type II, hydroxyethyl cellulose, 2-hydroxyethyl-β-cyclodextrin, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, 2-hydroxypropyl-β-cyclodextrin, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, Imidurea, indigo carmine, ion exchanger, iron oxide, isopropyl alcohol, isopropyl myristate, isopropyl palmitate, isotonic saline, kaolin, lactic acid, lactitol, lactose, lanolin, lanolin alcohol, anhydrous lanolin, lecithin, magnesium aluminum silicate, magnesium carbonate, magnesium carbonate at defined concentrations, magnesium carbonate anhydrous, magnesium carbonate hydroxide, magnesium hydroxide, magnesium lauryl sulfate, magnesium oxide, magnesium silicate, magnesium stearate, magnesium trisilicate,Magnesium trisilicate anhydrous, malic acid, malt, maltitol, maltitol solution, maltodextrin, maltol, maltose, mannitol, medium chain triglycerides, meglumine, menthol, methylcellulose, methyl methacrylate, methyl oleate, methylparaben, potassium methylparaben, sodium methylparaben, microcrystalline cellulose and sodium carboxymethylcellulose, mineral oil, light mineral oil, mineral oil and lanolin alcohol, oil, olive oil, monoethanolamine, montmorillonite, octyl gallate, oleic acid, palm oil Thymic acid, paraffin, peanut oil, petrolatum, petrolatum and lanolin alcohol, pharmaceutical glaze, phenol, liquefied phenol, phenoxyethanol, phenoxypropanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, polacrilin, polacrilin potassium, poloxamer, polydextrose, polyethylene glycol, ethylene oxide, polyacrylate, polyethylene-polyoxypropylene-block polymer, polymethacrylic acid, polyoxyethylene alkyl ether, polyoxyethylene Castor oil derivatives, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene stearate, polyvinyl alcohol, polyvinylpyrrolidone, potassium alginate, potassium benzoate, potassium bicarbonate, potassium bisulfite, potassium chloride, potassium citrate, potassium citrate anhydrous, potassium hydrogen phosphate, potassium metabisulfite, potassium dihydrogen phosphate, potassium propionate, potassium sorbate, povidone, propanol, propionic acid, propylene carbonate, propylene glycol, propylene glycol alginate, propylene gallate Pill, propylparaben, propylparaben potassium, propylparaben sodium, protamine sulfate, rapeseed oil, Ringer's solution, saccharin, saccharin ammonium, saccharin calcium, saccharin sodium, safflower oil, saponite, serum proteins, sesame oil, colloidal silica, colloidal silicon dioxide, sodium alginate, sodium ascorbate, sodium benzoate, sodium bicarbonate, sodium bisulfite, sodium chloride, anhydrous sodium citrate, anhydrous sodium citrate, sodium chloride, sodium cyclamate,Sodium edetate, sodium dodecyl sulfate, sodium lauryl sulfate, sodium disulfite, dibasic sodium phosphate, monobasic sodium phosphate, tribasic sodium phosphate, anhydrous sodium propionate, sodium propionate, sodium sorbate, sodium starch glycolate, sodium stearyl fumarate, sodium sulfite, sorbic acid, sorbitan esters (sorbitan fatty acid esters), sorbitol, 70% sorbitol solution, soybean oil, spermaceti, starch, corn starch, potato starch, pregelatinized starch, sterilized corn starch, stearic acid, refined stearic acid, stearyl alcohol, sucrose, sugar, compressible sugar, powdered sugar, granulated sugar, invert sugar, Sugartab, Sunset Yellow FCF, synthetic paraffin, talc, tartaric acid, tartrazine, tetrafluoroethane (HFC), cocoa butter , Thimerosal, Titanium dioxide, α-tocopherol, Tocopheryl acetate, α-tocopheryl acid succinate, β-tocopherol, δ-tocopherol, γ-tocopherol, Tragacanth, Triacetin, Tributyl citrate, Triethanolamine, Triethyl citrate, Trimethyl-β-cyclodextrin, Trimethyltetradecylammonium bromide, Tris buffer, Trisodium edetate, Vanillin, Type I Hydrogenated vegetable oil, water, soft water, hard water, non-carbonated water, pyrogen-free water, water for injection, sterile water for inhalation, sterile water for injection, sterile water for irrigation, wax, anionic emulsifying wax, carnauba wax, cationic emulsifying wax, cetyl ester wax, microcrystalline wax, nonionic emulsifying wax, suppository wax, white wax, yellow wax, white petrolatum, wool fat, xanthan gum, xylitol, zein, zinc propionate, zinc salts, zinc stearate or any excipient in Handbook of Pharmaceutical Excipients, Third Edition, A.H. Kibbe (Pharmaceutical Press, London, UK, 2000), which is incorporated by reference in its entirety. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980), which is incorporated by reference in its entirety,Various ingredients used in formulating pharmaceutically acceptable compositions and known techniques for their preparation are disclosed. Except insofar as any conventional agent is incompatible with the present pharmaceutical compositions, its use in the pharmaceutical compositions is contemplated. Additional active ingredients may also be incorporated into the present compositions.

[0055] In some embodiments, the aforementioned components may be present in the pharmaceutical composition at any concentration, such as, for example, at least A, where A is 0.0001% w / v, 0.001% w / v, 0.01% w / v, 0.1% w / v, 1% w / v, 2% w / v, 5% w / v, 10% w / v, 20% w / v, 30% w / v, 40% w / v, 50% w / v, 60% w / v, 70% w / v, 80% w / v, or 90% w / v. In some embodiments, the aforementioned components can be present in the pharmaceutical composition at any concentration, such as, for example, up to B, where B is 90% w / v, 80% w / v, 70% w / v, 60% w / v, 50% w / v, 40% w / v, 30% w / v, 20% w / v, 10% w / v, 5% w / v, 2% w / v, 1% w / v, 0.1% w / v, 0.001% w / v, or 0.0001% w / v. In other embodiments, the aforementioned components can be present in the pharmaceutical composition at any concentration range, such as, for example, from about A to about B. In some embodiments, A is 0.0001% and B is 90%.

[0056] Pharmaceutical compositions can be formulated to achieve a physiologically compatible pH. In some embodiments, the pH of the pharmaceutical composition can be at least 5, at least 5.5, at least 6, at least 6.5, at least 7, at least 7.5, at least 8, at least 8.5, at least 9, at least 9.5, at least 10, or at least 10.5 up to pH 11, depending on the formulation and route of administration. In certain embodiments, the pharmaceutical composition can include a buffering agent to achieve a physiologically compatible pH. Buffering agents can include any compound capable of buffering at a desired pH, such as, for example, phosphate buffer (e.g., PBS), triethanolamine, Tris, bicine, TAPS, Tricine, HEPES, TES, MOPS, PIPES, cacodylic acid, MES, etc. In certain embodiments, the buffer strength is at least 0.5 mM, at least 1 mM, at least 5 mM, at least 10 mM, at least 20 mM, at least 30 mM, at least 40 mM, at least 50 mM, at least 60 mM, at least 70 mM, at least 80 mM, at least 90 mM, at least 100 mM, at least 120 mM, at least 150 mM, or at least 200 mM. In some embodiments, the buffer strength is 300 mM or less (e.g., up to 200 mM, up to 100 mM, up to 90 mM, up to 80 mM, up to 70 mM, up to 60 mM, up to 50 mM, up to 40 mM, up to 30 mM, up to 20 mM, up to 10 mM, up to 5 mM, up to 1 mM).

[0057] CSA or a pharmaceutical composition comprising it can be administered to a subject via any suitable route of administration. The following descriptions of routes of administration are provided merely to illustrate exemplary embodiments and should not be construed as limiting the scope in any way.

[0058] Formulations suitable for oral administration may consist of (a) liquid solutions, such as an effective amount of the CSA of the present disclosure, dissolved in a diluent such as water, saline, or orange juice; (b) capsules, sachets, tablets, buccal tablets, and lozenges, each containing a predetermined amount of the active ingredient as a solid or granules; (c) powders; (d) suspensions in a suitable liquid; and (e) suitable emulsions. Liquid formulations may include diluents such as water and alcohols, e.g., ethanol, benzyl alcohol, and polyethylene alcohol, with or without the addition of a pharmaceutically acceptable surfactant. Capsule forms are, for example, the conventional hard- or soft-shell gelatin type containing surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch. Tablet forms may contain one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, gum arabic, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffers, disintegrants, wetting agents, preservatives, flavorings, and other pharmaceutically compatible excipients. Buccal forms may contain pastilles containing the CSA of the present disclosure in an inert base such as gelatin and glycerin or sucrose and gum arabic, emulsions, gels, etc., further containing flavorings, the active ingredient of the present disclosure in typically sucrose and gum arabic or tragacanth, and excipients known in the art.

[0059] The CSA of the present disclosure, alone or in combination with other suitable components, can be delivered via pulmonary administration and processed into an aerosol formulation for administration via inhalation. These aerosol formulations can be placed in an acceptable propellant under pressure, such as dichlorodifluoromethane, propane, or nitrogen. They can also be formulated as pharmaceuticals for non-pressurized formulations, such as in a nebulizer or atomizer. Such spray formulations can also be used to spray onto mucous membranes. In some embodiments, the CSA is formulated into a powder mixture or microparticles or nanoparticles. Suitable pulmonary formulations are known in the art. See, for example, Qian et al., Int J Pharm 366:218-220 (2009); Adjei and Garren, Pharmaceutical Research, 7(6):565-569 (1990); Kawashima et al., J Controlled Release 62(1-2):279-287 (1999); Liu et al., Pharm Res 10(2):228-232 (1993); WO 2007 / 133747 and WO 2007 / 141411.

[0060] Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions which may contain suspending agents, solubilizers, thickeners, stabilizers, and preservatives. The term "parenteral" means not through the digestive tract, but through some other route such as subcutaneous, intramuscular, intraspinal, or intravenous. The CSA of the present disclosure may be administered with a physiologically acceptable diluent in a pharmaceutical carrier such as water, saline, aqueous dextrose and related sugar solutions, alcohols such as ethanol or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, dimethyl sulfoxide, glycerol, ketals such as 2,2-dimethyl-153-dioxolane-4-methanol, ethers, poly(ethylene glycol) 400, oils, fatty acids, fatty acid esters or glycerides, or acetylated fatty acid glycerides with or without the addition of a pharmaceutically acceptable surfactant such as a soap or detergent, pectin, carbomer, methylcellulose, hydroxypropylmethylcellulose or carboxymethylcellulose, or suspending agents such as emulsifiers and other pharmaceutical adjuvants.

[0061] The oil that can be used in parenteral formulations includes petroleum, animal oil, vegetable oil or synthetic oil.Suitable oil examples include peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil.Suitable fatty acid for use in parenteral formulations includes oleic acid, stearic acid and isostearic acid.Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.

[0062] Suitable soaps for use in parenteral formulations include fatty acid alkali metal, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyldialkylammonium halides and alkylpyridinium halides; (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; (c) nonionic detergents such as, for example, fatty acid amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers; (d) amphoteric detergents such as, for example, alkyl-β-aminopropionates and 2-alkyl-imidazoline quaternary ammonium salts; and (e) mixtures thereof.

[0063] In some embodiments, parenteral formulations contain about 0.5% to about 25% by weight of the CSA of the present disclosure in solution. Preservatives and buffers may be used. To minimize or eliminate irritation at the injection site, such compositions may contain one or more nonionic surfactants having a hydrophilic-lipophilic balance (HLB) of about 12 to about 17. The amount of surfactant in such formulations will typically range from about 5% to about 15% by weight. Suitable surfactants include polyethylene glycol sorbitan fatty acid esters, such as sorbitan monooleate, and high molecular weight adducts of ethylene oxide with a hydrophobic base formed by the condensation of propylene glycol with propylene oxide. In some embodiments, parenteral formulations are provided in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid excipient for injection, e.g., water, immediately prior to use. Extemporaneous injection solutions and suspensions in some embodiments are prepared from sterile powders, granules, and tablets of the type previously described.

[0064] Injectable formulations are based on the present disclosure. The requirements for effective pharmaceutical carriers for injectable compositions are well known to those skilled in the art (see, for example, Pharmaceutics and Pharmacy Practice, J.B. Lippincott Company, Philadelphia, PA, Banker and Chalmers, eds., pp. 238-250 (1982) and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pp. 622-630 (1986)).

[0065] In addition to the pharmaceutical compositions described above, it will be appreciated by those skilled in the art that the CSA of the present disclosure may be formulated as an inclusion complex, such as a cyclodextrin inclusion complex or liposome.

[0066] In some embodiments, the CSA described herein can be modified into a depot form (see, e.g., U.S. Pat. No. 4,450,150) so that the manner in which the CSA of the present disclosure is released into the body to which it is administered can be controlled with respect to time and location within the body. A depot form of the CSA of the present disclosure can be, for example, an implantable composition comprising CSA and a porous or non-porous material, such as a polymer, in which the CSA is encapsulated or diffused by degradation of the material and / or the non-porous material. The depot is then implanted at a desired location within the subject's body, and the CSA is released from the implant at a predetermined rate.

[0067] In certain embodiments, the pharmaceutical composition comprising CSA is modified to have any type of in vivo release profile. In some embodiments, the pharmaceutical composition is an immediate release, controlled release, sustained release, extended release, delayed release, or two-stage release formulation. Methods for formulating peptides for controlled release are known in the art. See, for example, Qian et al., J Pharm 374:46-52 (2009) and WO 2008 / 130158, WO 2004 / 033036; WO 2000 / 032218; and WO 1999 / 040942. In an exemplary embodiment, the pharmaceutical composition is a modified release formulation, not an immediate release formulation. In an exemplary embodiment, the modified release formulation is a C for a 25 mg dose. max or a maximum observed plasma concentration, or a C of about 175 to about 210 ng / mL, and about 475 ng / mL to about 510 ng / mL for a 50 mg dose. max , for a dose of 25 mg T max , or about 2 to 5 hours C max and a T of about 2 to about 3 hours for the 50 mg dose. max It has.

[0068] In exemplary embodiments, CSA is administered to subject according to treatment regimen.In exemplary embodiments, CSA is administered to subject once a day, twice a day, three times a day, four times a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks or once a month.In exemplary embodiments, CSA is administered to subject twice a day by oral administration.

[0069] plasma concentration In an exemplary embodiment of the method of the present disclosure, a dose of CSA based on the subject's plasma concentration of CSA is administered to the subject during or after the initial period. In an exemplary embodiment, subsequent doses administered after the initial period are based on the subject's plasma concentration measured or determined during the initial period. In an exemplary embodiment, the initial period is about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, or more. For example, if the initial period is about 4 weeks, the subject's plasma concentration is measured at some point within the 4-week period. In exemplary cases, the subject's plasma concentration is measured about 1 week, about 2 weeks, or about 3 weeks after the initial administration of the initial dose. In an exemplary embodiment of the method of the present disclosure, the method includes determining the plasma concentration of CSA, for example, at the end of the initial period, e.g., at 4 weeks if the initial period is 4 weeks.

[0070] In exemplary embodiments of the disclosed methods, the method includes determining or measuring the plasma concentration of CSA in the subject. In exemplary aspects, the determining or measuring occurs about 1 week, about 2 weeks, or about 3 weeks after the initial administration of the first dose, or at the end of the initial period, e.g., about 4 weeks.

[0071] In an exemplary embodiment, the subject's plasma concentration of CSA is measured two or more times, e.g., two, three, four or more times, every two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, etc. In an exemplary case, the method includes determining a first plasma concentration of CSA after an initial period of time and determining a second plasma concentration after administering at least one subsequent dose of CSA to the subject after the initial period of time.

[0072] In an exemplary embodiment, the subject's plasma concentration of CSA is measured during an initial period, and then about four weeks thereafter. In an exemplary embodiment, the subject's plasma concentration of CSA is measured about two weeks after the first administration of the first dose, and then again about six weeks after the first administration of the first dose.

[0073] For purposes of this specification, the plasma concentration of CSA can be determined using any method known in the art. Suitable methods for determining the plasma concentration of a drug known in the art include, for example, gas chromatography (GC), high-performance liquid chromatography (HPLC), high-performance liquid chromatography-mass spectrometry (HPLC-MS), liquid chromatography-mass spectrometry (LCMS), immunoassays (e.g., competitive immunoassays, immunometric immunoassays, fluorescence polarization immunoassays (FPIA), enzyme-linked immunosorbent assays (EMITs), and enzyme-linked immunosorbent assays (ELISAs), or combinations thereof. See, for example, Wang et al., Nan Fan Yi Ke Da Xue Xue Bao 28(11):1993-1995 (2008); Dasgupta and Datta, Handbook of Drug Monitoring Methods, Chapter 3: Analytical Techniques for Measuring Concentrations of Therapeutic Drugs in Biological Fluids, Pages 67-86 (2008); Kang and Lee, Korean J Intern Med 24(1):1-10(2009);Glazko,Antiepileptic Drugs,3 rd, ed., New York: Raven Press, 1989, Pgs 159-176; and Steijns et al., Ther Drug Monit 24:432-435 (2002). In exemplary embodiments, the method includes determining the plasma concentration by performing an LC-MS / MS or quantitative microsphere assay. In exemplary embodiments, the method includes determining the plasma concentration by a competitive inhibition immunoassay in which free drug in the plasma sample competes for antibody binding sites with drug molecules coated on uniform microparticles. In exemplary embodiments, the plasma concentration of CSA is determined using a QMS™ Therapeutic Drug Monitoring (TDM) assay, a CEDIA™ Therapeutic Drug Monitoring (TDM) assay, or a DRI™ TDM assay (ThermoFisher Scientific, Waltham, MA).

[0074] In an exemplary embodiment, the plasma concentration of CSA is determined by measuring CSA in the subject's plasma. In an alternative embodiment, the plasma concentration of CSA is determined by measuring a metabolite of CSA in the subject's plasma. In an exemplary embodiment, the plasma concentration of CSA is the trough CSA concentration in plasma. In an exemplary embodiment, the plasma concentration of CSA is determined at the beginning of the day and / or before the first dose is administered to the subject.

[0075] Illustrative Embodiments In an exemplary embodiment, the cardiac myosin activator is OM, and the method includes repeatedly administering an initial dose of OM to the subject twice daily for at least or about two weeks, each initial dose being about 25 mg administered orally. In an exemplary embodiment, the therapeutic concentration range is about 200 ng / mL to about 1000 ng / mL, and the method includes repeatedly administering subsequent doses to the subject twice daily via oral administration, the subsequent doses being (i) about 25 mg when the plasma concentration of CSA is greater than or about 300 ng / mL but less than about 1000 ng / mL, (ii) about 37.5 mg when the plasma concentration of CSA is greater than or about 200 ng / mL but less than about 300 ng / mL, or (iii) about 50 mg when the plasma concentration of CSA is less than about 200 ng / mL. In alternative embodiments, subsequent doses are administered to the subject twice daily and / or orally to the subject, and the subsequent doses are (i) about 25 mg when the plasma concentration of CSA is greater than 200 ng / mL or about 200 ng / mL but less than about 1000 ng / mL, or (ii) about 50 mg when the plasma concentration of CSA is less than about 200 ng / mL.

[0076] In an exemplary embodiment, the method includes administering an initial dose of OM to a subject twice daily during an initial period of about 4 weeks, with each initial dose being about 25 mg administered via oral administration. In an exemplary embodiment, the method includes a second period following the initial period, during which a second series of doses is administered to the subject based on the subject's plasma concentration of CSA measured during the initial period, e.g., about 2 weeks after the first initial dose is administered. In an exemplary case, the method includes a third period following the second period, during which a third series of doses is administered to the subject based on the subject's plasma concentration of CSA measured during the second period, e.g., about 6 weeks after the first initial dose is administered. In an exemplary embodiment, each of the second and third series of doses is administered twice daily via oral administration. In an exemplary embodiment, the therapeutic concentration range is about 200 ng / mL to about 1000 ng / mL, and the second and third series of doses are as outlined below.

[0077] [Table 2]

[0078] In an exemplary embodiment, the second period is about 4 weeks, and the third period is at least about 4 weeks. In an exemplary embodiment, administration of CSA ceases when the subject's plasma concentration of CSA is greater than or about 1000 ng / mL. In an exemplary embodiment, the plasma concentration of CSA is measured or determined every 4, 6, 12, 24, or 48 weeks.

[0079] In an exemplary embodiment, a method of treating a subject with heart failure (HF) includes: (a) administering to the subject a series of initial doses of omecamtib mecarbil (OM) twice daily via oral administration for an initial period of about 4 weeks, wherein each initial dose is about 25 mg; and (b) administering to the subject a subsequent series of doses of OM twice daily via oral administration for a second period following the initial period, wherein each subsequent dose is: (i) about 25 mg when the subject's plasma concentration measured about 2 weeks from the beginning of the initial period is greater than or about 300 ng / mL, (ii) about 37.5 mg when the subject's plasma concentration measured about 2 weeks from the beginning of the initial period is greater than or about 200 ng / mL but less than 300 ng / mL, or (iii) about 50 mg when the subject's plasma concentration measured about 2 weeks from the beginning of the initial period is less than 200 ng / mL. In exemplary embodiments, the method further comprises measuring the subject's plasma concentration at about 2 weeks from the beginning of the first period.In exemplary cases, the second period is about 4 weeks after the first period.In some embodiments, the method further comprises administering a series of subsequent doses of OM to the subject twice a day via oral administration for a third period following the second period, and each subsequent dose administered during the third period is based on the subject's plasma concentration measured at about 6 weeks from the beginning of the first period.In exemplary embodiments, (A) when the subject's plasma concentration measured about 6 weeks from the beginning of the first period is less than 750 ng / mL, each dose in the third period is about the same as the subsequent dose in the second period; (B) when the subject's plasma concentration measured about 6 weeks from the beginning of the first period is greater than or about 750 ng / mL and less than 1000 ng / mL, and the subsequent dose administered in the second period is 25 mg or 37.5 mg, each dose in the third period is about 25 mg; (C) when the subject's plasma concentration measured about 6 weeks from the beginning of the first period is greater than or about 750 ng / mL and less than 1000 ng / mL, each dose in the third period is about 25 mg. (D) when the subject's plasma concentration measured about 6 weeks after the beginning of the first period is greater than or about 1000 ng / mL and the subsequent dose administered in the second period is about 50 mg, each dose in the third period is about 37.5 mg; (D) when the subject's plasma concentration measured about 6 weeks after the beginning of the first period is greater than or about 1000 ng / mL and the subsequent dose administered in the second period is about 25 mg, each dose in the third period is about 0 mg; and (E) when the subject's plasma concentration measured about 6 weeks after the beginning of the first period is greater than or about 1000 ng / mL and the subsequent dose administered in the second period is about 37.5 mg or about 50 mg, each dose in the third period is about 25 mg. In an exemplary case, the third period is at least or about 4 weeks after the second period. In an exemplary embodiment, the method further includes measuring the subject's plasma concentration about 6 weeks after the beginning of the first period.

[0080] Related Methods The present disclosure provides a method for preventing serious adverse events during treatment with a cardiac segment activator (CSA) in a subject. In an exemplary embodiment, the method includes (a) administering an initial dose of CSA to the subject over an initial period of time, and (b) subsequently administering doses of CSA to the subject based on the subject's plasma concentration of CSA at the end of the initial period of time. In an exemplary embodiment, the initial dose is a minimum effective dose (MED) of CSA. In an exemplary embodiment, CSA has reached a steady state in the subject by the end of the initial period of time or by the time the plasma concentration of CSA is determined. In an exemplary embodiment, the dose subsequently administered to the subject is one of two options: the subsequently administered dose is either the same as the initial dose or exceeds the initial dose. In alternative or additional exemplary embodiments, the dose subsequently administered to the subject is one of three options: the subsequently administered dose is (i) the same as the initial dose, (ii) more than the initial dose but below the maximum dose, or (iii) the maximum dose. In an exemplary embodiment, when the subject's plasma concentration of CSA exceeds the threshold concentration, the subsequently administered dose is the same as the initial dose. In an exemplary case, the threshold concentration is about 1.0 to about 1.5 times the minimum value of the target concentration range. In an exemplary embodiment, when the subject's plasma concentration of CSA is below the threshold concentration, the subsequently administered dose is greater than the initial dose. In an exemplary case, the threshold concentration is about 1.0 to about 1.5 times the minimum value of the target concentration range.

[0081] In an exemplary embodiment, a method for preventing serious adverse events during treatment with a cardiac segment activator (CSA) in a subject includes (a) administering an initial dose of CSA to the subject over an initial period of time, and (b) subsequently administering doses of CSA to the subject based on the subject's plasma concentration of CSA during or at the end of the initial period of time. In an exemplary embodiment, when the subject's plasma concentration of CSA is equal to or greater than the minimum value of the target concentration range, the subsequently administered dose is the same as the initial dose. In an exemplary embodiment, when the subject's plasma concentration of CSA is less than the minimum value of the target concentration range, the subsequently administered dose is greater than the initial dose. In an exemplary embodiment, when the subject's plasma concentration is greater than or about 1.5 times the minimum value of the target concentration range, the subsequently administered dose is the same as the initial dose. In an exemplary embodiment, when the subject's plasma concentration of CSA is less than 1.5 times the minimum value of the target concentration range but greater than or about the minimum value of the target concentration range, the subsequently administered dose is greater than the initial dose but less than the maximum dose. In an exemplary embodiment, when the subject's plasma concentration of CSA is below the minimum of the target concentration range, the subsequently administered dose is the maximum dose.

[0082] As used herein, the term "prevent" and words derived therefrom encompass reducing the occurrence or delaying the onset of the medical condition being prevented (e.g., a serious adverse event). In exemplary embodiments, the method delays the onset of a serious adverse event by 1 day, 2 days, 4 days, 6 days, 8 days, 10 days, 15 days, 30 days, 2 months, 4 months, 6 months, 1 year, 2 years, 4 years, or more. As used herein, the term "prevent" and words derived therefrom encompass reducing the risk of a serious adverse event. In exemplary embodiments, the method reduces the risk of a serious adverse event by 2-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or more.

[0083] The present disclosure provides a method for reducing the risk of serious adverse events during treatment with a cardiac segment activator (CSA) in a subject. In an exemplary embodiment, the method includes (a) administering an initial dose of CSA to the subject over an initial period of time, and (b) subsequently administering doses of CSA to the subject based on the subject's plasma concentration of CSA at the end of the initial period of time. In an exemplary embodiment, the initial dose is a minimum effective dose (MED) of CSA. In an exemplary embodiment, CSA has reached a steady state in the subject by the end of the initial period of time or by the time the plasma concentration of CSA is determined. In an exemplary embodiment, the dose subsequently administered to the subject is one of two options: the subsequently administered dose is either the same as the initial dose or exceeds the initial dose. In alternative or additional exemplary embodiments, the dose subsequently administered to the subject is one of three options: the subsequently administered dose is (i) the same as the initial dose, (ii) exceeds the initial dose but below the maximum dose, or (iii) is the maximum dose. In an exemplary embodiment, when the subject's plasma concentration of CSA exceeds the threshold concentration, the subsequently administered dose is the same as the initial dose. In an exemplary case, the threshold concentration is about 1.0 to about 1.5 times the minimum value of the target concentration range. In an exemplary embodiment, when the subject's plasma concentration of CSA is below the threshold concentration, the subsequently administered dose is greater than the initial dose. In an exemplary case, the threshold concentration is about 1.0 to about 1.5 times the minimum value of the target concentration range.

[0084] In an exemplary embodiment, a method for reducing the risk of a serious adverse event during treatment with a cardiac segment activator (CSA) in a subject includes (a) administering an initial dose of CSA to the subject over an initial period of time, and (b) subsequently administering doses of CSA to the subject based on the subject's plasma concentration of CSA during or at the end of the initial period of time. In an exemplary embodiment, when the subject's plasma concentration of CSA is equal to or greater than the minimum value of the target concentration range, the subsequently administered dose is the same as the initial dose. In an exemplary embodiment, when the subject's plasma concentration of CSA is less than the minimum value of the target concentration range, the subsequently administered dose is greater than the initial dose. In an exemplary embodiment, when the subject's plasma concentration is greater than or about 1.5 times the minimum value of the target concentration range, the subsequently administered dose is the same as the initial dose. In an exemplary embodiment, when the subject's plasma concentration of CSA is less than 1.5 times the minimum value of the target concentration range but greater than or about the minimum value of the target concentration range, the subsequently administered dose is greater than the initial dose but less than the maximum dose. In an exemplary embodiment, when the subject's plasma concentration of CSA is below the minimum of the target concentration range, the subsequently administered dose is the maximum dose.

[0085] As used herein, the term "reduce" and words derived therefrom may not be a 100% or complete reduction. Rather, there are various degrees of reduction that those skilled in the art will recognize as having potential benefit or therapeutic effect. In this regard, the risk of a serious adverse event may be reduced to any amount or level. In exemplary embodiments, the risk reduction provided by the methods of the present disclosure is at least or about a 10% reduction (e.g., at least or about a 20% reduction, at least or about a 30% reduction, at least or about a 40% reduction, at least or about a 50% reduction, at least or about a 60% reduction, at least or about a 70% reduction, at least or about a 80% reduction, at least or about a 90% reduction, at least or about a 95% reduction, at least or about a 98% reduction).

[0086] The present disclosure further provides a method for identifying a subject at risk for a serious adverse event during treatment with a cardiac segment activator (CSA). In an exemplary embodiment, the method includes (a) administering an initial dose of CSA to a subject over an initial period of time, and (b) determining the subject's plasma concentration of CSA during or at the end of the initial period of time. In an exemplary embodiment, the initial dose is a minimum effective dose (MED) of CSA. In an exemplary embodiment, the initial period of time is at least about two weeks. In an exemplary embodiment, CSA has reached a steady state in the subject by the end of the initial period of time or by the time the plasma concentration of CSA is determined. In an exemplary embodiment, the method includes determining the subject's steady-state plasma concentration of CSA. In an exemplary embodiment, when the subject's plasma concentration of CSA exceeds a threshold concentration, the subject is identified as being at risk for a serious adverse event during treatment with CSA. In an exemplary embodiment, such a subject is given subsequent doses of CSA, each subsequent dose being the same as the initial dose. In exemplary cases, the threshold concentration is about 1.0 to about 1.5 times the minimum of the target concentration range. In exemplary embodiments, the target concentration range is about 200 ng / mL to about 1200 ng / mL or about 200 ng / mL to about 1000 ng / mL.

[0087] In the method of the present disclosure, the serious adverse event is myocardial infarction or myocardial ischemia. In an exemplary embodiment, the serious event is non-ST elevation myocardial infarction. In an exemplary embodiment, the serious adverse event is one or more of: feeling hot, palpitations, chest or pharyngeal tightness, dizziness, tachycardia, ECG ST segment depression, and positive cardiac markers.

[0088] Methods for determining a treatment regimen for a subject are also provided. In exemplary embodiments, the method includes (a) administering a minimum effective dose (MED) dose of CSA to the subject over an initial period of time, wherein the CSA reaches a steady state in the subject during or by the end of the initial period, and (b) determining the subject's plasma concentration of CSA at the end of the initial period. In exemplary embodiments, the treatment regimen after the initial period includes a dose of CSA that is either the same as or greater than the initial dose. In exemplary embodiments, when the subject's plasma concentration of CSA is above a threshold concentration, in exemplary cases about 1.0 to about 1.5 times the minimum of the target concentration range, the treatment regimen after the initial period includes a dose of CSA that is the same as the initial dose. In exemplary embodiments, when the subject's plasma concentration of CSA is below a threshold concentration, in exemplary cases about 1.0 to about 1.5 times the minimum of the target concentration range, the treatment regimen after the initial period includes a dose of CSA that is greater than the initial dose. In alternative or additional exemplary embodiments, the treatment regimen after the initial period includes a dose that is one of three options: the subsequently administered dose is (i) the same as the initial dose, (ii) greater than the initial dose but less than the maximum dose, or (iii) the maximum dose. In exemplary embodiments, the treatment regimen after the initial period includes a dose of CSA that is (i) essentially the same as the initial dose when the plasma concentration of CSA is greater than or about 1.5 times the minimum of the target concentration range, (ii) greater than the initial dose but less than the maximum dose when the subject's plasma concentration of CSA is greater than or about the minimum of the target concentration range but less than about 1.5 times the minimum of the target concentration range, or (iii) the maximum dose when the plasma concentration of CSA is less than the minimum of the target concentration range.

[0089] Such methods of determining treatment regimens make it possible to optimize the effectiveness of treatment with CSA.

[0090] The following examples are offered merely to illustrate the present disclosure and in no way to limit its scope. [Example]

[0091] Example 1: This example describes a randomized, placebo-controlled, double-blind, parallel-group, multicenter, CV outcomes study of oral OM in subjects with HFrEF, including subjects currently hospitalized or previously hospitalized for HF.

[0092] Approximately 8,000 eligible subjects will be randomized in a 1:1 ratio to receive either OM or placebo. Randomization will be stratified by randomization setting (currently hospitalized for HF or recently and not currently hospitalized for HF) and region (5 strata: United States and Canada; Latin America, Western Europe, South Africa, and Australia; Eastern Europe including Russia; Asia). Approximately 25% or more of the total planned enrollment will include subjects hospitalized at randomization. The number of subjects with atrial fibrillation enrolled will be limited to 20% in each enrollment setting.

[0093] OM is provided as tablets, which are packaged in 14 blisters.

[0094] OM is administered orally twice a day by the subject, in the morning and evening, either fasting or after a meal. OM is swallowed whole (unchewed, crushed, or divided) and taken with water. Each morning and evening dose is administered at approximately the same time each day. If OM is not taken or has not been taken within approximately 12±3 hours of the most recent dose, that dose should be skipped, and the next dose should be administered at the usual time.

[0095] Subjects randomized to OM will begin receiving 25 mg twice daily. Predose blood samples were collected for all subjects at the Week 2 study visit. Results will be masked to the investigator. For subjects randomized to OM, predose PK collected at Week 2 will guide dose adjustments. A new supply of OM will be provided to subjects when PK is assessed for dose adjustment purposes, independent of randomized treatment group and PK assessment outcomes, to maintain blinding.

[0096] Subjects randomized to placebo will receive placebo throughout the study and will be subjected to all protocol procedures to maintain blinding of treatment group assignment and OM administration. Subjects will continue to receive OM until the morning of the end of study (EOS) visit.

[0097] A direct correlation has been observed between plasma concentrations of OM and increases in systolic ejection time, stroke volume, and left ventricular function (Cleland et al., 2011; Teerlink et al., 2011). Excessive exposure to OM can cause signs and symptoms of myocardial ischemia or infarction (e.g., increased heart rate, dizziness, dyspnea, hypotension, chest discomfort or pain, ST-segment depression / elevation and / or elevated troponin I or T on the ECG). No antidote currently exists for OM. In the event of overdose, healthcare providers should be particularly vigilant regarding signs and symptoms of myocardial ischemia. Standard medical therapy should be used to treat adverse signs or symptoms that do not prompt discontinuation of OM.

[0098] All subjects will have a pre-dose PK assessment at Week 2 to guide dose adjustments for subjects randomized to OM. Another pre-dose PK assessment will be conducted at Week 6 to reflect the PK results of the previous adjustment. Pharmacokinetics will be assessed at Weeks 24 and 48 and every 48 weeks throughout the study. Table 1 provides a summary of the dose adjustment rules.

[0099] [Table 3]

[0100] New investigational product supplies will be provided to all subjects at the Week 4 and Week 8 study visits, regardless of randomized treatment group and PK outcome, to maintain blinding. If Week 2 PK values ​​are not available at the time for dose adjustment, subjects randomized to OM will remain at the 25 mg twice daily dose until the results of the Week 6 PK assessment. If Week 6 PK values ​​are not available at the time for dose adjustment, subjects randomized to OM will be assigned to the lower dose regimen (25 mg twice daily).

[0101] PK will be assessed at weeks 12, 48, and every 48 weeks and is not subject to a PK-based dose adjustment approach. Subjects with plasma concentrations ≥ 1000 ng / mL at the evaluation after the 8-week visit will be required to discontinue OM administration, regardless of signs or symptoms. Additional visits will be scheduled and the subject's treatment assignment will be open-label.

[0102] Subjects randomized to placebo will receive placebo throughout the study but will be subjected to identical PK and refeeding procedures.

[0103] If OM cannot be taken or has not been taken within approximately 12±3 hours of the most recent dose, that dose should be skipped and the next dose should be taken at the usual time.

[0104] If a subject exhibits clinical signs or symptoms consistent with acute myocardial ischemia or infarction, the subject should receive prompt medical attention according to the institution's usual SoC, and OM administration should be withheld. Serial cardiac ischemic markers and ECGs should be analyzed locally. Results from local laboratory assessments of troponin (I or T), CK-MB, and BNP or NT-proBNP should be recorded on the CRF. Central laboratory PK samples, troponin I, CK-MB, and NT-proBNP, should be collected in all subjects experiencing an event as close as possible to the event, and the time of last OM administration is recorded. Results of PK assessments, if any, routinely remain blinded to the sponsoring organization and investigator.

[0105] Resumption of OM after a cardiac ischemic event may be considered after appropriate management of the case and evaluation of the possible cause of the event and its potential relevance to OM. The decision to restart a subject after a cardiac ischemic event should be discussed and agreed upon. Subjects experiencing an acute cardiac ischemic event suspected to be related to OM should not be re-administered. If restarted, subjects will begin OM 25 mg twice daily or placebo twice daily according to their initial group assignment. A new pre-dose PK assessment will be conducted 2 weeks after OM resumption, and dose adjustments will be made at the next OM dispensing visit. Adjustments will follow the same procedure as the week 4 study visit, limiting the maximum dose to that specified before the event.

[0106] The primary endpoint of this study was the combined time to CV death or first HF event, whichever occurred first. An HF event was defined as an urgent, unscheduled clinic / clinic / ED visit or hospitalization with a primary diagnosis of HF, where the patient presented with new or worsening HF symptoms at the time of presentation, had objective evidence of new or worsening HF, and received initiation or intensification of HF-specific therapy (Hicks et al., 2015). A change to oral diuretic therapy did not qualify as treatment initiation or intensification.

[0107] Secondary endpoints of the study include: (i) time to CV death, (ii) change in Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ TSS) from baseline through 24 weeks, (iii) time to first heart failure hospitalization, and (iv) time to death from any cause.

[0108] Additional endpoints include safety and exploratory endpoints.

[0109] Example 2: This example presents the inclusion and exclusion criteria for the study described in Example 1.

[0110] The inclusion criteria were as follows: 1. Subjects provided informed consent 2. Male or female, age ≥ 18 to ≤ 85 years at the time of signing the informed consent 3. History of chronic HF (defined as requiring treatment for HF for a minimum of 30 days prior to randomization) 4.LVEF ≤ 35%, per subject's most recent medical record, without acute decompensation 5. NYHA class II to IV at most recent screening evaluation 6. Treated with HF SoC therapy consistent with local treatment guidelines as determined by the investigator's judgment of the subject's clinical status, and if not contraindicated, will be offered oral SoC therapy for chronic HF (e.g., beta-blockers, renin-angiotensin-aldosterone system inhibitors). Subjects enrolled during or early after discharge from a HF hospitalization may resume or titrate their chronic HF therapy with oral SoC simultaneously with randomization with the goal of achieving optimized therapy in the study. 7. Current hospitalization with HF as the primary cause or prior HF hospitalization or urgent HF admission to the emergency department (ED) within 1 year prior to screening 8. B-type natriuretic peptide (BNP) level ≥ 125 pg / mL or NT-proBNP level ≥ 400 pg / mL at the most recent screening assessment (subjects receiving angiotensin receptor-neprilysin inhibitors [ARNi] must use NT-proBNP assessment; for subjects with atrial fibrillation, the cutoff levels are: BNP ≥ 375 pg / mL or NT-proBNP ≥ 1200 pg / mL).

[0111] The exclusion criteria were as follows: 9. Currently receiving treatment in another investigational device or drug study, or has completed treatment for another investigational device or drug study less than 30 days ago. Other investigational procedures while participating in this study are excluded. 10. Malignancy within 5 years prior to randomization with the following exceptions: localized basal cell carcinoma or squamous cell carcinoma of the skin in situ, cervical intraepithelial neoplasia, stage 1 prostate cancer, ductal carcinoma of the breast in situ. 11. Subject has a known sensitivity to any of the products or ingredients administered during the medication. 12. Subject unlikely to be available to complete all protocol-specified visits or procedures and / or follow all study procedures as specified to the best of the subject's and the investigator's knowledge 13. Inability to swallow study drug tablets (e.g., dysphagia, feeding tube) 14. Receiving mechanical hemodynamic support (e.g., intra-aortic balloon pump counterpulsation) or mechanical ventilation (including non-invasive mechanical ventilation, i.e., bilevel positive airway pressure [BiPAP] or continuous positive airway pressure [CPAP] devices) within 7 days prior to randomization. 15. Receiving IV inotropes (e.g., dobutamine, milrinone, levosimendan) or IV vasopressors (e.g., epinephrine, norepinephrine, dopamine, or vasopressin) within 3 days prior to randomization. 16. Receiving IV diuretics or IV vasodilators or supplemental oxygen therapy within 12 hours prior to randomization 17. Acute coronary syndrome (ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, unstable angina), stroke or transient ischemic attack, open heart surgery, percutaneous coronary intervention, or valvuloplasty within 3 months prior to randomization. 18. Initiation of implantable cardioverter-defibrillator or cardiac resynchronization therapy (CRT) (with or without implantable cardioverter-defibrillator) within 30 days prior to randomization 19. Severe uncorrected valvular heart disease or hypertrophic obstructive cardiomyopathy, active myocarditis, constrictive pericarditis, or clinically significant congenital heart disease 20. Untreated severe ventricular arrhythmia (e.g., ventricular tachycardia or ventricular fibrillation) 21. Long-term antiarrhythmic therapy excluding amiodarone. Note: For purposes of this exclusion criterion, digoxin, calcium channel blockers, and beta-blocker therapy are not considered long-term antiarrhythmic therapy. 22. Symptomatic bradycardia or second- or third-degree heart block without a pacemaker 23. Regularly scheduled outpatient intravenous infusions for HF (e.g., inotropes, vasodilators [e.g., nesiritide], diuretics) or regularly scheduled ultrafiltration 24. Systolic blood pressure >140mmHg or <85mmHg, or diastolic blood pressure >90mmHg, or heart rate >110 beats per minute or <50 beats per minute at screening 25. Estimated glomerular filtration rate (eGFR) <20 mL / min / 1.73 m 2 or undergoing dialysis at the time of screening 26. Liver dysfunction defined by total bilirubin (TBL) ≥ 2 times the upper limit of normal (ULN) or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 times the ULN at screening 27. Previously received OM 28. Severe concomitant non-CV disease predicted to reduce life expectancy to less than 2 years 29. Recipient of any major organ transplant (e.g., lung, liver, heart, bone marrow, kidney) 30. Female subjects of childbearing potential who do not want their partner to know about their participation in this clinical trial and who are unwilling to use two accepted methods of effective birth control or who practice strict abstinence (reliability of abstinence must be assessed by the investigator and must be in line with the preferred normal subject lifestyle) during treatment with IP (OM or placebo) and for an additional 5 days after the last dose of IP. If the female subject or her only male partner has undergone surgical contraception (tubal ligation / occlusion or vasectomy with medical evaluation of surgical success), an additional method of contraception is not required. Male subjects with female partners of childbearing potential who do not want their partners to know about their participation in this clinical trial. a) Women are considered to be of childbearing potential unless they have had a hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, or are postmenopausal. Menopause is defined as spontaneous and continuous amenorrhea for 12 months or more in women 55 years of age or older; or the absence of spontaneous menstruation for at least 2 years in women under 55 years of age; or under 55 years of age and have had spontaneous menstruation within the past year but are currently amenorrhea (e.g., spontaneous or secondary to a hysterectomy) and have a follicle-stimulating hormone (FSH) level greater than 40 IU / L or a postmenopausal estradiol level (less than 5 ng / dL), or according to the participating laboratory's definition of the "postmenopausal range." b) Two acceptable methods of effective birth control include the following two options: Use of combined hormonal and barrier birth control methods (i.e., intrauterine device and barrier method with spermicide, intrauterine device and hormonal birth control, hormonal birth control and barrier method with spermicide) Two barrier methods (each partner must use one barrier method, excluding the female condom) with at least one barrier method containing a spermicide (male and female condoms must not be used together due to the risk of breakage). c) Hormonal methods of birth control include oral, intravaginal, transdermal, injectable, or implantable. Barrier methods of birth control include diaphragms with spermicide, cervical caps with spermicide, male or female condoms with spermicide, and contraceptive sponges with spermicide. If spermicides are not commercially available in the local / regional area, barrier methods without spermicide are acceptable. Note: If additional medications are given during treatment that may alter contraceptive requirements (these additional medications may require an increase in the number of contraceptive methods and / or the length of time that contraception is utilized after the last dose of protocol-defined therapy), the investigator should discuss these changes with the study subject. 31. Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeeding during treatment with IP (OM or placebo) or within 5 days after the end of treatment with IP. 32. Scheduled discharge from the hospital to a long-term care facility (e.g., skilled nursing facility) or hospice. 33. History or evidence of any other clinically significant disorder (including cardiac arrhythmias), condition, or disease (other than those outlined above) that, if presented, the investigator or physician determines would pose a risk to the subject's safety or interfere with the evaluations, procedures, or completion of the study.

[0112] Example 3: This example demonstrates a Phase 2 pharmacokinetic, randomized, placebo-controlled trial called the Long-Term Oral Study of Myosin Activation to Increase Contractile Force in Heart Failure (COSMIC-HF), which was published in Teerlink et al., The Lancet 388:2895-2903 (2016), which is incorporated by reference in its entirety.

[0113] Impaired contractility is a hallmark of heart failure with reduced ejection fraction. This clinical trial evaluated the pharmacokinetics and effects of omecamtiv mecarbil, a cardiac myosin activator, on cardiac function and structure.

[0114] This phase 2 pharmacokinetic, randomized, placebo-controlled study was designed to investigate whether pharmacokinetically guided dose adjustment of omecamtiv mecarbil given orally for 20 weeks would result in well-tolerated plasma drug concentrations associated with improved ventricular systolic function and favorable ventricular remodeling.

[0115] method: This randomized, double-blind study, conducted at 87 sites in 13 countries, recruited patients with stable, symptomatic chronic heart failure and a left ventricular ejection fraction of 40% or less. Patients were randomly and equally assigned via an interactive web-based response system to receive oral omecamtiv mecarbir 25 mg twice daily (fixed-dose group), 25 mg twice daily with pharmacokinetically guided titration to 50 mg twice daily (pharmacokinetic-titration group), or placebo for 20 weeks. Maximum plasma omecamtiv mecarbir concentrations (primary endpoint) and changes in cardiac function and ventricular diameter were assessed. This study is registered with ClinicalTrials.gov, number NCT01786512.

[0116] Study design COSMIC-HF was an international, multicenter, randomized, parallel-group, placebo-controlled, double-blind study conducted at 87 sites in 13 countries. All patients provided written informed consent.

[0117] patient Eligible patients were 18–85 years of age, had chronic heart failure (New York Heart Association class II or III) treated with stable optimal pharmacological therapy for at least 4 weeks, had a plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration of at least 200 pg / mL (≥1200 pg / mL if the patient had atrial fibrillation, but the proportion of patients with atrial fibrillation was limited to approximately 20% of the study population), a left ventricular ejection fraction of ≤40%, and acceptable echocardiographic image quality (centrally determined by an echocardiographic central laboratory, Brigham and Women's Hospital, Boston, MA, USA). Patients had a diagnosis of acute myocardial infarction, unstable angina, or persistent angina at rest within 30 days prior to randomization, or were receiving long-term antiarrhythmic therapy (excluding amiodarone), or had severe chronic kidney disease (estimated glomerular filtration rate ≥1.73 m at screening). 2 Patients were excluded if they had a blood pressure (less than 30 mL / min per minute).

[0118] Randomization and Masking Randomization was stratified by the presence or absence of atrial fibrillation or atrial flutter based on a computer-generated schedule established prior to the start of the study. Patients were assigned in a 1:1:1 ratio to receive 25 mg oral omecamtiv mecarbil twice daily (fixed-dose group), 25 mg oral omecamtiv mecarbil titrated to 50 mg twice daily (pharmacokinetic-titration group), or oral placebo, with the following assignment obtained via an interactive web-based response system: All pills and packaging were identical. Packaging included box numbers that were matched by the distribution system to ensure the correct dose was received by the patient.

[0119] procedure Before randomization, patients entered a screening period of up to 30 days for 12-lead electrocardiographic and echocardiographic evaluations and laboratory testing for chemistry, hematology, NT-proBNP levels, and cysteine ​​C levels. Patients who were eligible at the end of screening were randomized.

[0120] All patients received study treatment or placebo for 20 weeks and were followed up 24 weeks after randomization. Patients in the pharmacokinetic-titration group received 25 mg of omecamtib mecarbil twice daily for 2 weeks to reach steady state. If the trough omecamtib mecarbil plasma concentration (pre-dose concentration) before the morning dose in week 2 was less than 200 ng / mL, the dose was titrated to 50 mg twice daily at week 8. If the pre-dose concentration was 200 ng / mL or greater, patients continued taking 25 mg twice daily until the end of the study. To assess pharmacokinetics in this population more rigorously than permitted by simple trough sampling, intensive pharmacokinetic sampling was performed over 8 hours each day at the end of weeks 2 and 12.

[0121] Patients attended the study clinic at weeks 2 and 8, and then every 4 weeks until week 24. Transthoracic echocardiograms were performed at baseline, weeks 12, and 20 and analyzed centrally. Blood samples were obtained from designated visits for analysis at a central laboratory. Plasma cardiac troponin I concentrations were measured at baseline and weeks 2, 8, 12, 16, 20, and 24 using a Siemens ADVIA Centaur Ultra troponin I assay (Siemens, Tarrytown, NY, USA). 9,10 Possible cardiac ischemia or infarction was reviewed by the trial's Clinical Events Committee if the investigator reported an event suggestive of myocardial ischemia or if the patient's troponin I concentration exceeded the upper 99th percentile reference limit of 0.04 ng / mL when the previous concentration was undetectable or if the value increased by more than 0.03 ng / mL compared with the previously detected value.

[0122] Outcome Primary endpoints were maximum omecamtiv mecarbil concentrations at visits at weeks 2 and 12 and predose concentrations at visits at weeks 2, 8, 12, 16, and 20. Secondary endpoints included change from baseline in systolic ejection time, stroke volume, left ventricular end-systolic and end-diastolic diameters, heart rate, and plasma NT-proBNP concentration at week 20. Additional prespecified exploratory echocardiographic endpoints included left ventricular fractional shortening, end-systolic and end-diastolic volumes, and ejection fraction. A clinical events committee reviewed all hospital admissions and deaths and myocardial ischemia or myocardial infarction, whether reported by the investigator or based on increases in plasma cardiac troponin I concentrations that met criteria for study endpoints.

[0123] statistical analysis The standard deviations (SD) for the maximum and minimum concentrations of omecamtiv mecarbil in plasma were assumed to be in the range of 40 to 140 ng / mL. 6~8,11~13Based on this criteria, the 142 patients in the pharmacokinetic-titration group were calculated to yield a two-sided 95% CI with a half-width of 6.6 to 23.0 ng / mL, which was considered sufficient for accurate population estimates of omecamtiv mecarbil concentrations, assuming that 5% of patients did not have evaluable concentrations of these omecamtiv mecarbil. Previous studies in similar patient populations have shown that omecamtiv mecarbil plasma concentrations as low as 100 to 200 ng / mL had some effect on cardiac function, but the effect on stroke volume appeared to plateau at concentrations above 400 ng / mL, and that plasma concentrations above 1200 ng / mL were not clinically tolerated. 7 Therefore, attempts were made to reach a maximum concentration greater than 200 ng / mL and to avoid exposure to concentrations greater than 1000 ng / mL. Furthermore, with 150 patients in each group and significance set at α = 0.05 (two-sided), it was estimated that the power to detect a treatment effect on the echocardiographic endpoints of systolic ejection time, stroke volume, and left ventricular end-systolic diameter would exceed 90%. Between-group differences in the change from baseline in echocardiographic variables, heart rate, and NT-proBNP concentration, were estimated by repeated measures models fitted separately for each variable and included stratification factors for the presence or absence of atrial fibrillation or atrial flutter at randomization, baseline value, treatment group, visit, and interaction of treatment group by visit. An unspecified covariance matrix was used to account for correlations between patients at visits. Unless otherwise indicated, least-squares mean differences with 95% CIs for the mean versus placebo are presented. Because the study was hypothesis-generating, all p-values ​​are nominal without multiplicity adjustment. This study is registered with ClinicalTrials.gov, number NCT01786512.

[0124] result One hundred fifty patients in the fixed-dose omecamtiv mecarbir group and 149 in the pharmacokinetic-titration and placebo groups were enrolled between March 17, 2014, and March 5, 2015. The mean maximum omecamtiv mecarbir concentrations at week 12 were 200 (SD 71) ng / mL in the fixed-dose group and 318 (129) ng / mL in the pharmacokinetic-titration group. At week 20, the least-squares mean differences for the pharmacokinetic-titration group versus the placebo group were as follows: systolic ejection time 25 ms (95% CI 18 to 32, p<0.0001), stroke volume 3.6 mL (0.5 to 6.7, p=0.0217), left ventricular end-systolic diameter -1.8 mm (-2.9 to -0.6, p=0.0027), left ventricular end-diastolic diameter -1.3 mm (-2.3 to 0.3, p=0.0128), heart rate -3.0 beats per minute (-5.1 to -0.8, p=0.0070), and plasma N-terminal pro-B-type natriuretic peptide concentration -970 pg / mL (-1672 to -268, p=0.0069). The frequency of adverse clinical events did not differ between groups.

[0125] Of 758 patients screened between March 17, 2014, and March 5, 2015, 448 were enrolled, of whom 149 were randomly assigned to the placebo group, 150 to the fixed-dose group, and 149 to the pharmacokinetic-dose-finding group (Figure 2). These groups were balanced for most baseline characteristics, and the majority of patients were receiving recommended pharmacologic therapy for chronic heart failure (Table 2). 285 patients (64%) had an implantable cardioverter-defibrillator, a cardiac resynchronization pacemaker, or both.

[0126] [Table 4]

[0127] [Table 5]

[0128] At week 8, the omecamtib mecarbil dose was titrated to 50 mg twice daily in 78 (53%) of 146 patients in the pharmacokinetic-titration group. At week 12, mean omecamtib mecarbil concentrations were 165 (SD 68) ng / mL in the fixed-dose group and 263 (116) ng / mL in the pharmacokinetic-titration group, with mean maximum concentrations of 200 (71) ng / mL and 318 (129) ng / mL, respectively (Table 3). At week 12, 63 (46%) of 137 patients with available measurements in the fixed-dose group and 110 (87%) of 127 in the pharmacokinetic-titration group had maximum plasma drug concentrations of 200 ng / mL or greater. Maximum concentrations were less than 1000 ng / mL in all patients; only one patient in the pharmacokinetic-titration group had a maximum concentration greater than 750 ng / mL. The maximum omecamtiv mecarbil concentration observed in plasma at any time during the study was 453 ng / mL in the fixed-dose group and 831 ng / mL in the pharmacokinetic-titration group.

[0129] [Table 6]

[0130] All prespecified secondary efficacy endpoints in the pharmacokinetic-titration group were significantly different from those in the placebo group at week 20 (Figure 3). Placebo-corrected increases at week 20 were seen in both omecamtiv mecarbil groups for systolic ejection fraction (11 ms, 95% CI 5-18, p=0.0007 in the fixed-dose group and 25 ms, 18-32, p<0.0001 in the pharmacokinetic-titration group) and stroke volume (5 mL, 2-8, p=0.0036 and 4 mL, 1-7, p=0.0217, respectively). Left ventricular end-systolic and end-diastolic diameters and heart rate were reduced in the pharmacokinetic-titration omecamtiv mecarbil group, but not in the fixed-dose group, compared with the placebo group at week 20. However, plasma NT-proBNP concentrations at week 20 decreased in both omecamtiv mecarbil groups (-822 pg / mL, 95% CI -1516 to -127, p=0.0205 in the fixed-dose group and -970 pg / mL, -1672 to 268, p=0.0069 in the pharmacokinetic-titrated group), which persisted for 4 weeks after omecamtiv mecarbil was discontinued (-1327 pg / mL, -2056 to -597, p=0.0004 and -1306 pg / mL, -2046 to -566, p=0.0006, respectively). Furthermore, decreases in left ventricular end-diastolic and end-systolic volumes and increases in fractional shortening were seen at week 20 in the pharmacokinetic-titrated group compared with placebo.

[0131] Similar proportions of patients in the three groups completed the course of study drug and placebo (Table 3). The frequencies of adverse events, serious adverse events, and deaths were similar across randomized groups. Approximately one-quarter of enrolled patients had plasma cardiac troponin I concentrations above the 99th percentile upper reference limit (0.04 ng / mL) at baseline, with proportions similar across groups. At week 20, cardiac troponin I concentrations increased in subjects receiving fixed-dose and titrated omecamtiv mecarbil compared with placebo. The median change from baseline was 0.001 ng / mL in the fixed-dose omecamtiv mecarbil group and 0.006 ng / mL in the pharmacokinetic-titrated group, with no change seen in the placebo group (Table 4). The maximum change from baseline at any time point during 20 weeks of treatment achieved significance in the omecamtiv mecarbil group compared with the placebo group (p = 0.0029 in the fixed-dose group and p < 0.0001 in the pharmacokinetic-titration group). Among these increases, 92% were < 0.1 ng / mL and 97% were < 0.2 ng / mL in patients assigned to omecamtiv mecarbil, compared with 95% and 97%, respectively, in patients assigned to placebo. Plasma concentrations of cardiac troponin I returned to baseline levels within 4 weeks of discontinuation of omecamtiv mecarbil. Maximum omecamtiv mecarbil concentrations were not well predicted by the maximum change from baseline in cardiac troponin I concentrations (Figure 4). Two hundred seventy-eight potential adverse events that caused increases in cardiac troponin I concentrations were submitted to a clinical events committee for review. None of these were considered to be myocardial ischemia or myocardial infarction.

[0132] [Table 7]

[0133] [Table 8]

[0134] In COSMIC-HF, target plasma drug concentrations were achievable with oral administration of omecamtiv mecarbil in patients with chronic heart failure and reduced ejection fraction, with nearly twice as many patients in the pharmacokinetic-titration group as in the fixed-dose group reaching target concentrations. Patients in the pharmacokinetic-titration group experienced increases in ventricular systolic ejection time duration and stroke volume, as well as decreases in left ventricular diameter and volume, NT-proBNP plasma concentrations, and heart rate compared with placebo. These effects on cardiac function were consistent with previous preclinical studies of short-term intravenous omecamtiv mecarbil. 4,5 and clinical trials 6~8 The results were similar to those seen in

[13] . No increase in the clinical occurrence of tachycardia, hypotension, atrial or ventricular arrhythmias, cardiac ischemia, or myocardial infarction was seen with the oral drug. The incidence of clinical adverse events in this study was similar for placebo and omecamtiv mecarbil, although safety assessments were limited by the small sample size, and patients receiving omecamtiv mecarbil had slightly elevated plasma concentrations of cardiac troponin I, which returned to baseline values ​​after treatment was discontinued. Our results support the hypothesis that direct and selective enhancement of systolic function can reduce myocardial wall load (indicated by a decrease in plasma NT-proBNP concentrations) and potentially sympathetic activation (indicated by a decrease in heart rate), and may promote favorable ventricular remodeling in patients with chronic heart failure and reduced ejection fraction.

[0135] Omecamtiv mecarbil is a selective cardiac myosin activator that binds to the motor domain of myosin, increasing the likelihood that actin filaments will productively bind together to generate force during systole. 4 This mechanism of action directly improves cardiac contractility by specifically modulating sarcomere function. In preclinical studies, omecamtiv mecarbil did not increase calcium transients in cardiomyocytes and has no known activity other than its effect on cardiac myosin that could explain its effects on cardiovascular function. Animal 4,5 and in humans, 6~8The pharmacodynamic property of omecamtiv mecarbil is an increase in systolic ejection duration, a result that reflects the drug's mechanism of action: an increase in the number of myosin heads interacting with actin filaments promotes a prolonged contraction duration even when cytosolic calcium concentrations are reduced in muscle cells.

[0136] Systolic ejection time in patients with systolic heart failure is 10-70 ms shorter than that in healthy controls. 14 The exact mechanism underlying this decrease in systolic ejection time is unknown, but the effect is proportional to the decrease in stroke volume. In an analysis of 2077 patients from the ARIC trial, 15 Decreased systolic ejection duration was directly related to decreased fractional shortening and predicted future risk of heart failure. Consistent with studies of intravenous administration in healthy volunteers and patients with acute and chronic heart failure, 6~8 Chronic oral administration of omecamtiv mecarbil in this study was associated with a prolongation of systolic ejection duration, with an average increase of 11 to 25 ms, resulting in a near-normal systolic ejection duration.

[0137] In modern models of the pathogenesis of heart failure, decline in systolic function triggers multiple pathophysiological adaptations, including activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system, as well as deleterious ventricular remodeling, leading to deterioration of cardiac function and symptoms. This hypothesis has been supported by studies in which blockade of the RAAS and sympathetic nervous system (e.g., with angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, mineralocorticoid receptor blockers, and beta-blockers) or enhancement of vasodilatory peptides (e.g., with neprilysin inhibitors) slowed or prevented the progression of heart failure. However, until now, pharmacological therapies have been available to test the hypothesis that direct and selective enhancement of cardiac function can also slow the progression of heart failure. Although our study was not designed to specifically test this hypothesis, 20 weeks of omecamtiv mecarbil administration was associated with decreases in left ventricular end-diastolic diameter and volume. Although ventricular diameter was not reassessed after omecamtiv mecarbil was discontinued, the reduction in plasma NT-proBNP concentrations persisted, suggesting that the effect on cardiac dimensions does not simply reflect a short-term direct effect on systolic function. 4,5 and clinical trials 6~8 The heart rate reduction associated with omecamtiv mecarbil in patients with HF is also consistent with reduced sympathetic activation. Thus, taken together, these results from COSMIC-HF appear to support the hypothesis that directly improving systolic function can reverse the maladaptive structural changes associated with the progression of heart failure.

[0138] In several previous trials, therapies that improved ventricular remodeling also had beneficial effects on clinical outcomes. In a meta-analysis of the relationship between drug- or device-related changes in ventricular volumes and mortality, 16 A mean reduction in end-diastolic or end-systolic volume of 11 mL was associated with a potential beneficial effect on mortality of 65-75%. 17A 5% reduction in ventricular volume was associated with a 14-20% reduction in the combined endpoint of death or hospital admission for heart failure. Plasma concentrations of natriuretic peptides are also strong predictors of adverse clinical outcomes, including cardiovascular death. 18,19 In some studies, it was a stronger predictor of clinical outcome than left ventricular ejection fraction or volume. 20 Similar changes were observed after treatment with omecamtiv mecarbil, and these results warrant further investigation of the effects of this drug on cardiovascular outcomes.

[0139] COSMIC-HF compared the ability of the two dosing strategies to produce well-tolerated plasma concentrations. Target plasma concentrations above 200 ng / mL were achieved in 110 of 127 patients (87%) with pharmacokinetic titration, compared with 63 of 137 patients (46%) who received fixed-dose omecamtiv mecarbil. Importantly, no patients in either group had plasma concentrations above 1000 ng / mL. However, a small and potentially concerning increase in plasma cardiac troponin I concentrations was observed in omecamtiv mecarbil recipients, which resolved after treatment was stopped. As shown in previous studies of patients with acute heart failure, these increases did not correlate with maximum omecamtiv mecarbil plasma concentrations. 8 The magnitude of troponin release was similar to that of healthy endurance athletes, 21 and within acceptable limits of diurnal variation for patients without heart failure. 22 None of the elevated cardiac troponin I concentrations was considered to be indicative of myocardial ischemia, and all occurred in association with improved contractile function, reduced ventricular volumes, and decreased plasma NT-proBNP concentrations. It is unclear whether elevated troponin I concentrations are related to myocardial injury or other mechanisms (e.g., exosome transport). 23 ), and the effect of omecamtiv mecarbir on clinical events will need to be addressed in large-scale outcome trials.

[0140] COSMIC-HF is a phase 2, pharmacokinetic study without formal hypothesis testing; therefore, the echocardiographic results should be considered hypothesis-generating. The study was prospectively powered and evaluated secondary efficacy endpoints of systolic ejection time, stroke volume, and left ventricular end-systolic diameter. All results in the pharmacokinetic-titrated omecamtiv mecarbil group for all prespecified secondary efficacy endpoints were significantly different from those in the placebo group, but no adjustments for multiple comparisons were made. With these caveats, our results support the hypothesis that direct and specific improvement of cardiac systolic function by a cardiac myosin activator leads to favorable ventricular remodeling. The effects on long-term morbidity and mortality were not tested, and the risks and benefits of omecamtiv mecarbil will only be able to be evaluated in a large-scale outcome trial.

[0141] This example demonstrates that pharmacokinetically guided dosing of omecamtiv mecarbil achieved plasma concentrations associated with improved cardiac function and reduced ventricular diameter.

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[0143] The following references are cited throughout Example 3: 1 Braunwald E, Ross J Jr, Sonnenblick EH. Mechanisms of contraction of the normal and failing heart.N Engl J Med 1967;277:1012-22. 2 Packer M.The search for the positive ideal inotropic agent.N Engl J Med 1993;329:201-02. 3 Hasenfuss G, Teerlink JR. Cardiac inotropes: current agents and future directions. Eur Heart J 2011;32:1838-45. 4 Malik FI,Hartman JJ,Elias KA,et al.Cardiac myosin activation:a potential therapeutic approach for systolic heart failure.Science 2011;331:1439-43. 5 Shen YT,Malik FI,Zhao X,et al.Improvement of cardiac function by a cardiac myosin activator in conscious dogs with systolic heart failure.Circ Heart Fail 2010;3:522-27. 6 Teerlink JR,Clarke CP,Saikali KG,et al.Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator,omecamtiv mecarbil:a first-in-man study.Lancet 2011;378:667-75. 7 Cleland JG,Teerlink JR,Senior R,et al.The effects of the cardiac myosin activator,omecamtiv mecarbil,on cardiac function in systolic heart failure:a double-blind,placebo-controlled,crossover,dose-ranging phase 2 trial.Lancet 2011;378:676-83. 8 Teerlink JR,Felker GM,McMurray JJV,et al.Acute treatment with omecamtiv mecarbil to increase contractility in acute heart failure:the ATOMIC AHF study.J Am Coll Cardiol 2016;67:1444-55. 9 Apple FS.A new season for cardiac troponin assays:it’s time to keep a scorecard.Clin Chem 2009;55:1303-06. 10 Thygesen K,Alpert JS,Jaffe AS,et al.Third universal definition of myocardial infarction.J Am Coll Cardiol 2012;60:1581-98. 11 Palaparthy R,Banfield C,Alvarez P,et al.Relative bioavailability,food effect,and safety of the single-dose pharmacokinetics of omecamtiv mecarbil following administration of different modified-release formulations in healthy subjects.Int J Clin Pharmacol Ther 2016;54:217-27. 12 Vu T,Ma P,Xiao JJ,Wang YM,Malik FI,Chow AT.Population pharmacokinetic-pharmacodynamic modeling of omecamtiv mecarbil,a cardiac myosin activator,in healthy volunteers and patients with stable heart failure.J Clin Pharmacol 2015;55:1236-47. 13 Greenberg BH,Chou W,Saikali KG,et al.Safety and tolerability of omecamtiv mecarbil during exercise in patients with ischemic cardiomyopathy and angina.JACC Heart Fail 2015;3:22-29. 14 Weissler AM,Harris WS,Schoenfeld CD.Systolic time intervals in heart failure in man.Circulation 1968;37:149-59. 15 Biering-Sorensen T,Roca GQ,et al.Systolic ejection time is an independent predictor of incident heart failure in a community based cohort free of heart failure.J Card Fail 2015;21:S84. 16 Kramer DG,Trikalinos TA,Kent DM,Antonopoulos GV,Konstam MA,Udelson JE.Quantitative evaluation of drug or device effects on ventricular remodeling as predictors of therapeutic effects on mortality in patients with heart failure and reduced ejection fraction:a meta-analytic approach.J Am Coll Cardiol 2010;56:392-406. 17 Solomon SD,Foster E,Bourgoun M,et al.Effect of cardiac resynchronization therapy on reverse remodeling and relation to outcome:multicenter automatic defibrillator implantation trial:cardiac resynchronization therapy.Circulation 2010;122:985-92. 18 Cleland JG,McMurray JJ,Kjekshus J,et al.Plasma concentration of amino-terminal pro-brain natriuretic peptide in chronic heart failure:prediction of cardiovascular events and interaction with the effects of rosuvastatin:a report from CORONA(Controlled Rosuvastatin Multinational Trial in Heart Failure).J Am Coll Cardiol 2009;54:1850-59. 19 Rahimi K,Bennett D,Conrad N,et al.Risk prediction in patients with heart failure:a systematic review and analysis.JACC Heart Fail 2014;2:440-46. 20 Cleland J, Freemantle N, Ghio S, et al. Predicting the long-term effects of cardiac resynchronization therapy on mortality from baseline variables and the early response a report from the CARE-HF(Cardiac Resynchronization in Heart Failure) Trial. J Am Coll Cardiol 2008;52:438-45. 21 Shave R, Baggish A, George K, et al.Exercise-induced cardiac troponin elevation: evidence, mechanisms, and implications.J Am Coll Cardiol 2010;56:169-76. 22 Klinkenberg LJ, van Dijk JW, Tan FE, van Loon LJ, van Dieijen-Visser MP, Meex SJ. Circulating cardiac troponin T exhibits a diurnal rhythm. J Am Coll Cardiol 2014;63:1788-95. 23 Waldenstrom A, Ronquist G. Role of exosomes in myocardial remodeling. Circ Res 2014;114:315-24.

[0144] All references, including publications, patent applications, and patents, cited in this specification are herein incorporated by reference to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and set forth in its entirety.

[0145] The use of the terms "a," "an," and "the" with respect to the description of this disclosure (and particularly with respect to the claims that follow) should be construed to encompass both the singular and the plural unless otherwise indicated herein or clearly contradicted by context. The terms "comprise," "have," "include," and "containing" should be construed as open-ended terms (i.e., meaning "including, but not limited to") unless otherwise specified.

[0146] The recitation of ranges of values ​​herein is merely a shorthand way of referring individually to each of the separate values ​​falling within that range, and each of the endpoints, unless otherwise indicated herein, and each separate value and endpoint is incorporated herein as if it were individually set forth herein.

[0147] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any examples or exemplary language (e.g., "etc.") provided herein is intended merely to further clarify the disclosure and does not impose limitations on the scope of the disclosure unless otherwise asserted. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

[0148] Preferred embodiments of the disclosure are described herein, including the best mode known to the inventors for carrying out the disclosure. Variations of these preferred embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors expect those skilled in the art to adopt such variations as necessary, and the inventors intend the disclosure to be practiced otherwise than as specifically described herein. Accordingly, this disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Furthermore, any combination of the above-described elements in all possible variations thereof is encompassed by the disclosure unless otherwise indicated or clearly contradicted by context.

Claims

1. 1. A method of treating a subject having heart failure (HF), comprising: a. administering to the subject an initial dose of a cardiac segment activator (CSA) over an initial period of time; b. subsequently administering to the subject a dose of the CSA based on the subject's plasma concentration of the CSA. A method comprising:

2. 10. The method of claim 1, wherein the subsequent doses administered to the subject are the same as or greater than the initial dose.

3. 3. The method of claim 2, wherein when the subject's plasma concentration of CSA exceeds a threshold concentration, the dose subsequently administered to the subject is the same as the initial dose, and optionally, the threshold concentration is about 1.0 to about 1.5 times the minimum of a target concentration range.

4. 4. The method of claim 2 or 3, wherein when the subject's plasma concentration of the CSA is at or above the minimum value of the target concentration range, the subsequently administered dose is the same as the initial dose.

5. 4. The method of claim 2 or 3, wherein when the subject's plasma concentration of the CSA is greater than or about 1.5 times the minimum value of the target concentration range, the subsequently administered dose is the same as the initial dose.

6. 3. The method of claim 2, wherein when the subject's plasma concentration of the CSA is below a threshold concentration, the subsequent dose administered to the subject is greater than the initial dose, and optionally, the threshold concentration is about 1.0 to about 1.5 times the minimum of a target concentration range.

7. 7. The method of claim 6, wherein the subsequently administered dose is greater than the initial dose when the subject's plasma concentration of the CSA is less than the minimum of the target concentration range.

8. 8. The method of claim 6 or 7, wherein when the subject's plasma concentration of CSA is less than 1.5 times the minimum value of the target concentration range but is greater than or about the minimum value of the target concentration range, the subsequently administered dose is greater than the initial dose but less than the maximum dose.

9. 9. The method of claim 6, wherein when the subject's plasma concentration of the CSA is less than the minimum value of the target concentration range, the subsequently administered dose is the maximum dose.

10. 10. The method of claim 8 or 9, wherein the maximum dose is about 2.0 times the initial dose.

11. 11. The method of any one of claims 1 to 10, wherein the maximum dose is from about 45 mg to about 75 mg.

12. 12. The method of claim 11, wherein the maximum dose is from about 45 mg to about 55 mg.

13. 13. The method of claim 12, wherein the maximum dose is about 50 mg.

14. 14. The method of any one of claims 8-13, wherein when the subject's plasma concentration of the CSA is less than 1.5 times the minimum value of the target concentration range but is greater than or at about the minimum value of the target concentration range, the subsequent dose administered to the subject is about 1.5 times the initial dose.

15. 15. The method of any one of claims 1-14, wherein when the subject's plasma concentration of CSA is less than 1.5 times the minimum value of the target concentration range but greater than or at about the minimum value of the target concentration range, the dose subsequently administered to the subject is greater than about 30 mg and less than about 45 mg.

16. 16. The method of claim 15, wherein when the subject's plasma concentration of CSA is less than 1.5 times the minimum value of the target concentration range but is greater than or at about the minimum value of the target concentration range, the dose subsequently administered to the subject is about 35 mg to about 40 mg.

17. 17. The method of claim 16, wherein when the subject's plasma concentration of CSA is less than 1.5 times the minimum value of the target concentration range but is greater than or at about the minimum value of the target concentration range, the dose subsequently administered to the subject is about 37.5 mg.

18. 18. The method of any one of claims 1 to 17, wherein the initial dose is a minimum effective dose (MED) of the CSA.

19. 19. The method of claim 18, wherein the MED is from about 20 mg to about 30 mg.

20. 20. The method of claim 19, wherein the MED is about 25 mg.

21. 21. The method of any one of claims 1-20, wherein the CSA reaches a steady state in the subject by the end of the initial period of time.

22. 22. The method of any one of claims 1 to 21, wherein the initial period of time is about 1 to 3 weeks.

23. 23. The method of claim 22, wherein the initial period of time is at least or about two weeks.

24. 24. The method of any one of claims 1 to 23, wherein the target concentration range is from about 200 ng / mL to about 1200 ng / mL.

25. 25. The method of any one of claims 1 to 24, wherein the target concentration range is from about 200 ng / mL to about 1000 ng / mL.

26. 26. The method of claim 25, wherein the target concentration range is about 200 ng / mL to about 1000 ng / mL, the MED is about 25 mg, and the maximum dose is about 50 mg.

27. 1. A method of treating a subject having heart failure (HF), comprising: (a) administering to the subject an initial dose of a cardiac segment activator (CSA) over an initial period of time; and (b) subsequently administering to the subject: (i) about 25 mg of the CSA when the subject's plasma concentration is greater than or about 300 ng / mL, (ii) about 37.5 mg of the CSA when the subject's plasma concentration is greater than or about 200 ng / mL but less than 300 ng / mL, or (iii) about 50 mg when the subject's plasma concentration is less than 200 ng / mL.

28. The method of any one of claims 1 to 27, wherein the subject has chronic heart failure.

29. 29. The method of any one of claims 1 to 28, wherein the subject has New York Heart Association Class II or III heart failure.

30. 30. The method of any one of claims 1 to 29, wherein the subject has a left ventricular ejection fraction of about 40% or less.

31. The method of any one of claims 1 to 30, wherein the subject has a plasma concentration of NT-proBNP of at least about 200 pg / mL.

32. The method of any one of claims 1 to 31, wherein the CSA is an activator of cardiac myosin.

33. 34. The method of claim 33, wherein the activator of cardiac myosin is omecamtiv mecarbil (OM).

34. 33. The method of claim 32, wherein the OM is omecamtiv mecarbil dihydrochloride hydrate.

35. 35. The method of claim 33 or 34, comprising administering to the subject an initial dose of about 25 mg of OM for at least about two weeks.

36. 36. The method of any one of claims 33-35, wherein the first dose of OM is administered orally to the subject.

37. 37. The method of any one of claims 33-36, wherein the initial dose of OM is administered to the subject twice daily.

38. 38. The method of any one of claims 33 to 37, wherein the subsequent doses are given to the subject twice daily.

39. 39. The method of any one of claims 33 to 38, wherein the subsequent doses administered to the subject are administered orally to the subject.

40. 40. The method of any one of claims 33-39, comprising: (a) administering an initial dose of OM to the subject over an initial period of time; and (b) subsequently administering to the subject: (i) about 25 mg of OM when the subject's plasma concentration of OM is greater than or about 300 ng / mL, (ii) about 37.5 mg of COMSA when the subject's plasma concentration of OM is greater than or about 200 ng / mL but less than 300 ng / mL, and (iii) about 50 mg of OM when the subject's plasma concentration of OM is less than 200 ng / mL.

41. 41. The method of any one of claims 1 to 40, comprising determining the plasma concentration of the CSA after the first period of time.

42. 42. The method of claim 41, comprising determining a first plasma concentration of the CSA after the initial period of time, and determining a second plasma concentration of the CSA after the subject has taken at least one subsequent dose of the CSA.

43. 43. The method of any one of claims 1 to 42, wherein the plasma concentration is determined by performing an LC-MS / MS or quantitative microsphere assay.

44. 1. A method for determining a therapeutic regimen for a subject, comprising: (a) administering to the subject a minimally effective dose (MED) dose of a cardiac segment activator (CSA) over an initial period of time, wherein the CSA reaches a steady state in the subject by the end of the initial period; (b) determining the subject's plasma concentration of the CSA at the end of the initial period; and (c) determining a therapeutic regimen based on the subject's plasma concentration of the CSA.

45. 45. The method of claim 44, comprising determining a treatment regimen based on the subject's steady-state plasma concentration of the CSA.

46. 46. ​​The method of claim 44 or 45, wherein the treatment regimen comprises a dose administered to the subject after the initial period of time that is the same as or greater than the initial dose.

47. 47. The method of claim 46, wherein the dose administered to the subject after the initial period of time is the same as the initial dose when the subject's plasma concentration of CSA is above a threshold concentration, and optionally, the threshold concentration is about 1.0 to about 1.5 times the minimum of a target concentration range.

48. 48. The method of claim 47, wherein when the subject's plasma concentration of the CSA is at or above the minimum value of a target concentration range, the dose administered to the subject after the initial period of time is the same as the initial dose.

49. 48. The method of claim 47, wherein when the subject's plasma concentration of the CSA is greater than or about 1.5 times the minimum value of the target concentration range, the dose administered to the subject after the initial period is the same as the initial dose.

50. 47. The method of claim 46, wherein the dose administered to the subject after the initial period of time is greater than the initial dose when the subject's plasma concentration of the CSA is less than a threshold concentration, and optionally, the threshold concentration is about 1.0 to about 1.5 times the minimum of a target concentration range.

51. 51. The method of claim 50, wherein the dose administered to the subject after the initial period of time is greater than the initial dose when the subject's plasma concentration of the CSA is less than the minimum of the target concentration range.

52. 51. The method of claim 50, wherein when the subject's plasma concentration of CSA is less than 1.5 times the minimum value of the target concentration range but greater than or at about the minimum value of the target concentration range, the dose administered to the subject after the initial period of time is greater than the initial dose but less than the maximum dose.

53. 53. The method of any one of claims 50-52, wherein when the subject's plasma concentration of the CSA is less than the minimum value of the target concentration range, the dose administered to the subject after the initial period of time is the maximum dose.

54. 54. The method of claim 52 or 53, wherein the maximum dose is about 2.0 times the initial dose.

55. 55. The method of any one of claims 52 to 54, wherein the maximum dose is from about 45 mg to about 75 mg.

56. 56. The method of claim 55, wherein the maximum dose is from about 45 mg to about 55 mg.

57. 57. The method of claim 56, wherein the maximum dose is about 50 mg.

58. 58. The method of any one of claims 52-57, wherein when the subject's plasma concentration of the CSA is less than 1.5 times the minimum value of the target concentration range but is greater than or at about the minimum value of the target concentration range, the dose administered to the subject after the initial period of time is about 1.5 times the initial dose.

59. 59. The method of any one of claims 52-58, wherein when the subject's plasma concentration of CSA is less than 1.5 times the minimum value of the target concentration range but greater than or at about the minimum value of the target concentration range, the dose administered to the subject after the initial period of time is greater than about 30 mg and less than about 45 mg.

60. 60. The method of claim 59, wherein when the subject's plasma concentration of CSA is less than 1.5 times the minimum value of the target concentration range but greater than or at about the minimum value of the target concentration range, the dose administered to the subject after the initial period of time is about 35 mg to about 40 mg.

61. 61. The method of claim 60, wherein when the subject's plasma concentration is less than 1.5 times the minimum value of the target concentration range but greater than or at about the minimum value of the target concentration range, the dose administered to the subject after the first period of time is about 37.5 mg.

62. 62. The method of any one of claims 44-61, wherein the initial dose is the minimum effective dose (MED) of the CSA.

63. 63. The method of claim 62, wherein the MED is from about 20 mg to about 30 mg.

64. 64. The method of claim 63, wherein the MED is about 25 mg.

65. 65. The method of any one of claims 44-64, wherein the CSA reaches a steady state in the subject by the end of the initial period of time.

66. 66. The method of any one of claims 44 to 65, wherein the initial period of time is about 1 to 3 weeks.

67. 66. The method of claim 65, wherein the period is at least or about two weeks.

68. 68. The method of any one of claims 44 to 67, wherein the target concentration range is from about 200 ng / mL to about 1200 ng / mL.

69. 69. The method of any one of claims 44 to 68, wherein the target concentration range is from about 200 ng / mL to about 1000 ng / mL.

70. 70. The method of claim 69, wherein the target concentration range is about 200 ng / mL to about 1000 ng / mL, the MED is about 25 mg, and the maximum dose is about 50 mg.

71. 71. The method of claim 70, wherein the treatment regimen comprises: (i) about 25 mg of CSA when the subject's plasma concentration of CSA is greater than or about 300 ng / mL, (ii) about 37.5 mg of CSA when the subject's plasma concentration of CSA is greater than or about 200 ng / mL but less than 300 ng / mL, or (iii) about 50 mg when the subject's plasma concentration of CSA is less than 200 ng / mL.

72. 72. The method of any one of claims 44 to 71, wherein the subject has chronic heart failure.

73. 73. The method of any one of claims 44-72, wherein the subject has New York Heart Association Class II or III heart failure.

74. 74. The method of any one of claims 44 to 73, wherein the subject has a left ventricular ejection fraction of about 40% or less.

75. 75. The method of any one of claims 44 to 74, wherein the subject has a plasma concentration of NT-proBNP of at least about 200 pg / mL.

76. The method of any one of claims 44 to 75, wherein the CSA is an activator of cardiac myosin.

77. 77. The method of claim 76, wherein the activator of cardiac myosin is omecamtiv mecarbil (OM).

78. 78. The method of claim 77, wherein the OM is omecamtiv mecarbil dihydrochloride hydrate.

79. 79. The method of claim 77 or 78, wherein the initial dose is about 25 mg and the initial period is at least about 2 weeks.

80. 80. The method of any one of claims 77-79, wherein the first dose of OM is administered orally to the subject.

81. 81. The method of any one of claims 77-80, wherein the initial dose of OM is administered to the subject twice daily.

82. 82. The method of any one of claims 77-81, wherein the subsequently administered doses are given to the subject twice daily.

83. 83. The method of any one of claims 77 to 82, wherein the subsequent doses administered to the subject are administered orally to the subject.

84. 84. The method of any one of claims 77-83, wherein the treatment regimen comprises: (i) about 25 mg of OM when the subject's plasma concentration of OM is greater than or about 300 ng / mL, (ii) about 37.5 mg of OM when the subject's plasma concentration of OM is greater than or about 200 ng / mL but less than 300 ng / mL, or (iii) about 50 mg of OM when the subject's plasma concentration of OM is less than 200 ng / mL.

85. 85. The method of any one of claims 44-84, comprising determining a first plasma concentration of the CSA after the initial period of time, and determining a second plasma concentration of the CSA after the subject has taken at least one subsequent dose of the CSA.

86. 86. The method of any one of claims 44 to 85, wherein the plasma concentration of the CSA is determined by performing an LC-MS / MS or quantitative microsphere assay.

87. 1. A method of treating a subject with heart failure (HF), comprising: (a) administering to the subject an initial series of doses of omecamtib mecarbil (OM) twice daily via oral administration for an initial period of about 4 weeks, wherein each initial dose is about 25 mg; and (b) administering to the subject a subsequent series of doses of OM twice daily via oral administration for a second period following the initial period, wherein each subsequent dose (i) is administered from the beginning of the initial period (ii) about 25 mg when the subject's plasma concentration measured at about two weeks is greater than or about 300 ng / mL, (ii) about 37.5 mg when the subject's plasma concentration measured at about two weeks from the beginning of the first period is greater than or about 200 ng / mL but less than 300 ng / mL, or (iii) about 50 mg when the subject's plasma concentration measured at about two weeks from the beginning of the first period is less than 200 ng / mL.

88. 88. The method of claim 87, further comprising measuring the subject's plasma concentration at about two weeks from the beginning of the initial period.

89. 89. The method of claim 87 or 88, wherein the second period of time is about 4 weeks after the first period of time.

90. 90. The method of any one of claims 87-89, further comprising administering a subsequent series of doses of OM to the subject twice daily via oral administration for a third time period following the second time period, wherein each subsequent dose administered during the third time period is based on the subject's plasma concentration measured at about 6 weeks from the beginning of the first time period.

91. a. when the subject's plasma concentration measured at about 6 weeks from the beginning of the first time period is less than 750 ng / mL, each dose during the third time period is about the same as the subsequent dose during the second time period; b. when the subject's plasma concentration measured at about 6 weeks from the beginning of the first period is greater than or about 750 ng / mL and less than 1000 ng / mL, and the subsequent dose administered during the second period is 25 mg or 37.5 mg, then each dose during the third period is about 25 mg; c. when the subject's plasma concentration measured at about 6 weeks from the beginning of the first period is greater than or about 750 ng / mL and less than 1000 ng / mL, and the subsequent dose administered during the second period is about 50 mg, each dose during the third period is about 37.5 mg; d. when the subject's plasma concentration measured at about 6 weeks from the beginning of the first period is greater than or about 1000 ng / mL and the subsequent dose administered during the second period is about 25 mg, then each dose during the third period is about 0 mg; and e. The method of claim 90, wherein when the subject's plasma concentration measured about 6 weeks from the beginning of the first time period is greater than or about 1000 ng / mL and the subsequent dose administered during the second time period is about 37.5 mg or about 50 mg, each dose during the third time period is about 25 mg.

92. 92. The method of any one of claims 87-91, further comprising measuring the subject's plasma concentration at about 6 weeks from the beginning of the initial period.

93. 93. The method of any one of claims 90-92, wherein the third period of time is at least or about 4 weeks after the second period of time.

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