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WO2024081611A1 - Methods for treating heart failure by administering cardiac sarcomere activators - Google Patents

Methods for treating heart failure by administering cardiac sarcomere activators Download PDF

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Publication number
WO2024081611A1
WO2024081611A1 PCT/US2023/076419 US2023076419W WO2024081611A1 WO 2024081611 A1 WO2024081611 A1 WO 2024081611A1 US 2023076419 W US2023076419 W US 2023076419W WO 2024081611 A1 WO2024081611 A1 WO 2024081611A1
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csa
subject
dose level
symptoms
signs
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Fady Malik
Polina GERMAN
Stuart KUPFER
Stephen B. HEITNER
Punag DIVANJI
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Cytokinetics Inc
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Cytokinetics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/465—Nicotine; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the cardiac sarcomere is the basic unit of muscle contraction in the heart.
  • the cardiac sarcomere is a highly ordered cytoskeletal structure composed of cardiac muscle myosin, actin and a set of regulatory proteins.
  • cardiac muscle myosin activators would lead to promising treatments for acute and chronic heart failure.
  • Cardiac muscle myosin is the cytoskeletal motor protein in the cardiac muscle cell. It is directly responsible for converting chemical energy into the mechanical force, resulting in cardiac muscle contraction.
  • Omecamtiv mecarbil is a first in class, small molecule cardiac myosin activator, which is a type of myotrope that acts directly on the muscle fiber.
  • Omecamtiv mecarbil augments cardiac contractility by selectively binding to cardiac myosin increasing the number of force generators (myosin heads) that can bind to the actin filament and undergo a powerstroke once the cardiac cycle starts.
  • myosin heads force generators
  • omecamtiv mecarbil In patients with chronic heart failure with reduced ejection fraction, treatment with omecamtiv mecarbil for 20 weeks increased left ventricular systolic function, decreased left ventricular systolic and diastolic volumes suggestive of beneficial reverse cardiac remodeling, and reduced natriuretic peptide concentrations and heart rate.
  • HFrEF heart failure with reduced ejection fraction
  • Myotropes represent a new class of drugs that improve myocardial function by directly augmenting cardiac sarcomere function.
  • the cardiac myosin activator, omecamtiv mecarbil is the first of this class and it increases systolic function by selectively facilitating the actin-myosin interaction, increasing contractile force without altering the cardiomyocyte calcium transient.
  • HF with reduced ejection fraction (HFrEF) remains a progressive clinical syndrome and many patients develop worsening over time despite optimal guideline-based treatment. Regardless of terminology, these patients have a high burden of symptoms, recurrent HF hospitalizations, high mortality, and account for a large proportion of the total costs of HF care.
  • RAAS renin-angiotensin-aldosterone system
  • Selected patients with advanced HF may be candidates for other therapies such as cardiac transplantation or mechanical cardiac support, but these therapies are costly, highly invasive, and have limited availability.
  • Intravenous inotropic therapy can be used for palliation of symptoms in selected patients but may be associated with increased mortality.
  • a method of treating heart failure in a subject in need thereof comprising: a) administering to the subject a first dose level of a cardiac sarcomere activator (CSA) for an initial period of time; and b) administering to the subject a second dose level of the CSA for a second period of time, wherein the second dose level is greater than the first dose level, wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof, and wherein administering the CSA is withheld if the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction.
  • CSA cardiac sarcomere activator
  • the method further comprises step c) administering to the subject a third dose level of the CSA, wherein the third dose level is greater than the second dose level, wherein the method does not include taking a blood sample from the subject to determine the plasma concentration of the CSA, and wherein administering the CSA is withheld if the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction.
  • Also provided herein is a method of treating heart failure in a subject in need thereof, comprising: a) administering to the subject a first dose level of a cardiac sarcomere activator (CSA) for an initial period of time; and b) administering to the subject a second dose level of the CSA in accordance with a determination that the subject has not experienced one or more signs or symptoms of acute myocardial ischemia or myocardial infarction, wherein the second dose level is greater than the first dose level, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the first administration of the first dose level of the CSA, and wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof.
  • CSA cardiac sarcomere activator
  • Also provided herein is a method of treating heart failure in a subject in need thereof, comprising: a) administering to the subject a first dose level of a cardiac sarcomere activator (CSA) for an initial period of time; and b) administering to the subject a second dose level of the CSA in accordance with a determination that one or more signs or symptoms of acute myocardial ischemia or myocardial infarction experienced by the subject are not associated with the CSA, wherein the second dose level is about the same as the first dose level, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the first administration of the first dose level of the CSA, and wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof.
  • CSA cardiac sarcomere activator
  • CSA cardiac sarcomere activator
  • a method of treating heart failure in a subject in need thereof comprising: a) administering to the subject a first dose level of a cardiac sarcomere activator (CSA) for an initial period of time; and b) discontinuing the administration in accordance with a determination that one or more signs or symptoms of acute myocardial ischemia or myocardial infarction experienced by the subject are associated with the CSA, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the first administration of the first dose level of the CSA, and wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof.
  • CSA cardiac sarcomere activator
  • Figure 1 A shows the primary endpoint in the patient population evaluated, wherein the primary endpoint was the composite of time to a heart failure event or cardiovascular death, whichever occurred first.
  • Figure IB shows the incidence of cardiovascular death in the patient population evaluated.
  • Figure 1C shows the incidence of heart failure events in the patient population evaluated.
  • Figure ID shows the incidence of all deaths in the patient population evaluated.
  • Figure 2A, 2B, and 2C show the primary outcome of the trial as a composite of heart failure event or cardiovascular death, according to subgroups that were prespecified in the protocol. Race was self-reported by patients. Baseline NT-proBNP subgroups exclude subjects in atrial fibrillation/flutter at screening.
  • Figure 3 shows a multiplicity testing propagation approach.
  • Figure 4 shows a design of a clinical trial of omecamtiv mecarbil.
  • Figure 5 shows progressively greater improvement in the primary composite endpoint (PCE) with decreasing left ventricular ejection fraction (LVEF) as indicated by the continuously improving hazard ratio.
  • Figure 6 shows the incidence of the primary composite endpoint (PCE) increased with decreasing ejection fraction (EF) and omecamtiv mecarbil (circles) producing increasing greater absolute reductions in the PCE with decreasing EF as compared to placebo (stars).
  • Figure 8 shows the difference in the incidence of the primary composite endpoint increased disproportionately between the placebo (stars) and omecamtiv mecarbil (circles) treatment groups with lower ejection fractions.
  • Figure 9 shows that absolute risk reduction by omecamtiv mecarbil progressively increased with decreasing ejection fraction (EF).
  • Figure 10 shows the beneficial effect of treatment with omecamtiv mecarbil on the primary outcome was driven predominantly by the significant reduction in heart failure events.
  • Figure 11 shows the incidence rate of heart failure hospitalizations increases with decreasing ejection fraction in both the placebo (stars) and omecamtiv mecarbil (circles) treated patients, but was significantly impacted by treatment with omecamtiv mecarbil, and showed a progressively greater reduction in the absolute difference with decreasing ejection fraction.
  • Figure 12A shows OM had no overall effect on cardiovascular death, neither in the overall population, nor as a function of baseline ejection fraction (EF).
  • Figure 12B shows OM the incidence of cardiovascular death increased comparably in both the placebo (stars) and omecamtiv mecarbil (circles) arms with decreasing ejection fraction (EF).
  • Figure 13A shows the distribution of baseline ejection fractions in GALACTIC -HF.
  • Figure 13B shows the distribution of ejection fractions in GALACTIC-HF.
  • Figure 14A shows Kaplan-Meier curves comparing patients with and without more advanced heart failure (HF) for each endpoint (CV Death or HF event)
  • Figure 14B shows Kaplan-Meier curves comparing patients with and without more advanced heart failure (HF) for each endpoint (CV Death).
  • Figure 15A shows event rates for primary endpoints by treatment assignment and advanced heart failure (HF) criteria met (specific advanced HF criteria).
  • HF advanced heart failure
  • Figure 15B shows shows event rates for primary endpoints by treatment assignment and advanced heart failure (HF) criteria met (total number of advanced HF criteria met).
  • HF advanced heart failure
  • Figure 16A shows outcomes according to baseline NT-proBNP in the prespecified analysis population (no atrial fibrillation/flutter at baseline) randomized (primary composite outcome) (placebo - stars; omecamtiv mecarbil - circles).
  • Figure 16B shows outcomes according to baseline NT-proBNP in the prespecified analysis population (no atrial fibrillation/flutter at baseline) randomized (HF hospitalization) (placebo - stars; omecamtiv mecarbil - circles).
  • Figure 16C shows outcomes according to baseline NT-proBNP in the prespecified analysis population (no atrial fibrillation/flutter at baseline) randomized (CV death) (placebo - stars; omecamtiv mecarbil - circles).
  • Figure 16D shows outcomes according to baseline NT-proBNP in the prespecified analysis population (no atrial fibrillation/flutter at baseline) randomized (all-cause mortality) (placebo - stars; omecamtiv mecarbil - circles).
  • Figure 17A shows outcomes according to baseline NT-proBNP in the prespecified analysis population in all patients randomized (primary composite outcome) (placebo - stars; omecamtiv mecarbil - circles).
  • Figure 17B shows outcomes according to baseline NT-proBNP in the prespecified analysis population in all patients randomized (HF hospitalization) (placebo - stars; omecamtiv mecarbil - circles).
  • Figure 17C shows outcomes according to baseline NT-proBNP in the prespecified analysis population in all patients randomized (CV death) (placebo - stars; omecamtiv mecarbil - circles).
  • Figure 17D shows outcomes according to baseline NT-proBNP in the prespecified analysis population in all patients randomized (all-cause mortality) (placebo - stars; omecamtiv mecarbil - circles).
  • Figure 18A shows effect of randomized treatment on outcomes according to baseline NT-proBNP concentration (shown as a continuous measure) in the prespecified analysis population (no atrial fibrillation/flutter at baseline) randomized (primary composite outcome).
  • Figure 18B shows effect of randomized treatment on outcomes according to baseline NT-proBNP concentration (shown as a continuous measure) in the prespecified analysis population (no atrial fibrillation/flutter at baseline) randomized (HF hospitalization).
  • Figure 18C shows effect of randomized treatment on outcomes according to baseline NT-proBNP concentration (shown as a continuous measure) in the prespecified analysis population (no atrial fibrillation/flutter at baseline) randomized (CV death).
  • Figure 18D shows effect of randomized treatment on outcomes according to baseline NT-proBNP concentration (shown as a continuous measure) in the prespecified analysis population (no atrial fibrillation/flutter at baseline) randomized (all cause mortality).
  • Figure 19A shows effect of randomized treatment on outcomes according to baseline NT-proBNP concentration (shown as a continuous measure) in the prespecified analysis population in all patients randomized (primary composite outcome).
  • Figure 19B shows effect of randomized treatment on outcomes according to baseline NT-proBNP concentration (shown as a continuous measure) in the prespecified analysis population in all patients randomized (HF hospitalization).
  • Figure 19C shows effect of randomized treatment on outcomes according to baseline NT-proBNP concentration (shown as a continuous measure) in the prespecified analysis population in all patients randomized (CV death).
  • Figure 19D shows effect of randomized treatment on outcomes according to baseline NT-proBNP concentration (shown as a continuous measure) in the prespecified analysis population in all patients randomized (all cause mortality).
  • Figure 20A shows effect of omecamtiv mecarbil, compared with placebo, on NT- proBNP after randomization in the prespecified analysis population (no atrial fibrillation/flutter at baseline and all NT-proBNP concentrations).
  • Figure 20B shows effect of omecamtiv mecarbil, compared with placebo, on NT- proBNP after randomization in the prespecified analysis population (no atrial fibrillation/flutter at baseline, NT-proBNP > median).
  • Figure 20C shows effect of omecamtiv mecarbil, compared with placebo, on NT- proBNP after randomization in the prespecified analysis population (no atrial fibrillation/flutter at baseline, NT-proBNP ⁇ median).
  • Figure 20D shows effect of omecamtiv mecarbil, compared with placebo, on NT- proBNP in all patients randomized (all NT-proBNP concentrations).
  • Figure 20E shows effect of omecamtiv mecarbil, compared with placebo, on NT- proBNP in all patients randomized (NT-proBNP > median).
  • Figure 20F shows effect of omecamtiv mecarbil, compared with placebo, on NT- proBNP in all patients randomized (NT-proBNP ⁇ median).
  • Figure 21 A shows the proportion of patients having AFF as a function of the percentage of LVEF.
  • Figure 2 IB shows effect of omecamtiv mecarbil in patients with or without AFF who were or were not receiving digoxin.
  • Figure 21C shows the effect of omecamtiv mecarbil in patients with or without AFF on mortality, for cardiovascular death or all-cause death, and heart failure hospitalization.
  • Figure 2 ID shows the effect of omecamtiv mecarbil in patients with or without AFF who were or were not receiving digoxin on mortality, for cardiovascular death or all-cause death, and heart failure hospitalization.
  • Figure 2 IE shows the effect of omecamtiv mecarbil in patients with AFF as compared to placebo on the occurrence of serious adverse events.
  • Figure 2 IF shows arithmetic mean pharmacokinetic concentration-time profiles for digoxin administration alone and digoxin administration with omecamtiv mecarbil.
  • Figure 21G shows geometric mean pharmacokinetic parameters for digoxin administration alone and digoxin administration with omecamtiv mecarbil.
  • Figure 22 shows Kaplan-Meier curves for primary composite endpoint by EF quartile.
  • Figure 23 A shows outcomes according to baseline systolic blood pressure (SBP) in all patients randomized (primary composite outcome) (placebo - stars; omecamtiv mecarbil - circles).
  • Figure 23B shows the treatment effect of omecamtiv mecarbil on primary composite outcomes according to baseline systolic blood pressure (SBP).
  • Figure 24 shows the incidence of stroke (fatal and non-fatal stroke events) in all patients randomized.
  • Figure 25 shows the treatment effect of omecamtiv mecarbil in patients with or without a history of stroke as compared to placebo on the occurrence of stroke (fatal and non- fatal stroke events) (placebo - stars; omecamtiv mecarbil - circles).
  • Figure 26 shows the treatment effect of omecamtiv mecarbil in patients with or without a history of atrial fibrillation as compared to placebo on the occurrence of stroke (fatal and non-fatal stroke events) (placebo - stars; omecamtiv mecarbil - circles).
  • Figure 27 shows the treatment effect of omecamtiv mecarbil in patients without an atrial fibrillation / atrial flutter (AFF) at screening and those without a history of AFF as compared to placebo on the occurrence of new-onset AFF (placebo - stars; omecamtiv mecarbil - circles).
  • AFF atrial fibrillation / atrial flutter
  • Described herein are methods of treating heart failure using a cardiac sarcomere activator (e.g., omecamtiv mecarbil or a pharmaceutically acceptable salt and/or hydrate thereof). Treatment methods may include adjusting a dose level, for example to increase, decrease, maintain, or discontinue a dose level, based on one or more signs or symptoms of acute myocardial ischemia or myocardial infarction e.g., chest pain, shortness of breath, and/or unstable angina).
  • CSA cardiac sarcomere activator
  • a dose level of the CSA may be increased without taking a blood sample from the subject if the subject does not experience signs or symptoms of acute myocardial ischemia or myocardial infarction, including but not limited to, chest pain and shortness of breath.
  • Reference to “about” a value or parameter herein includes (and describes) that value or parameter per se, and any value or parameter 5% above or 5% below said parameter.
  • description to “about X” includes description of “X” and “X +/- 5%”.
  • NYHA classification or “NYHA class” refers to the New York Heart Association functional classification of heart failure symptoms. Descriptions of each of NYHA classes I, II, III, and IV can be found in “Classes of Heart Failure”, American Heart Association, https://www.heart.org/en/health-topics/heart-failure/what-is-heart-failure/classes-of-heart- failure, adapted from: 1) Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart Association. Criteria Committee. “Nomenclature and criteria for diagnosis of diseases of the heart and great vessels”. 9th ed.
  • NYHA class I indicates that the patient has no limitation of physical activity; ordinary physical activity does not cause undue fatigue, palpitation, dyspnea (shortness of breath).
  • NYHA class II indicates that the patient has slight limitation of physical activity; comfortable at rest; ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of breath).
  • NYHA class III indicates that the patient has marked limitation of physical activity; comfortable at rest; less than ordinary physical activity causes fatigue, palpitation, or dyspnea.
  • NYHA class IV indicates that the patient is unable to carry on any physical activity without discomfort; symptoms of heart failure at rest; if any physical activity is undertaken, discomfort increases.
  • pharmaceutically acceptable salt refers to a salt of any of the compounds herein that are known to be non-toxic and are commonly used in the pharmaceutical literature.
  • the pharmaceutically acceptable salt of a compound retains the biological effectiveness of the compounds described herein and are not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, p- toluenesulfonic acid, stearic acid and salicylic acid.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines including naturally occurring substituted amines; cyclic amines; and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds (see, e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19).
  • bases compounds see, e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.
  • the terms “patient,” “individual,” and “subject” refer to an animal, such as a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows and humans. In some embodiments, the patient or subject is a human, for example a human that has been or will be the object of treatment, observation or experiment. The compounds, compositions and methods described herein can be useful in both human therapy and veterinary applications.
  • therapeutically effective amount refers to that amount of a compound disclosed and/or described herein that is sufficient to affect treatment, as defined herein, when administered to a patient in need of such treatment.
  • a therapeutically effective amount of a compound may be an amount sufficient to treat a disease responsive to modulation of the cardiac sarcomere.
  • the therapeutically effective amount will vary depending upon, for example, the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound, the dosing regimen to be followed, timing of administration, the manner of administration, all of which can readily be determined by one of ordinary skill in the art.
  • the therapeutically effective amount may be ascertained experimentally, for example by assaying blood concentration of the chemical entity, or theoretically, by calculating bioavailability.
  • Treatment includes one or more of: inhibiting a disease or disorder; slowing or arresting the development of clinical symptoms of a disease or disorder; and/or relieving a disease or disorder (i.e., causing relief from or regression of clinical symptoms).
  • the term covers both complete and partial reduction or prevention of the condition or disorder, and complete or partial reduction of clinical symptoms of a disease or disorder.
  • compounds described and/or disclosed herein may prevent an existing disease or disorder from worsening, assist in the management of the disease or disorder, or reduce or eliminate the disease or disorder.
  • Reference to any dose amount of a compound or pharmaceutically acceptable salt thereof described herein refers to the amount (e.g., equivalent mass) of said compound without any salt (e.g., omecamtiv mecarbil anhydrous free base).
  • a CSA induces the activation of by, e.g., sensitizing cardiac myofilaments to Ca2+, activating troponin or tropomyosin, or directly activating the cardiac myosin.
  • a CSA promotes sarcomere responsiveness to calcium (Ca2+).
  • the CSA is omecamtiv mecarbil or a pharmaceutically acceptable salt (e.g., omecamtiv mecarbil hydrochloride salt) or a pharmaceutically acceptable hydrate of a pharmaceutically acceptable salt (e.g, omecamtiv mecarbil dihydrochloride hydrate).
  • Omecamtiv mecarbil also known as CK-1827452 or AMG 423, is a first in class direct activator of cardiac myosin that directly targets the contractile mechanisms of cardiac myocytes intended to enhance efficiency of myocardial contraction in patients suffering from a cardiovascular condition, such as heart failure.
  • the free base of omecamtiv mecarbil is described chemically as methyl 4-(2-fluoro-3-(3-(6-methylpyridin-3- yl)ureido)benzyl)piperazine-l -carboxylate having the structural formula:
  • Omecamtiv mecarbil is disclosed in U.S. Patent No. 7,507,735 titled “Compounds, Compositions and Method”, the entirety of which is incorporated herein by reference.
  • omecamtiv mecarbil and method of making omecamtiv mecarbil can be found in, e.g., Example 3 column 55 and 56 of the above referenced patent, which are incorporated herein by reference.
  • Omecamtiv mecarbil was the subject of several Phase 2 clinical trials, including Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF), which evaluated omecamtiv mecarbil in patients with chronic heart failure and left ventricular systolic dysfunction (see, e.g., NCT01786512).
  • COSMIC-HF Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure
  • GALACTIC-HF Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure
  • was a Phase 3 global cardiovascular outcomes study which demonstrated a statistically significant effect of treatment with omecamtiv mecarbil to reduce risk of the primary composite endpoint of cardiovascular death or heart failure events compared to placebo in patients treated with standard of care (see, e.g., NCT02929329).
  • Omecamtiv mecarbil may be in the form of a salt or a hydrate of a salt, such as omecamtiv mecarbil dihydrochloride hydrate or omecamtiv mecarbil dihydrochloride monohydrate.
  • the molecular formula of omecamtiv mecarbil dihydrochloride hydrate is C20H24FN5O3-2HCI-H2O, with a relative molecular weight of 492.37 g/mol.
  • omecamtiv mecarbil is in the form of a base (e.g., omecamtiv mecarbil anhydrous free base).
  • omecamtiv mecarbil is in the form of a salt (e.g., omecamtiv mecarbil hydrochloride salt). In some embodiments, omecamtiv mecarbil is in the form of a salt hydrate (e.g., omecamtiv mecarbil dihydrochloride monohydrate).
  • a salt hydrate e.g., omecamtiv mecarbil dihydrochloride monohydrate.
  • Omecamtiv mecarbil dihydrochloride salt forms are disclosed in U.S. Patent No. 9,988,354 titled “Salt of Omecamtiv Mecarbil and Process for Preparing Salt”, the entirety of which in incorporated herein by reference.
  • omecamtiv mecarbil Other salts or crystalline forms of omecamtiv mecarbil are described in, for example, W02020011626 titles “Crystalline 2-fluoro ⁇ 3-niirotoluene and process for the preparation thereof’, W02020014406 titled “Solid state forms of omecamtiv mecarbil & omecamtiv mecarbil dihcl”, W02021070123 titled “Solid forms of omecamtiv mecarbil dihydrochloride and processes thereof’, WO2021053175 titled “Saits of omecamtiv mecarbil and solid forms thereof', WO2021053189 titled “Salts of omecamtiv mecarbil and solid forms thereof”, WO2021136477 titled “Cocrystal of dihydrochloride of co pound i and preparation method therefor and use thereof’, and W02021070124 titled “Alternate processes for the preparation of omecamtiv mecarbil”.
  • Described herein are methods of treating heart failure in a subject in need thereof with a CSA (e.g., omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof).
  • the CSA can be used to treat heart failure, such as, reducing the risk of cardiovascular death and heart failure events in subjects with symptomatic chronic heart failure with reduced ejection fraction.
  • dosing regimens of the CSA in the treatment of heart failure in which the dose levels of the CSA may be adjusted without taking a blood sample from the subject, unless the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction.
  • subsequent dose level of the CSA may be increased without a blood test.
  • Benefits of a blood-test-free dose adjustment regimen include, but are not limited to, improved patient compliance, lower health care costs, ease of dosing, decreased barriers to care, broader availability, broader uptake, and less invasive procedures.
  • administration of the CSA may be withheld. Subsequent treatment may be determined based on whether the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction experienced by the subject are related to the administration of the CSA.
  • a first dose level (e.g., 25 mg BID or 30 mg BID) of the CSA may be given to the subject for an initial period of time (e.g., about 2 weeks or at least 2 weeks.). If the subject experiences no signs or symptoms of acute myocardial ischemia or myocardial infarction (e.g., chest pain or shortness of breath) during the initial period of time, a second dose level (e.g., 37.5 mg BID or 45 mg BID) of the CSA may be given to the subject for a second period of time (e.g., about 2 weeks or at least 2 weeks) wherein the second dose level may be greater than the first dose level. If the subject experiences no signs or symptoms of acute myocardial ischemia or myocardial infarction during the second period of time, a third dose level of the CSA may be given to the subject, wherein the third dose level may be greater than the second dose level.
  • a second dose level e.g., 37.5 mg BID or 45 mg BID
  • administration of the CSA may be withheld. If the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are not related to the CSA, administration of the CSA may be resumed at the same dose level being administered before the CSA was withheld.
  • administration of the CSA may be withheld, and if the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are not related to the CSA, the administration of the CSA may be resumed at the same dose level as the first dose level.
  • administration of the CSA may be withheld, and if the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are not related to the CSA, the administration of the CSA may be resumed at the same dose level as the second dose level.
  • measurement of the plasma concentration of the CSA may be conducted as part of any routine clinical assessment of the ischemic event and may inform whether the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related or not to the CSA.
  • a routine clinical assessment of the ischemic event may include, for example, electrocardiogram (ECG), biomarkers including but not limited to troponin, potential invasive or non-invasive testing such as stress testing, coronary computed tomography angiography (CTA), or invasive angiography.
  • administration of the CSA may be discontinued or the dose level of the CSA may be decreased.
  • administration of the CSA may be withheld, and if the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related to the CSA, administration of the CSA may be discontinued.
  • administration of the CSA may be withheld, and if the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related to the CSA, subsequent administration of the CSA is decrease to the first dose level.
  • administration of the CSA may be withheld, and if the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related to the CSA, subsequent administration of the CSA is decrease to the second dose level or the first dose level.
  • treatment does not include taking a blood sample from the subject to determine the plasma concentration of the CSA.
  • a second dose level of the CSA may be given to the subject for a second period of time without taking a blood sample from the subject to determine the plasma concentration of the CSA.
  • a third dose level of the CSA may be given to the subject without taking a blood sample from the subject to determine the plasma concentration of the CSA.
  • the signs or symptoms of acute myocardial ischemia or myocardial infarction comprise chest pain and shortness of breath.
  • the signs or symptoms of acute myocardial ischemia or myocardial infarction comprise chest pain.
  • the signs or symptoms of acute myocardial ischemia or myocardial infarction comprise shortness of breath. In some embodiments, in conjunction with embodiments above or below, the signs or symptoms of acute myocardial ischemia or myocardial infarction comprise chest pain.
  • the signs or symptoms of acute myocardial ischemia or myocardial infarction comprise one or more symptoms of unstable angina, neck or jaw pain, back pain, shoulder or arm pain, fast or irregular heartbeat, nausea, vomiting, sweating, fatigue, chest pressure, tightness, heaviness, discomfort or squeezing, burning feeling, difficulty in breathing, fullness, numbness, feeling weak, light-headed, and/or faint.
  • treatment does not include taking a blood sample from the subject to determine the plasma concentration of the CSA except if the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction.
  • determination of the plasma concentration of the CSA may be conducted to determine if the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related to the CSA.
  • determination of the plasma concentration of the CSA may be conducted to determine if the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related to the CSA. For example, if the subject’s plasma concentration of the CSA is above 1200 ng/mL after administration of the CSA, then the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction may be related to the CSA.
  • the subject’s plasma concentration of the CSA is less than or about 1200 ng/mL after administration of the CSA, then the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are not likely to be related to the CSA.
  • treatment comprises an initial period of time. In some embodiments, in conjunction with embodiments above or below, treatment comprises an initial period of time and a second period of time. In some embodiments, in conjunction with embodiments above or below, treatment comprises an initial period of time, a second period of time, and a third period of time.
  • the initial period of time is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, at least 1 week (e.g., 1 week or 1.5 weeks), at least 2 weeks (e.g., 2 weeks, 2.5 weeks, 3 weeks, or 3.5 weeks), at least 4 weeks (e.g., 4 weeks, 4.5 weeks, 5 weeks, or 5.5 weeks), from 1 to 2 weeks, from 1 to 3 weeks, or from 1 to 4 weeks.
  • the second period of time is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, at least 1 week (e.g, 1 week or 1.5 weeks), at least 2 weeks (e.g, 2 weeks, 2.5 weeks, 3 weeks, or 3.5 weeks), at least 4 weeks (e.g., 4 weeks, 4.5 weeks, 5 weeks, or 5.5 weeks), from 1 to 2 weeks, from 1 to 3 weeks, or from 1 to 4 weeks, or for about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or as long as the subject does not experience one or more signs or symptoms of acute myocardial ischemia or myocardial infarction.
  • 1 week e.g, 1 week or 1.5 weeks
  • at least 2 weeks e.g, 2 weeks, 2.5 weeks, 3 weeks, or 3.5 weeks
  • at least 4 weeks e.g., 4 weeks, 4.5 weeks, 5 weeks, or 5.5 weeks
  • from 1 to 2 weeks, from 1 to 3 weeks, or from 1 to 4 weeks or for about 1
  • the third period of time is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, at least 1 week (e.g., 1 week or 1.5 weeks), at least 2 weeks (e.g., 2 weeks, 2.5 weeks, 3 weeks, or 3.5 weeks), at least 4 weeks (e.g., 4 weeks, 4.5 weeks, 5 weeks, or 5.5 weeks), from 1 to 2 weeks, from 1 to 3 weeks, or from 1 to 4 weeks, or for about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or as long as the subject does not experience one or more signs or symptoms of acute myocardial ischemia or myocardial infarction.
  • 1 week e.g., 1 week or 1.5 weeks
  • at least 2 weeks e.g., 2 weeks, 2.5 weeks, 3 weeks, or 3.5 weeks
  • at least 4 weeks e.g., 4 weeks, 4.5 weeks, 5 weeks, or 5.5 weeks
  • treatment comprises administering to a subject in need thereof a first dose level of a CSA (e.g., omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof) for an initial period of time.
  • a CSA e.g., omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof
  • the first dose level is from about 20 mg to about 50 mg twice daily.
  • the treatment comprises administering to the subject a first dose level of the CSA for an initial period of time, wherein the first dose level is from about 20 mg to about 50 mg twice daily, from about 25 mg to about 40 mg twice daily, from about 30 mg to 40 mg twice daily, from about 40 mg to 50 mg twice daily, or from about 35 mg to 40 mg twice daily.
  • the treatment comprises administering to the subject a first dose level of the CSA for an initial period of time, wherein the first dose level is from about 20 mg to about 35 mg twice daily, from about 25 to about 35 twice daily, or from about 30 mg to about 35 mg twice daily.
  • the treatment comprises administering to the subject a first dose level of the CSA for an initial period of time, wherein the first dose level is from about 20 mg to about 30 mg twice daily or from about 25 mg to 30 mg twice daily. In some embodiments, the treatment comprises administering to the subject a first dose level of the CSA for an initial period of time, wherein the first dose level is from about 20 to about 25 mg twice daily.
  • the treatment comprises administering to the subject a first dose level of the CSA for an initial period of time, wherein the first dose level 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, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg or about 35 mg twice daily.
  • the treatment comprises administering to the subject a first dose level of the CSA for an initial period of time, wherein the first dose level is from about 20 to about 25 mg twice daily.
  • the treatment comprises administering to the subject a first dose level of the CSA for an initial period of time, wherein first dose level is about 20.5 mg, about 21.5 mg, about 22.5 mg, about 23.5 mg, about 24.5 mg, about 25.5 mg, about 26.5 mg, about 27.5 mg, about 28.5 mg, or about 29.5 mg twice daily.
  • treatment comprises administering to a subject in need thereof a second dose level of a CSA (e.g. omecamtiv mecarbil) for a second period of time.
  • a CSA e.g. omecamtiv mecarbil
  • the second dose level is greater than or the same as the first dose level.
  • the second dose level is greater than the first dose level.
  • the second dose level is the same as the first dose level.
  • treatment comprises administering to a subject in need thereof a third dose level of a CSA (e.g. omecamtiv mecarbil).
  • a CSA e.g. omecamtiv mecarbil
  • the third dose level is greater than or the same as the second dose level. In some embodiments, the third dose level is less than or the same as the second dose level. In some embodiments, the third dose level is greater than the second dose level. In some embodiments, the third dose level is the same as the second dose level. In some embodiments, the third dose level is less than the second dose level. In some embodiments, the third dose level is greater than or the same as the first dose level. In some embodiments, the third dose level is greater than the first dose level. In some embodiments, the third dose level is the same as the first dose level.
  • the third dose level is the same as the first dose level.
  • treatment comprises administering to a subject in need thereof a fourth dose level of a CSA (e.g. omecamtiv mecarbil).
  • a CSA e.g. omecamtiv mecarbil
  • the fourth dose level is the same as or more than the third dose level.
  • the fourth dose level is the same as or less than the third dose level.
  • the fourth dose level is the same as the third dose level.
  • the fourth dose level is the same as the second dose level.
  • the fourth dose level is the same as the first dose level.
  • treatment comprises administering to a subject in need thereof a second dose level of a CSA (e.g. omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof,) for a second period of time.
  • a CSA e.g. omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof
  • the second dose level of the CSA is from about 35 mg to about 50 mg twice daily, from about 35 mg to about 40 mg twice daily, from about 40 mg to 45 mg twice daily, from about 45 mg to 50 mg twice daily, or from about 40 mg to about 50 mg twice daily.
  • the second dose level is from about 35 mg to about 45 mg twice daily, or from about 40 to about 50 twice daily.
  • the second dose level is about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg or about 50 mg twice daily. In some embodiments, the second dose level is about 30.5 mg, about 31.5 mg, about 32.5 mg, about 33.5 mg, about 34.5 mg, about 35.5 mg, about 36.5 mg, about 37.5 mg, about 38.5 mg, or about 39.5 mg twice daily.
  • treatment comprises administering to a subject in need thereof a third dose level of a CSA (e.g. omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof,) for a third period of time.
  • a CSA e.g. omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof.
  • the third dose level of the CSA is from about 40 mg to about 60 mg twice daily, from about 45 mg to about 55 mg twice daily, from about 40 mg to 50 mg twice daily, from about 50 mg to 60 mg twice daily, or from about 48 mg to about 52 mg twice daily.
  • the third dose level is about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg or about 55 mg twice daily. In some embodiments, the third dose level is about 44.5 mg, about
  • treatment comprises administering to the subject a first dose level of the CSA of about 25 mg twice daily for an initial period of time.
  • treatment comprises administering to the subject a first dose level of the CSA of about 25 mg twice daily for an initial period of time, and administering to the subject a second dose level of the CSA of about 37.5 mg twice daily for a second period of time, wherein the subject experiences no signs or symptoms of acute myocardial ischemia or myocardial infarction during the initial period of time.
  • the first period of time is about 2 weeks, or at least 2 weeks.
  • the second period of time is about 2 weeks, or at least 2 weeks, or indefinite, or until the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction.
  • indefinite means that administration continues as long as its benefits the patient and/or there are no significant side effects or other reasons to stop treatment.
  • treatment comprises administering to the subject a first dose level of the CSA of about 25 mg twice daily for an initial period of time, administering to the subject a second dose level of the CSA of about 37.5 mg twice daily for a second period of time, and administering to the subject a third dose level of the CSA of about 50 mg twice daily, wherein the subject experiences no signs or symptoms of acute myocardial ischemia or myocardial infarction during the initial period of time or the second period of time.
  • the first period of time, and the second period of time are both about 2 weeks, or at least 2 weeks.
  • the third period of time is about 2 weeks, or at least 2 weeks, or indefinite, or until the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction.
  • indefinite means that administration continues as long as its benefits the patient and/or there are no significant side effects or other reasons to stop treatment.
  • treatment comprises administering to the subject a first dose level of the CSA of about 25 mg twice daily for an initial period of time, and administering to the subject a second dose level of the CSA of about 25 mg twice daily, wherein the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction during the initial period of time, and wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are not related to the CSA.
  • treatment comprises administering to the subject a first dose level of the CSA of about 25 mg twice daily for an initial period of time, and administration of the CSA is discontinued, wherein the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction during the initial period of time, and wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related to the CSA.
  • treatment comprises administering to the subject a first dose level of the CSA of about 25 mg twice daily for an initial period of time, administering to the subject a second dose level of the CSA of about 37.5 mg twice daily for a second period of time, and administering to the subject a third dose level of the CSA of about 37.5 mg twice daily, wherein the subject experiences no signs or symptoms of acute myocardial ischemia or myocardial infarction during the initial period of time but experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction during the second period of time, and wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are not related to the CSA.
  • treatment comprises administering to the subject a first dose level of the CSA of about 25 mg twice daily for an initial period of time, administering to the subject a second dose level of the CSA of about 37.5 mg twice daily for a second period of time, and administering to the subject a third dose level of the CSA of about 25 mg twice daily, wherein the subject experiences no signs or symptoms of acute myocardial ischemia or myocardial infarction during the initial period of time but experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction during the second period of time, and wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related to the CSA.
  • treatment comprises administering to the subject a first dose level of the CSA of about 25 mg twice daily for an initial period of time, administering to the subject a second dose level of the CSA of about 37.5 mg twice daily for a second period of time, and administering to the subject a third dose level of the CSA of about 50 mg twice daily for a third period of time, wherein the subject experiences no signs or symptoms of acute myocardial ischemia or myocardial infarction during the initial period of time or the second period of time.
  • the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction during the third period of time, and the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related to the CSA, the subject is administered a fourth dose level of the CSA of about 37.5 mg twice daily or about 25 mg twice daily.
  • treatment comprises administering to the subject a first dose level of the CSA of about 30 mg twice daily for an initial period of time.
  • treatment comprises administering to the subject a first dose level of the CSA of about 30 mg twice daily for an initial period of time, and administering to the subject a second dose level of the CSA of about 45 mg twice daily for a second period of time, wherein the subject experiences no signs or symptoms of acute myocardial ischemia or myocardial infarction during the initial period of time.
  • the first period of time is about 2 weeks, or at least 2 weeks.
  • the second period of time is about 2 weeks, or at least 2 weeks, or indefinite, or until the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction.
  • indefinite means that administration continues as long as its benefits the patient and/or there are no significant side effects or other reasons to stop treatment.
  • the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the initiation of the first dose level. In some embodiments, in conjunction with embodiments above or below, the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the initiation of the second dose level. In some embodiments, in conjunction with embodiments above or below, the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the initiation of the third dose level.
  • the subject has chronic heart failure, severe heart failure, or a New York Hear Association (NYHA) Class II or III heart failure.
  • the subject has heart failure classified as Class III or IV as determined using the NYHA classification.
  • the subject has chronic heart failure with reduced ejection fraction.
  • the subject has advanced heart failure.
  • the subject does not exhibit atrial fibrillation or atrial flutter.
  • the subject is an inpatient.
  • the subject is an outpatient.
  • the subject has low blood pressure, symptomatic hypotension, impaired renal function, or bradycardia.
  • the subject has not previously been treated with one or more of an angiotensin-converting enzyme inhibitor, an angiotensin II receptor blocker, a beta blocker, a diuretic, an aldosterone antagonist, an inotrope, neprilysin inhibitors, digitalis, and digoxin.
  • an angiotensin-converting enzyme inhibitor an angiotensin II receptor blocker, a beta blocker, a diuretic, an aldosterone antagonist, an inotrope, neprilysin inhibitors, digitalis, and digoxin.
  • Atrial Fibrillation/Flutter AF/F
  • the subject in conjunction with embodiments above or below, is without AF/F. In some embodiments, in conjunction with embodiments above or below, the subject is with AF/F. In some embodiments, in conjunction with embodiments above or below, the subject is taking digoxin. In some embodiments, in conjunction with embodiments above or below, the subject is not taking digoxin. In some embodiments, the subject is without AFF and the subject is not taking digoxin. In some embodiments, the subject is without AFF and the subject is taking digoxin. In some embodiments, the subject is with AFF and the subject is not taking digoxin. In some embodiments, the subject is with AFF and the subject is taking digoxin. In some embodiments, the subject is with AFF and the subject is taking digoxin.
  • the subject has low left ventricular ejection fraction (LVEF), such as about 40% or lower (e.g., about 40%, about 39%, about 38%, about 37%, or about 36%), or about 39% or lower, or about 38% or lower, or about 37% or lower, or about 36% or lower, or about 35% or lower (e.g., about 35%, about 34%, about 33%, about 32%, about 31%), or about 34% or lower, or about 33% or lower, or about 32% or lower, or about 31% or lower, or about 30% or lower, or about 29% or lower, or about 28% or lower, or about 27% or lower, or about 26% or lower, or about 25% or lower, or about 24% or lower, or about 23% or lower, or about 22% or lower.
  • LVEF left ventricular ejection fraction
  • the subject in conjunction with embodiment about or below, has a LVEF of about 30%, about 29%, about 28%, about 27%, about 26%, about 25%, about 24%, about 23%, about 22%, about 21%, about 20%, about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, or about 10%.
  • the subject has a LVEF of less than 40%.
  • the subject has a LVEF of less than 35%.
  • the subject has a LVEF of less than 30%.
  • the subject has a LVEF of less than 28%.
  • the subject has a LVEF of less than 25%.
  • the subject has a LVEF of less than 22%.
  • the subject has a LVEF of less than 35% and the subject is without AF/F. In some embodiments, the subject has a LVEF of less than 30% and the subject is without AF/F. In some embodiments, the subject has a LVEF of less than 28% and the subject is without AF/F. In some embodiments, the subject has a LVEF of less than 25% and the subject is without AF/F. In some embodiments, the subject has a LVEF of less than 22% and the subject is without AF/F. In some embodiments, the subject has a LVEF of less than 35%, the subject is without AF/F, and the subject is not taking digoxin.
  • the subject has a LVEF of less than 30%, the subject is without AF/F, and the subject is not taking digoxin. In some embodiments, the subject has a LVEF of less than 28%, the subject is without AF/F, and the subject is not taking digoxin. In some embodiments, the subject has a LVEF of less than 25%, the subject is without AF/F, and the subject is not taking digoxin. In some embodiments, the subject has a LVEF of less than 22%, the subject is without AF/F, and the subject is not taking digoxin.
  • the subject has advanced heart failure (HF).
  • HF heart failure
  • Subjects with advanced HF may have markers of more severe disease, including but not limited to, lower ejection fraction, greater NYHA class, higher NT-proBNP concentrations, lower systolic blood pressure, worse renal function, and worse quality of life as assessed by the KCCQ TSS.
  • Subjects with advanced HF may less likely be treated with renin-angiotensin-aldosterone system (RAAS) modulators and beta blockers at baseline but more likely to have cardiac resynchronization therapy (CRT) or an implantable cardioverter defibrillator (ICD).
  • RAAS renin-angiotensin-aldosterone system
  • CRT cardiac resynchronization therapy
  • ICD implantable cardioverter defibrillator
  • the subject has high NT-proBNP level, such as at least about 1500 pg/mL (e.g., 1500, 1600, 1700, 1800, and 1900 pg/mL), at least about 2000 pg/mL (e.g., 2000, 2100, 2200, 2300, and 2400 pg/mL), at least about 2500 pg/mL (e.g, 2500, 2600, 2700, 2800, and 2900 pg/mL), or at least 3000 pg/mL (e.g, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 7000, 8000, 9000, 10,000, 15,000, and 20,000 pg/ml).
  • 1500 pg/mL e.g., 1500, 1600, 1700, 1800, and 1900 pg/mL
  • 2000 pg/mL e.g., 2000, 2100, 2200, 2300, and 2400 pg/mL
  • the subject has NT-proBNP level of at least about 1500 pg/mL. In some embodiments, the subject has NT-proBNP level of at least about 2000 pg/mL. In some embodiments, the subject has NT-proBNP level of at least about 2500 pg/mL. In some embodiments, the subject has NT -proBNP level of at least about 3000 pg/mL. In some embodiments, in conjunction with embodiments above or below, the subject is without AF/F.
  • the subject has NT-proBNP level of at least about 1500 pg/mL and the subject is without AF/F. In some embodiments, the subject has NT-proBNP level of at least about 2000 pg/mL and the subject is without AF/F. In some embodiments, the subject has NT-proBNP level of at least about 2500 pg/mL and the subject is without AF/F. In some embodiments, the subject has NT-proBNP level of at least about 3000 pg/mL and the subject is without AF/F.
  • the subject has NT-proBNT level of at least about 200 pg/mL (e.g., 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, and 1400 pg/mL). In some embodiments, the subject has NT-proBNT level of from about 200 pg/mL to about 1500 pg/mL.
  • SBP Systolic Blood Pressure
  • the subject in conjunction with embodiments above or below, has low SBP, such as less than 100 mm Hg (e.g., 99, 98, 97, 96, 95, 94, 93, 91, 90, 89, 88, 87, 86, and 85 mm/Hg). In some embodiments, the subject has a SBP of at least or about 100 mm Hg.
  • the subject in conjunction with embodiments above or below, has hepatic impairment (e.g., mild, moderate, or severe hepatic impairment). In some embodiments, the subject has normal hepatic function.
  • hepatic impairment e.g., mild, moderate, or severe hepatic impairment.
  • the subject has normal hepatic function.
  • treatment is effective to reduce the risk of heart failure events in the subject.
  • a heart failure event includes, but is not limited to, urgent clinic visit, emergency department visit, or hospitalization for subjectively and objectively worsening heart failure leading to treatment intensification beyond a change in oral diuretic therapy.
  • treatment may be more effective in subjects with lower baseline ejection fraction.
  • treatment is effective to reduce the risk of death, such as fatal stroke in a subject.
  • treatment is effective to reduce the risk of fatal stroke or non-fatal stroke in a subject (e.g., patient with chronic heart failure).
  • Embodiment 1 A method of treating heart failure in a subject in need thereof, comprising: a) administering to the subject a first dose level of a cardiac sarcomere activator (CSA) for an initial period of time; and b) administering to the subject a second dose level of the CSA for a second period of time, wherein the second dose level is greater than the first dose level, wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof, and wherein administering the CSA is withheld if the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction.
  • CSA cardiac sarcomere activator
  • Embodiment 2 The method of embodiment 1, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction comprise chest pain and shortness of breath.
  • Embodiment 3 The method of embodiment 1 or 2, wherein the method further comprises step c) administering to the subject a third dose level of the CSA, wherein the third dose level is greater than the second dose level, wherein the method does not include taking a blood sample from the subject to determine the plasma concentration of the CSA, and wherein administering the CSA is withheld if the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction.
  • Embodiment 4 The method of any one of embodiments 1 to 3, wherein if the CSA is withheld for a period of time, and if the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are not related to the CSA, administration of the CSA is resumed at the same dose level being administered before the CSA was withheld. [0126] Embodiment 5. The method of any one of embodiments 1 to 3, wherein if the CSA is withheld for a period of time, and if it is determined that the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related to the CSA, then the CSA’s dose level is decreased or discontinued.
  • Embodiment 6 The method of embodiment 5, wherein administration of the CSA is decreased.
  • Embodiment 7 The method of embodiment 6, wherein administration of the CSA is decreased to the first dose level.
  • Embodiment 8 The method of embodiment 6, wherein administration of the CSA is decreased to the second dose level.
  • Embodiment 9 The method of embodiment 5, wherein administration of the CSA is discontinued.
  • Embodiment 10 The method of any one of embodiments 1 to 9, wherein the first dose level of the CSA is about 25 mg twice daily.
  • Embodiment 11 The method of any one of embodiments 1 to 10, wherein the second dose level of the CSA is about 37.5 mg twice daily.
  • Embodiment 12 The method of any one of embodiments 3 to 11, wherein the third dose level of the CSA is about 50 mg twice daily.
  • Embodiment 13 The method of any one of embodiments 1 to 12, wherein the initial period of time is about 2 weeks.
  • Embodiment 14 The method of any one of embodiments 1 to 12, wherein the initial period of time is at least 2 weeks.
  • Embodiment 15 The method of any one of embodiments 1 to 14, wherein the second period of time is about 2 weeks.
  • Embodiment 16 The method of any one of embodiments 1 to 14, wherein the second period of time is at least 2 weeks.
  • Embodiment 17 The method of any one of embodiments 1 to 16, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after initiation of the first dose level.
  • Embodiment 18 The method of any one of embodiments 1 to 17, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after initiation of the second dose level.
  • Embodiment 19 The method of any one of embodiments 1 to 18, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after initiation of the third dose level.
  • Embodiment 20 The method of any one of embodiments 1 to 19, wherein the method does not include taking a blood sample from the subject to determine the subject’s CSA plasma concentration except if the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction.
  • Embodiment 21 The method of any one of embodiments 1 to 20, wherein if the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction, the method further comprises determining the plasma concentration of the CSA to assess whether the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related to the CSA.
  • Embodiment 22 The method of embodiment 21, wherein determining the plasma concentration of the CSA comprises taking a blood sample from the subject.
  • Embodiment 23 The method of any one of embodiments 1 to 22, wherein the subject has chronic heart failure, severe heart failure, or a New York Heart Association Class II or III heart failure.
  • Embodiment 24 The method of any one of embodiments 1 to 23, wherein the subject has a left ventricular ejection fraction of about 35% or lower.
  • Embodiment 25 The method of any one of embodiments 1 to 24, wherein the subject has a plasma concentration of NT-proBNP of at least about 200 pg/mL.
  • Embodiment 26 The method of any one of embodiments 1 to 25, wherein the CSA is omecamtiv mecarbil dihydrochloride hydrate.
  • Embodiment 27 The method of any one of embodiments 1 to 26, wherein the CSA is administered orally to the subject.
  • Embodiment 28 A method of treating heart failure in a subject in need thereof, comprising: a) administering to the subject a first dose level of a cardiac sarcomere activator (CSA) for an initial period of time; and b) administering to the subject a second dose level of the CSA in accordance with a determination that the subject has not experienced one or more signs or symptoms of acute myocardial ischemia or myocardial infarction, wherein the second dose level is greater than the first dose level, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the first administration of the first dose level of the CSA, and wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof.
  • CSA cardiac sarcomere activator
  • Embodiment 29 The method of embodiment 28, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction comprise chest pain and shortness of breath.
  • Embodiment 30 The method of embodiment 28 or 29, wherein the first dose level of the CSA is about 25 mg twice daily.
  • Embodiment 31 The method of any one of embodiments 28 to 30, wherein the second dose level of the CSA is about 37.5 mg twice daily.
  • Embodiment 32 The method of any one of embodiments 28 to 31, wherein the method further comprises step c) administering to the subject a third dose level of the CSA in accordance with a subsequent determination at about 4 weeks after the first administration of the first dose level of the CSA that the subject has not experienced the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction, wherein the third dose level is greater than the second dose level.
  • Embodiment 33 The method of embodiment 32, wherein the third dose level of the CSA is about 50 mg twice daily.
  • Embodiment 34 A method of treating heart failure in a subject in need thereof, comprising: a) administering to the subject a first dose level of a cardiac sarcomere activator (CSA) for an initial period of time; and b) administering to the subject a second dose level of the CSA in accordance with a determination that one or more signs or symptoms of acute myocardial ischemia or myocardial infarction experienced by the subject are not associated with the CSA, wherein the second dose level is about the same as the first dose level, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the first administration of the first dose level of the CSA, and wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof.
  • CSA cardiac sarcomere activator
  • Embodiment 35 The method of embodiment 34, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction comprise chest pain and shortness of breath.
  • Embodiment 36 The method of embodiment 34 or 35, wherein the first and the second dose levels of the CSA are about 25 mg twice daily.
  • Embodiment 37 The method of embodiment 34 or 35, wherein the first and the second dose levels of the CSA are about 37.5 mg twice daily.
  • Embodiment 38 A method of treating heart failure in a subject in need thereof, comprising: a) administering to the subject a first dose level of a cardiac sarcomere activator (CSA) for an initial period of time; and b) administering to the subject a second dose level of the CSA in accordance with a determination that one or more signs or symptoms of acute myocardial ischemia or myocardial infarction experienced by the subject are associated with the CSA, wherein the second dose level is less than the first dose level, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the first administration of the first dose level of the CSA, and wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof.
  • Embodiment 39 The method of embodiment 38, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction comprise chest
  • Embodiment 40 The method of embodiment 38 or 39, wherein the first dose level of the CSA is about 37.5 mg twice daily.
  • Embodiment 41 The method of embodiment 40, wherein the second dose level of the CSA is about 25 mg twice daily.
  • Embodiment 42 The method of embodiment 38 or 39, wherein the first dose level of the CSA is about 50 mg twice daily.
  • Embodiment 43 The method of embodiment 42, wherein the second dose level of the CSA is about 37.5 mg twice daily.
  • Embodiment 44 A method of treating heart failure in a subject in need thereof, comprising: a) administering to the subject a first dose level of a cardiac sarcomere activator (CSA) for an initial period of time; and b) discontinuing the administration in accordance with a determination that one or more signs or symptoms of acute myocardial ischemia or myocardial infarction experienced by the subject are associated with the CSA, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the first administration of the first dose level of the CSA, and wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof.
  • CSA cardiac sarcomere activator
  • Embodiment 45 The method of embodiment 44, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction comprise chest pain and shortness of breath.
  • Embodiment 46 The method of embodiment 44 or 45, wherein the first dose level of the CSA is about 25 mg twice daily.
  • Embodiment 47 The method of any one of embodiments 28 to 46, wherein the subject has chronic heart failure, severe heart failure, or a New York Heart Association Class II or III heart failure.
  • Embodiment 48 The method of any one of embodiments 28 to 47, wherein the subject has a left ventricular ejection fraction of about 35% or lower.
  • Embodiment 49 The method of any one of embodiments 28 to 48, wherein the subject has a plasma concentration of NT-proBNP of at least about 200 pg/mL.
  • Embodiment 50 The method of any one of embodiments 28 to 49, wherein the CSA is omecamtiv mecarbil dihydrochloride hydrate.
  • Embodiment 51 The method of any one of embodiments 28 to 50, wherein the CSA is administered orally to the subject.
  • ACEi refers to angiotensinconverting enzyme inhibitor
  • ARB refers to angiotensin receptor blocker
  • ARNi refers to angiotensin receptor-neprilysin inhibitor
  • BB beta blocker
  • CRT refers to cardiac resynchronization therapy
  • ED refers to emergency department
  • eGFR refers to estimated glomerular filtration rate
  • HF refers to heart failure
  • hsTn high-sensitivity troponin I
  • ICD refers to implantable cardioverter-defibrillator
  • KCCQ refers to Kansas City Cardiomyopathy Questionnaire
  • LVEF refers to left ventricular ejection fraction
  • MAGGIC refers to Meta- Analysis Global Group in Chronic HF
  • MRA refers to mineralocorticoid receptor antagonist
  • NEJM refers to The New England Journal of Medicine
  • NT -proBNP refers to N-terminal pro-B-type natriuretic peptide
  • NT-proBNP N-terminal pro-B-type natriuretic peptide
  • the primary outcome was a composite of the time to a heart failure event or cardiovascular death, whichever occurred first.
  • a heart failure event was defined as an urgent clinic visit, emergency department visit or hospitalization for subjectively and objectively worsening heart failure leading to treatment intensification beyond changed oral diuretic therapy.
  • Secondary outcomes were: the time to cardiovascular death; change in KCCQ Total Symptom Score (TSS) from baseline to Week 24 (scale from 0 to 100; higher score indicates fewer symptoms); time to first heart failure hospitalization; and time to allcause death.
  • TSS KCCQ Total Symptom Score
  • a sample size of approximately 8,000 patients was chosen to provide 90% power to detect a hazard ratio of 0.8 for cardiovascular death assuming the following: a 10% annualized rate of cardiovascular death in the first year and 7% thereafter; a 24-month enrollment period; total study duration set to 48 months; a 3 -month treatment lag with a treatment effect hazard ratio of 0.8 thereafter, 10% annual rate of study drug discontinuation, and 10% of subjects lost to endpoint determination either through non-cardiovascular death or study discontinuation over the course of the trial.
  • the study was event-driven and was ended after approximately 1590 cardiovascular deaths.
  • the overall type I error was 0.05 for 2-sided testing across primary and secondary endpoints with control for multiplicity testing.
  • the mean differences in the KCCQ TSS change from baseline to Week 24 were estimated using a mixed model stratified by randomization setting (inpatient and outpatient) containing baseline TSS value, region, baseline eGFR, scheduled visit, treatment group, and the interaction of treatment group with scheduled visit.
  • a joint omnibus F-test was used to test the treatment effect for the KCCQ TSS.
  • An overall pooled estimate for the KCCQ TSS treatment difference to placebo were conducted using a likelihood based approach.
  • the prespecified safety analyses included: serious adverse events; adverse events associated with discontinuation of study treatment; “adverse events of interest” i.e., ventricular arrhythmias requiring treatment and positively adjudicated major cardiac ischemic events (including myocardial infarction, hospitalization for unstable angina, coronary revascularization).
  • the safety analyses were performed in patients who underwent randomization and received at least one dose of omecamtiv mecarbil or placebo with the same exclusion of the 24 subjects as in the full analysis set. All analyses were performed with the use of SAS software, version 9.4 (SAS Institute).
  • a first heart failure event or death from cardiovascular causes occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI] 0.86, 0.99; P 0.025; Figure 1 A and Table 2).
  • 1177 (28.6%) in patients receiving omecamtiv mecarbil and 1236 (30.1%) in the placebo group experienced a first heart failure event (hazard ratio, 0.93; 95% CI, 0.86 to 1.00; P 0.063; Figure IB and Table 2); death from cardiovascular causes contributed 346 events (8.4%) and 371 events (9.0%) (Table 2).
  • the effect of omecamtiv mecarbil was generally consistent across most prespecified subgroups with statistically the largest potential interaction observed for the ejection fraction subgroup (interaction effect p 0.003; Figure 3).
  • NA denotes not applicable because P values for efficacy outcomes are reported only for outcomes that were included in the hierarchical-testing strategy
  • the primary outcome was a composite of heart failure events (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or death from cardiovascular causes.
  • the total symptom score on the Kansas City Cardiomyopathy Questionnaire (KCCQ) ranges from 0 to 100, with higher scores indicating fewer symptoms and physical limitations associated with heart failure. fNon-significant. After statistical significance on the primary endpoint, CV death was tested against an alpha of 0.048 and change from baseline in the KCCQ TSS was tested against an alpha of 0.002.
  • Omecamtiv mecarbil was withheld because of concern of active myocardial infarction or ischemia in 103 patients in the omecamtiv mecarbil group and in 101 patients in the placebo group. Only three patients had concentrations of omecamtiv mecarbil over 1000 ng/mL, none of whom experienced a myocardial ischemic event. The three patients had blood concentrations of omecamtiv mecarbil measured at 1004 ng/mL, 1099 ng/mL, and 1158 ng/mL.
  • Continuous variables were summarized as means ⁇ standard deviations (SD) or medians and first and third quartiles (QI, Q3), as appropriate.
  • Categorical variables were summarized as counts and percentages.
  • the safety population included all patients who underwent randomization and received at least one dose of omecamtiv mecarbil or placebo.
  • the change from baseline on NT-proBNP analysis included all participants who underwent randomization.
  • the difference column is the exponentiated change from baseline on the log scale using a mixed model containing the log baseline value, region, baseline eGFR, scheduled visit, treatment group and interaction of treatment with scheduled visit.
  • Table 4 summarizes the adverse events reported in 1% or more of patients.
  • Continuous variables were summarized via means and standard deviations or medians and interquartile ranges, as appropriate.
  • Categorical variables are summarized with counts and percentages.
  • Tests of trend across categories were conducted via linear regression, Cuzick’s non-parametric trend test, and Chi-squared tests of trend, respectively.
  • Treatment effects on continuous outcomes were assessed via linear regression models adjusted for the corresponding baseline value of the parameter of interest.
  • Survival analyses were conducted using Poisson regression models to estimate incidence rates, rate differences, and rate ratios and Cox proportional hazards models to estimate hazard ratios.
  • Treatment effect hazard ratios were adjusted for eGFR and stratified by region and inpatient status as in the primary GALACTIC -HF analysis.
  • ACEi indicates angiotensin-converting enzyme inhibitor
  • ARB angiotensin receptor blocker
  • ARNi angiotensin receptor-neprilysin inhibitor
  • BB beta blocker
  • CRT cardiac resynchronization therapy
  • ED emergency department
  • eGFR estimated glomerular filtration rate
  • hsTnl high-sensitivity troponin I
  • ICD implantable cardioverter-defibrillator
  • KCCQ Kansas City Cardiomyopathy Guestionnaire
  • LVEF left ventricular ejection fraction
  • MAGGIC Meta-Analysis Global Group in Chronic HF
  • MRA mineralocorticoid receptor antagonist
  • NT-proBNP N-terminal pro-B-type natriuretic peptide
  • NYHA New York Heart Association
  • SBP sysys
  • Patients with lower ejection fraction were more likely to have a non-ischemic etiology of heart failure, NYHA III/IV functional class, lower body mass index, lower systolic blood pressure, higher heart rate, higher NT -proBNP, higher cardiac troponin I, and were less likely to have coronary artery disease, hypertension, type 2 diabetes mellitus, or atrial fibrillation/ flutter.
  • Lower ejection fraction was associated with greater symptom burden in patients enrolled as inpatients (lower KCCQ-TSS), but there was no meaningful difference in the outpatients. There was no difference in the proportion of patients receiving triple therapy [(ACEi, ARB, or ARNi) + MRA + BB] among the EF quartiles.
  • Patients with lower ejection fractions had higher use of ARNi, ivabradine, digitalis glycosides, cardiac resynchronization therapy and implantable cardioverter defibrillators compared to patients with higher ejection fractions.
  • Quartiles and Treatment Group Within each randomization setting subgroup least squares mean is from the mixed model which includes baseline total symptom score value, region, baseline eGFR, scheduled visit, treatment group and interaction of treatment with scheduled visit as covariates.
  • Omecamtiv mecarbil significantly decreased the primary endpoint of the time-to- first heart failure event or cardiovascular death in the overall trial population (HR 0.92; p 0.025).
  • the statistical analysis plan pre-specified the assessment of the primary endpoint in the ejection fraction subgroups above and below the median value ( ⁇ 28%) and there was a significant modification of the treatment effect of omecamtiv mecarbil by ejection fraction (interaction effect, p 0.004).
  • Table 8A Total heart failure events/hospitalizations by ejection fraction quartiles: Other Outcomes and Safety of Omecamtiv Mecarbil by Ejection Fraction
  • *Values represent treatment effects as evaluated by between-group differences of change from baseline to Week 24. Least squares mean is from the mixed model which includes baseline total symptom score value, region, baseline eGFR, scheduled visit, treatment group and interaction of treatment with scheduled visit as covariates. Troponin I assay had limit of detection of 6 ng/L with an upper reference limit of 40 ng/L.
  • Omecamtiv mecarbil treatment resulted in a small reduction in heart rate (treatment difference of 1.1 to 1.9 bpm across the EF quartiles) and increase in troponin I (median 3-5 ng/L across the EF quartiles; limit of detection, 6 ng/L; upper reference limit, 40 ng/L) which did not differ by EF quartile. There was no significant effect on systolic blood pressure, serum potassium or creatine across the EF quartiles compared to placebo.
  • Omecamtiv mecarbil provided similar benefit in patients with and without a history of stroke.
  • the time to first stroke event was significantly reduced in patients allocated to omecamtiv mecarbil.
  • a history of stroke was present in 754 (9.2%) participants, who were older and more likely to be non-White, have atrial fibrillation/ flutter, hypertension, diabetes mellitus, or ischemic heart disease, worse NYHA class and eGFR, and higher baseline NT- proBNP or troponin.
  • Multivariate predictors of the incident 194 first stroke events included non-White race, history of stroke or percutaneous coronary intervention (PCI), and elevated baseline troponin or systolic blood pressure (Table 10B).
  • PCI percutaneous coronary interventions.
  • AFF atrial fibrillation or atrial flutter.
  • SBP systolic blood pressure.
  • LVEF left ventricular ejection fraction.
  • NYHA New York Heart Association.
  • SBP systolic blood pressure.
  • eGFR estimated glomerular filtration rate.
  • BMI Body Mass Index.
  • ACEi Angiotensin-converting enzyme inhibitors.
  • ARB Angiotensin receptor blockers.
  • ARNi Angiotensin receptor neprilysin inhibitor.
  • BB Beta blockers.
  • MRA Mineralocorticoid receptor antagonists.
  • SGLT2 Sodium-glucose cotransporter 2.
  • CRT Cardiac resynchronization therapy.
  • ICD implantable cardioverter-defibrillator.
  • KCCQ TSS Kansas City Cardiomyopathy Questionnaire Total Symptom Score
  • RAAS renin-angiotensin-aldosterone system
  • CRT cardiac resynchronization therapy
  • ICD implantable cardioverter defibrillator
  • FIGURES 14A and 14B Kaplan-Meier curves comparing patients with and without more advanced HF for each of these endpoints are shown in FIGURES 14A and 14B.
  • the event rate and treatment effect of omecamtiv mecarbil was assessed based on which and how many advanced heart HF criteria were met (FIGURES 15A and 15B).
  • the observed benefits of omecamtiv mecarbil were greatest in patients meeting all 3 advanced HF criteria, which were also the group with the highest overall risk.
  • NT-proBNP was measured at baseline and at 2, 6, 24, 48 and 96 weeks after randomization.
  • Plasma NT-proBNP was measured in a central laboratory (Q Squared Solutions) using the Roche Elecsys NT-proBNP two-site electrochemiluminescence immunoassay (analytical range 50-35000 pg/mL).
  • NT-proBNP measurement at baseline was available for 8206 of the 8232 patients randomized. Of these, 5971 patients did not have AF/F on their baseline ECG. The median (QI, Q3) NT-proBNP level at baseline was 1675 (812-3579) pg/ml among patients not in AF/F and 1998 (993-4079) pg/mL in all patients randomized.
  • Table 15 Baseline characteristics of patients according to pre-randomization NT-proBNP level ( ⁇ median or >median) in the prespecified analysis population (no atrial fibrillation/flutter at baseline) and in all patients randomized.
  • ACE angiotensin-converting enzyme
  • ARB angiotensin-receptor blocker
  • ARNI angiotensin receptor- neprilysin inhibitor
  • BMI body mass index
  • CRT-P/D cardiac resynchronization therapy with or without a defibrillator
  • GFR glomerular filtration rate
  • ICD implantable cardioverter-defibrillator
  • KCCQ-TSS Kansas City Cardiomyopathy Questionnaire total symptom score - range from 0 to 100, with higher scores indicating fewer symptoms
  • LVEF left ventricular ejection fraction
  • Ml myocardial infarction
  • MRA mineralocorticoid receptor antagonist
  • NT-proBNP N-terminal pro-B-type natriuretic peptide
  • NYHA New York Heart association.
  • renin-angiotensin system blockers including sacubitril-valsartan
  • mineralocorticoid receptor antagonists include beta-blockers
  • Table 16 shows the effect of omecamtiv mecarbil on the prespecified morbidity and mortality endpoints, according to baseline NT-proBNP level divided at the median, as prespecified, in patients without AF/F and in the overall trial population. Additional analyses of the effect of omecamtiv mecarbil examining NT-proBNP as a continuous variable are shown in (FIGURES 18A-18D and 19A-19D)
  • omecamtiv mecarbil had more benefit on the primary endpoint in participants with a NT -proBNP greater than the median (HR 0.81, 95% CI 0.73-0.90) than in patients with a NT-proBNP less than or equal to the median (HR 0.94, 0.80-1.09); P for interaction ⁇ .035.
  • HR 0.88, 0.80-0.96 in patients with NT-proBNP >median and 1.01, 0.90- 1.15 in participants with a NT -proBNP less than or equal to the median; P for interaction ⁇ .095.
  • Table 17 shows the effect of omecamtiv mecarbil on physiologic measures and on plasma biomarkers according to baseline NT-proBNP level divided at the median, in patients without AF/F and in the overall trial population.
  • Table 17 Change from baseline to 24 weeks in physiologic measures and biomarkers according to baseline NT-proBNP level ( ⁇ median or >median) in relation to randomized treatment assignment in the prespecified analysis population (no atrial fibrillation/flutter at baseline) and in all patients randomized.
  • B D M beats per minute
  • Rate is per 100 person-years
  • Atrial fibrillation is common in patients with heart failure and contributes to morbidity and mortality. Atrial fibrillation has not modified the treatment effect of renin- angiotensin-aldosterone inhibitors that have proven beneficial in heart failure, but may modify the treatment effect of beta-blockers.
  • renin- angiotensin-aldosterone inhibitors that have proven beneficial in heart failure, but may modify the treatment effect of beta-blockers.
  • Figure 21 A depicts the frequency of AFF in patients having LVEF ⁇ 35%. AFF was observed to coincide with higher LVEF (but less than 35%).
  • AFF at baseline was associated with a modestly increased adjusted risk of cardiovascular death or heart failure events (HR 1.17, 95% CI 1.09, 1.27).
  • Atrial fibrillation or flutter at baseline modified the treatment effect of omecamtiv mecarbil, even after multivariable adjustment, with greater benefit observed in patients not in AFF.
  • the treatment effect modification by AFF was concentrated in patients using digoxin in AFF with minimal evidence of effect modification in non-users in AFF.
  • Digoxin did not modify the treatment effect of omecamtiv mecarbil in patients not in AFF.
  • Figures 21F and 21G depict data from a study evaluating any drug-drug interaction between digoxin and omecamtiv mecarbil, showing PK values for digoxin.
  • SBP stolic blood pressure
  • HFrEF heart failure and reduced ejection fraction
  • Hazard ratios (HRs) and 95% confidence intervals (Cis) for the treatment effect on the primary outcome were of 0.81, 0.70-0.94; 0.88, 0.76-1.03; 1.03, 0.88-1.19; 0.87, 0.73-1.03; and 1.07, 0.90-1.28 in each SBP subgroup, respectively.
  • baseline SBP had a linear inverse relation with the primary event rate and a linear direct relation with the treatment effect ( Figures 23A and 23B). No significant change in SBP and no difference in adverse events with omecamtiv mecarbil, compared with placebo, occurred during follow-up in each subgroup.
  • Omecamtiv mecarbil did not change SBP from baseline and was well tolerated independently from SBP at baseline, including in patients having low baseline blood pressure ( ⁇ 100 mmHg) for whom the use of other HFrEF therapies cannot be tolerated or may be associated with the added cost of increased averse events or worsening renal function. Omecamtiv mecarbil tended to have a larger effect on the primary outcome, compared with placebo, in the patients with lower SBP at baseline ( ⁇ 100 mmHg).
  • OM was observed to be moderately bound to plasma proteins (81.5%) and the protein binding was independent of drug concentration up to 4000 ng/mL. After a single 35 mg dose of radiolabeled OM to healthy subjects, the blood to plasma ratio of total radioactivity was approximately 0.4, indicating that radioactivity did not disproportionately partition into blood components. The volume of distribution at steady state was approximately 4.8-6.6 L/kg.
  • OM Clearance of OM after oral administration was primarily through metabolism in the liver.
  • the total systemic clearance was found to be 11.7 L/hr with mean renal clearance of 1 L/hr, accounting for less than 10% of the systemic clearance.
  • the median half-life of OM was found to be approximately 23-32 hours in patients with heart failure.
  • OM was observed to be extensively metabolized in the liver by multiple metabolic pathways, including CYP3A4 and CYP2D6. Following oral administration of radiolabeled OM to healthy subjects, approximately 49% of the dose was excreted in urine (primarily as metabolites with 8% of parent compound recovered) and 38% in feces (primarily as unchanged drug).
  • OM was found to be metabolized in vitro by multiple CYP enzymes including CYP3A4 and CYP2D6 and is a substrate of P-gp and BCRP. OM may be administered with drugs that are inhibitors or inducers of CYP3 A4, CYP2D6, P-gp or BCRP. The effect of coadministered drugs on OM plasma exposures is presented in Table 21.
  • CYP2D6 metabolic genotype had no clinically relevant effect on the pharmacokinetics of OM, indicating that inhibitors of CYP2D6 have no clinically relevant effect on OM exposures.
  • OM was found to be an inhibitor of P-gp, BCRP, MATE1, MATE 2-K, CYP2C8 and an inducer of CYP3 A4.
  • Clinical studies and the results of physiologically based pharmacokinetic modeling indicate that OM is a weak inhibitor of CYP2C8 and BCRP, and a weak inducer of CYP3 A4.
  • OM may be administered with drugs that are substrates of CYP3 A4, CYP2C8, P-gp or BCRP. A summary of results from clinical studies is provided in

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Abstract

Methods for treating heart failure are described herein. The treatment methods include administering a cardiac sarcomere activator (e.g., omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof) to a subject in need thereof. Treatment methods may include adjusting a dose level, for example to increase, decrease, maintain, or discontinue a dose level, based on one or more signs or symptoms of acute myocardial ischemia or myocardial infarction. Provided herein are also blood-test-free dose adjustment regimens for treating heart failure.

Description

METHODS FOR TREATING HEART FAILURE BY ADMINISTERING CARDIAC
SARCOMERE ACTIVATORS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to and benefit of U.S. Provisional Patent Application No. 63/379,126, filed October 11, 2022, the disclosure of which is hereby incorporated herein by reference in its entirety.
BACKGROUND
[0002] The cardiac sarcomere is the basic unit of muscle contraction in the heart. The cardiac sarcomere is a highly ordered cytoskeletal structure composed of cardiac muscle myosin, actin and a set of regulatory proteins. The discovery and development of small molecule cardiac muscle myosin activators would lead to promising treatments for acute and chronic heart failure. Cardiac muscle myosin is the cytoskeletal motor protein in the cardiac muscle cell. It is directly responsible for converting chemical energy into the mechanical force, resulting in cardiac muscle contraction.
[0003] Current positive inotropic agents, such as beta-adrenergic receptor agonists or inhibitors of phosphodiesterase activity, increase the concentration of intracellular calcium, thereby increasing cardiac sarcomere contractility. However, the increase in calcium levels increase the velocity of cardiac muscle contraction and shortens systolic ejection time, which has been linked to potentially life-threatening side effects. In contrast, cardiac muscle myosin activators work by a mechanism that directly stimulates the activity of the cardiac muscle myosin motor protein, without increasing the intracellular calcium concentration. They accelerate the rate-limiting step of the myosin enzymatic cycle and shift it in favor of the force-producing state. Rather than increasing the velocity of cardiac contraction, this mechanism instead lengthens the systolic ejection time, which results in increased cardiac muscle contractility and cardiac output in a potentially more oxygen-efficient manner.
[0004] A characteristic of heart failure with reduced ejection fraction is decreased systolic function leading to reduce cardiac output and increased filling pressures. To date, no drugs directly addressing systolic function have improved outcomes. Omecamtiv mecarbil is a first in class, small molecule cardiac myosin activator, which is a type of myotrope that acts directly on the muscle fiber. Omecamtiv mecarbil, augments cardiac contractility by selectively binding to cardiac myosin increasing the number of force generators (myosin heads) that can bind to the actin filament and undergo a powerstroke once the cardiac cycle starts. In early clinical studies using short-term intravenous administration, omecamtiv mecarbil improved cardiac performance. In patients with chronic heart failure with reduced ejection fraction, treatment with omecamtiv mecarbil for 20 weeks increased left ventricular systolic function, decreased left ventricular systolic and diastolic volumes suggestive of beneficial reverse cardiac remodeling, and reduced natriuretic peptide concentrations and heart rate.
[0005] Many therapies have been developed that improve cardiovascular outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, none of the currently available drugs directly improve the central defect of HFrEF, reduced systolic function. Moreover, severe impairment of systolic function is often associated with lower blood pressure and greater difficulty tolerating target doses of guideline-directed medical therapies. Myotropes represent a new class of drugs that improve myocardial function by directly augmenting cardiac sarcomere function. The cardiac myosin activator, omecamtiv mecarbil, is the first of this class and it increases systolic function by selectively facilitating the actin-myosin interaction, increasing contractile force without altering the cardiomyocyte calcium transient.
[0006] Despite significant improvements in prognosis with contemporary medical therapy, HF with reduced ejection fraction (HFrEF) remains a progressive clinical syndrome and many patients develop worsening over time despite optimal guideline-based treatment. Regardless of terminology, these patients have a high burden of symptoms, recurrent HF hospitalizations, high mortality, and account for a large proportion of the total costs of HF care. As HF progresses, many patients become progressively intolerant of neuro-hormonal blockade with beta-blockers or renin-angiotensin-aldosterone system (RAAS) modulators due to hypotension or renal dysfunction, limiting their options for medical therapy. Selected patients with advanced HF may be candidates for other therapies such as cardiac transplantation or mechanical cardiac support, but these therapies are costly, highly invasive, and have limited availability. Intravenous inotropic therapy can be used for palliation of symptoms in selected patients but may be associated with increased mortality. Thus, there is a clear unmet need for effective and safe chronic medical therapies for patients with more advanced stages of HF.
[0007] The identification of safe drugs that increase cardiac performance has been a goal of heart failure therapeutics for more than a century, yet those that have been developed have consistently increased the incidence of myocardial ischemia, ventricular arrhythmias, or death due to their mechanism increasing intracellular calcium transients. As a selective cardiac myosin activator, omecamtiv mecarbil has been shown to have no effect on these transients. [0008] Despite prior developments in this area, there remains a need for treating heart failure in patients.
BRIEF SUMMARY
[0009] Methods for treating heart failure are described herein. In some aspects, provided is a method of treating heart failure in a subject in need thereof, comprising: a) administering to the subject a first dose level of a cardiac sarcomere activator (CSA) for an initial period of time; and b) administering to the subject a second dose level of the CSA for a second period of time, wherein the second dose level is greater than the first dose level, wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof, and wherein administering the CSA is withheld if the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction. In some embodiments, the method further comprises step c) administering to the subject a third dose level of the CSA, wherein the third dose level is greater than the second dose level, wherein the method does not include taking a blood sample from the subject to determine the plasma concentration of the CSA, and wherein administering the CSA is withheld if the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction.
[0010] Also provided herein is a method of treating heart failure in a subject in need thereof, comprising: a) administering to the subject a first dose level of a cardiac sarcomere activator (CSA) for an initial period of time; and b) administering to the subject a second dose level of the CSA in accordance with a determination that the subject has not experienced one or more signs or symptoms of acute myocardial ischemia or myocardial infarction, wherein the second dose level is greater than the first dose level, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the first administration of the first dose level of the CSA, and wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof. [0011] Also provided herein is a method of treating heart failure in a subject in need thereof, comprising: a) administering to the subject a first dose level of a cardiac sarcomere activator (CSA) for an initial period of time; and b) administering to the subject a second dose level of the CSA in accordance with a determination that one or more signs or symptoms of acute myocardial ischemia or myocardial infarction experienced by the subject are not associated with the CSA, wherein the second dose level is about the same as the first dose level, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the first administration of the first dose level of the CSA, and wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof.
[0012] Also provided herein is a method of treating heart failure in a subject in need thereof, comprising: a) administering to the subject a first dose level of a cardiac sarcomere activator (CSA) for an initial period of time; and b) administering to the subject a second dose level of the CSA in accordance with a determination that one or more signs or symptoms of acute myocardial ischemia or myocardial infarction experienced by the subject are associated with the CSA, wherein the second dose level is less than the first dose level, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the first administration of the first dose level of the CSA, and wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof.
[0013] Also provided is a method of treating heart failure in a subject in need thereof, comprising: a) administering to the subject a first dose level of a cardiac sarcomere activator (CSA) for an initial period of time; and b) discontinuing the administration in accordance with a determination that one or more signs or symptoms of acute myocardial ischemia or myocardial infarction experienced by the subject are associated with the CSA, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the first administration of the first dose level of the CSA, and wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] Figure 1 A shows the primary endpoint in the patient population evaluated, wherein the primary endpoint was the composite of time to a heart failure event or cardiovascular death, whichever occurred first.
[0015] Figure IB shows the incidence of cardiovascular death in the patient population evaluated.
[0016] Figure 1C shows the incidence of heart failure events in the patient population evaluated.
[0017] Figure ID shows the incidence of all deaths in the patient population evaluated. [0018] Figure 2A, 2B, and 2C show the primary outcome of the trial as a composite of heart failure event or cardiovascular death, according to subgroups that were prespecified in the protocol. Race was self-reported by patients. Baseline NT-proBNP subgroups exclude subjects in atrial fibrillation/flutter at screening.
[0019] Figure 3 shows a multiplicity testing propagation approach.
[0020] Figure 4 shows a design of a clinical trial of omecamtiv mecarbil.
[0021] Figure 5 shows progressively greater improvement in the primary composite endpoint (PCE) with decreasing left ventricular ejection fraction (LVEF) as indicated by the continuously improving hazard ratio.
[0022] Figure 6 shows the incidence of the primary composite endpoint (PCE) increased with decreasing ejection fraction (EF) and omecamtiv mecarbil (circles) producing increasing greater absolute reductions in the PCE with decreasing EF as compared to placebo (stars). [0023] Figure 7 shows analysis of ejection fraction as a continuous variable (interaction effect, p = 0.004) demonstrated a progressively larger treatment effect of omecamtiv mecarbil with decreasing ejection fraction (EF).
[0024] Figure 8 shows the difference in the incidence of the primary composite endpoint increased disproportionately between the placebo (stars) and omecamtiv mecarbil (circles) treatment groups with lower ejection fractions.
[0025] Figure 9 shows that absolute risk reduction by omecamtiv mecarbil progressively increased with decreasing ejection fraction (EF).
[0026] Figure 10 shows the beneficial effect of treatment with omecamtiv mecarbil on the primary outcome was driven predominantly by the significant reduction in heart failure events.
[0027] Figure 11 shows the incidence rate of heart failure hospitalizations increases with decreasing ejection fraction in both the placebo (stars) and omecamtiv mecarbil (circles) treated patients, but was significantly impacted by treatment with omecamtiv mecarbil, and showed a progressively greater reduction in the absolute difference with decreasing ejection fraction.
[0028] Figure 12A shows OM had no overall effect on cardiovascular death, neither in the overall population, nor as a function of baseline ejection fraction (EF).
[0029] Figure 12B shows OM the incidence of cardiovascular death increased comparably in both the placebo (stars) and omecamtiv mecarbil (circles) arms with decreasing ejection fraction (EF).
[0030] Figure 13A shows the distribution of baseline ejection fractions in GALACTIC -HF. [0031] Figure 13B shows the distribution of ejection fractions in GALACTIC-HF.
[0032] Figure 14A shows Kaplan-Meier curves comparing patients with and without more advanced heart failure (HF) for each endpoint (CV Death or HF event)
[0033] Figure 14B shows Kaplan-Meier curves comparing patients with and without more advanced heart failure (HF) for each endpoint (CV Death).
[0034] Figure 15A shows event rates for primary endpoints by treatment assignment and advanced heart failure (HF) criteria met (specific advanced HF criteria).
[0035] Figure 15B shows shows event rates for primary endpoints by treatment assignment and advanced heart failure (HF) criteria met (total number of advanced HF criteria met).
[0036] Figure 16A shows outcomes according to baseline NT-proBNP in the prespecified analysis population (no atrial fibrillation/flutter at baseline) randomized (primary composite outcome) (placebo - stars; omecamtiv mecarbil - circles).
[0037] Figure 16B shows outcomes according to baseline NT-proBNP in the prespecified analysis population (no atrial fibrillation/flutter at baseline) randomized (HF hospitalization) (placebo - stars; omecamtiv mecarbil - circles).
[0038] Figure 16C shows outcomes according to baseline NT-proBNP in the prespecified analysis population (no atrial fibrillation/flutter at baseline) randomized (CV death) (placebo - stars; omecamtiv mecarbil - circles).
[0039] Figure 16D shows outcomes according to baseline NT-proBNP in the prespecified analysis population (no atrial fibrillation/flutter at baseline) randomized (all-cause mortality) (placebo - stars; omecamtiv mecarbil - circles).
[0040] Figure 17A shows outcomes according to baseline NT-proBNP in the prespecified analysis population in all patients randomized (primary composite outcome) (placebo - stars; omecamtiv mecarbil - circles).
[0041] Figure 17B shows outcomes according to baseline NT-proBNP in the prespecified analysis population in all patients randomized (HF hospitalization) (placebo - stars; omecamtiv mecarbil - circles).
[0042] Figure 17C shows outcomes according to baseline NT-proBNP in the prespecified analysis population in all patients randomized (CV death) (placebo - stars; omecamtiv mecarbil - circles).
[0043] Figure 17D shows outcomes according to baseline NT-proBNP in the prespecified analysis population in all patients randomized (all-cause mortality) (placebo - stars; omecamtiv mecarbil - circles). [0044] Figure 18A shows effect of randomized treatment on outcomes according to baseline NT-proBNP concentration (shown as a continuous measure) in the prespecified analysis population (no atrial fibrillation/flutter at baseline) randomized (primary composite outcome).
[0045] Figure 18B shows effect of randomized treatment on outcomes according to baseline NT-proBNP concentration (shown as a continuous measure) in the prespecified analysis population (no atrial fibrillation/flutter at baseline) randomized (HF hospitalization). [0046] Figure 18C shows effect of randomized treatment on outcomes according to baseline NT-proBNP concentration (shown as a continuous measure) in the prespecified analysis population (no atrial fibrillation/flutter at baseline) randomized (CV death).
[0047] Figure 18D shows effect of randomized treatment on outcomes according to baseline NT-proBNP concentration (shown as a continuous measure) in the prespecified analysis population (no atrial fibrillation/flutter at baseline) randomized (all cause mortality). [0048] Figure 19A shows effect of randomized treatment on outcomes according to baseline NT-proBNP concentration (shown as a continuous measure) in the prespecified analysis population in all patients randomized (primary composite outcome).
[0049] Figure 19B shows effect of randomized treatment on outcomes according to baseline NT-proBNP concentration (shown as a continuous measure) in the prespecified analysis population in all patients randomized (HF hospitalization).
[0050] Figure 19C shows effect of randomized treatment on outcomes according to baseline NT-proBNP concentration (shown as a continuous measure) in the prespecified analysis population in all patients randomized (CV death).
[0051] Figure 19D shows effect of randomized treatment on outcomes according to baseline NT-proBNP concentration (shown as a continuous measure) in the prespecified analysis population in all patients randomized (all cause mortality).
[0052] Figure 20A shows effect of omecamtiv mecarbil, compared with placebo, on NT- proBNP after randomization in the prespecified analysis population (no atrial fibrillation/flutter at baseline and all NT-proBNP concentrations).
[0053] Figure 20B shows effect of omecamtiv mecarbil, compared with placebo, on NT- proBNP after randomization in the prespecified analysis population (no atrial fibrillation/flutter at baseline, NT-proBNP > median).
[0054] Figure 20C shows effect of omecamtiv mecarbil, compared with placebo, on NT- proBNP after randomization in the prespecified analysis population (no atrial fibrillation/flutter at baseline, NT-proBNP < median). [0055] Figure 20D shows effect of omecamtiv mecarbil, compared with placebo, on NT- proBNP in all patients randomized (all NT-proBNP concentrations).
[0056] Figure 20E shows effect of omecamtiv mecarbil, compared with placebo, on NT- proBNP in all patients randomized (NT-proBNP > median).
[0057] Figure 20F shows effect of omecamtiv mecarbil, compared with placebo, on NT- proBNP in all patients randomized (NT-proBNP < median).
[0058] Figure 21 A shows the proportion of patients having AFF as a function of the percentage of LVEF.
[0059] Figure 2 IB shows effect of omecamtiv mecarbil in patients with or without AFF who were or were not receiving digoxin.
[0060] Figure 21C shows the effect of omecamtiv mecarbil in patients with or without AFF on mortality, for cardiovascular death or all-cause death, and heart failure hospitalization.
[0061] Figure 2 ID shows the effect of omecamtiv mecarbil in patients with or without AFF who were or were not receiving digoxin on mortality, for cardiovascular death or all-cause death, and heart failure hospitalization.
[0062] Figure 2 IE shows the effect of omecamtiv mecarbil in patients with AFF as compared to placebo on the occurrence of serious adverse events.
[0063] Figure 2 IF shows arithmetic mean pharmacokinetic concentration-time profiles for digoxin administration alone and digoxin administration with omecamtiv mecarbil.
[0064] Figure 21G shows geometric mean pharmacokinetic parameters for digoxin administration alone and digoxin administration with omecamtiv mecarbil.
[0065] Figure 22 shows Kaplan-Meier curves for primary composite endpoint by EF quartile.
[0066] Figure 23 A shows outcomes according to baseline systolic blood pressure (SBP) in all patients randomized (primary composite outcome) (placebo - stars; omecamtiv mecarbil - circles).
[0067] Figure 23B shows the treatment effect of omecamtiv mecarbil on primary composite outcomes according to baseline systolic blood pressure (SBP).
[0068] Figure 24 shows the incidence of stroke (fatal and non-fatal stroke events) in all patients randomized.
[0069] Figure 25 shows the treatment effect of omecamtiv mecarbil in patients with or without a history of stroke as compared to placebo on the occurrence of stroke (fatal and non- fatal stroke events) (placebo - stars; omecamtiv mecarbil - circles). [0070] Figure 26 shows the treatment effect of omecamtiv mecarbil in patients with or without a history of atrial fibrillation as compared to placebo on the occurrence of stroke (fatal and non-fatal stroke events) (placebo - stars; omecamtiv mecarbil - circles).
[0071] Figure 27 shows the treatment effect of omecamtiv mecarbil in patients without an atrial fibrillation / atrial flutter (AFF) at screening and those without a history of AFF as compared to placebo on the occurrence of new-onset AFF (placebo - stars; omecamtiv mecarbil - circles).
DETAILED DESCRIPTION
[0072] Described herein are methods of treating heart failure using a cardiac sarcomere activator (e.g., omecamtiv mecarbil or a pharmaceutically acceptable salt and/or hydrate thereof). Treatment methods may include adjusting a dose level, for example to increase, decrease, maintain, or discontinue a dose level, based on one or more signs or symptoms of acute myocardial ischemia or myocardial infarction e.g., chest pain, shortness of breath, and/or unstable angina). Provided herein are also blood-test-free dose adjustment regimens for treating heart failure in a subject in need thereof using a cardiac sarcomere activator (CSA). For example, a dose level of the CSA may be increased without taking a blood sample from the subject if the subject does not experience signs or symptoms of acute myocardial ischemia or myocardial infarction, including but not limited to, chest pain and shortness of breath.
Definitions
[0073] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
[0074] Reference to “about” a value or parameter herein includes (and describes) that value or parameter per se, and any value or parameter 5% above or 5% below said parameter. For example, description to “about X” includes description of “X” and “X +/- 5%”.
[0075] “NYHA classification” or “NYHA class” refers to the New York Heart Association functional classification of heart failure symptoms. Descriptions of each of NYHA classes I, II, III, and IV can be found in “Classes of Heart Failure”, American Heart Association, https://www.heart.org/en/health-topics/heart-failure/what-is-heart-failure/classes-of-heart- failure, adapted from: 1) Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart Association. Criteria Committee. “Nomenclature and criteria for diagnosis of diseases of the heart and great vessels”. 9th ed. Boston, MA: Lippincott Williams and Wilkins; March 1, 1994; and 2) Criteria Committee, New York Heart Association, Inc. Diseases of the Heart and Blood Vessels. Nomenclature and Criteria for diagnosis, 6th edition Boston, Little, Brown and Co. 1964, p 114. Briefly, NYHA class I indicates that the patient has no limitation of physical activity; ordinary physical activity does not cause undue fatigue, palpitation, dyspnea (shortness of breath). NYHA class II indicates that the patient has slight limitation of physical activity; comfortable at rest; ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of breath). NYHA class III indicates that the patient has marked limitation of physical activity; comfortable at rest; less than ordinary physical activity causes fatigue, palpitation, or dyspnea. NYHA class IV indicates that the patient is unable to carry on any physical activity without discomfort; symptoms of heart failure at rest; if any physical activity is undertaken, discomfort increases.
[0076] The term “pharmaceutically acceptable salt” refers to a salt of any of the compounds herein that are known to be non-toxic and are commonly used in the pharmaceutical literature. In some embodiments, the pharmaceutically acceptable salt of a compound retains the biological effectiveness of the compounds described herein and are not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, p- toluenesulfonic acid, stearic acid and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines including naturally occurring substituted amines; cyclic amines; and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts. [0077] If the compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the compound is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds (see, e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19). Those skilled in the art will recognize various synthetic methodologies that may be used to prepare pharmaceutically acceptable addition salts.
[0078] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.
[0079] The terms “patient,” “individual,” and “subject” refer to an animal, such as a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows and humans. In some embodiments, the patient or subject is a human, for example a human that has been or will be the object of treatment, observation or experiment. The compounds, compositions and methods described herein can be useful in both human therapy and veterinary applications.
[0080] The term “therapeutically effective amount” or “effective amount” refers to that amount of a compound disclosed and/or described herein that is sufficient to affect treatment, as defined herein, when administered to a patient in need of such treatment. A therapeutically effective amount of a compound may be an amount sufficient to treat a disease responsive to modulation of the cardiac sarcomere. The therapeutically effective amount will vary depending upon, for example, the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound, the dosing regimen to be followed, timing of administration, the manner of administration, all of which can readily be determined by one of ordinary skill in the art. The therapeutically effective amount may be ascertained experimentally, for example by assaying blood concentration of the chemical entity, or theoretically, by calculating bioavailability.
[0081] “ Treatment” (and related terms, such as “treat”, “treated”, "treating") includes one or more of: inhibiting a disease or disorder; slowing or arresting the development of clinical symptoms of a disease or disorder; and/or relieving a disease or disorder (i.e., causing relief from or regression of clinical symptoms). The term covers both complete and partial reduction or prevention of the condition or disorder, and complete or partial reduction of clinical symptoms of a disease or disorder. Thus, compounds described and/or disclosed herein may prevent an existing disease or disorder from worsening, assist in the management of the disease or disorder, or reduce or eliminate the disease or disorder.
[0082] Reference to any dose amount of a compound or pharmaceutically acceptable salt thereof described herein (e.g, 25 mg, 37.5 mg, 50 mg, etc. of omecamtiv mecarbil) refers to the amount (e.g., equivalent mass) of said compound without any salt (e.g., omecamtiv mecarbil anhydrous free base).
Cardiac Sarcomere Activators (CSA)
[0083] In some embodiments, a CSA induces the activation of by, e.g., sensitizing cardiac myofilaments to Ca2+, activating troponin or tropomyosin, or directly activating the cardiac myosin. In some embodiments, a CSA promotes sarcomere responsiveness to calcium (Ca2+). In some embodiments, the CSA is omecamtiv mecarbil or a pharmaceutically acceptable salt (e.g., omecamtiv mecarbil hydrochloride salt) or a pharmaceutically acceptable hydrate of a pharmaceutically acceptable salt (e.g, omecamtiv mecarbil dihydrochloride hydrate).
Omecamtiv mecarbil (OM)
[0084] Omecamtiv mecarbil, also known as CK-1827452 or AMG 423, is a first in class direct activator of cardiac myosin that directly targets the contractile mechanisms of cardiac myocytes intended to enhance efficiency of myocardial contraction in patients suffering from a cardiovascular condition, such as heart failure. The free base of omecamtiv mecarbil is described chemically as methyl 4-(2-fluoro-3-(3-(6-methylpyridin-3- yl)ureido)benzyl)piperazine-l -carboxylate having the structural formula:
Figure imgf000014_0001
[0085] Omecamtiv mecarbil is disclosed in U.S. Patent No. 7,507,735 titled “Compounds, Compositions and Method”, the entirety of which is incorporated herein by reference.
Description of omecamtiv mecarbil and method of making omecamtiv mecarbil can be found in, e.g., Example 3 column 55 and 56 of the above referenced patent, which are incorporated herein by reference.
[0086] Omecamtiv mecarbil was the subject of several Phase 2 clinical trials, including Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF), which evaluated omecamtiv mecarbil in patients with chronic heart failure and left ventricular systolic dysfunction (see, e.g., NCT01786512). Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF), was a Phase 3 global cardiovascular outcomes study, which demonstrated a statistically significant effect of treatment with omecamtiv mecarbil to reduce risk of the primary composite endpoint of cardiovascular death or heart failure events compared to placebo in patients treated with standard of care (see, e.g., NCT02929329).
[0087] Omecamtiv mecarbil may be in the form of a salt or a hydrate of a salt, such as omecamtiv mecarbil dihydrochloride hydrate or omecamtiv mecarbil dihydrochloride monohydrate. The molecular formula of omecamtiv mecarbil dihydrochloride hydrate is C20H24FN5O3-2HCI-H2O, with a relative molecular weight of 492.37 g/mol. In some embodiments, omecamtiv mecarbil is in the form of a base (e.g., omecamtiv mecarbil anhydrous free base). In some embodiments, omecamtiv mecarbil is in the form of a salt (e.g., omecamtiv mecarbil hydrochloride salt). In some embodiments, omecamtiv mecarbil is in the form of a salt hydrate (e.g., omecamtiv mecarbil dihydrochloride monohydrate). Omecamtiv mecarbil dihydrochloride salt forms are disclosed in U.S. Patent No. 9,988,354 titled “Salt of Omecamtiv Mecarbil and Process for Preparing Salt”, the entirety of which in incorporated herein by reference. Other salts or crystalline forms of omecamtiv mecarbil are described in, for example, W02020011626 titles “Crystalline 2-fluoro~3-niirotoluene and process for the preparation thereof’, W02020014406 titled “Solid state forms of omecamtiv mecarbil & omecamtiv mecarbil dihcl”, W02021070123 titled “Solid forms of omecamtiv mecarbil dihydrochloride and processes thereof’, WO2021053175 titled “Saits of omecamtiv mecarbil and solid forms thereof', WO2021053189 titled "Salts of omecamtiv mecarbil and solid forms thereof”, WO2021136477 titled “Cocrystal of dihydrochloride of co pound i and preparation method therefor and use thereof’, and W02021070124 titled “Alternate processes for the preparation of omecamtiv mecarbil”.
[0088] A pharmaceutical formulation of omecamtiv mecarbil for oral administration is disclosed in U.S. Patent No. 9,951,015 titled “Heterocyclic Compounds and Their Uses”, the entirety of which is incorporated herein by reference. Methods
[0089] Described herein are methods of treating heart failure in a subject in need thereof with a CSA (e.g., omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof). The CSA can be used to treat heart failure, such as, reducing the risk of cardiovascular death and heart failure events in subjects with symptomatic chronic heart failure with reduced ejection fraction. Also described herein are dosing regimens of the CSA in the treatment of heart failure, in which the dose levels of the CSA may be adjusted without taking a blood sample from the subject, unless the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction. For example, if the subject experiences no signs or symptoms of acute myocardial ischemia or myocardial infarction after administration of an initial dose level of the CSA for a period of time, subsequent dose level of the CSA may be increased without a blood test. Benefits of a blood-test-free dose adjustment regimen include, but are not limited to, improved patient compliance, lower health care costs, ease of dosing, decreased barriers to care, broader availability, broader uptake, and less invasive procedures. If the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction, administration of the CSA may be withheld. Subsequent treatment may be determined based on whether the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction experienced by the subject are related to the administration of the CSA.
[0090] In another example, a first dose level (e.g., 25 mg BID or 30 mg BID) of the CSA may be given to the subject for an initial period of time (e.g., about 2 weeks or at least 2 weeks.). If the subject experiences no signs or symptoms of acute myocardial ischemia or myocardial infarction (e.g., chest pain or shortness of breath) during the initial period of time, a second dose level (e.g., 37.5 mg BID or 45 mg BID) of the CSA may be given to the subject for a second period of time (e.g., about 2 weeks or at least 2 weeks) wherein the second dose level may be greater than the first dose level. If the subject experiences no signs or symptoms of acute myocardial ischemia or myocardial infarction during the second period of time, a third dose level of the CSA may be given to the subject, wherein the third dose level may be greater than the second dose level.
[0091] If the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction during the initial period of time and/or the second period of time, administration of the CSA may be withheld. If the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are not related to the CSA, administration of the CSA may be resumed at the same dose level being administered before the CSA was withheld. For example, if the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction after given a first dose level of CSA, administration of the CSA may be withheld, and if the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are not related to the CSA, the administration of the CSA may be resumed at the same dose level as the first dose level. If the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction after given a second dose level of CSA, administration of the CSA may be withheld, and if the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are not related to the CSA, the administration of the CSA may be resumed at the same dose level as the second dose level. If the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction, measurement of the plasma concentration of the CSA may be conducted as part of any routine clinical assessment of the ischemic event and may inform whether the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related or not to the CSA. A routine clinical assessment of the ischemic event may include, for example, electrocardiogram (ECG), biomarkers including but not limited to troponin, potential invasive or non-invasive testing such as stress testing, coronary computed tomography angiography (CTA), or invasive angiography.
[0092] If the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related to the CSA, administration of the CSA may be discontinued or the dose level of the CSA may be decreased. For example, if the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction after given a first dose level of CSA, administration of the CSA may be withheld, and if the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related to the CSA, administration of the CSA may be discontinued. If the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction after given a second dose level of CSA, administration of the CSA may be withheld, and if the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related to the CSA, subsequent administration of the CSA is decrease to the first dose level. If the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction after given a third dose level of CSA, administration of the CSA may be withheld, and if the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related to the CSA, subsequent administration of the CSA is decrease to the second dose level or the first dose level.
[0093] In some embodiments, in conjunction with embodiments above or below, treatment does not include taking a blood sample from the subject to determine the plasma concentration of the CSA. For example, if the subject experiences no signs or symptoms of acute myocardial ischemia or myocardial infarction (e.g., chest pain, shortness of breath, or unstable angina) during the initial period of time, a second dose level of the CSA may be given to the subject for a second period of time without taking a blood sample from the subject to determine the plasma concentration of the CSA. If the subject experiences no signs or symptoms of acute myocardial ischemia or myocardial infarction (e.g., chest pain, shortness of breath, or unstable angina) during the second period of time, a third dose level of the CSA may be given to the subject without taking a blood sample from the subject to determine the plasma concentration of the CSA. In some embodiments, in conjunction with embodiments above or below, the signs or symptoms of acute myocardial ischemia or myocardial infarction comprise chest pain and shortness of breath. In some embodiments, in conjunction with embodiments above or below, the signs or symptoms of acute myocardial ischemia or myocardial infarction comprise chest pain. In some embodiments, in conjunction with embodiments above or below, the signs or symptoms of acute myocardial ischemia or myocardial infarction comprise shortness of breath. In some embodiments, in conjunction with embodiments above or below, the signs or symptoms of acute myocardial ischemia or myocardial infarction comprise chest pain. In some embodiments, in conjunction with embodiments above or below, the signs or symptoms of acute myocardial ischemia or myocardial infarction comprise one or more symptoms of unstable angina, neck or jaw pain, back pain, shoulder or arm pain, fast or irregular heartbeat, nausea, vomiting, sweating, fatigue, chest pressure, tightness, heaviness, discomfort or squeezing, burning feeling, difficulty in breathing, fullness, numbness, feeling weak, light-headed, and/or faint.
[0094] In some embodiments, in conjunction with embodiments above or below, treatment does not include taking a blood sample from the subject to determine the plasma concentration of the CSA except if the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction. For example, if the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction during the initial period of time, determination of the plasma concentration of the CSA may be conducted to determine if the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related to the CSA. If the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction during the second period of time, determination of the plasma concentration of the CSA may be conducted to determine if the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related to the CSA. For example, if the subject’s plasma concentration of the CSA is above 1200 ng/mL after administration of the CSA, then the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction may be related to the CSA. If the subject’s plasma concentration of the CSA is less than or about 1200 ng/mL after administration of the CSA, then the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are not likely to be related to the CSA.
[0095] In some embodiments, in conjunction with embodiments above or below, treatment comprises an initial period of time. In some embodiments, in conjunction with embodiments above or below, treatment comprises an initial period of time and a second period of time. In some embodiments, in conjunction with embodiments above or below, treatment comprises an initial period of time, a second period of time, and a third period of time. In some embodiments, the initial period of time is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, at least 1 week (e.g., 1 week or 1.5 weeks), at least 2 weeks (e.g., 2 weeks, 2.5 weeks, 3 weeks, or 3.5 weeks), at least 4 weeks (e.g., 4 weeks, 4.5 weeks, 5 weeks, or 5.5 weeks), from 1 to 2 weeks, from 1 to 3 weeks, or from 1 to 4 weeks. In some embodiments, the second period of time is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, at least 1 week (e.g, 1 week or 1.5 weeks), at least 2 weeks (e.g, 2 weeks, 2.5 weeks, 3 weeks, or 3.5 weeks), at least 4 weeks (e.g., 4 weeks, 4.5 weeks, 5 weeks, or 5.5 weeks), from 1 to 2 weeks, from 1 to 3 weeks, or from 1 to 4 weeks, or for about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or as long as the subject does not experience one or more signs or symptoms of acute myocardial ischemia or myocardial infarction. In some embodiments, the third period of time is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, at least 1 week (e.g., 1 week or 1.5 weeks), at least 2 weeks (e.g., 2 weeks, 2.5 weeks, 3 weeks, or 3.5 weeks), at least 4 weeks (e.g., 4 weeks, 4.5 weeks, 5 weeks, or 5.5 weeks), from 1 to 2 weeks, from 1 to 3 weeks, or from 1 to 4 weeks, or for about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or as long as the subject does not experience one or more signs or symptoms of acute myocardial ischemia or myocardial infarction.
[0096] In some embodiments, in conjunction with embodiments above or below, treatment comprises administering to a subject in need thereof a first dose level of a CSA (e.g., omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof) for an initial period of time. In some embodiments, the first dose level is from about 20 mg to about 50 mg twice daily.
[0097] In some embodiments, the treatment comprises administering to the subject a first dose level of the CSA for an initial period of time, wherein the first dose level is from about 20 mg to about 50 mg twice daily, from about 25 mg to about 40 mg twice daily, from about 30 mg to 40 mg twice daily, from about 40 mg to 50 mg twice daily, or from about 35 mg to 40 mg twice daily. In some embodiments, the treatment comprises administering to the subject a first dose level of the CSA for an initial period of time, wherein the first dose level is from about 20 mg to about 35 mg twice daily, from about 25 to about 35 twice daily, or from about 30 mg to about 35 mg twice daily. In some embodiments, the treatment comprises administering to the subject a first dose level of the CSA for an initial period of time, wherein the first dose level is from about 20 mg to about 30 mg twice daily or from about 25 mg to 30 mg twice daily. In some embodiments, the treatment comprises administering to the subject a first dose level of the CSA for an initial period of time, wherein the first dose level is from about 20 to about 25 mg twice daily. In some embodiments, the treatment comprises administering to the subject a first dose level of the CSA for an initial period of time, wherein the first dose level 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, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg or about 35 mg twice daily. In some embodiments, the treatment comprises administering to the subject a first dose level of the CSA for an initial period of time, wherein the first dose level is from about 20 to about 25 mg twice daily. In some embodiments, the treatment comprises administering to the subject a first dose level of the CSA for an initial period of time, wherein first dose level is about 20.5 mg, about 21.5 mg, about 22.5 mg, about 23.5 mg, about 24.5 mg, about 25.5 mg, about 26.5 mg, about 27.5 mg, about 28.5 mg, or about 29.5 mg twice daily.
[0098] In some embodiments, in conjunction with embodiments above or below, treatment comprises administering to a subject in need thereof a second dose level of a CSA (e.g. omecamtiv mecarbil) for a second period of time. In some embodiments, the second dose level is greater than or the same as the first dose level. In some embodiments, the second dose level is greater than the first dose level. In some embodiments, the second dose level is the same as the first dose level.
[0099] In some embodiments, in conjunction with embodiments above or below, treatment comprises administering to a subject in need thereof a third dose level of a CSA (e.g. omecamtiv mecarbil). In some embodiments, the third dose level is greater than or the same as the second dose level. In some embodiments, the third dose level is less than or the same as the second dose level. In some embodiments, the third dose level is greater than the second dose level. In some embodiments, the third dose level is the same as the second dose level. In some embodiments, the third dose level is less than the second dose level. In some embodiments, the third dose level is greater than or the same as the first dose level. In some embodiments, the third dose level is greater than the first dose level. In some embodiments, the third dose level is the same as the first dose level.
[0100] In some embodiments, in conjunction with embodiments above or below, treatment comprises administering to a subject in need thereof a fourth dose level of a CSA (e.g. omecamtiv mecarbil). In some embodiments, the fourth dose level is the same as or more than the third dose level. In some embodiments, the fourth dose level is the same as or less than the third dose level. In some embodiments, the fourth dose level is the same as the third dose level. In some embodiments, the fourth dose level is the same as the second dose level. In some embodiments, the fourth dose level is the same as the first dose level.
[0101] In some embodiments, in conjunction with embodiments above or below, treatment comprises administering to a subject in need thereof a second dose level of a CSA (e.g. omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof,) for a second period of time. In some embodiments, the second dose level of the CSA is from about 35 mg to about 50 mg twice daily, from about 35 mg to about 40 mg twice daily, from about 40 mg to 45 mg twice daily, from about 45 mg to 50 mg twice daily, or from about 40 mg to about 50 mg twice daily. In some embodiments, the second dose level is from about 35 mg to about 45 mg twice daily, or from about 40 to about 50 twice daily. In some embodiments, the second dose level is about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg or about 50 mg twice daily. In some embodiments, the second dose level is about 30.5 mg, about 31.5 mg, about 32.5 mg, about 33.5 mg, about 34.5 mg, about 35.5 mg, about 36.5 mg, about 37.5 mg, about 38.5 mg, or about 39.5 mg twice daily.
[0102] In some embodiments, in conjunction with embodiments above or below, treatment comprises administering to a subject in need thereof a third dose level of a CSA (e.g. omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof,) for a third period of time. In some embodiments, the third dose level of the CSA is from about 40 mg to about 60 mg twice daily, from about 45 mg to about 55 mg twice daily, from about 40 mg to 50 mg twice daily, from about 50 mg to 60 mg twice daily, or from about 48 mg to about 52 mg twice daily. In some embodiments, the third dose level is about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg or about 55 mg twice daily. In some embodiments, the third dose level is about 44.5 mg, about
45.5 mg, about 46.5 mg, about 47.5 mg, about 48.5 mg, about 49.5 mg, about 50.5 mg, about
51.5 mg, about 52.5 mg, or about 53.5 mg twice daily.
[0103] In some embodiments, in conjunction with embodiments above or below, treatment comprises administering to the subject a first dose level of the CSA of about 25 mg twice daily for an initial period of time. In some embodiments, treatment comprises administering to the subject a first dose level of the CSA of about 25 mg twice daily for an initial period of time, and administering to the subject a second dose level of the CSA of about 37.5 mg twice daily for a second period of time, wherein the subject experiences no signs or symptoms of acute myocardial ischemia or myocardial infarction during the initial period of time. In some embodiments, the first period of time is about 2 weeks, or at least 2 weeks. In some embodiments, the second period of time is about 2 weeks, or at least 2 weeks, or indefinite, or until the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction. In this context, indefinite means that administration continues as long as its benefits the patient and/or there are no significant side effects or other reasons to stop treatment.
[0104] In some embodiments, treatment comprises administering to the subject a first dose level of the CSA of about 25 mg twice daily for an initial period of time, administering to the subject a second dose level of the CSA of about 37.5 mg twice daily for a second period of time, and administering to the subject a third dose level of the CSA of about 50 mg twice daily, wherein the subject experiences no signs or symptoms of acute myocardial ischemia or myocardial infarction during the initial period of time or the second period of time. In some embodiments, the first period of time, and the second period of time are both about 2 weeks, or at least 2 weeks. In some embodiments, the third period of time is about 2 weeks, or at least 2 weeks, or indefinite, or until the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction. In this context, indefinite means that administration continues as long as its benefits the patient and/or there are no significant side effects or other reasons to stop treatment.
[0105] In some embodiments, treatment comprises administering to the subject a first dose level of the CSA of about 25 mg twice daily for an initial period of time, and administering to the subject a second dose level of the CSA of about 25 mg twice daily, wherein the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction during the initial period of time, and wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are not related to the CSA. In some embodiments, treatment comprises administering to the subject a first dose level of the CSA of about 25 mg twice daily for an initial period of time, and administration of the CSA is discontinued, wherein the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction during the initial period of time, and wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related to the CSA.
[0106] In some embodiments, treatment comprises administering to the subject a first dose level of the CSA of about 25 mg twice daily for an initial period of time, administering to the subject a second dose level of the CSA of about 37.5 mg twice daily for a second period of time, and administering to the subject a third dose level of the CSA of about 37.5 mg twice daily, wherein the subject experiences no signs or symptoms of acute myocardial ischemia or myocardial infarction during the initial period of time but experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction during the second period of time, and wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are not related to the CSA. In some embodiments, treatment comprises administering to the subject a first dose level of the CSA of about 25 mg twice daily for an initial period of time, administering to the subject a second dose level of the CSA of about 37.5 mg twice daily for a second period of time, and administering to the subject a third dose level of the CSA of about 25 mg twice daily, wherein the subject experiences no signs or symptoms of acute myocardial ischemia or myocardial infarction during the initial period of time but experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction during the second period of time, and wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related to the CSA.
[0107] In some embodiments, treatment comprises administering to the subject a first dose level of the CSA of about 25 mg twice daily for an initial period of time, administering to the subject a second dose level of the CSA of about 37.5 mg twice daily for a second period of time, and administering to the subject a third dose level of the CSA of about 50 mg twice daily for a third period of time, wherein the subject experiences no signs or symptoms of acute myocardial ischemia or myocardial infarction during the initial period of time or the second period of time. If the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction during the third period of time, and the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related to the CSA, the subject is administered a fourth dose level of the CSA of about 37.5 mg twice daily or about 25 mg twice daily.
[0108] In some embodiments, in conjunction with embodiments above or below, treatment comprises administering to the subject a first dose level of the CSA of about 30 mg twice daily for an initial period of time. In some embodiments, treatment comprises administering to the subject a first dose level of the CSA of about 30 mg twice daily for an initial period of time, and administering to the subject a second dose level of the CSA of about 45 mg twice daily for a second period of time, wherein the subject experiences no signs or symptoms of acute myocardial ischemia or myocardial infarction during the initial period of time. In some embodiments, the first period of time is about 2 weeks, or at least 2 weeks. In some embodiments, the second period of time is about 2 weeks, or at least 2 weeks, or indefinite, or until the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction. In this context, indefinite means that administration continues as long as its benefits the patient and/or there are no significant side effects or other reasons to stop treatment.
[0109] In some embodiments, in conjunction with embodiments above or below, the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the initiation of the first dose level. In some embodiments, in conjunction with embodiments above or below, the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the initiation of the second dose level. In some embodiments, in conjunction with embodiments above or below, the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the initiation of the third dose level.
Patients
[0110] In some embodiments, in conjunction with embodiments above or below, the subject has chronic heart failure, severe heart failure, or a New York Hear Association (NYHA) Class II or III heart failure. In some embodiments, the subject has heart failure classified as Class III or IV as determined using the NYHA classification. In some embodiments, the subject has chronic heart failure with reduced ejection fraction. In some embodiments, the subject has advanced heart failure. In some embodiments, the subject does not exhibit atrial fibrillation or atrial flutter. In some embodiments, the subject is an inpatient. In some embodiments, the subject is an outpatient. In some embodiments, the subject has low blood pressure, symptomatic hypotension, impaired renal function, or bradycardia. In some embodiments, the subject has not previously been treated with one or more of an angiotensin-converting enzyme inhibitor, an angiotensin II receptor blocker, a beta blocker, a diuretic, an aldosterone antagonist, an inotrope, neprilysin inhibitors, digitalis, and digoxin.
Atrial Fibrillation/Flutter (AF/F)
[OHl] In some embodiments, in conjunction with embodiments above or below, the subject is without AF/F. In some embodiments, in conjunction with embodiments above or below, the subject is with AF/F. In some embodiments, in conjunction with embodiments above or below, the subject is taking digoxin. In some embodiments, in conjunction with embodiments above or below, the subject is not taking digoxin. In some embodiments, the subject is without AFF and the subject is not taking digoxin. In some embodiments, the subject is without AFF and the subject is taking digoxin. In some embodiments, the subject is with AFF and the subject is not taking digoxin. In some embodiments, the subject is with AFF and the subject is taking digoxin.
Ejection Fraction
[0112] In some embodiments, in conjunction with embodiments above or below, the subject has low left ventricular ejection fraction (LVEF), such as about 40% or lower (e.g., about 40%, about 39%, about 38%, about 37%, or about 36%), or about 39% or lower, or about 38% or lower, or about 37% or lower, or about 36% or lower, or about 35% or lower (e.g., about 35%, about 34%, about 33%, about 32%, about 31%), or about 34% or lower, or about 33% or lower, or about 32% or lower, or about 31% or lower, or about 30% or lower, or about 29% or lower, or about 28% or lower, or about 27% or lower, or about 26% or lower, or about 25% or lower, or about 24% or lower, or about 23% or lower, or about 22% or lower. In some embodiments, in conjunction with embodiment about or below, the subject has a LVEF of about 30%, about 29%, about 28%, about 27%, about 26%, about 25%, about 24%, about 23%, about 22%, about 21%, about 20%, about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, or about 10%. In some embodiments, the subject has a LVEF of less than 40%. In some embodiments, the subject has a LVEF of less than 35%. In some embodiments, the subject has a LVEF of less than 30%. In some embodiments, the subject has a LVEF of less than 28%. In some embodiments, the subject has a LVEF of less than 25%. In some embodiments, the subject has a LVEF of less than 22%.
[0113] In some embodiments, the subject has a LVEF of less than 35% and the subject is without AF/F. In some embodiments, the subject has a LVEF of less than 30% and the subject is without AF/F. In some embodiments, the subject has a LVEF of less than 28% and the subject is without AF/F. In some embodiments, the subject has a LVEF of less than 25% and the subject is without AF/F. In some embodiments, the subject has a LVEF of less than 22% and the subject is without AF/F. In some embodiments, the subject has a LVEF of less than 35%, the subject is without AF/F, and the subject is not taking digoxin. In some embodiments, the subject has a LVEF of less than 30%, the subject is without AF/F, and the subject is not taking digoxin. In some embodiments, the subject has a LVEF of less than 28%, the subject is without AF/F, and the subject is not taking digoxin. In some embodiments, the subject has a LVEF of less than 25%, the subject is without AF/F, and the subject is not taking digoxin. In some embodiments, the subject has a LVEF of less than 22%, the subject is without AF/F, and the subject is not taking digoxin.
Advanced Heart Failure
[0114] In some embodiments, in conjunction with embodiments above or below, the subject has advanced heart failure (HF). Subjects with advanced HF may have markers of more severe disease, including but not limited to, lower ejection fraction, greater NYHA class, higher NT-proBNP concentrations, lower systolic blood pressure, worse renal function, and worse quality of life as assessed by the KCCQ TSS. Subjects with advanced HF may less likely be treated with renin-angiotensin-aldosterone system (RAAS) modulators and beta blockers at baseline but more likely to have cardiac resynchronization therapy (CRT) or an implantable cardioverter defibrillator (ICD).
N-terminal pro-B-type natriuretic peptide (NT-proBNP) Level
[0115] In some embodiments, in conjunction with embodiments above or below, the subject has high NT-proBNP level, such as at least about 1500 pg/mL (e.g., 1500, 1600, 1700, 1800, and 1900 pg/mL), at least about 2000 pg/mL (e.g., 2000, 2100, 2200, 2300, and 2400 pg/mL), at least about 2500 pg/mL (e.g, 2500, 2600, 2700, 2800, and 2900 pg/mL), or at least 3000 pg/mL (e.g, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 7000, 8000, 9000, 10,000, 15,000, and 20,000 pg/ml). In some embodiments, the subject has NT-proBNP level of at least about 1500 pg/mL. In some embodiments, the subject has NT-proBNP level of at least about 2000 pg/mL. In some embodiments, the subject has NT-proBNP level of at least about 2500 pg/mL. In some embodiments, the subject has NT -proBNP level of at least about 3000 pg/mL. In some embodiments, in conjunction with embodiments above or below, the subject is without AF/F.
[0116] In some embodiments, the subject has NT-proBNP level of at least about 1500 pg/mL and the subject is without AF/F. In some embodiments, the subject has NT-proBNP level of at least about 2000 pg/mL and the subject is without AF/F. In some embodiments, the subject has NT-proBNP level of at least about 2500 pg/mL and the subject is without AF/F. In some embodiments, the subject has NT-proBNP level of at least about 3000 pg/mL and the subject is without AF/F.
[0117] In some embodiments, in conjunction with embodiments above or below, the subject has NT-proBNT level of at least about 200 pg/mL (e.g., 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, and 1400 pg/mL). In some embodiments, the subject has NT-proBNT level of from about 200 pg/mL to about 1500 pg/mL.
Systolic Blood Pressure (SBP)
[0118] In some embodiments, in conjunction with embodiments above or below, the subject has low SBP, such as less than 100 mm Hg (e.g., 99, 98, 97, 96, 95, 94, 93, 91, 90, 89, 88, 87, 86, and 85 mm/Hg). In some embodiments, the subject has a SBP of at least or about 100 mm Hg.
Hepatic Impairment
[0119] In some embodiments, in conjunction with embodiments above or below, the subject has hepatic impairment (e.g., mild, moderate, or severe hepatic impairment). In some embodiments, the subject has normal hepatic function.
[0120] In some embodiments, in conjunction with embodiments above or below, treatment is effective to reduce the risk of heart failure events in the subject. A heart failure event includes, but is not limited to, urgent clinic visit, emergency department visit, or hospitalization for subjectively and objectively worsening heart failure leading to treatment intensification beyond a change in oral diuretic therapy. In some embodiments, treatment may be more effective in subjects with lower baseline ejection fraction.
[0121] In some embodiments, in conjunction with embodiments above or below, treatment is effective to reduce the risk of death, such as fatal stroke in a subject. In some embodiments, treatment is effective to reduce the risk of fatal stroke or non-fatal stroke in a subject (e.g., patient with chronic heart failure). Enumerated Embodiments
[0122] Embodiment 1. A method of treating heart failure in a subject in need thereof, comprising: a) administering to the subject a first dose level of a cardiac sarcomere activator (CSA) for an initial period of time; and b) administering to the subject a second dose level of the CSA for a second period of time, wherein the second dose level is greater than the first dose level, wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof, and wherein administering the CSA is withheld if the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction.
[0123] Embodiment 2. The method of embodiment 1, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction comprise chest pain and shortness of breath.
[0124] Embodiment 3. The method of embodiment 1 or 2, wherein the method further comprises step c) administering to the subject a third dose level of the CSA, wherein the third dose level is greater than the second dose level, wherein the method does not include taking a blood sample from the subject to determine the plasma concentration of the CSA, and wherein administering the CSA is withheld if the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction.
[0125] Embodiment 4. The method of any one of embodiments 1 to 3, wherein if the CSA is withheld for a period of time, and if the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are not related to the CSA, administration of the CSA is resumed at the same dose level being administered before the CSA was withheld. [0126] Embodiment 5. The method of any one of embodiments 1 to 3, wherein if the CSA is withheld for a period of time, and if it is determined that the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related to the CSA, then the CSA’s dose level is decreased or discontinued.
[0127] Embodiment 6. The method of embodiment 5, wherein administration of the CSA is decreased.
[0128] Embodiment 7. The method of embodiment 6, wherein administration of the CSA is decreased to the first dose level.
[0129] Embodiment 8. The method of embodiment 6, wherein administration of the CSA is decreased to the second dose level.
[0130] Embodiment 9. The method of embodiment 5, wherein administration of the CSA is discontinued. [0131] Embodiment 10. The method of any one of embodiments 1 to 9, wherein the first dose level of the CSA is about 25 mg twice daily.
[0132] Embodiment 11 The method of any one of embodiments 1 to 10, wherein the second dose level of the CSA is about 37.5 mg twice daily.
[0133] Embodiment 12. The method of any one of embodiments 3 to 11, wherein the third dose level of the CSA is about 50 mg twice daily.
[0134] Embodiment 13. The method of any one of embodiments 1 to 12, wherein the initial period of time is about 2 weeks.
[0135] Embodiment 14. The method of any one of embodiments 1 to 12, wherein the initial period of time is at least 2 weeks.
[0136] Embodiment 15. The method of any one of embodiments 1 to 14, wherein the second period of time is about 2 weeks.
[0137] Embodiment 16. The method of any one of embodiments 1 to 14, wherein the second period of time is at least 2 weeks.
[0138] Embodiment 17. The method of any one of embodiments 1 to 16, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after initiation of the first dose level.
[0139] Embodiment 18. The method of any one of embodiments 1 to 17, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after initiation of the second dose level.
[0140] Embodiment 19. The method of any one of embodiments 1 to 18, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after initiation of the third dose level.
[0141] Embodiment 20. The method of any one of embodiments 1 to 19, wherein the method does not include taking a blood sample from the subject to determine the subject’s CSA plasma concentration except if the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction.
[0142] Embodiment 21. The method of any one of embodiments 1 to 20, wherein if the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction, the method further comprises determining the plasma concentration of the CSA to assess whether the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related to the CSA.
[0143] Embodiment 22. The method of embodiment 21, wherein determining the plasma concentration of the CSA comprises taking a blood sample from the subject. [0144] Embodiment 23. The method of any one of embodiments 1 to 22, wherein the subject has chronic heart failure, severe heart failure, or a New York Heart Association Class II or III heart failure.
[0145] Embodiment 24. The method of any one of embodiments 1 to 23, wherein the subject has a left ventricular ejection fraction of about 35% or lower.
[0146] Embodiment 25. The method of any one of embodiments 1 to 24, wherein the subject has a plasma concentration of NT-proBNP of at least about 200 pg/mL.
[0147] Embodiment 26. The method of any one of embodiments 1 to 25, wherein the CSA is omecamtiv mecarbil dihydrochloride hydrate.
[0148] Embodiment 27. The method of any one of embodiments 1 to 26, wherein the CSA is administered orally to the subject.
[0149] Embodiment 28. A method of treating heart failure in a subject in need thereof, comprising: a) administering to the subject a first dose level of a cardiac sarcomere activator (CSA) for an initial period of time; and b) administering to the subject a second dose level of the CSA in accordance with a determination that the subject has not experienced one or more signs or symptoms of acute myocardial ischemia or myocardial infarction, wherein the second dose level is greater than the first dose level, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the first administration of the first dose level of the CSA, and wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof.
[0150] Embodiment 29. The method of embodiment 28, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction comprise chest pain and shortness of breath.
[0151] Embodiment 30. The method of embodiment 28 or 29, wherein the first dose level of the CSA is about 25 mg twice daily.
[0152] Embodiment 31. The method of any one of embodiments 28 to 30, wherein the second dose level of the CSA is about 37.5 mg twice daily.
[0153] Embodiment 32. The method of any one of embodiments 28 to 31, wherein the method further comprises step c) administering to the subject a third dose level of the CSA in accordance with a subsequent determination at about 4 weeks after the first administration of the first dose level of the CSA that the subject has not experienced the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction, wherein the third dose level is greater than the second dose level. [0154] Embodiment 33. The method of embodiment 32, wherein the third dose level of the CSA is about 50 mg twice daily.
[0155] Embodiment 34. A method of treating heart failure in a subject in need thereof, comprising: a) administering to the subject a first dose level of a cardiac sarcomere activator (CSA) for an initial period of time; and b) administering to the subject a second dose level of the CSA in accordance with a determination that one or more signs or symptoms of acute myocardial ischemia or myocardial infarction experienced by the subject are not associated with the CSA, wherein the second dose level is about the same as the first dose level, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the first administration of the first dose level of the CSA, and wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof.
[0156] Embodiment 35. The method of embodiment 34, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction comprise chest pain and shortness of breath.
[0157] Embodiment 36. The method of embodiment 34 or 35, wherein the first and the second dose levels of the CSA are about 25 mg twice daily.
[0158] Embodiment 37. The method of embodiment 34 or 35, wherein the first and the second dose levels of the CSA are about 37.5 mg twice daily.
[0159] Embodiment 38. A method of treating heart failure in a subject in need thereof, comprising: a) administering to the subject a first dose level of a cardiac sarcomere activator (CSA) for an initial period of time; and b) administering to the subject a second dose level of the CSA in accordance with a determination that one or more signs or symptoms of acute myocardial ischemia or myocardial infarction experienced by the subject are associated with the CSA, wherein the second dose level is less than the first dose level, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the first administration of the first dose level of the CSA, and wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof. [0160] Embodiment 39. The method of embodiment 38, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction comprise chest pain and shortness of breath.
[0161] Embodiment 40. The method of embodiment 38 or 39, wherein the first dose level of the CSA is about 37.5 mg twice daily. [0162] Embodiment 41. The method of embodiment 40, wherein the second dose level of the CSA is about 25 mg twice daily.
[0163] Embodiment 42. The method of embodiment 38 or 39, wherein the first dose level of the CSA is about 50 mg twice daily.
[0164] Embodiment 43. The method of embodiment 42, wherein the second dose level of the CSA is about 37.5 mg twice daily.
[0165] Embodiment 44. A method of treating heart failure in a subject in need thereof, comprising: a) administering to the subject a first dose level of a cardiac sarcomere activator (CSA) for an initial period of time; and b) discontinuing the administration in accordance with a determination that one or more signs or symptoms of acute myocardial ischemia or myocardial infarction experienced by the subject are associated with the CSA, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the first administration of the first dose level of the CSA, and wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof.
[0166] Embodiment 45. The method of embodiment 44, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction comprise chest pain and shortness of breath.
[0167] Embodiment 46. The method of embodiment 44 or 45, wherein the first dose level of the CSA is about 25 mg twice daily.
[0168] Embodiment 47. The method of any one of embodiments 28 to 46, wherein the subject has chronic heart failure, severe heart failure, or a New York Heart Association Class II or III heart failure.
[0169] Embodiment 48. The method of any one of embodiments 28 to 47, wherein the subject has a left ventricular ejection fraction of about 35% or lower.
[0170] Embodiment 49. The method of any one of embodiments 28 to 48, wherein the subject has a plasma concentration of NT-proBNP of at least about 200 pg/mL.
[0171] Embodiment 50. The method of any one of embodiments 28 to 49, wherein the CSA is omecamtiv mecarbil dihydrochloride hydrate.
[0172] Embodiment 51. The method of any one of embodiments 28 to 50, wherein the CSA is administered orally to the subject. EXAMPLES
[0173] The application may be better understood by reference to the following non-limiting examples, which are provided as exemplary embodiments of the application. The following examples are presented in order to more fully illustrate embodiments and should in no way be construed, however, as limiting the broad scope of the application. While certain embodiments of the present application have been shown and described herein, it will be obvious that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the spirit and scope of the invention. It should be understood that various alternatives to the embodiments described herein may be employed in practicing the methods described herein. [0174] The following abbreviations are used in the Examples: ACEi refers to angiotensinconverting enzyme inhibitor; ARB refers to angiotensin receptor blocker; ARNi refers to angiotensin receptor-neprilysin inhibitor; BB refers to beta blocker; CRT refers to cardiac resynchronization therapy; ED refers to emergency department; eGFR refers to estimated glomerular filtration rate; HF refers to heart failure; hsTn refers to high-sensitivity troponin I; ICD refers to implantable cardioverter-defibrillator; KCCQ refers to Kansas City Cardiomyopathy Questionnaire; LVEF refers to left ventricular ejection fraction; MAGGIC refers to Meta- Analysis Global Group in Chronic HF; MRA refers to mineralocorticoid receptor antagonist; NEJM refers to The New England Journal of Medicine; NT -proBNP refers to N-terminal pro-B-type natriuretic peptide; NYHA refers to New York Heart Association; SBP refers to systolic blood pressure; and SGLT2 refers to sodium-glucose cotransporter 2.
[0175] The endpoints of studies and event definitions were based on ACC/AHA standards for endpoint definitions in cardiovascular clinical trials as described in Hicks et al. 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials, J Am Coll Cardiol 2018;71 : 1021-34.
Patient Eligibility
[0176] Patient eligibility requirements included age 18-85 years, New York Heart Association functional class (NYHA) II-IV symptoms, and ejection fraction of 35% or less. Participants were currently hospitalized for heart failure (in-patients) or had either an urgent visit to the emergency department or a hospitalization for heart failure (outpatients) within one year prior to randomization. Participants had N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration > 400 pg/mL or BNP > 125 pg/mL at screening (if in atrial fibrillation/flutter: NT-proBNP >1,200 pg/mL or BNP >375 pg/mL). Patients were required to receive standard drug and device therapy for heart failure consistent with regional clinical practice guidelines and dose levels optimized according to investigator judgment.
[0177] Key exclusion criteria for patients included current hemodynamic or clinical instability requiring mechanical or intravenous medication, systolic blood pressure (SBP) < 85 mmHg, estimated glomerular filtration rate (eGFR) < 20 mL/min/1.73 m2, recent acute coronary syndrome events or cardiovascular procedures (including planned), and other conditions that would adversely affect participation in the trial.
Study Procedures
[0178] All eligible participants were randomized 1 : 1 to oral administration of either placebo or omecamtiv mecarbil (pharmacokinetic-guided dosing: 25, 37.5 or 50 mg) twice daily. Pre-dose plasma concentrations of omecamtiv mecarbil were measured at weeks 2 and 6 with respective dose adjustments on weeks 4 and 8. The patient and investigator were blinded to the plasma concentrations and dispensed dose. The full schedule of assessments is provided in the protocol available at NEJM.org. Study drug was temporarily withheld if the participant experienced clinical signs or symptoms consistent with acute myocardial infarction or ischemia.
Study Outcomes
[0179] The primary outcome was a composite of the time to a heart failure event or cardiovascular death, whichever occurred first. A heart failure event was defined as an urgent clinic visit, emergency department visit or hospitalization for subjectively and objectively worsening heart failure leading to treatment intensification beyond changed oral diuretic therapy. Secondary outcomes were: the time to cardiovascular death; change in KCCQ Total Symptom Score (TSS) from baseline to Week 24 (scale from 0 to 100; higher score indicates fewer symptoms); time to first heart failure hospitalization; and time to allcause death. All deaths, HF events, major cardiac ischemic events (myocardial infarction/ unstable angina hospitalization, and coronary revascularization), and strokes were adjudicated by a blinded external Clinical Events Committee (Duke Clinical Research Institute) using standardized definitions.
Summary of Results
[0180] Over a median of 21.8 months, the primary outcome occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% CI 0.86, 0.99; P=0.025); 808 patients (19.6%) receiving omecamtiv mecarbil and 798 patients (19.4%) receiving placebo died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11; P=0.86), 1177 (28.6%) and 1236 (30.1%) experienced a first heart failure event (hazard ratio, 0.93; 95% CI, 0.86 to 1.00; P=0.063), and 1067 (25.9%) and 1065 (25.9%) died from any cause (hazard ratio 1.00; 95% CI, 0.92 to 1.09). The frequency of cardiac ischemic and ventricular arrhythmia events did not differ between treatment groups.
[0181] Patients enrolled as in patients were more symptomatic as suggested by their lower KCCQ total symptom score at baseline; those receiving omecamtiv mecarbil had a 2.5 point improvement in this score compared to those on placebo.
Statistical Analysis
[0182] A sample size of approximately 8,000 patients was chosen to provide 90% power to detect a hazard ratio of 0.8 for cardiovascular death assuming the following: a 10% annualized rate of cardiovascular death in the first year and 7% thereafter; a 24-month enrollment period; total study duration set to 48 months; a 3 -month treatment lag with a treatment effect hazard ratio of 0.8 thereafter, 10% annual rate of study drug discontinuation, and 10% of subjects lost to endpoint determination either through non-cardiovascular death or study discontinuation over the course of the trial. The study was event-driven and was ended after approximately 1590 cardiovascular deaths. The overall type I error was 0.05 for 2-sided testing across primary and secondary endpoints with control for multiplicity testing. A single interim efficacy analysis was conducted after approximately two-thirds of the targeted number of cardiovascular deaths accrued with a one-sided alpha of 0.0005. Given the negligible impact of this interim on the final alpha, the full 0.05 was used in the final analysis consistent with the Haybittle-Peto approach. Efficacy analyses were performed according to randomized treatment group assignment (intention-to-treat) on the full analysis set which included all randomized patients except for 24 subjects from a single site excluded due to Good Clinical Practice violations. Time-to-event data were evaluated with Kaplan- Meier estimates and Cox proportional-hazards models stratified by randomization setting and region with treatment group and baseline eGFR as covariates. The mean differences in the KCCQ TSS change from baseline to Week 24 were estimated using a mixed model stratified by randomization setting (inpatient and outpatient) containing baseline TSS value, region, baseline eGFR, scheduled visit, treatment group, and the interaction of treatment group with scheduled visit. A joint omnibus F-test was used to test the treatment effect for the KCCQ TSS. An overall pooled estimate for the KCCQ TSS treatment difference to placebo were conducted using a likelihood based approach. The prespecified safety analyses included: serious adverse events; adverse events associated with discontinuation of study treatment; “adverse events of interest” i.e., ventricular arrhythmias requiring treatment and positively adjudicated major cardiac ischemic events (including myocardial infarction, hospitalization for unstable angina, coronary revascularization). The safety analyses were performed in patients who underwent randomization and received at least one dose of omecamtiv mecarbil or placebo with the same exclusion of the 24 subjects as in the full analysis set. All analyses were performed with the use of SAS software, version 9.4 (SAS Institute).
Enrollment Randomization, Treatment and Follow-up
[0183] 8 ,256 participants were randomized and 24 patients were excluded prior to database lock due to Good Clinical Practice violations. Accordingly, 8,232 patients were included in the efficacy analysis. At the end of the trial, 16 patients had unknown vital status (omecamtiv mecarbil: nine patients withdrew consent; placebo: six patients withdrew consent and one lost to follow-up). The baseline characteristics were balanced between the two treatment groups (Table 1). The overall median duration of follow-up was 21.8 months (QI, Q3; 15.4, 28.6 months).
Table 1. Baseline characteristics of patients
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Outcomes
[0184] A first heart failure event or death from cardiovascular causes occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI] 0.86, 0.99; P=0.025; Figure 1 A and Table 2). For the two components of this time-to-first event composite, 1177 (28.6%) in patients receiving omecamtiv mecarbil and 1236 (30.1%) in the placebo group experienced a first heart failure event (hazard ratio, 0.93; 95% CI, 0.86 to 1.00; P=0.063; Figure IB and Table 2); death from cardiovascular causes contributed 346 events (8.4%) and 371 events (9.0%) (Table 2). The effect of omecamtiv mecarbil was generally consistent across most prespecified subgroups with statistically the largest potential interaction observed for the ejection fraction subgroup (interaction effect p = 0.003; Figure 3).
[0185] The secondary outcome of time to death from cardiovascular causes occurred in 808 (19.6%) patients receiving omecamtiv mecarbil and 798 patients (19.4%) receiving placebo (hazard ratio, 1.01; 95% CI, 0.92 to 1.11; P=0.86; Figure 1C and Table 2). The pre-specified analysis of change from baseline to week 24 KCCQ total symptom score improvement by randomization setting (inpatient mean difference [95% CI]: 2.50 [0.54, 4.46], outpatient: - 0.46 [-1.40, 0.48], joint p = 0.028) did not meet the threshold of p=0.002 based upon the multiplicity control testing procedure, thus it and the other two secondary outcomes are considered exploratory. A first hospitalization for heart failure occurred in 1142 patients (27.7%) in the omecamtiv mecarbil group and in 1179 (28.7%) in the placebo group (hazard ratio 0.95; 95% CI, 0.87 to 1.03; Table 2), while death due to all causes occurred in 1067 (25.9%) and 1065 (25.9%) patients, respectively (hazard ratio 1.00; 95% CI, 0.92 to 1.09; Figure ID and Table 2).
[0186] The cumulative incidences of the primary outcome, heart failure events, death from cardiovascular causes and death from any cause were estimated with the use of the Kaplan- Meier method. Hazard ratios and 95% confidence intervals were estimated with the use of Cox regression models stratified by randomization location and region and treatment with omecamtiv mecarbil or placebo as explanatory variables. Analyses are based upon all participants who underwent randomization. The inset in each panel of Figures 1 A-1D shows the same data on an enlarged y axis.
[0187] Other outcomes of interest included the effects of omecamtiv mecarbil on vital signs and selected laboratory values (Table 3). There was no significant difference in the change in systolic blood pressure at 24 or 48 weeks between the omecamtiv mecarbil and placebo groups; there was a small but significant decrease in heart rate in participants assigned to omecamtiv mecarbil compared to placebo at both timepoints. Omecamtiv mecarbil significantly decreased NT -proBNP concentrations at Week 24 compared to placebo.
Table 2. Primary and Secondary Cardiovascular Outcomes
Figure imgf000040_0001
Figure imgf000041_0001
NA denotes not applicable because P values for efficacy outcomes are reported only for outcomes that were included in the hierarchical-testing strategy *The primary outcome was a composite of heart failure events (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or death from cardiovascular causes. The total symptom score on the Kansas City Cardiomyopathy Questionnaire (KCCQ) ranges from 0 to 100, with higher scores indicating fewer symptoms and physical limitations associated with heart failure. fNon-significant. After statistical significance on the primary endpoint, CV death was tested against an alpha of 0.048 and change from baseline in the KCCQ TSS was tested against an alpha of 0.002.
[0188] In addition, the impact of LVEF on the therapeutic effect of omecamtiv mecarbil in cardiovascular outcomes was analyzed. The patient population data demonstrated that patients with more severely reduced ejection fraction were more likely to be younger, male, non-white, from the Americas or Western Europe, had ischemic cardiomyophathy, normal sinus rhythm, and other clinical markers of more severe HFrEF when compared to patients with less severely reduced ejection fraction. There was a significant heterogeneity in the effect of omecamtiv mecarbil on the primary composite endpoint with respect to LVEF (continuous interaction, p = 0.002). Omecamtiv mecarbil had progressively greater improvement in the primary composite endpoint with decreasing LVEF as demonstrated by the continuously improving hazard ratio (Figure 5). The incidence of the PCE increased with decreasing EF and omecamtiv mecarbil produced increasingly greater absolute reductions in the PCE with decreasing EF (Figure 6). Safety
[0189] Excluding the discontinuations due to death, the study drug was stopped in 847 patients (20.6%) of 4110 patients receiving omecamtiv mecarbil and 897 patients (21.9%) of 4101 patients receiving placebo with 371 (9.0%) in the omecamtiv mecarbil group and 382 (9.3%) receiving placebo discontinuing due to an adverse event. Patients receiving omecamtiv mecarbil had no change in potassium or creatinine concentrations during the course of the trial compared to placebo. Patients receiving omecamtiv mecarbil had increased median concentrations of high sensitivity troponin-I from baseline of 0.004 ng/mL (lower limit of quantification, 0.010 ng/mL) compared to placebo at week 24. A total of 200 (4.9%) of participants receiving omecamtiv mecarbil had a positively adjudicated major cardiac ischemic event compared to a total of 188 (4.6%) receiving placebo, with myocardial infarction consisting of 122 (3.0%) and 118 (2.9%) of these events. Ventricular arrhythmias were similar in patients receiving omecamtiv mecarbil compared to placebo (Table 3). There was no evidence of an increase in the risk of myocardial ischemic events, ventricular arrhythmias, or death from cardiovascular causes or any cause associated with administration of omecamtiv mecarbil. Omecamtiv mecarbil was withheld because of concern of active myocardial infarction or ischemia in 103 patients in the omecamtiv mecarbil group and in 101 patients in the placebo group. Only three patients had concentrations of omecamtiv mecarbil over 1000 ng/mL, none of whom experienced a myocardial ischemic event. The three patients had blood concentrations of omecamtiv mecarbil measured at 1004 ng/mL, 1099 ng/mL, and 1158 ng/mL. At week 6, 26.8% of patients had a blood concentration of omecamtiv mecarbil below 200 ng/mL, 65% of patients had a blood concentration of omecamtiv mecarbil between 200 and 750 ng/mL, and 0.2% of patients had a blood concentration of omecamtiv mecarbil between 750 and 1000 ng/mL. Only one patient had a blood concentration of omecamtiv mecarbil above 1000 at 1004 ng/mL.
Table 3, Laboratory Parameters and Safety Outcomes
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
[0190] Continuous variables were summarized as means ± standard deviations (SD) or medians and first and third quartiles (QI, Q3), as appropriate. Categorical variables were summarized as counts and percentages. The safety population included all patients who underwent randomization and received at least one dose of omecamtiv mecarbil or placebo. The change from baseline on NT-proBNP analysis included all participants who underwent randomization. The difference column is the exponentiated change from baseline on the log scale using a mixed model containing the log baseline value, region, baseline eGFR, scheduled visit, treatment group and interaction of treatment with scheduled visit.
Adverse Events
[0191] Table 4 summarizes the adverse events reported in 1% or more of patients.
T able 4 Treatment-emergent serious adverse events by preferred term report.
Figure imgf000044_0002
Figure imgf000045_0001
Outcomes by Ejection Fraction
Baseline characteristics for patients were further evaluated by quartiles of EF
[0192] Continuous variables were summarized via means and standard deviations or medians and interquartile ranges, as appropriate. Categorical variables are summarized with counts and percentages. Tests of trend across categories were conducted via linear regression, Cuzick’s non-parametric trend test, and Chi-squared tests of trend, respectively. Treatment effects on continuous outcomes were assessed via linear regression models adjusted for the corresponding baseline value of the parameter of interest. Survival analyses were conducted using Poisson regression models to estimate incidence rates, rate differences, and rate ratios and Cox proportional hazards models to estimate hazard ratios. Treatment effect hazard ratios were adjusted for eGFR and stratified by region and inpatient status as in the primary GALACTIC -HF analysis. To allow for potentially non-linear associations between ejection fraction and time-to-event outcomes, restricted cubic splines were utilized in the Poisson regression models with 3 knots. All analyses were conducted using STATA 16 (College Station, TX). P-values <0.05 were considered statistically significant. Due to the exploratory nature of these analyses, no adjustments were made for multiple comparisons.
[0193] Of the 8,232 participants analyzed, there were 4,456 patients with an EF <28%, the median ejection fraction in the trial (Tables 5 and 6; FIGURES 13A and 13B). Method of ejection fraction measurement is shown in Table 6A.
Table 5: Baseline characteristics of GALACTIC -HF patients Ejection Fraction Quartiles
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
includes American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, or Multiple self-identified races ACEi indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor-neprilysin inhibitor; BB, beta blocker; CRT, cardiac resynchronization therapy; ED, emergency department; eGFR, estimated glomerular filtration rate; hsTnl, high-sensitivity troponin I; ICD, implantable cardioverter-defibrillator; KCCQ, Kansas City Cardiomyopathy Guestionnaire; LVEF, left ventricular ejection fraction; MAGGIC, Meta-Analysis Global Group in Chronic HF; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure; SGLT2, sodium-glucose co-transporter 2. Table 6: Baseline Characteristics by Ejection Fraction Quartile:
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Table 6A: Method of ejection fraction measurement:
Figure imgf000052_0002
Figure imgf000053_0001
[0194] Due to digit preference for ejection fraction assessment, over 70% of the patients had an EF <30%. When assessed by quartiles, patients with lower ejection fractions were younger, more likely to be male and non-white, and less likely to be enrolled in Eastern Europe or Russia and more likely to be enrolled in the United States, Canada, Western Europe, South Africa, or Australasia. Patients with lower ejection fraction were more likely to have a non-ischemic etiology of heart failure, NYHA III/IV functional class, lower body mass index, lower systolic blood pressure, higher heart rate, higher NT -proBNP, higher cardiac troponin I, and were less likely to have coronary artery disease, hypertension, type 2 diabetes mellitus, or atrial fibrillation/ flutter. Lower ejection fraction was associated with greater symptom burden in patients enrolled as inpatients (lower KCCQ-TSS), but there was no meaningful difference in the outpatients. There was no difference in the proportion of patients receiving triple therapy [(ACEi, ARB, or ARNi) + MRA + BB] among the EF quartiles. Patients with lower ejection fractions had higher use of ARNi, ivabradine, digitalis glycosides, cardiac resynchronization therapy and implantable cardioverter defibrillators compared to patients with higher ejection fractions.
Relationship between Ejection Fraction and Clinical Outcomes
[0195] Within the group of patients with HFrEF enrolled in GALACTIC -HF, the incidence of clinical outcomes increased with decreasing ejection fraction (Table 7).
Table 7. Clinical Outcomes
Figure imgf000053_0002
Figure imgf000054_0001
Figure imgf000055_0001
1per 100 patient years; ARR = absolute risk reduction
[0196] As noted by the rates in the placebo group, the incidence of the primary outcome of first heart failure event or cardiovascular death in patients in the lowest EF quartile (EF <22%; 35.6 per 100 patient-years) was almost 80% greater than in the highest EF quartile (EF >33%; 20 per 100 patient-years). The incidence of first heart failure event was 90% greater (28.3 versus 14.9 events per 100 patient-years) and of cardiovascular death was 68% greater (14.1 versus 8.4 deaths per 100 patient-years) in the lowest EF compared to the highest EF quartile. Participants in the placebo group had significant improvements in the KCCQ-TSS at Week 24 compared to baseline, with greater improvements in those enrolled as inpatients, but there was no modification of this effect by EF quartile (Table 8).
Table 8. Change from baseline in KCCQ Total Symptom Score by Ejection Fraction
Quartiles and Treatment Group
Figure imgf000055_0002
Within each randomization setting subgroup least squares mean is from the mixed model which includes baseline total symptom score value, region, baseline eGFR, scheduled visit, treatment group and interaction of treatment with scheduled visit as covariates.
Influence of Ejection Fraction on the Treatment Effect of Omecamtiv Mecarbil
[0197] Omecamtiv mecarbil significantly decreased the primary endpoint of the time-to- first heart failure event or cardiovascular death in the overall trial population (HR 0.92; p=0.025). The statistical analysis plan pre-specified the assessment of the primary endpoint in the ejection fraction subgroups above and below the median value (<28%) and there was a significant modification of the treatment effect of omecamtiv mecarbil by ejection fraction (interaction effect, p = 0.004). In patients with EF <28%, there was a 16% reduction in the time-to-first heart failure event or cardiovascular death (HR 0.84, 95%CI 0.77-0.92; p = 0.0003) compared to no difference in patients with EF >28% (HF 1.04, 95%CI 0.94-1.16; p = 0.45). Analysis by quartiles of ejection fraction of the modifying effect on the primary composite endpoint (interaction p = 0.013; Table 7, FIGURE 22) by treatment with omecamtiv mecarbil demonstrated a 15 and 17% relative risk reduction in the lower two quartiles of ejection fraction, respectively. Analysis of ejection fraction as a continuous variable (interaction effect, p = 0.004) demonstrated a progressively larger treatment effect of omecamtiv mecarbil with decreasing ejection fraction (FIGURE 7; Table 7). The difference in the incidence of the primary composite endpoint increased disproportionately between the placebo and omecamtiv mecarbil treatment groups with lower ejection fractions (FIGURE 8, such that absolute risk reduction by omecamtiv mecarbil progressively increased with decreasing ejection fraction (FIGURE 9). In the lowest ejection fraction quartile, omecamtiv mecarbil resulted in an absolute reduction of 7.4 events per 100 patient-years, with a number- needed-to-treat of 11.8 patients over 3-years necessary to prevent an event (Table 7).
[0198] The beneficial effect of treatment with omecamtiv mecarbil on the primary outcome was driven predominantly by the significant reduction in heart failure events and ejection fraction was a significant modifier of this treatment effect (interaction p = 0.004 by ejection fraction quartile, interaction p = 0.001 by ejection fraction as continuous variable; Table 7). Ejection fraction had a similar modifying effect on the progressive reduction of heart failure hospitalizations by omecamtiv mecarbil (interaction p = 0.004 by ejection fraction quartile, interaction p = 0.001 by ejection fraction as continuous variable; FIGURE 10; Table 7). Consistent with the primary composite endpoint, the incidence rate of heart failure hospitalizations increases with decreasing ejection fraction in both the placebo and omecamtiv mecarbil treated patients (FIGURE 11), but was significantly impacted by treatment with omecamtiv mecarbil, and showed a progressively greater reduction in the absolute difference with decreasing ejection fraction. Ejection fraction significantly modified the treatment of effect of omecamtiv mecarbil on total heart failure events and hospitalizations as well (interaction p = 0.006 and 0.009, respectively; Table 8A). Omecamtiv mecarbil had no overall effect on cardiovascular death, neither in the overall population nor as a function of baseline ejection fraction (interaction p = 0.14 by ejection fraction quartile; FIGURE 12A, Table 7). As expected, the incidence of cardiovascular death increased comparably in both the placebo and omecamtiv mecarbil arms with decreasing ejection fraction (FIGURE 12B, Table 7). Similarly, there was no effect of omecamtiv mecarbil on all-cause mortality (Table 7). The proportional hazards assumption was evaluated for all hazard ratios presented in Table 2 via a test of Schoenfeld residuals. No significant violations were detected (all p > 0.2).
Table 8A: Total heart failure events/hospitalizations by ejection fraction quartiles:
Figure imgf000057_0001
Other Outcomes and Safety of Omecamtiv Mecarbil by Ejection Fraction
[0199] Despite the reduction in heart failure events with omecamtiv mecarbil, there was no consistent beneficial effect on symptoms as a function of EF as assessed by the KCCQ-TSS in either the subjects enrolled from the inpatient or outpatient settings. However, there was a greater reduction in NT -proBNP by omecamtiv mecarbil in patients with lower ejection fraction such that the lowest EF quartile had a 22% reduction (p<0.001) while the highest EF quartile showed only a 3% change (p=0.54; interaction p <0.001) (Table 9).
Table 9. Omecamtiv Mecarbil Treatment Effects from Baseline to Week 24 of Selected Vital
Signs and Laboratory Values
Figure imgf000058_0001
Figure imgf000059_0001
*Values represent treatment effects as evaluated by between-group differences of change from baseline to Week 24. Least squares mean is from the mixed model which includes baseline total symptom score value, region, baseline eGFR, scheduled visit, treatment group and interaction of treatment with scheduled visit as covariates. Troponin I assay had limit of detection of 6 ng/L with an upper reference limit of 40 ng/L.
[0200] Omecamtiv mecarbil treatment resulted in a small reduction in heart rate (treatment difference of 1.1 to 1.9 bpm across the EF quartiles) and increase in troponin I (median 3-5 ng/L across the EF quartiles; limit of detection, 6 ng/L; upper reference limit, 40 ng/L) which did not differ by EF quartile. There was no significant effect on systolic blood pressure, serum potassium or creatine across the EF quartiles compared to placebo. There were also no significant differences noted in the incidence of adverse events between the omecamtiv mecarbil and placebo treated groups, except for an apparent reduction in the incidence of adjudicated stroke for patients treated with omecamtiv mecarbil (Table 10 and Table 10A). [0201] Omecamtiv mecarbil provided similar benefit in patients with and without a history of stroke. The time to first stroke event was significantly reduced in patients allocated to omecamtiv mecarbil. A history of stroke was present in 754 (9.2%) participants, who were older and more likely to be non-White, have atrial fibrillation/ flutter, hypertension, diabetes mellitus, or ischemic heart disease, worse NYHA class and eGFR, and higher baseline NT- proBNP or troponin. Patients with a history of stroke had similar beneficial effect of omecamtiv mecarbil on the primary endpoint (HR 0.86; 95%CI 0.70,1.07; p=0.18) as in patients with no stroke (HR 0.93; 95%CI 0.87,1.00; p=0.06). Multivariate predictors of the incident 194 first stroke events included non-White race, history of stroke or percutaneous coronary intervention (PCI), and elevated baseline troponin or systolic blood pressure (Table 10B). Patients randomized to omecamtiv mecarbil had a significant 35% reduction in the risk of first fatal or non-fatal stroke (Figure 24) and a 42% reduction in fatal stroke (HR: 0.56; 95%CI 0.31, 0.99; p = 0.048). The effect of omecamtiv mecarbil on risk of non-fatal and fatal stroke by history of stroke is shown in Figure 25 (with history of stroke— HR: 0.23; 95%C1 0.09, 0.56; p=0.001, and no history of stroke- HR: 0.78; 95%C1 0.57, 1.06; p=0.11). The effect of omecamtiv mecarbil on risk of non-fatal and fatal stroke by history of atrial fibrillation is shown in Figure 26 (with history of atrial fibrillation— HR: 0.49; 95%C1 0.32, 0.76; p=0.001, and no history of atrial fibrillation— HR: 0.81; 95%C1 0.55, 1.19; p=0.29). The effect of omecamtiv mecarbil on new onset atrial fibrillation/flutter is shown in Figure 27 (no AF/F at screening— HR: 0.70; 95%C1 0.50, 0.99; p=0.044, and no history of AF/F— HR: 0.60; 95%C1 0.37, 1.00; p=0.048). Omecamtiv mecarbil significantly reduced non-fatal and fatal strokes in patients with heart failure with reduced ejection fraction in the context of significantly reducing new onset atrial fibrillation. Characteristics by baseline history of stroke are shown in Table 10C.
Table 10. Other Outcomes and Adverse Events of Special Interest
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Table 10 A. Adjudicated type of first stroke event
Figure imgf000062_0002
Table 10B. Multivariate predictors of non-fatal and fatal stroke.
Figure imgf000062_0003
Figure imgf000063_0001
Cl= 95% confidence interval. PCI = percutaneous coronary interventions. AFF = atrial fibrillation or atrial flutter. SBP = systolic blood pressure.
Table IOC. Characteristics by baseline history of stroke
Figure imgf000063_0002
Figure imgf000064_0001
percutaneous coronary interventions. LVEF = left ventricular ejection fraction. NYHA = New York Heart Association. KCCQ - Kansas City Cardiomyopathy Questionnaire. SBP = systolic blood pressure. eGFR = estimated glomerular filtration rate. BMI = Body Mass Index. ACEi = Angiotensin-converting enzyme inhibitors. ARB = Angiotensin receptor blockers. ARNi = Angiotensin receptor neprilysin inhibitor. BB = Beta blockers. MRA = Mineralocorticoid receptor antagonists. SGLT2 = Sodium-glucose cotransporter 2. CRT = Cardiac resynchronization therapy. ICD = implantable cardioverter-defibrillator.
[0202] The evaluation of EF by quartiles in the current analysis has subgroups of approximately 2,000 patients with 578 to 979 events in each quartile, subgroups in themselves larger than many studies. These investigations are supported by analyses of ejection fraction as a continuous variable incorporating the data from all 8,232 patients. While the statistical analysis plan from GALACTIC-HF pre-specified multiple sub-groups for evaluation and is subject to issues related to multiplicity testing, the univariate interaction p-value for the treatment-covariate interaction was 0.004, making it highly unlikely to be due to chance. In addition, there is biological plausibility for this effect modification and the findings are internally consistent.
Patients having More Advanced Heart Failure
Statistical Approach
[0203] Baseline characteristics for patients classified as more advanced HF compared to those without were evaluated using appropriate summary statistics. Outcomes for patients with or without more advanced HF were compared using Cox proportional hazards models and Kaplan-Meier curves. Interaction terms were used to assess whether omecamtiv mecarbil had a differential effect on outcome by advanced HF status. Absolute event rates were described using rate per 100 patient-years. As a sensitivity analysis, the event rates and treatment effect of omecamtiv mecarbil for patients was assessed by specific advanced HF criteria met, as well as the total number of criteria met. For quality-of-life data as assessed by the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ TSS), linear regression adjusted for baseline scores was used to compare treatment effects of omecamtiv mecarbil compared to placebo. Safety and tolerability data for patients with advanced HF vs. those without were summarized using descriptive statistics. P value < 0.05 was considered statistically significant for all analyses.
Results
[0204] Of patients enrolled in GALACTIC-HF, 2258 (27%) met the specified criteria for more advanced HF, of which 1106 were randomized to treatment with omecamtiv mecarbil and 1152 to placebo. Baseline characteristics stratified by those patients with or without more advanced HF are shown in Table 11.
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
[0205] As anticipated, patients with more advanced HF had markers of more severe disease, including lower ejection fraction, greater NYHA class, higher NT-proBNP concentrations, lower systolic blood pressure, worse renal function, and worse quality of life as assessed by the KCCQ TSS. Patients with more advanced HF were less likely to be treated with renin-angiotensin-aldosterone system (RAAS) modulators and beta blockers at baseline but more likely to have cardiac resynchronization therapy (CRT) or an implantable cardioverter defibrillator (ICD). Patients with more advanced HF were at significantly higher risk, with event rates for placebo treated patients that were approximately twice those of patients without more advanced HF for the primary endpoint (42.6 events/100 pt-years vs. 21.3), cardiovascular mortality (17.3 events/100 patient-years vs. 8.5), and all-cause mortality (21.7 events/100 pt-years vs. 11.9).
Efficacy and Safety of Omecamtiv Mecarbil in More Advanced Heart Failure
[0206] Patients classified as more advanced HF had a greater treatment benefit from omecamtiv mecarbil treatment than those without more advanced HF. For the primary endpoint, patients with more advanced HF had a 20% risk reduction (HR = 0.80, 95% CI 0.71 to 0.90), whereas patients without more advanced HF had no significant treatment effect (HR = 0.99. 95% CI 0.91 to 1.08, p value for interaction = 0.005). These results were similar for cardiovascular mortality (patients with more advanced HF (HR = 0.88, 95% CI 0.75 to 0.1.03) compared to patients with less advanced HF (HR = 1.10, 95% CI 0.97 to 1.25, p value for interaction = 0.028)). Kaplan-Meier curves comparing patients with and without more advanced HF for each of these endpoints are shown in FIGURES 14A and 14B. As an additional sensitivity analysis, the event rate and treatment effect of omecamtiv mecarbil was assessed based on which and how many advanced heart HF criteria were met (FIGURES 15A and 15B). The observed benefits of omecamtiv mecarbil were greatest in patients meeting all 3 advanced HF criteria, which were also the group with the highest overall risk. The combination of a 20% relative risk reduction in the primary endpoint in the context of high baseline risk translated to an absolute risk reduction of 8.3 events/100 patientt-years (NNT = 12). These results were broadly consistent across a variety of other secondary outcomes from the GALACTIC-HF trial, as shown in Table 12. For the KCCQ, we did not identify a differential effect on the total symptom score (TSS) by advanced HF status (advanced HF inpatient 1.1 increase and outpatient 1.7 decrease in TSS, compared to nonadvanced HF (inpatient 3.3 increase, outpatient 0.2 decrease in TSS, p for interaction = 0.09). [0207] Safety data for omecamtiv mecarbil vs. placebo by advanced HF category are summarized in Table 13.
Table 12. Event Rates by Treatment Assignment and Advanced HF classification
Figure imgf000069_0001
Figure imgf000070_0001
1per 100 patient years; ARR = absolute risk reduction
Table 13. Safety by Treatment Status and Advanced HF Classification
Figure imgf000070_0002
[0208] Patients with more advanced HF were more likely to have treatment emergent serious adverse events than patients without, but these were similar between omecamtiv mecarbil treated patients (67%) and placebo (69%). There were no significant differences in serious adverse events related to ventricular tachyarrhythmias between omecamtiv mecarbil and placebo in the more advanced HF patients (7.9% for omecamtiv vs. 8.1% for placebo). In more advanced HF patients, there were numerically more myocardial infarctions with omecamtiv mecarbil compared to placebo (3.8% vs. 2.5% %, p = 0.08) but fewer strokes (1.6% vs. 2.7%, p = 0.08). Data on tolerability and changes in biomarkers are shown in Table 4. As in the overall trial, treatment with omecamtiv mecarbil in patients with more advanced HF did not lead to changes in blood pressure, worsening of renal function, or worsening of potassium compared to placebo. Heart rate was modestly lowered with omecamtiv mecarbil compared to placebo (1.9 beats/minute difference in change from 0 to 24 weeks, p < 0.001 for omecamtiv mecarbil vs. placebo). In the more advanced HF population, treatment with omecamtiv mecarbil was associated with a significant decrease in NT-proBNP and a small increase in circulating cardiac troponin (Table 14).
Table 14. Tolerability by Treatment and Advanced HF status
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Effect of OM by baseline NT-ProBNP Level
NT-proBNP and cardiac troponin I measurements
[0209] NT-proBNP was measured at baseline and at 2, 6, 24, 48 and 96 weeks after randomization. Plasma NT-proBNP was measured in a central laboratory (Q Squared Solutions) using the Roche Elecsys NT-proBNP two-site electrochemiluminescence immunoassay (analytical range 50-35000 pg/mL).
Statistical Analysis
[0210] Although the primary outcome was a composite of heart failure event or cardiovascular death, the trial was designed to provide 90% power to detect a hazard ratio of 0.8 for cardiovascular death, giving a sample size of approximately 8,000 patients. The trial was event-driven, with a target of approximately 1590 cardiovascular deaths. Efficacy analyses were performed according to randomized treatment group assignment (intention-to- treat) on the full analysis set which included all randomized patients except for 24 subjects from a single site excluded due to Good Clinical Practice violations. Baseline characteristics were summarized as frequencies with percentages, means with standard deviation (SD), or medians with interquartile ranges. Differences in baseline characteristics were tested using the Cochrane- Armitage trend test for categorical variables and the analysis of variance test for continuous variables. The difference between treatment groups in NT-proBNP at the time points after randomization in surviving patients was analyzed using an analysis of covariance model, with treatment-group assignment as a fixed-effect factor and baseline NT-proBNP as a covariate. The results of the analyses of covariance are presented as least-squares mean differences with corresponding 95%CIs. Time-to-event data were evaluated with Kaplan- Meier estimates and Cox proportional-hazards models with baseline hazards stratified by randomization setting and region and with treatment group and baseline eGFR as covariates. The safety analyses were performed in patients who underwent randomization and received at least one dose of omecamtiv mecarbil or placebo. All analyses were conducted using STATA version 15.1 (College Station, TX) and SAS version 9.4 (SAS Institute, Cary, NC). A P-value of 0.05 was considered statistically significant.
Results [0211] A NT-proBNP measurement at baseline was available for 8206 of the 8232 patients randomized. Of these, 5971 patients did not have AF/F on their baseline ECG. The median (QI, Q3) NT-proBNP level at baseline was 1675 (812-3579) pg/ml among patients not in AF/F and 1998 (993-4079) pg/mL in all patients randomized.
[0212] Baseline characteristics according to median baseline NT-proBNP concentration are presented in Table 15 for participants without AF/F and in the overall population.
Table 15. Baseline characteristics of patients according to pre-randomization NT-proBNP level (<median or >median) in the prespecified analysis population (no atrial fibrillation/flutter at baseline) and in all patients randomized.
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
‘Percentages may not total 100 because of rounding
ACE = angiotensin-converting enzyme; ARB = angiotensin-receptor blocker; ARNI = angiotensin receptor- neprilysin inhibitor; BMI = body mass index; CRT-P/D = cardiac resynchronization therapy with or without a defibrillator; GFR = glomerular filtration rate; ICD = implantable cardioverter-defibrillator; KCCQ-TSS = Kansas City Cardiomyopathy Questionnaire total symptom score - range from 0 to 100, with higher scores indicating fewer symptoms; LVEF = left ventricular ejection fraction; Ml = myocardial infarction; MRA = mineralocorticoid receptor antagonist; NT-proBNP = N-terminal pro-B-type natriuretic peptide; NYHA = New York Heart association.
[0213] Compared to those with NT-proBNP level less than or equal to the median (< median), patients with a level greater than median (>median) were older, more often from Western Europe or Latin America, and less frequently from Asia. Participants with a NT- proBNP level greater than median had a lower mean body mass index, eGFR (and larger proportion of patients with eGFR <60 mL/min/1.73m2) and systolic blood pressure, but higher heart rate and troponin I. They were also more likely to have a lower ejection fraction, and considerably worse NYHA functional class and KCCQ-TSS. These differences were seen both in participants without AF/F and in the overall population. Some differences were only seen in patients without AF/F and not in the overall population. Participants without AF/F, with a NT-proBNP level greater than median, were more likely to have diabetes and an ischemic etiology, than those with a NT-proBNP less than or equal to the median (these differences were not significant in the overall population).
[0214] With respect to heart failure treatment, patients with a NT-proBNP level greater than median were less often treated with renin-angiotensin system blockers (including sacubitril-valsartan), mineralocorticoid receptor antagonists and beta-blockers, but had more often prescribed a diuretic and digoxin (even in patients without AF/F) and were more likely to have an implanted cardiac device.
[0215] Generally, these differences were also observed whether patients were enrolled as an outpatient or an inpatient, and in patients with AF/F. Hospitalization and mortality outcomes in relation to baseline concentration of NT-proBNP
[0216] Event rates were higher in patients with a NT-proBNP greater than the median, compared with less than or equal to the median, in participants without AF/F and in the overall population, as shown by comparison of the placebo groups in Table 16. When NT- proBNP was examined as a continuous variable, the rate of the primary endpoint rose steeply with increasing NT-proBNP concentration (FIGURES 16A-16D and 17A-17D). The same was observed whether patients were enrolled as an outpatient or an inpatient, and in patients with AF/F.
Effect of omecamtiv mecarbil on outcomes according to baseline concentration of NT- proBNP
[0217] Table 16 shows the effect of omecamtiv mecarbil on the prespecified morbidity and mortality endpoints, according to baseline NT-proBNP level divided at the median, as prespecified, in patients without AF/F and in the overall trial population. Additional analyses of the effect of omecamtiv mecarbil examining NT-proBNP as a continuous variable are shown in (FIGURES 18A-18D and 19A-19D)
Table 16. Outcomes according to baseline NT-proBNP level (less than or equal to the median or greater than the median) in relation to randomized treatment assignment in the prespecified analysis population (no atrial fibrillation/flutter at baseline) and in all patients randomized
Figure imgf000077_0001
Figure imgf000078_0001
1per 100 person-years
2a composite of time to heart failure hospitalization or cardiovascular death, whichever came first
3NTproBNP median values hospitalization for HF
AF/F = atrial fibrillation/flutter OM = omecamtiv mecarbil HF = heart failure
Numbers of patients in subgroups
No AF/F NTproBNP < median: placebo = 1511 /OM = 1476. NTproBNP > median: placebo = 1495/OM = 1489 All patients: NTproBNP < median: placebo = 2032/OM = 2073 NTproBNP > median: placebo = 2067/OM = 2034
Primary composite outcome
[0218] Among patients without AF/F, compared to placebo, omecamtiv mecarbil had more benefit on the primary endpoint in participants with a NT -proBNP greater than the median (HR 0.81, 95% CI 0.73-0.90) than in patients with a NT-proBNP less than or equal to the median (HR 0.94, 0.80-1.09); P for interaction^.035. A similar interaction was seen in the overall population: HR 0.88, 0.80-0.96 in patients with NT-proBNP >median and 1.01, 0.90- 1.15 in participants with a NT -proBNP less than or equal to the median; P for interaction^.095.
[0219] When NT -proBNP was examined as a continuous variable, the increasing beneficial effect of omecamtiv mecarbil with increasing NT -proBNP became clearer as shown in FIGURES 18A-18D and 19A-19D
[0220] Qualitatively similar findings were seen in participants enrolled in both the outpatient and inpatient setting. A completely different pattern was observed in patients with AF/F at baseline, with a higher event rate in the omecamtiv mecarbil groups, compared with the placebo group, especially in patients with a NT-proBNP less than or equal to the median. Secondary outcomes
[0221] Examination of the secondary hospitalization and mortality outcomes in patients without AF/F suggested the interaction between baseline NT-proBNP level and the effect of omecamtiv mecarbil was more evident for heart failure hospitalization than for cardiovascular or all-cause death (Table 16 and FIGURES 18A-18D and 19A-19D). While both hospitalization and mortality were reduced by omecamtiv mecarbil in participants without AF/F and a NT-proBNP greater than the median, the mortality benefits were lost when the overall population was analyzed, because of the absence of an effect of omecamtiv mecarbil in patients with AF/F. Even the larger benefit of omecamtiv mecarbil on heart failure hospitalization was attenuated by the addition of patients with AF/F in the overall population.
[0222] Table 17 shows the effect of omecamtiv mecarbil on physiologic measures and on plasma biomarkers according to baseline NT-proBNP level divided at the median, in patients without AF/F and in the overall trial population.
Table 17. Change from baseline to 24 weeks in physiologic measures and biomarkers according to baseline NT-proBNP level (<median or >median) in relation to randomized treatment assignment in the prespecified analysis population (no atrial fibrillation/flutter at baseline) and in all patients randomized.
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0002
AF/F = atria fibrillation/flutter BP = blood pressure B DM = beats per minute OM = omecamtiv mecarbil
Figure imgf000081_0001
proBNP = N-terminal pro-B-type natriuretic peptide
[0223] Changes from baseline (to) to the 24-week visit are provided. Omecamtiv mecarbil did not have a significant effect on systolic blood pressure in any subgroup but did reduce heart rate, significantly, by 1-2 beats per minute in in all 4 patient subgroups. Omecamtiv mecarbil also increased troponin I, significantly, and by a similar proportional amount, in all 4 patient subgroups. By contrast, omecamtiv mecarbil reduced NT-proBNP only in patients with a baseline value NT-proBNP greater than the median at baseline, as shown in more detail in Figures 20A-F.
Safety outcomes
[0224] The occurrence of adverse events according to treatment assignment according to NT -proBNP category is shown Table 18.
Table 18. Adverse events according to baseline NT-proBNP level (less than or equal to the median or greater than the median) in relation to randomized treatment assignment in the prespecified analysis population (no atrial fibrillation/flutter at baseline) and in all patients randomized.
Figure imgf000081_0003
Figure imgf000082_0001
tachycardia
Numbers of patients in subgroups
No AF/F NTproBNP < median: placebo = 1511/OM = 1476. NTproBNP >median: placebo = 1495/OM = 1489
All patients NTproBNP < median: placebo = 2032/OM = 2073 NTproBNP >median: placebo = 2067/OM = 2034
Rate is per 100 person-years
[0225] Comparison of the placebo groups showed no substantial difference in any adverse event in patients with a baseline NT-proBNP concentration greater than the median compared to less than or equal to the median. Similarly, there was no strong or consistent evidence that any adverse event was more common with omecamtiv mecarbil, compared to placebo, in any of the 4 subgroups of patients.
[0226] In GALACTIC-HF, the benefit of omecamtiv mecarbil appeared to be larger in patients with higher baseline NT -proBNP levels, especially in patients without AF/F.
Effect of OM by baseline Atrial Fibrillation/Flutter (AF/F)
[0227] Atrial fibrillation is common in patients with heart failure and contributes to morbidity and mortality. Atrial fibrillation has not modified the treatment effect of renin- angiotensin-aldosterone inhibitors that have proven beneficial in heart failure, but may modify the treatment effect of beta-blockers. Here we report the effect of omecamtiv mecarbil according to baseline status of in patients either without AF/F or with AF/F. Further exploration of digoxin use within the two subpopulations was also assessed.
Results
[0228] A determination of AF/F at baseline was available the 8232 patients randomized. Of these, 5987 patients did not have AF/F on their baseline ECG. Baseline characteristics according to median baseline AF/F status are presented in Table 19 for participants without AF/F and with AF/F.
Table 19. Baseline characteristics of patients according to pre-randomization atrial fibrillation/flutter status (no atrial fibrillation/flutter at baseline or having atrial fibrillation/flutter at baseline) in all patients randomized.
Figure imgf000083_0001
Figure imgf000084_0001
[0229] Figure 21 A depicts the frequency of AFF in patients having LVEF <35%. AFF was observed to coincide with higher LVEF (but less than 35%). [0230] The influence of AFF on the effectiveness of OM on the primary and secondary outcome in patients who were or were not receiving digoxin was evaluated. In one of 24 prespecified subgroups, patients with AFF (n = 2245, 27%) were older, more likely to be randomized as an inpatient, less likely to have a history of ischemic etiology or myocardial infarction, had a worse NYHA class, worse quality of life, lower eGFR, and higher NT- proBNP at baseline. AFF at baseline was associated with a modestly increased adjusted risk of cardiovascular death or heart failure events (HR 1.17, 95% CI 1.09, 1.27). Using a multivariable covariate-interaction model, the treatment effect of OM appeared to be modified by AFF (interaction p = 0.012), with patients without AFF deriving greater benefit (Figure 21B, top panel). As further shown in Figure 21B, the presence of AFF was also found to modify the treatment effect of omecamtiv mecarbil as considered for cardiovascular (CV) death (interaction p =0.002), all-cause death (interaction p < 0.001), with patients without AFF deriving greater benefit. However, as illustrated in Figure 21E, treatment with omecamtiv mecarbil led to a significant reduction in serious adverse events for patients having atrial fibrillation/flutter at baseline (interaction p = 0.046), with the omecamtiv mecarbil treatment arm having 55 events per 2974 patients and the placebo arm having 78 events per 3013 patients over the course of the study. The treatment effect modification by AFF was significantly more pronounced in digoxin users than in non-users (p=0.004), with strong evidence of effect modification in digoxin users in AFF (p=0.001) and minimal evidence of effect modification in non-users (p=0.52) or digoxin users not in AFF (Figure 2 IB, bottom panel). In Figure 21D, the effect of digoxin use (digoxin or no digoxin) in tandem with omecamtiv mecarbil for patients with AFF and without AFF is shown for cardiovascular death, all-cause death and heart failure hospitalization.
[0231] Atrial fibrillation or flutter at baseline modified the treatment effect of omecamtiv mecarbil, even after multivariable adjustment, with greater benefit observed in patients not in AFF. The treatment effect modification by AFF was concentrated in patients using digoxin in AFF with minimal evidence of effect modification in non-users in AFF. Digoxin did not modify the treatment effect of omecamtiv mecarbil in patients not in AFF.
[0232] At 6 weeks, omecamtiv mecarbil PK values were similar in those taking and those not taking digoxin (median 286 vs. 280 ng/ml, p = 0.78). In patients in whom digoxin doses were known, digoxin doses were similar in both treatment arms (0.12 mg vs. 0.12mg, p = 0.85) and similar in patients with and without AFF at baseline (.12 mg vs .12 mg, p = 0.44). In patients in AFF at baseline taking omecamtiv mecarbil, there was less troponin I increase at 6 weeks in those taking digoxin (+29%, +21% to +38%) vs those not taking digoxin (+45%, +38% to 53%) (p=0.026).
[0233] Figures 21F and 21G depict data from a study evaluating any drug-drug interaction between digoxin and omecamtiv mecarbil, showing PK values for digoxin.
[0234] Patients in atrial fibrillation/flutter at baseline were less likely to benefit from OM than patients without AFF, although this effect modification appeared to be driven by digoxin use in those patients, and suggests that the when considering OM, the combination of AFF and digoxin is a potential risk factor.
[0235] Among patients with EF < 30%, without AFF, and without taking digoxin at baseline, OM led to significant clinical benefits and reductions in resource utilization, as presented in Table 20.
Table 20. Outcomes and resources used in the prespecified analysis population (EF < 30%, no AFF, and no digoxin).
Figure imgf000086_0001
Figure imgf000087_0001
treat. 0M= omecamtiv mecarbil + standard care. Pbo= placebo + standard care.
Effect of OM by baseline Systolic Blood Pressure (SBP)
[0236] Systolic blood pressure (SBP) is a major predictor of outcomes in patients with heart failure and reduced ejection fraction (HFrEF). Omecamtiv mecarbil directly improves cardiac function and reduced the primary composite endpoint of an episode of worsening HF (urgent clinic visit, emergency department visit, or hospitalization) or cardiovascular death in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure trial (GALACTIC -HF). This trial provided data on the efficacy and tolerability of omecamtiv mecarbil according to baseline SBP values. In contrast to other HFrEF therapies, which may not be tolerated in patients with low baseline blood pressure (e. , <100 mmHg), the present study was able to enroll patients with SBP at baseline of 85 mmHg or greater.
Results
[0237] The 8232 randomized patients were subdivided according to SBP at baseline: <100 mmHg (n = 1473), 101-110 mmHg (n = 1734), 111-120 mmHg (n = 1824), 121- 130 mmHg (n = 1627), and >130 mmHg (n = 1574). Significant differences between these subgroups were found with respect of multiple baseline characteristics. The primary composite endpoint occurred in 715 (48.5%), 682 (39.3%), 679 (37.2%), 556 (34.2%), and 498 (31.6%) patients in each SBP subgroup, respectively. Hazard ratios (HRs) and 95% confidence intervals (Cis) for the treatment effect on the primary outcome were of 0.81, 0.70-0.94; 0.88, 0.76-1.03; 1.03, 0.88-1.19; 0.87, 0.73-1.03; and 1.07, 0.90-1.28 in each SBP subgroup, respectively. When examined as a continuous variable, baseline SBP had a linear inverse relation with the primary event rate and a linear direct relation with the treatment effect (Figures 23A and 23B). No significant change in SBP and no difference in adverse events with omecamtiv mecarbil, compared with placebo, occurred during follow-up in each subgroup.
[0238] Omecamtiv mecarbil did not change SBP from baseline and was well tolerated independently from SBP at baseline, including in patients having low baseline blood pressure (<100 mmHg) for whom the use of other HFrEF therapies cannot be tolerated or may be associated with the added cost of increased averse events or worsening renal function. Omecamtiv mecarbil tended to have a larger effect on the primary outcome, compared with placebo, in the patients with lower SBP at baseline (<100 mmHg).
Effect of food
[0239] Administration of OM with a high-fat, high-calorie meal in healthy subjects had no clinically significant effect on its systemic exposure.
Distribution
[0240] OM was observed to be moderately bound to plasma proteins (81.5%) and the protein binding was independent of drug concentration up to 4000 ng/mL. After a single 35 mg dose of radiolabeled OM to healthy subjects, the blood to plasma ratio of total radioactivity was approximately 0.4, indicating that radioactivity did not disproportionately partition into blood components. The volume of distribution at steady state was approximately 4.8-6.6 L/kg.
Elimination
[0241] Clearance of OM after oral administration was primarily through metabolism in the liver. The total systemic clearance was found to be 11.7 L/hr with mean renal clearance of 1 L/hr, accounting for less than 10% of the systemic clearance. The median half-life of OM was found to be approximately 23-32 hours in patients with heart failure. OM was observed to be extensively metabolized in the liver by multiple metabolic pathways, including CYP3A4 and CYP2D6. Following oral administration of radiolabeled OM to healthy subjects, approximately 49% of the dose was excreted in urine (primarily as metabolites with 8% of parent compound recovered) and 38% in feces (primarily as unchanged drug).
Patients with Hepatic Impairment
[0242] The pharmacokinetics of a single dose of OM 25 mg were evaluated in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. The pharmacokinetics (Cmax and AUC) of OM in patients with mild or moderate hepatic impairment were similar to those in patients with normal hepatic function. Drug Interactions— Effects of Other Drugs on the Pharmacokinetics of OM
[0243] OM was found to be metabolized in vitro by multiple CYP enzymes including CYP3A4 and CYP2D6 and is a substrate of P-gp and BCRP. OM may be administered with drugs that are inhibitors or inducers of CYP3 A4, CYP2D6, P-gp or BCRP. The effect of coadministered drugs on OM plasma exposures is presented in Table 21.
Table 21 : Change in OM Pharmacokinetics in the Presence of Co-administered Drugs
Figure imgf000089_0001
<-> = no change; f increase; f=decrease; Cl: Confidence Interval; NA: not applicable; SD: single dose a Ratios for Cmax and AUG compare co-administration of the drug with OM versus administration of OM alone. b PM (N=8): poor CYP2D6 metabolizer; EM (N=16): extensive CYP2D6 metabolizer.
CYP2D6 metabolic genotype had no clinically relevant effect on the pharmacokinetics of OM, indicating that inhibitors of CYP2D6 have no clinically relevant effect on OM exposures.
Drug Interactions— Effects of OM on the Pharmacokinetics of Other Drugs
[0244] In vitro, OM was found to be an inhibitor of P-gp, BCRP, MATE1, MATE 2-K, CYP2C8 and an inducer of CYP3 A4. Clinical studies and the results of physiologically based pharmacokinetic modeling indicate that OM is a weak inhibitor of CYP2C8 and BCRP, and a weak inducer of CYP3 A4. OM may be administered with drugs that are substrates of CYP3 A4, CYP2C8, P-gp or BCRP. A summary of results from clinical studies is provided in
Table 22.
Table 22: Change in Pharmacokinetics Co-administered Drugs in the Presence of OM
Figure imgf000090_0001
<-> = no change; f increase; J. =decrease; BID = twice daily; Cl: Confidence Interval; NA: not applicable; SD: single dose a Ratios for Cmax and AUG compare co-administration of the drug with CM versus administration of CM alone.

Claims

CLAIMS What is claimed is:
1. A method of treating heart failure in a subject in need thereof, comprising: a) administering to the subject a first dose level of a cardiac sarcomere activator (CSA) for an initial period of time; and b) administering to the subject a second dose level of the CSA for a second period of time, wherein the second dose level is greater than the first dose level, wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof, and wherein administering the CSA is withheld if the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction.
2. The method of claim 1, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction comprise chest pain and shortness of breath.
3. The method of claim 1 or 2, wherein the method further comprises step c) administering to the subject a third dose level of the CSA, wherein the third dose level is greater than the second dose level, wherein the method does not include taking a blood sample from the subject to determine the plasma concentration of the CSA, and wherein administering the CSA is withheld if the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction.
4. The method of any one of claims 1 to 3, wherein if the CSA is withheld for a period of time, and if the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are not related to the CSA, administration of the CSA is resumed at the same dose level being administered before the CSA was withheld.
5. The method of any one of claims 1 to 3, wherein if the CSA is withheld for a period of time, and if it is determined that the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related to the CSA, then the CSA’s dose level is decreased or discontinued.
6. The method of claim 5, wherein administration of the CSA is decreased.
7. The method of claim 6, wherein administration of the CSA is decreased to the first dose level.
8. The method of claim 6, wherein administration of the CSA is decreased to the second dose level.
9. The method of claim 5, wherein administration of the CSA is discontinued.
10. The method of any one of claims 1 to 9, wherein the first dose level of the CSA is about 25 mg twice daily.
11. The method of any one of claims 1 to 10, wherein the second dose level of the CSA is about 37.5 mg twice daily.
12. The method of any one of claims 3 to 11, wherein the third dose level of the CSA is about 50 mg twice daily.
13. The method of any one of claims 1 to 12, wherein the initial period of time is about 2 weeks.
14. The method of any one of claims 1 to 12, wherein the initial period of time is at least 2 weeks.
15. The method of any one of claims 1 to 14, wherein the second period of time is about 2 weeks.
16. The method of any one of claims 1 to 14, wherein the second period of time is at least 2 weeks.
17. The method of any one of claims 1 to 16, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after initiation of the first dose level.
18. The method of any one of claims 1 to 17, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after initiation of the second dose level.
19. The method of any one of claims 1 to 18, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after initiation of the third dose level.
20. The method of any one of claims 1 to 19, wherein the method does not include taking a blood sample from the subject to determine the subject’s CSA plasma concentration except if the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction.
21. The method of any one of claims 1 to 20, wherein if the subject experiences one or more signs or symptoms of acute myocardial ischemia or myocardial infarction, the method further comprises determining the plasma concentration of the CSA to assess whether the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are related to the CSA.
22. The method of claim 21, wherein determining the plasma concentration of the CSA comprises taking a blood sample from the subject.
23. The method of any one of claims 1 to 22, wherein the subject has chronic heart failure, severe heart failure, or a New York Heart Association Class II or III heart failure.
24. The method of any one of claims 1 to 23, wherein the subject has a left ventricular ejection fraction of about 35% or lower.
25. The method of any one of claims 1 to 24, wherein the subject has a plasma concentration of NT -proBNP of at least about 200 pg/mL.
26. The method of any one of claims 1 to 25, wherein the CSA is omecamtiv mecarbil dihydrochloride hydrate.
27. The method of any one of claims 1 to 26, wherein the CSA is administered orally to the subject.
28. A method of treating heart failure in a subject in need thereof, comprising: a) administering to the subject a first dose level of a cardiac sarcomere activator (CSA) for an initial period of time; and b) administering to the subject a second dose level of the CSA in accordance with a determination that the subject has not experienced one or more signs or symptoms of acute myocardial ischemia or myocardial infarction, wherein the second dose level is greater than the first dose level, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the first administration of the first dose level of the CSA, and wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof.
29. The method of claim 28, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction comprise chest pain and shortness of breath.
30. The method of claim 28 or 29, wherein the first dose level of the CSA is about 25 mg twice daily.
31. The method of any one of claims 28 to 30, wherein the second dose level of the CSA is about 37.5 mg twice daily.
32. The method of any one of claims 28 to 31, wherein the method further comprises step c) administering to the subject a third dose level of the CSA in accordance with a subsequent determination at about 4 weeks after the first administration of the first dose level of the CSA that the subject has not experienced the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction, wherein the third dose level is greater than the second dose level.
33. The method of claim 32, wherein the third dose level of the CSA is about 50 mg twice daily.
34. A method of treating heart failure in a subject in need thereof, comprising: a) administering to the subject a first dose level of a cardiac sarcomere activator (CSA) for an initial period of time; and b) administering to the subject a second dose level of the CSA in accordance with a determination that one or more signs or symptoms of acute myocardial ischemia or myocardial infarction experienced by the subject are not associated with the CSA, wherein the second dose level is about the same as the first dose level, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the first administration of the first dose level of the CSA, and wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof.
35. The method of claim 34, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction comprise chest pain and shortness of breath.
36. The method of claim 34 or 35, wherein the first and the second dose levels of the CSA are about 25 mg twice daily.
37. The method of claim 34 or 35, wherein the first and the second dose levels of the CSA are about 37.5 mg twice daily.
38. A method of treating heart failure in a subject in need thereof, comprising: a) administering to the subject a first dose level of a cardiac sarcomere activator (CSA) for an initial period of time; and b) administering to the subject a second dose level of the CSA in accordance with a determination that one or more signs or symptoms of acute myocardial ischemia or myocardial infarction experienced by the subject are associated with the CSA, wherein the second dose level is less than the first dose level, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the first administration of the first dose level of the CSA, and wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof.
39. The method of claim 38, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction comprise chest pain and shortness of breath.
40. The method of claim 38 or 39, wherein the first dose level of the CSA is about 37.5 mg twice daily.
41. The method of claim 40, wherein the second dose level of the CSA is about 25 mg twice daily.
42. The method of claim 38 or 39, wherein the first dose level of the CSA is about 50 mg twice daily.
43. The method of claim 42, wherein the second dose level of the CSA is about 37.5 mg twice daily.
44. A method of treating heart failure in a subject in need thereof, comprising: a) administering to the subject a first dose level of a cardiac sarcomere activator (CSA) for an initial period of time; and b) discontinuing the administration in accordance with a determination that one or more signs or symptoms of acute myocardial ischemia or myocardial infarction experienced by the subject are associated with the CSA, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction are evaluated at about 2 weeks after the first administration of the first dose level of the CSA, and wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt and/or hydrate thereof.
45. The method of claim 44, wherein the one or more signs or symptoms of acute myocardial ischemia or myocardial infarction comprise chest pain and shortness of breath.
46. The method of claim 44 or 45, wherein the first dose level of the CSA is about 25 mg twice daily.
47. The method of any one of claims 28 to 46, wherein the subject has chronic heart failure, severe heart failure, or a New York Heart Association Class II or III heart failure.
48. The method of any one of claims 28 to 47, wherein the subject has a left ventricular ejection fraction of about 35% or lower.
49. The method of any one of claims 28 to 48, wherein the subject has a plasma concentration of NT -proBNP of at least about 200 pg/mL.
50. The method of any one of claims 28 to 49, wherein the CSA is omecamtiv mecarbil dihydrochloride hydrate.
51. The method of any one of claims 28 to 50, wherein the CSA is administered orally to the subject.
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