Mavacamten for use in the treatment of hypertrophic cardiomyopathy

Abstract

To provide a therapeutic agent and a method for the treatment of hypertrophic cardiomyopathy (HCM) and related cardiac disorders.SOLUTION: The present invention provides a method comprising administering a compound 1, represented by the structural formula below, to a subject in need of the treatment of hypertrophic cardiomyopathy (HCM), wherein the therapeutically effective amount is a total daily dosage of about 2 mg to 50 mg or about 5 mg to 30 mg.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 62 / 541,591, filed August 4, 2017; U.S. Provisional Application No. 62 / 584,537, filed November 10, 2017; U.S. Provisional Application No. 62 / 639,922, filed March 7, 2018, and U.S. Provisional Application No. 62 / 671,585, filed May 15, 2018, the contents of which are incorporated by reference in their entireties herein. [Background technology]

[0002] Genetic (hereditary) hypertrophic cardiomyopathy (HCM) comprises a group of highly penetrant, monogenic, autosomal dominant myocardial diseases. HCM is caused by one or more of over 1,000 known point mutations in any one of the proteins that contribute to the functional unit of the myocardium (sarcomere). Approximately 1 in 500 individuals in the general population are known to have left ventricular hypertrophy that is not explained by other known causes (e.g., hypertension or valvular disease), and many of these cases can be shown to have HCM once other genetic (e.g., lysosomal storage diseases), metabolic, or infiltrative causes have been ruled out.

[0003] Medical therapies for HCM are limited to treating symptoms and do not address the underlying cause of the disease (disruption of normal sarcomere function). Currently available therapies are variably effective in alleviating symptoms but typically show diminishing efficacy with increasing disease duration. Thus, patients are managed empirically with beta-blockers, non-dihydropyridine calcium channel blockers, and / or disopyramide. None of these agents are labeled for the treatment of HCM, and rigorous clinical trial evidence is virtually unavailable to guide their use. Compounding this unfortunate situation is the fact that no new medical therapies for HCM have been identified for many years. Approximately 60% of patients with HCM develop an obstructed left ventricular outflow tract, which impedes blood flow and creates a pressure gradient between the LV cavity and the aorta. For patients with hemodynamically significant outflow tract obstruction (gradients of 50 mmHg or greater), surgical myectomy or alcohol septal ablation can be utilized to relieve the hemodynamic obstruction, but this is associated with significant clinical morbidity and mortality. Novel therapeutic agents and methods are provided that address the long-felt need for improved treatment of HCM and related cardiac disorders. Summary of the Invention

[0004] In one embodiment, a method for treating hypertrophic cardiomyopathy (HCM) is provided, comprising administering a therapeutically effective amount of compound 1 as described herein to a subject in need of treatment for hypertrophic cardiomyopathy (HCM), wherein the pharmacologic effective amount is a total daily dose of about 2 mg-50 mg or about 5 mg-30 mg.

[0005] In another aspect, the present disclosure provides a method for treating myocardial diastolic dysfunction, comprising administering a therapeutically effective amount of compound 1 as described herein to a subject in need of treating myocardial diastolic dysfunction, wherein the pharmacologic effective amount is about 2mg-50mg or about 5mg-30mg total daily dose.

[0006] In another aspect, provided herein is a method for treating hypertrophic cardiomyopathy in an individual in need thereof, comprising administering to the individual an amount of Compound 1 effective to achieve and maintain a plasma concentration of Compound 1 of 200-750 ng / mL. In some embodiments, the plasma concentration of Compound 1 is achieved and maintained at 350-700 ng / mL. In some embodiments, the effective amount to achieve and maintain a desired plasma concentration of Compound 1 is 2-15 mg of Compound 1. In some embodiments, the effective amount to achieve and maintain a desired plasma concentration of Compound 1 is 2.5-15 mg of Compound 1. In some embodiments, the effective amount to achieve and maintain a desired plasma concentration of Compound 1 is 2-20 mg of Compound 1. In some embodiments, the effective amount to achieve and maintain a desired plasma concentration of Compound 1 is 2.5-20 mg of Compound 1. In some embodiments, the daily dose of Compound 1 is adjusted after the initial administration based on the predetermined plasma concentration. In some embodiments, the HCM is obstructive HCM (oHCM). In some embodiments, the HCM is non-obstructive HCM. [Brief description of the drawings]

[0007] [Figure 1] Resting LVEF (%; 2DE) in the TTE analysis population is shown. [Figure 2A] 1 shows the change from baseline in resting LVEF (2DE) versus plasma concentration of Compound 1 (MYK-461). [Figure 2B] 1 shows the change from baseline in resting LVOT-VTI (left ventricular outflow tract-velocity time integral (cm)) versus plasma concentration of Compound 1 (MYK-461). [Diagram 3] The study scheme is shown. The abbreviations used in the figure are: CPET (cardiopulmonary exercise testing); D (days); EOS (end of study); HSE (hemodynamic stress echocardiogram); LVEF (left ventricular ejection fraction); PK (pharmacokinetic sample); QD (once daily); RE / V (resting echocardiogram / Valsalva); W (weeks). [Figure 4]1 shows the change from baseline in post-exercise LVOT gradient over time. [Diagram 5] 1 shows stressed ejection fraction (EF) percentage at weeks 0, 4, and 12 in subjects receiving Compound 1 therapy. [Figure 6] 1 shows resting LVOT gradients in subjects receiving Compound 1 (10, 15, or 20 mg) from weeks 0 to 12. [Figure 7] 1 is a plot of resting LVOT slope versus Compound 1 concentration. [Figure 8] 1 is a plot of resting left ventricular ejection fraction (LVEF) (%) versus Compound 1 concentration. [Figure 9] 1 is a plot of the mean resting LVOT gradient measured during each week of the study. Compound 1 administration is discontinued after week 12. [Figure 10] 1 is a plot of the mean resting left ventricular ejection fraction (LVEF) (%) measured during each week of the study. Compound 1 administration is discontinued after week 12. [Figure 11] FIG. 1 illustrates the type of plot that may be obtained when measuring oxygen consumption (mL / kg / min) and arterial blood lactate (mM / L) during cardiopulmonary exercise testing. [Figure 12] Maximal VO2 (pVO2) values ​​measured during cardiopulmonary exercise testing (CPET) at baseline (week 0, solid bars) and after 12 weeks (hatched bars) are shown. [Figure 13] Maximal circulatory power measured during cardiopulmonary exercise testing (CPET) at baseline (week 0, solid bars) and after 12 weeks (hatched bars) is shown. [Figure 14] A plot of absolute change in pVO2 against absolute change in left ventricular ejection fraction (LVEF). [Figure 15] 1 is a plot of N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations (pg / mL) at weeks 0, 4, 8, and 12 in subjects receiving Compound 1. [Figure 16]1 is a plot of N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration (pg / mL) versus Compound 1 concentration (ng / mL). [Figure 17] NYHA functional class of subjects at baseline (week 0), 12 weeks after Compound 1 administration, and 16 weeks after Compound 1 administration (12 weeks on Compound 1, 4 weeks off Compound 1). [Figure 18] Shown is the mean dyspnea symptom score for each subject at the times indicated (Day 1-Week 12). Compound 1 was administered up to Week 12. [Figure 19] 1 is a plot of the mean post-exercise resting LVOT gradient (mmHg) at weeks 4, 12, and 16 of the Pioneer-HCM-B study (12 weeks of Compound 1 administration, 4 weeks off). [Figure 20] 1 is a plot of the change in resting LVEF (%) at weeks 1-8, 12, and 16 of the Pioneer-HCM-B study (12 weeks of Compound 1 administration, 4 weeks off treatment). [Figure 21] 1 illustrates improvement in NYHA functional class in individuals after 12 weeks in the Pioneer-HCM-B study, with reversal of improvement after a 4-week withdrawal of Compound 1. [Figure 22] Figure 1 illustrates the rapid improvement in peak dyspnea throughout the Pioneer-HCM-B study, and shows that improvement was reversed after a 4-week withdrawal of Compound 1. [Figure 23] Figure 1 illustrates improvements in max VO2 by week 12 during the Pioneer-HCM-B study. [Figure 24] Plot of resting LVOT (mmHg) as a function of Compound 1 concentration. Cohort B is open squares and Cohort A is closed squares. [Diagram 25] The study design for a pivotal trial to confirm safety and efficacy in patients with obstructive hypertrophic cardiomyopathy (oHCM) is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Described herein are methods for treating hypertrophic cardiomyopathy (HCM) in a subject, comprising specific dosing regimens that are highly effective in treating the patient and are well tolerated by the patient.

[0009] definition While various embodiments and aspects of the invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments and aspects are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be used in practicing the invention.

[0010] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. All documents, or portions of documents, including but not limited to patents, patent applications, articles, books, manuals, and treatises, are expressly incorporated herein by reference in their entirety for all purposes.

[0011] Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. See, for example, Singleton et al., Dictionary of Microbiology and Molecular Biology, 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., Molecular Cloning, A Laboratory Manual, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, devices, and materials similar or equivalent to those described herein can be used in the practice of the present invention. The following definitions are provided to facilitate understanding of some terms frequently used herein and are not intended to limit the scope of the present disclosure.

[0012] As used herein, the terms "a" or "an" mean one or more.

[0013] "Comprise," "include," and "have," as well as their derivatives, are used interchangeably herein as inclusive open-ended terms. For example, the use of "comprising," "including," or "having" means that any element that is comprised, had, or included is not the only element encompassed by the subject matter of the clause containing that verb.

[0014] As used herein, the term "about" refers to a range of values ​​including the specified value that one of ordinary skill in the art would consider similar to the specified value. In some embodiments, the term "about" refers to within a standard deviation using measurements generally accepted in the art. In some embodiments, about refers to a range extending to + / - 10% of the specified value. In some embodiments, about refers to the specified value.

[0015] As used herein, "treatment" or "treating" or "alleviating" or "ameliorating" are used interchangeably herein. These terms refer to an approach to obtain a beneficial or desired result, including but not limited to a therapeutic benefit. Therapeutic benefit refers to the eradication or amelioration of the underlying disorder for which the treatment is being performed. Therapeutic benefit is also achieved by the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such that an improvement is observed in the patient, although the patient may still be affected by the underlying disorder. Treatment includes slowing the onset of clinical symptoms of the disease by administration of the composition; suppressing the disease, i.e., causing a reduction in clinical symptoms of the disease; inhibiting the disease, i.e., preventing the onset of clinical symptoms by administration of the composition after the first appearance of symptoms; and / or relieving the disease, i.e., causing a regression of clinical symptoms by administration of the composition after the first appearance of clinical symptoms. For example, certain methods described herein treat hypertrophic cardiomyopathy (HCM) by reducing or decreasing the incidence or progression of HCM, or treat HCM by reducing the symptoms of HCM. Symptoms of HCM, or test results indicative of HCM, would be known to or could be quantified by one of skill in the art, and include, but are not limited to, shortness of breath (especially during exercise), chest pain (especially during exercise), syncope (especially during or immediately after exercise), rapid, pounding, or thumping heartbeat, atrial and ventricular arrhythmias, heart murmurs, enlarged and non-dilating left ventricle, myocardial hypertrophy, left ventricular wall thickening, elevated pressure gradient across the left ventricular outflow tract (LVOT), elevated post-exercise LVOT gradient, and high left ventricular ejection fraction (LVEF).

[0016] An "effective amount" or "pharmaceutical effective amount" is an amount sufficient to accomplish a stated purpose (e.g., to achieve an effect on the one for which it is administered, to treat a disease, to reduce an enzyme activity, to reduce one or more symptoms of a disease or condition, to reduce viral replication in cells). An example of an "effective amount" is an amount sufficient to contribute to the treatment or reduction of a symptom(s) of a disease, which may also be referred to as a "therapeutically effective amount". A "reduction" of a symptom(s) (and grammatical equivalents of this expression) refers to a decrease in the severity or frequency of the symptom(s), or the elimination of the symptom(s). Efficacy may also be expressed as a "-fold" increase or decrease. For example, a therapeutically effective amount may have an effect at least 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more over a control.

[0017] "Patient" or "subject in need thereof" refers to an organism suffering from or susceptible to a disease or condition that can be treated by the methods provided herein. The term does not necessarily indicate that the subject has been diagnosed with a specific disease, but typically refers to an individual under medical supervision. Non-limiting examples include humans, other mammals, bovine, rats, mice, dogs, cats, monkeys, goats, sheep, cows, deer, and other non-mammalian animals. In some embodiments, the patient, subject, or subject in need thereof is a human.

[0018] Hypertrophic cardiomyopathy (HCM) is clinically defined as unexplained left ventricular (LV) hypertrophy without known cause (e.g., pressure overload, systemic disease, or infiltrative processes). The phenotypic hallmark of HCM is myocardial hypercontractility with reduced LV compliance, reflected clinically as reduced ventricular size, often ultranormal ejection fraction, increased wall thickening, and diastolic dysfunction. Some of the symptoms and signs that HCM patients have include, but are not limited to, shortness of breath (especially during exercise), chest pain (especially during exercise), syncope (especially during or immediately after exercise), rapid, pounding, or thumping heartbeat, and heart murmurs.

[0019] Obstructive HCM (oHCM) is defined as a pressure gradient of at least 30 mmHg (i.e., 30 mmHg or more) across the LVOT in an individual at rest, during or immediately after a Valsalva maneuver, or after exercise. In some embodiments, an individual with oHCM has an LVOT pressure gradient of at least 40 mmHg, 45 mmHg, or 50 mmHg. In some embodiments, the pressure gradient across the LVOT in an individual is measured at rest. In some embodiments, the pressure gradient across the LVOT in an individual is measured while or immediately after a Valsalva maneuver is being performed. In some embodiments, the pressure gradient across the LVOT in an individual is measured after exercise. The degree of obstruction and the appearance of clinical symptoms associated with heart failure are the primary criteria for invasive intervention. oHCM can lead to severe symptoms of heart failure, arrhythmias, and / or death. Relieving obstruction improves symptoms and function.

[0020] As used herein, "Valsalva gradient" refers to the pressure gradient across the LVOT in an individual while the individual is performing a Valsalva maneuver.

[0021] Diastolic dysfunction includes, but is not limited to, hypertrophic cardiomyopathy (HCM), heart failure with preserved ejection fraction (HFpEF) (including both impaired active relaxation and impaired ventricular stiffness (diabetic HFpEF)); dilated cardiomyopathy (DCM), ischemic cardiomyopathy, cardiac allograft vasculopathy, restrictive cardiomyopathies (including inflammatory subgroups (e.g., Löffler and EMF), infiltrative subgroups (e.g., amyloid, sarcoid, and X-ray), storage subgroups (e.g., hemochromatosis, Fabry disease, and glycogen storage disease), idiopathic / inherited cardiomyopathy (IDC), and idiopathic / inherited cardiomyopathy (IDC). It is present or is a key feature of a range of diseases including the inherited subgroup (e.g., Troponin I (beta myosin HC), Troponin T (cardiac alpha actin), and Desmin-related (usually involving skeletal muscle)), the congenital heart disease subgroup (including pressure overload RV, Tetralogy of Fallot (pre-operative and early post-operative diastolic dysfunction and post-operative systolic dysfunction) and Pulmonary stenosis)), and valvular heart disease (e.g., Aortic stenosis (including elderly post-AVR / TAVR forms and congenital forms)).

[0022] method In one aspect, provided herein is a method of treating hypertrophic cardiomyopathy (HCM) comprising administering to a subject in need of treatment for hypertrophic cardiomyopathy (HCM) a therapeutically effective amount of a compound 1 having the formula: [ka] or a pharma- ceutically acceptable salt thereof, the therapeutically effective amount is about 2mg-50mg total daily dose. In some embodiments, the total daily dose is about 1mg-50mg. In some embodiments, the total daily dose of compound 1 is about 2mg-30mg, 10mg-20mg, 2mg-10mg, or 2mg-5mg. In some embodiments, the total daily dose of compound 1 is 2.5mg-15mg. In some embodiments, the total daily dose of compound 1 is 5mg-15mg. In some embodiments, the total daily dose of compound 1 is 2mg-15mg. In some embodiments, the total daily dose of compound 1 is 2.5mg-15mg. In some embodiments, the total daily dose of compound 1 is 1mg-15mg. In some embodiments, the effective amount for achieving and maintaining a desired plasma concentration of compound 1 is 2.5-20mg of compound 1.

[0023] In one embodiment, the present invention is directed to the treatment of hypertrophic cardiomyopathy in an individual in need thereof. In another embodiment, the treatment is directed to obstructive HCM in a subject. In a further embodiment, the treatment comprises administering a therapeutically effective amount of Compound 1 to the subject. In yet another embodiment, the therapeutically effective amount is administered such that the plasma concentration of Compound 1 in the subject is 225-600 ng / mL. In some embodiments, the therapeutically effective amount is administered such that the plasma concentration of Compound 1 in the subject is 350-700 ng / mL. In some embodiments, the plasma concentration of Compound 1 is 150-600 ng / mL. In some embodiments, the plasma concentration of Compound 1 is 200-400 ng / mL. In another embodiment, the treatment comprises administering Compound 1 to the subject, whereby the LVOT in the subject is decreased without a significant change in LVEF. In yet another embodiment, the treatment comprises co-administering one or more beta blockers to the subject in addition to Compound 1.

[0024] Individuals with hypertrophic cardiomyopathy may be symptomatic or asymptomatic. In general, symptomatic individuals are those who have evidence of cardiac condition or symptoms that indicate the presence of cardiac condition (e.g., limitation of physical activity), while those who do not experience such limitations are considered asymptomatic. As a non-limiting example, individuals with NYHA classification II, III, or IV are considered symptomatic, and individuals with NYHA classification I are considered asymptomatic. In some embodiments, individuals treated with the methods described herein have symptomatic hypertrophic cardiomyopathy. In some embodiments, individuals treated with the methods described herein have asymptomatic hypertrophic cardiomyopathy.

[0025] In some embodiments, the subject has not been on beta-blocker therapy for a period of at least 1-8 weeks prior to initiating treatment with Compound 1. In some embodiments, the subject has not been on beta-blocker therapy for a period of at least 1, 2, 3, or 4 weeks prior to initiating treatment with Compound 1. In some embodiments, the subject has not been on beta-blocker therapy for a period of at least 2 weeks prior to initiating treatment with Compound 1. In some embodiments, the subject has not been on beta-blocker therapy for a period of at least 3 weeks prior to initiating treatment with Compound 1. In some embodiments, the subject has not been on beta-blocker therapy for a period of at least 4 weeks prior to initiating treatment with Compound 1.

[0026] In some embodiments, Compound 1 is administered in combination with beta-blocker therapy. In such combination therapy, the beta-blocker therapy and Compound 1 are generally administered according to the label directions.

[0027] In some embodiments, the subject has not received Ca channel blocker therapy for a period of at least 1-8 weeks prior to initiating treatment with Compound 1. In some embodiments, the subject has not received Ca channel blocker therapy for a period of at least 1, 2, 3, or 4 weeks prior to initiating treatment with Compound 1. In some embodiments, the subject has not received Ca channel blocker therapy for a period of at least 2 weeks prior to initiating treatment with Compound 1. In some embodiments, the subject has not received Ca channel blocker therapy for a period of at least 3 weeks prior to initiating treatment with Compound 1. In some embodiments, the subject has not received Ca channel blocker therapy for a period of at least 4 weeks prior to initiating treatment with Compound 1.

[0028] In some embodiments, Compound 1 is administered in combination with Ca channel blocker therapy. In such combination therapy, the Ca channel blocker therapy and Compound 1 are generally administered according to the label directions.

[0029] In the methods described herein, it may be desirable to co-administer Compound 1 with an additional agent, hi some embodiments, the additional agent is selected from the group consisting of beta-blocker therapy and Ca channel blocker therapy.

[0030] In some embodiments, the HCM treated by the methods provided herein is obstructive HCM (oHCM).

[0031] In some embodiments, oHCM is characterized as having a pressure gradient of at least 30 mmHg (e.g., about 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 mmHg or more) across the left ventricular outflow tract (LVOT) in the subject at rest.

[0032] In some embodiments, oHCM is characterized as having a pressure gradient of at least 35 mmHg (e.g., about 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 mmHg or more) across the left ventricular outflow tract (LVOT) in the subject at rest.

[0033] In some embodiments, oHCM is characterized as having a pressure gradient of at least 40 mmHg (e.g., about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 mmHg or more) across the left ventricular outflow tract (LVOT) in the subject at rest.

[0034] In some embodiments, oHCM is characterized as having a pressure gradient of at least 45 mmHg (e.g., about 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 mmHg or more) across the left ventricular outflow tract (LVOT) in the subject at rest.

[0035] In some embodiments, oHCM is characterized as having a pressure gradient of at least 50 mmHg (e.g., about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 mmHg or more) across the left ventricular outflow tract (LVOT) in the subject at rest.

[0036] In some embodiments, oHCM is characterized as having a pressure gradient of at least 30 mmHg (e.g., about 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 mmHg or more) across the left ventricular outflow tract (LVOT) in the subject during or immediately after a Valsalva maneuver is being performed.

[0037] In some embodiments, oHCM is characterized as having a pressure gradient of at least 35 mmHg (e.g., about 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 mmHg or more) across the left ventricular outflow tract (LVOT) in the subject during or immediately after a Valsalva maneuver is being performed.

[0038] In some embodiments, oHCM is characterized as having a pressure gradient of at least 40 mmHg (e.g., about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 mmHg or more) across the left ventricular outflow tract (LVOT) in the subject during or immediately after a Valsalva maneuver is being performed.

[0039] In some embodiments, oHCM is characterized as having a pressure gradient of at least 45 mmHg (e.g., about 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 mmHg or more) across the left ventricular outflow tract (LVOT) in the subject during or immediately after a Valsalva maneuver is being performed.

[0040] In some embodiments, oHCM is characterized as having a pressure gradient of at least 50 mmHg (e.g., about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 mmHg or more) across the left ventricular outflow tract (LVOT) in the subject during or immediately after a Valsalva maneuver is being performed.

[0041] In some embodiments, oHCM is characterized as having a pressure gradient of at least 30 mmHg (e.g., about 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 mmHg or more) across the left ventricular outflow tract (LVOT) in the subject after exercise.

[0042] In some embodiments, oHCM is characterized as having a pressure gradient of at least 35 mmHg (e.g., about 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 mmHg or more) across the left ventricular outflow tract (LVOT) in the subject after exercise.

[0043] In some embodiments, oHCM is characterized as having a pressure gradient of at least 40 mmHg (e.g., about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 mmHg or more) across the left ventricular outflow tract (LVOT) in the subject after exercise.

[0044] In some embodiments, oHCM is characterized as having a pressure gradient of at least 45 mmHg (e.g., about 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 mmHg or more) across the left ventricular outflow tract (LVOT) in the subject following exercise.

[0045] In some embodiments, oHCM is characterized as having a pressure gradient of at least 50 mmHg (e.g., about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 mmHg or more) across the left ventricular outflow tract (LVOT) in the subject following exercise.

[0046] In some embodiments, Compound 1 is administered orally. In some embodiments, Compound 1 is administered in a unit dosage form containing 2 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, or 25 mg of Compound 1. In some embodiments, Compound 1 is administered daily in a single, divided, or continuous dose.

[0047] In some embodiments, Compound 1 is administered once a day at a daily dose of 2.5, 5, 10, 15, 20, or 25 mg. In some embodiments, Compound 1 is administered twice a day. In some embodiments, Compound 1 is administered three times a day.

[0048] In some embodiments, Compound 1 is administered daily for at least 12 weeks. In some embodiments, Compound 1 is administered daily for at least 10 weeks. In some embodiments, Compound 1 is administered daily for at least 8 weeks. In some embodiments, Compound 1 is administered daily for at least 6 weeks. In some embodiments, Compound 1 is administered daily for at least 4 weeks. In some embodiments, Compound 1 is administered daily for at least 2 weeks.

[0049] In some embodiments, Compound 1 is administered daily for at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, or 84 days.

[0050] In some embodiments, the therapeutically effective amount is sufficient to reduce the post-exercise or resting LVOT gradient in the subject to which the compound is administered to less than 30 mmHg (e.g., about 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5 mmHg). In some embodiments, the therapeutically effective amount is sufficient to reduce the post-exercise gradient LVOT in the subject to which the compound is administered to less than 10 mmHg (e.g., about 9, 8, 7, 6, 5 mmHg). Post-exercise (stress) gradient LVOT can be measured by any method known in the art.

[0051] In some embodiments, the therapeutically effective amount of Compound 1 is sufficient to improve, stabilize, or delay the New York Heart Association (NYHA) functional class of a subject. The NYHA functional class grades the severity of heart failure symptoms into one of four functional classes. The NYHA functional class is widely used in clinical practice and research because it provides a standard description of severity that can be used to assess response to treatment and guide management. The NYHA functional class based on symptom severity and physical activity: Class I: No limitations in physical activity. Ordinary physical activity does not cause excessive shortness of breath, fatigue, or palpitations. Grade II: Mild limitations in physical activity. No symptoms at rest, but ordinary physical activity causes excessive shortness of breath, fatigue, or palpitations. Grade III: Significant limitations in physical activity. No symptoms at rest, but excessive shortness of breath, fatigue, or palpitations occur with less than normal physical activity. Grade IV: Symptoms are present with any physical activity. Symptoms may be present at rest. Symptoms are aggravated with any attempted physical activity.

[0052] Administration of Compound 1 may be used to treat all NYHA functional classes of heart failure, but particularly those in the II-IV classes of the NYHA functional classification system.

[0053] In some embodiments, administering a therapeutically effective amount of compound 1 reduces the New York Heart Association (NYHA) functional class of the subject. In some embodiments, the NYHA functional class is reduced from IV to III, or from IV to II, or from IV to I. In some embodiments, the NYHA functional class is reduced from III to II. In some embodiments, the NYHA functional class is reduced from III to I. In some embodiments, the NYHA functional class is reduced from II to I.

[0054] In some embodiments, the therapeutically effective amount is a total daily dose of about 2mg to about 10mg (e.g., about 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10mg / day). In some embodiments, the therapeutically effective amount is a total daily dose of about 5mg to about 25mg (e.g., about 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, 15, 16, 17, 17.5, 18, 19, 20, 21, 22, 23, 24, or 25mg / day). In some embodiments, the therapeutically effective amount is a total daily dose of about 15mg to about 20mg (e.g., about 15, 16, 17, 18, 19, or 20mg / day). In some embodiments, the therapeutically effective amount is a total daily dose of about 2mg. In some embodiments, the therapeutically effective amount is a total daily dose of about 2.5mg. In some embodiments, the therapeutically effective amount is about 5 mg total daily dosage. In some embodiments, the therapeutically effective amount is about 7.5 mg total daily dosage. In some embodiments, the therapeutically effective amount is about 10 mg total daily dosage. In some embodiments, the therapeutically effective amount is about 12.5 mg total daily dosage. In some embodiments, the therapeutically effective amount is about 15 mg total daily dosage. In some embodiments, the therapeutically effective amount is about 20 mg total daily dosage. In some embodiments, the therapeutically effective amount is about 25 mg total daily dosage.

[0055] In some embodiments, the total daily dose is adjusted according to the requirements of individual patients. For example, the total daily dose can be adjusted according to the response profile of the subject 1-8 weeks after starting compound 1 therapy (e.g., 1, 2, 3, 4, 5, 6, 7, 8 weeks, or any days in between). In some embodiments, when the New York Heart Association (NYHA) functional class of the subject is reduced, the total daily dose is reduced. As a non-limiting example of this reduction, in some embodiments, when the New York Heart Association (NYHA) functional class of the subject is reduced from III to I, from III to II, or from II to I, the total daily dose is reduced from 5 mg to 2.5 mg. In some embodiments, when the New York Heart Association (NYHA) functional class of the subject is not reduced or worsens, the total daily dose is increased. As a non-limiting example, in some embodiments, the total daily dose is increased from 5 mg to 7.5 mg, or 10 mg, or 15 mg.

[0056] In some embodiments, the individual subject requirements used to adjust the total daily dose are the subject's resting left ventricular ejection fraction and the maximum resting left ventricular outflow tract (LVOT) gradient.For example, in some embodiments, the total daily dose is 5mg, and when the subject's resting left ventricular ejection fraction (LVEF) is 55% or more and the maximum resting left ventricular outflow tract (LVOT) gradient is 30mmHg or more, the dose is increased.In some embodiments, when the subject's resting left ventricular ejection fraction (LVEF) is 55% or more and the maximum resting left ventricular outflow tract (LVOT) gradient is 30mmHg or more and less than 50mmHg, the total daily dose is increased to 7.5mg.In some embodiments, when the subject's resting left ventricular ejection fraction (LVEF) is 55% or more and the maximum resting left ventricular outflow tract (LVOT) gradient is 50mmHg or more, the total daily dose is increased to 10mg. In a further non-limiting example, the total daily dose is 5 mg and is increased to 7.5 mg when the subject's resting left ventricular ejection fraction (LVEF) is 54-46% and the maximum resting left ventricular outflow tract (LVOT) gradient is 50 mmHg or greater.

[0057] In some embodiments, the therapeutically effective amount can be adjusted according to the subject's left ventricular ejection fraction (LVEF) level.

[0058] In some embodiments, the method provided herein further comprises measuring the left ventricular ejection fraction (LVEF) in the subject before administering the compound to obtain a first LVEF value (baseline).In some embodiments, the method provided herein further comprises measuring the LVEF in the subject after a period of time (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days) from the imitation of the compound to obtain a second LVEF value, and calculating the percentage change of the second LVEF value compared to the first LVEF value.Therefore, in some embodiments, the total daily dosage is adjusted according to the percentage change of LVEF.

[0059] In some embodiments, the second LVEF is measured 4 weeks after administration of the compound. In some embodiments, when the percentage change is less than 10% (e.g., about 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less), the total daily dose is increased by 10 mg. In some embodiments, when the percentage change is 10% or more and less than 15% (e.g., about 10%, 11%, 12%, 13%, or 14%), the total daily dose is increased by 5 mg. In some embodiments, when the percentage change is 15% or more and less than 20% (e.g., about 15%, 16%, 17%, 18%, or 19%), the total daily dose remains the same. In some embodiments, when the percentage change is 20% or more (e.g., about 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30% or more), the total daily dose is reduced by 5 mg.

[0060] In some embodiments, the therapeutically effective amount can be adjusted according to the subject's body weight. In some embodiments, the method provided herein further comprises measuring the subject's body weight before administering compound 1. In some embodiments, when the subject's body weight is 60 kg or less, the first daily dosage is about 10 mg. In some embodiments, when the subject's body weight is more than 60 kg, the first daily dosage is about 15 mg. In some embodiments, the compound is administered at this therapeutically effective amount for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days.

[0061] In some embodiments, when the subject weighs 60 kg or less, the daily dosage for the first 4 weeks of treatment is about 10 mg. In some embodiments, when the subject weighs more than 60 kg, the daily dosage for the first 4 weeks of treatment is about 15 mg.

[0062] In each of the methods described herein, in some embodiments, the individual weighs at least 45 kg.

[0063] In some embodiments, the therapeutically effective amount can be adjusted according to the plasma concentration of Compound 1. In some embodiments, the method further includes measuring the plasma concentration of Compound 1 at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days after administration of Compound 1. In some embodiments, the therapeutically effective amount of the daily dose of Compound 1 can be adjusted as described herein.

[0064] In some embodiments, the therapeutically effective dose can be adjusted based on the "trough" measurement. A "trough" measurement (concentration or any pharmacodynamic measurement) refers to a measurement obtained immediately before the next dose. For example, for once-daily (QD) dosing, a trough measurement occurs approximately every 24 hours immediately before the patient takes the next dose (typically a tablet or capsule). For pharmacokinetic reasons, such measurements are used as a way to standardize evaluation and minimize variability. When an individual "achieves and maintains" a certain plasma concentration of Compound 1, the individual's trough measurement does not fall below the minimum baseline level or exceed the maximum baseline level.

[0065] Adjustments to the dosage can also be made based on the individual's ability to metabolize Compound 1. Individuals who are unable to metabolize Compound 1 poorly can include individuals with mutated forms of the CYP 2C19 or CYP 3A4 enzymes. Individuals who are unable to metabolize Compound 1 poorly can be administered a lower starting dose and / or the dose can be adjusted to a lower amount, such as 1 mg. For example, in some embodiments, an individual who is unable to metabolize Compound 1 poorly is administered an initial dose of 2.5 mg, and if the trough measurement of Compound 1 in the individual's serum is above the desired maximum level, this dose can be adjusted downward to 1 mg. In some embodiments, an individual who is unable to metabolize Compound 1 poorly is administered an initial dose of 1 mg. In some embodiments, an individual who is unable to metabolize Compound 1 poorly is of Japanese descent.

[0066] In some embodiments, the method further comprises measuring the plasma concentration of Compound 1 two weeks after administration.

[0067] In some embodiments, the subject has a left ventricular wall thickness of 15 mm or more (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 mm or more) prior to treatment.

[0068] In some embodiments, the subject has a weight of about 18 to about 37 kg / m prior to treatment. 2 In some embodiments, the subject has a body mass index (BMI) of about 18 to about 50 kg / m prior to treatment. 2 or higher (e.g., about 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 kg / m 2 ).

[0069] In some embodiments, the subject has an LVEF of 55% or greater (e.g., 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, or 80% or greater) prior to treatment.

[0070] In some embodiments, the subject has a LVOT gradient of 30 mmHg or greater (e.g., about 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 mmHg or greater) prior to treatment.

[0071] In some embodiments, the subject has a post-exercise LVOT gradient of 50 mmHg or greater (e.g., about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 mmHg or greater) prior to treatment.

[0072] In another aspect, provided herein is a method of treating myocardial diastolic dysfunction in a subject in need thereof, comprising administering a therapeutically effective amount of a compound 1 having the formula: [ka] or a pharma- ceutical acceptable salt thereof, wherein the therapeutically effective amount is about 2 mg-50 mg total daily dosage.

[0073] In some embodiments, the therapeutically effective amount is a total daily dosage of about 2 mg-30 mg. In some embodiments, the therapeutically effective amount is a total daily dosage of about 2 mg. In some embodiments, the therapeutically effective amount is a total daily dosage of about 10 mg-15 mg.

[0074] Subjects in need of treatment for diastolic dysfunction include subjects from a patient population characterized by non-obstructive hypertrophic cardiomyopathy (non-oHCM) or subjects characterized by heart failure with preserved ejection fraction (HFpEF). Subjects in need of treatment for diastolic dysfunction include subjects exhibiting left ventricular stiffness measured by echocardiography or left ventricular stiffness measured by cardiac magnetic resonance.

[0075] In some embodiments, the subject in need of treatment for diastolic dysfunction is a subject from a patient population characterized by HFpEF. In some embodiments, patients with HFpEF have an ejection fraction of 50% or greater and have evidence of abnormal diastolic function. Abnormalities in diastolic function include impaired left ventricular relaxation, filling, diastolic distensibility, or stiffness. These characteristics can be measured using echocardiography. In some embodiments, the following echocardiographic values: septal e'<7 cm / sec; lateral wall e'<10 cm / sec; mean E / e' ratio >14; LA volume index >34 mL / m 2When at least one of the following conditions is met, the subject is considered to have diastolic function abnormality: maximum TR velocity > 2.8 m / sec. In some embodiments, when at least three of the above conditions are met, the subject is considered to have diastolic function abnormality.

[0076] In some embodiments, the subject in need of treatment for diastolic dysfunction exhibits left ventricular stiffness as measured by echocardiography. The subject may have the following characteristics as measured by echocardiography: mitral E / A ratio >0.8; septal e' <7 cm / sec; lateral wall e' <10 cm / sec; mean E / e' >= 14; LA volume index >34 mL / m 2 A subject is considered to have left ventricular stiffness when at least one of the following is met: maximum TR velocity > 2.8 m / sec. In some embodiments, a subject is considered to have left ventricular stiffness when at least three of the above values ​​are met.

[0077] Further determinants for diagnosing diastolic dysfunction using echocardiography are described in J Am Soc Echocardiogr. 29(4):277-314 (2016), the contents of which are incorporated herein by reference for all purposes.

[0078] In some embodiments, the subject in need of treatment for diastolic dysfunction exhibits left ventricular stiffness as measured by cardiac magnetic resonance, which is used to quantify maximum filling rate, time to maximum filling rate, and maximum diastolic strain rate. Thus, in some embodiments, the subject has left ventricular stiffness as measured by cardiac magnetic resonance when at least one of the following characteristics is met: abnormal maximum filling rate, time to maximum filling rate, or maximum diastolic strain rate.

[0079] A subject with diastolic dysfunction may also show increased levels of biomarkers in blood. For example, brain natriuretic peptide (BNP) or N-terminal pro-brain natriuretic peptide (NT-proBNP) is present at elevated levels in the blood of an individual with diastolic dysfunction. Thus, in some embodiments, a subject in need of treatment for diastolic dysfunction shows elevated serum blood levels of brain natriuretic peptide (BNP) or N-terminal pro-brain natriuretic peptide (NT-proBNP). In some embodiments, the subject's serum blood level of BNP is elevated when the concentration is at least 35, 45, 55, 65, 75, 85, 95, 100, 105, 115 pg / mL. In some embodiments, the subject's serum blood level of BNP is elevated when the concentration is at least 35 pg / mL. In some embodiments, the subject's serum blood level of BNP is elevated when the concentration is at least 85 pg / mL. In some embodiments, the subject's serum blood level of pro-NT BNP is elevated when the concentration of pro-NT BNP is at least 95, 105, 115, 125, 135, 145, 155, 165, or 175 pg / mL. In some embodiments, the subject's serum blood level of pro-NT BNP is elevated when the concentration is at least 125 pg / mL. In some embodiments, the subject's serum blood level of pro-NT BNP is elevated when the concentration is at least 155 pg / mL.

[0080] Those skilled in the art will recognize that blood samples can be taken from a number of different locations on the body, with the arm and finger being two of the most common locations, hi some embodiments, blood is taken from the subject's arm.

[0081] In some aspects, the method of treating hypertrophic cardiomyopathy includes achieving and maintaining a particular plasma concentration of Compound 1 during the course of treatment. For example, in some embodiments, the method of treating HCM includes achieving and maintaining a plasma concentration of Compound 1 of 200-750 ng / mL. In some embodiments, the plasma concentration of Compound 1 is 350-700 ng / mL.

[0082] The amount of compound 1 to achieve and maintain the desired plasma concentration varies depending on the individual. In some embodiments, the amount administered to achieve and maintain the desired plasma concentration of compound 1 is 2-15 mg. In some embodiments, the amount administered to achieve and maintain the desired plasma concentration of compound 1 is 2.5-15 mg. In some embodiments, the amount administered to achieve and maintain the desired plasma concentration of compound 1 is 5 mg. In some embodiments, the amount administered to achieve and maintain the desired plasma concentration of compound 1 is 2 mg. In some embodiments, the amount administered to achieve and maintain the desired plasma concentration of compound 1 is 2.5 mg. In some embodiments, the amount administered to achieve and maintain the desired plasma concentration of compound 1 is 10 mg. In some embodiments, the amount administered to achieve and maintain the desired plasma concentration of compound 1 is 15 mg. In some embodiments, the amount administered to an individual to achieve and maintain the desired plasma concentration is adjusted during treatment based on the measured levels. When the plasma concentration of compound 1 is above the upper threshold, the amount of compound 1 administered is reduced, and when the plasma concentration of compound 1 is below the lower threshold, the amount of compound 1 administered is increased. As a non-limiting example, the amount of compound 1 administered can be reduced from 5 mg to 2 mg, from 5 to 2.5 mg, from 10 mg to 7.5 mg, from 7.5 mg to 5 mg, from 15 to 12.5 mg, or from 12.5 mg to 10 mg. As a further non-limiting example, the amount of compound 1 administered can be increased from 5 mg to 7.5 mg, from 5 mg to 10 mg, from 5 mg to 7.5 mg, from 10 mg to 12.5 mg, or from 10 mg to 15 mg.

[0083] In some embodiments, provided herein is a method for treating hypertrophic cardiomyopathy in an individual in need thereof, comprising administering to the individual an amount of Compound 1 effective to achieve and maintain a plasma concentration of Compound 1 of 200-750 ng / mL. In some embodiments, provided herein is a method for treating hypertrophic cardiomyopathy in an individual in need thereof, comprising administering to the individual an amount of Compound 1 effective to achieve and maintain a plasma concentration of Compound 1 of 350-700 ng / mL.

[0084] In some embodiments, provided herein is a method for treating hypertrophic cardiomyopathy in an individual in need thereof, comprising administering to the individual an amount of Compound 1 effective to achieve and maintain a plasma concentration of Compound 1 between 150-1000 ng / mL. In some embodiments, provided herein is a method for treating hypertrophic cardiomyopathy in an individual in need thereof, comprising administering to the individual an amount of Compound 1 effective to achieve and maintain a plasma concentration of Compound 1 between 200-1000 ng / mL.

[0085] In some embodiments, 2-15 mg of compound 1 achieves and maintains a plasma concentration of compound 1 of 200-750 ng / mL. In some embodiments, 5-15 mg of compound 1 achieves and maintains a plasma concentration of compound 1 of 200-750 ng / mL. In some embodiments, about 2.5 mg of compound 1 achieves and maintains a plasma concentration of compound 1 of 200-750 ng / mL. In some embodiments, about 5 mg of compound 1 achieves and maintains a plasma concentration of compound 1 of 200-750 ng / mL. In some embodiments, about 10 mg of compound 1 achieves and maintains a plasma concentration of compound 1 of 200-750 ng / mL. In some embodiments, about 15 mg of compound 1 achieves and maintains a plasma concentration of compound 1 of 200-750 ng / mL.

[0086] In some embodiments, 2-15 mg of compound 1 achieves and maintains a plasma concentration of compound 1 of 350-700 ng / mL. In some embodiments, 5-15 mg of compound 1 achieves and maintains a plasma concentration of compound 1 of 350-700 ng / mL. In some embodiments, about 2.5 mg of compound 1 achieves and maintains a plasma concentration of compound 1 of 350-700 ng / mL. In some embodiments, about 5 mg of compound 1 achieves and maintains a plasma concentration of compound 1 of 350-700 ng / mL. In some embodiments, about 10 mg of compound 1 achieves and maintains a plasma concentration of compound 1 of 350-700 ng / mL. In some embodiments, about 15 mg of compound 1 achieves and maintains a plasma concentration of compound 1 of 350-700 ng / mL.

[0087] In some embodiments, 2-15 mg of compound 1 achieves and maintains a plasma concentration of compound 1 of 200-400 ng / mL. In some embodiments, 5-15 mg of compound 1 achieves and maintains a plasma concentration of compound 1 of 200-400 ng / mL. In some embodiments, about 2.5 mg of compound 1 achieves and maintains a plasma concentration of compound 1 of 200-400 ng / mL. In some embodiments, about 5 mg of compound 1 achieves and maintains a plasma concentration of compound 1 of 200-400 ng / mL. In some embodiments, about 10 mg of compound 1 achieves and maintains a plasma concentration of compound 1 of 200-400 ng / mL. In some embodiments, about 15 mg of compound 1 achieves and maintains a plasma concentration of compound 1 of 200-400 ng / mL.

[0088] In some embodiments, provided herein is a method of treating hypertrophic cardiomyopathy (HCM) in an individual in need thereof, comprising: administering to the individual a daily dose of 5 mg of Compound 1 for at least one week; increasing the daily dose to 10 mg when the individual's plasma concentration of Compound 1 falls below 200 ng / mL; or reducing the daily dose to 2.5 mg when the individual has a plasma concentration of Compound 1 greater than 750 ng / mL; or When the plasma concentration of Compound 1 in an individual is between 200-750 ng / mL, the daily dose should be maintained at 5 mg. A method is provided, comprising:

[0089] In some embodiments, after at least one week of administration of 5 mg of Compound 1, When the plasma concentration of Compound 1 in the individual exceeds 350 ng / mL, the daily dose is reduced to 10 mg; When the plasma concentration of Compound 1 in the individual exceeds 700 ng / mL, the daily dose is reduced to 2.5 mg; When the plasma concentration of Compound 1 in an individual is 350 ng / mL-700 ng / mL, the daily dose is maintained at 5 mg.

[0090] In some embodiments, increasing the daily dose is only performed if the individual has a Valsalva slope of 30 mmHg or greater in addition to the plasma concentration of Compound 1 described above. If the individual has a Valsalva slope of less than 30 mmHg and the individual has a plasma concentration of Compound 1 below the stated concentration, the individual's daily dose is maintained.

[0091] In some embodiments, the individual is administered 5 mg of Compound 1 for at least 2 weeks. In some embodiments, the individual is administered 5 mg of Compound 1 for at least 4 weeks. In some embodiments, the individual is administered 5 mg of Compound 1 for at least 6 weeks. In some embodiments, the individual is administered 5 mg of Compound 1 for at least 8 weeks.

[0092] In some embodiments, after administering 5 mg of Compound 1 for at least one week, the daily dose is increased to 10 mg, and a daily dose of 10 mg of Compound 1 is administered for at least one week, and the method further comprises: increasing the daily dose to 15 mg when the individual's plasma concentration of Compound 1 falls below 200 ng / mL; or reducing the daily dose to 5 mg when the individual has a plasma concentration of Compound 1 greater than 750 ng / mL; or When the plasma concentration of Compound 1 in an individual is between 200-750 ng / mL, the daily dose should be maintained at 10 mg. Includes.

[0093] In some embodiments, after administering 5 mg of Compound 1 for at least one week, the daily dose is increased to 10 mg, and a daily dose of 10 mg of Compound 1 is administered for at least one week, and the method further comprises: increasing the daily dose to 15 mg when the individual's plasma concentration of Compound 1 falls below 350 ng / mL; or reducing the daily dose to 5 mg when the plasma concentration of Compound 1 in the individual exceeds 700 ng / mL; or When the plasma concentration of Compound 1 in an individual is 350-700 ng / mL, the daily dose is maintained at 10 mg. Includes.

[0094] In some embodiments, increasing the daily dose is only performed if the individual has a Valsalva slope of 30 mmHg or greater in addition to the plasma concentration of Compound 1 described above. If the individual has a Valsalva slope of less than 30 mmHg and the individual has a plasma concentration of Compound 1 below the stated concentration, the individual's daily dose is maintained.

[0095] In some embodiments, the individual is administered 10 mg of Compound 1 for at least 2 weeks. In some embodiments, the individual is administered 10 mg of Compound 1 for at least 4 weeks. In some embodiments, the individual is administered 10 mg of Compound 1 for at least 6 weeks. In some embodiments, the individual is administered 10 mg of Compound 1 for at least 8 weeks.

[0096] In some embodiments, after administering 5 mg of Compound 1 for at least one week, the daily dose is reduced to 2 mg and 2 mg of Compound 1 is administered for at least one additional week, and the method further comprises: increasing the daily dose to 5 mg when the individual's plasma concentration of Compound 1 falls below 200 ng / mL; or When the plasma concentration of Compound 1 in an individual is 200-750 ng / mL, the daily dose should be maintained at 2 mg. Includes.

[0097] In some embodiments, after administering 5 mg of Compound 1 for at least one week, the daily dose is reduced to 2.5 mg and 2 mg of Compound 1 is administered for at least one additional week, and the method further comprises: increasing the daily dose to 5 mg when the plasma concentration of Compound 1 falls below 350 ng / mL; or When the plasma concentration of Compound 1 is between 350-700 ng / mL, the daily dose should be maintained at 2 mg. Includes.

[0098] In some embodiments, increasing the daily dose is only performed if the individual has a Valsalva slope of 30 mmHg or greater in addition to the plasma concentration of Compound 1 described above. If the individual has a Valsalva slope of less than 30 mmHg and the individual has a plasma concentration of Compound 1 below the stated concentration, the individual's daily dose is maintained.

[0099] In some embodiments, an individual is administered 2 mg of Compound 1 for at least 2 weeks. In some embodiments, an individual is administered 2 mg of Compound 1 for at least 4 weeks. Alternatively, in some embodiments, 2.5 mg of Compound 1 can be administered instead of 2 mg.

[0100] In some embodiments, the HCM is obstructive HCM (oHCM). In some embodiments, the HCM is non-obstructive HCM.

[0101] In some embodiments, provided herein is a method of treating hypertrophic cardiomyopathy (HCM) in an individual in need thereof by achieving and maintaining a plasma concentration of Compound 1 of 200-750 ng / mL, comprising: a) administering to the individual a daily dose of Compound 1 selected from the group consisting of 2.5, 5, 10, and 15 mg. A method is provided, comprising:

[0102] In some embodiments, the plasma concentration of Compound 1 is 350-700 ng / mL.

[0103] In some embodiments, the daily dose of compound 1 in step a) above is selected from the group consisting of 2, 2.5, 5, 10, 12.5, and 15 mg.

[0104] In some embodiments, the method further comprises: b) increasing the daily dose to the next higher dose when the plasma concentration of Compound 1 in the individual falls below 200 ng / mL; or b-ii) reducing the daily dose to the next lower dose when the plasma concentration of Compound 1 in the individual exceeds 750 ng / mL; or b-iii) maintaining said daily dose of Compound 1 when the individual's plasma concentration of Compound 1 is between 200-750 ng / mL; Includes.

[0105] In some embodiments, the method further comprises: b) increasing the daily dose to the next higher dose when the plasma concentration of Compound 1 in the individual falls below 350 ng / mL; or b-ii) reducing the daily dose to the next lower dose when the plasma concentration of Compound 1 in the individual exceeds 700 ng / mL; or b-iii) maintaining said daily dose of Compound 1 when the individual's plasma concentration of Compound 1 is between 350-700 ng / mL; Includes.

[0106] In some embodiments, increasing the daily dose (step bi) is performed only if the individual has a Valsalva gradient of 30 mmHg or greater in addition to the plasma concentration of Compound 1 described above. If the individual has a Valsalva gradient of less than 30 mmHg and the individual has a plasma concentration of Compound 1 below the recited concentration, the individual's daily dose is maintained.

[0107] In some embodiments, the method further comprises: c) Repeat step b) every 2-4 weeks. Includes.

[0108] In some embodiments, the method further comprises: c) Repeat step b) every 2-6 weeks. Includes.

[0109] In some embodiments, the method further comprises: c) Repeat step b) every 2-8 weeks. Includes.

[0110] In some embodiments, the method further comprises: c) Repeat step b) every 2-12 weeks. Includes.

[0111] In some embodiments, step b) is repeated every 2 weeks. In some embodiments, step b) is repeated every 4 weeks. In some embodiments, step b) is repeated every 6 weeks. In some embodiments, step b) is repeated every 8 weeks. In some embodiments, step b) is repeated every 10 weeks. In some embodiments, step b) is repeated every 12 weeks.

[0112] In some embodiments, the HCM is obstructive HCM (oHCM). In some embodiments, the HCM is non-obstructive HCM.

[0113] In some embodiments, provided herein is a method for treating hypertrophic cardiomyopathy (HCM) in an individual in need thereof by achieving and maintaining a plasma concentration of Compound 1 of 200-750 ng / mL in the individual, comprising administering a daily dose of 2.5-15 mg of Compound 1, increasing the daily dose when the plasma concentration of Compound 1 in the individual is less than 200 ng / mL, or decreasing the daily dose when the plasma concentration of Compound 1 in the individual is greater than 750 ng / mL.

[0114] In some embodiments, provided herein is a method for treating hypertrophic cardiomyopathy (HCM) in an individual in need thereof by achieving and maintaining a plasma concentration of Compound 1 of 350-700 ng / mL in the individual, comprising administering a daily dose of 2.5-15 mg of Compound 1, increasing the daily dose when the plasma concentration of Compound 1 in the individual is less than 350 ng / mL, or decreasing the daily dose when the plasma concentration of Compound 1 in the individual is greater than 700 ng / mL.

[0115] In some embodiments, provided herein is a method for treating hypertrophic cardiomyopathy (HCM) in an individual in need thereof by achieving and maintaining a plasma concentration of Compound 1 of 200-400 ng / mL in the individual, comprising administering a daily dose of 2.5-15 mg of Compound 1, increasing the daily dose when the plasma concentration of Compound 1 in the individual is less than 200 ng / mL, or decreasing the daily dose when the plasma concentration of Compound 1 in the individual is greater than 400 ng / mL.

[0116] In some embodiments, increasing the daily dose of Compound 1 is only performed if the individual's Valsalva slope is 30 mmHg or greater in addition to the above plasma concentration of Compound 1. If the individual's Valsalva slope is less than 30 mmHg and the individual's plasma concentration of Compound 1 is below the stated concentration, the individual's daily dose is maintained.

[0117] In some embodiments, the HCM is obstructive HCM (oHCM). In some embodiments, the HCM is non-obstructive HCM.

[0118] In some embodiments, provided herein is a method of treating hypertrophic cardiomyopathy (HCM) in an individual in need thereof by achieving and maintaining a plasma concentration of Compound 1 of 200-750 ng / mL, comprising: a) administering a daily dose of 2.5-15 mg of Compound 1 for at least one week; b) measuring the plasma concentration of Compound 1 in the individual; c) increasing the daily dose of Compound 1 when the plasma concentration of Compound 1 in the individual is less than 200 ng / mL; or reducing the daily dose of Compound 1 when the plasma concentration of Compound 1 in the individual exceeds 750 ng / mL; or When the plasma concentration of Compound 1 in the individual is between 200-750 ng / mL, continuing the same daily dose of Compound 1. A method is provided, comprising:

[0119] In some embodiments, increasing the daily dose in step c) is performed only if the individual's Valsalva slope is 30 mmHg or greater in addition to the above plasma concentration of Compound 1. If the individual's Valsalva slope is less than 30 mmHg and the individual's plasma concentration of Compound 1 is below the stated concentration, the individual's daily dose is maintained.

[0120] In some embodiments, the method further comprises: d) Repeat steps a)-c) every 1-12 weeks. Includes.

[0121] In some embodiments, provided herein is a method of treating hypertrophic cardiomyopathy (HCM) in an individual in need thereof by achieving and maintaining a plasma concentration of Compound 1 of 350-700 ng / mL in the individual, comprising: a) administering a daily dose of 2-15 mg of Compound 1 for at least one week; b) measuring the plasma concentration of Compound 1 in said individual; c) increasing the daily dose of Compound 1 when the plasma concentration of Compound 1 in the individual is less than 350 ng / mL; or reducing the daily dose of Compound 1 when the plasma concentration of Compound 1 in the individual exceeds 700 ng / mL; or Continue the same daily dose of Compound 1 when the individual's plasma concentration of Compound 1 is between 350-700 ng / mL. A method is provided, comprising:

[0122] In some embodiments, increasing the daily dose in step c) is performed only if the individual's Valsalva slope is 30 mmHg or greater in addition to the above plasma concentration of Compound 1. If the individual's Valsalva slope is less than 30 mmHg and the individual's plasma concentration of Compound 1 is below the stated concentration, the individual's daily dose is maintained.

[0123] In some embodiments, the method further comprises: d) Repeat steps a)-c) every 1-12 weeks. Includes.

[0124] In some embodiments, steps a)-c) are repeated every 2 weeks. In some embodiments, steps a)-c) are repeated every 4 weeks. In some embodiments, steps a)-c) are repeated every 6 weeks. In some embodiments, steps a)-c) are repeated every 8 weeks. In some embodiments, steps a)-c) are repeated every 10 weeks. In some embodiments, steps a)-c) are repeated every 12 weeks.

[0125] In some embodiments, the daily dose of compound 1 is selected from the group consisting of 2, 2.5, 5, 7.5, 10, 12.5, and 15 mg, and in step c), the daily dose of compound 1 is increased to the next higher amount of compound 1 or decreased to the next lower amount of compound 1. In some embodiments, the daily dose of compound 1 is selected from the group consisting of 2.5, 5, 10, and 15 mg, and in step c), the daily dose of compound 1 is increased to the next higher amount of compound 1 or decreased to the next lower amount of compound 1. In some embodiments, the initial daily dose of compound 1 in step a) is 5 mg.

[0126] In some embodiments, the HCM is obstructive HCM (oHCM). In some embodiments, the HCM is non-obstructive HCM.

[0127] In some embodiments, provided herein is a method for treating hypertrophic cardiomyopathy (HCM) in an individual in need thereof, comprising administering to the individual a total daily dose of an amount selected from the group consisting of 2 mg, 5 mg, 10 mg, and 15 mg. In some embodiments, the total daily dose of Compound 1 is selected from the group consisting of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg.

[0128] In some embodiments, the total daily dose of Compound 1 is 2 mg. In some embodiments, the total daily dose of Compound 1 is 2.5 mg. In some embodiments, the total daily dose of Compound 1 is 5 mg. In some embodiments, the total daily dose of Compound 1 is 7.5 mg. In some embodiments, the total daily dose of Compound 1 is 10 mg. In some embodiments, the total daily dose of Compound 1 is 12.5 mg. In some embodiments, the total daily dose of Compound 1 is 15 mg.

[0129] In some embodiments, the HCM is obstructive HCM (oHCM). In some embodiments, the HCM is non-obstructive HCM.

[0130] In some embodiments, provided herein is a method of treating hypertrophic cardiomyopathy (HCM) in an individual in need thereof, comprising: a) administering to the individual a daily dose of 2-15 mg of Compound 1 for at least one week; b) monitoring the individual; c) adjusting the daily dose of Compound 1 based on pharmacokinetic and / or pharmacodynamic measures; A method is provided, comprising:

[0131] In some embodiments, the monitoring in step b) uses a non-invasive monitoring technique, including but not limited to measuring peak oxygen update (VO2) levels, assessing NYHA functional class, measuring Valsalva slope, measuring cardiac activity using echocardiograms, and combinations thereof. In some embodiments, the non-invasive monitoring technique used is measuring peak VO2.

[0132] In some embodiments, the monitoring in step b) comprises measuring the plasma concentration of Compound 1 in the individual, or measuring the plasma concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP) in the individual.

[0133] The results from the monitoring step are used to adjust the daily dose of Compound 1 to best treat the individual. For example, in some embodiments, the adjusting step includes: increasing the daily dose of Compound 1 when the individual does not demonstrate clinical improvement in one or more of the non-invasive monitoring techniques; or reducing the daily dose of Compound 1 when the individual shows clinical regression in one or more of the non-invasive monitoring techniques; or continuing the same daily dose of Compound 1 when the individual shows clinical improvement in one or more of the non-invasive monitoring techniques. Includes.

[0134] The assessment of clinical improvement, stagnation, or regression depends on the monitoring technique used. For example, when assessing max VO2 levels, an increase in max VO2 of 2.0 mL / Kg / min or more from baseline is considered clinical improvement, a decrease in max VO2 of 2.0 mL / Kg / min or more from baseline is considered clinical regression, and a change in max VO2 of less than 2.0 mL / Kg / min from baseline is considered no clinical change. Echocardiography is particularly useful for assessing left ventricular stiffness. A subject is considered to have abnormal left ventricular stiffness when at least one of the following characteristics is met: mitral valve E / A ratio >0.8; E / e' >= 14; septal e' <7 cm / sec; lateral wall e' <10 cm / sec. Clinical improvement or regression of left ventricular stiffness is when at least a 5% change is observed in one of the listed characteristics, whereas a change of less than 5% is considered no clinical improvement.

[0135] In some embodiments, the plasma concentration of Compound 1 is monitored and the adjusting step comprises: increasing the daily dose of Compound 1 when the plasma concentration of Compound 1 in the individual is less than 200 ng / mL; or reducing the daily dose of Compound 1 when the plasma concentration of Compound 1 in the individual exceeds 750 ng / mL; or When the plasma concentration of Compound 1 in the individual is between 200-750 ng / mL, continuing the same daily dose of Compound 1. Includes.

[0136] In some embodiments, the plasma concentration of Compound 1 is monitored and the adjusting step comprises: increasing the daily dose of Compound 1 when the plasma concentration of Compound 1 in the individual is less than 350 ng / mL; or reducing the daily dose of Compound 1 when the plasma concentration of Compound 1 in the individual exceeds 700 ng / mL; or Continue the same daily dose of Compound 1 when the individual's plasma concentration of Compound 1 is between 350-700 ng / mL. Includes.

[0137] In some embodiments, increasing the daily dose is only performed if the individual has a Valsalva slope of 30 mmHg or greater in addition to the plasma concentration of Compound 1 described above. If the individual has a Valsalva slope of less than 30 mmHg and the individual has a plasma concentration of Compound 1 below the stated concentration, the individual's daily dose is maintained.

[0138] In some embodiments, the method further comprises: d) Repeat steps a)-c) every 1-12 weeks. Includes.

[0139] In some embodiments, steps a)-c) are repeated every 2 weeks. In some embodiments, steps a)-c) are repeated every 4 weeks. In some embodiments, steps a)-c) are repeated every 6 weeks. In some embodiments, steps a)-c) are repeated every 8 weeks. In some embodiments, steps a)-c) are repeated every 10 weeks. In some embodiments, steps a)-c) are repeated every 12 weeks.

[0140] In some embodiments, the method further comprises: d) Repeat steps a)-c) every 1-12 weeks. Includes.

[0141] In some embodiments, steps a)-c) are repeated every 2 weeks. In some embodiments, steps a)-c) are repeated every 4 weeks. In some embodiments, steps a)-c) are repeated every 6 weeks. In some embodiments, steps a)-c) are repeated every 8 weeks. In some embodiments, steps a)-c) are repeated every 10 weeks. In some embodiments, steps a)-c) are repeated every 12 weeks.

[0142] In some embodiments, the daily dose of compound 1 is selected from the group consisting of 2, 2.5, 5, 7.5, 10, 12.5, and 15 mg, and in step c), the daily dose of compound 1 is increased to the next higher amount of compound 1 or decreased to the next lower amount of compound 1. In some embodiments, the daily dose of compound 1 is selected from the group consisting of 2, 2.5, 5, 10, and 15 mg, and in step c), the daily dose of compound 1 is increased to the next higher amount of compound 1 or decreased to the next lower amount of compound 1. In some embodiments, the initial daily dose of compound 1 in step a) is 5 mg.

[0143] In some embodiments, the HCM is obstructive HCM (oHCM). In some embodiments, the HCM is non-obstructive HCM.

[0144] Also contemplated herein is a method of treating hypertrophic cardiomyopathy (HCM) in an individual in need thereof by administering a loading dose to the individual. The "loading dose" establishes a baseline amount of Compound 1 in the individual's plasma to rapidly achieve and maintain a desired plasma concentration of Compound 1. The "loading dose" time frame includes 3 days, 5 days, 7 days, 10 days, or 14 days. The amount of the "loading dose" includes a total daily dose of 15 mg once daily, 12.5 mg once daily, 10 mg once daily, or 7.5 mg once daily. After completion of the "loading dose", dose adjustments as described herein can be used to readjust dosing levels to achieve and maintain a desired plasma concentration.

[0145] Thus, in some embodiments, provided herein is a method of treating hypertrophic cardiomyopathy (HCM) in an individual in need thereof, comprising: a) administering to an individual a loading dose of Compound 1 for 3-14 days; b) measuring the plasma concentration of Compound 1 in the individual; c) adjusting the daily dose of the compound based on the plasma concentrations described in this application to achieve and maintain the desired plasma concentration of Compound 1. A method is provided, comprising:

[0146] In some embodiments, provided herein is a method for eliminating symptoms associated with hypertrophic cardiomyopathy (HCM), remission of hypertrophic cardiomyopathy, or reducing the incidence of hypertrophic cardiomyopathy in an individual in need thereof. The method includes administering a therapeutically effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof to a subject in need thereof, wherein the therapeutically effective amount is a total daily dose of about 2mg-50mg. In some embodiments, the total daily dose of Compound 1 is about 2mg-30mg, 10mg-20mg, 2mg-10mg, or 2mg-5mg. In some embodiments, the total daily dose of Compound 1 is 2.5mg-15mg. In some embodiments, the total daily dose of Compound 1 is 5mg-15mg. In some embodiments, the total daily dosage of Compound 1 is 2 mg-15 mg. In some embodiments, the total daily dosage of Compound 1 is 2.5 mg-15 mg. In some embodiments, the methods of eliminating symptoms associated with the development of HCM, ameliorating HCM, or reducing the incidence of HCM further comprise a dose adjustment step as described herein to achieve and maintain a desired plasma concentration.

[0147] In some embodiments, provided herein is a method for preventing or delaying the onset of hypertrophic cardiomyopathy (HCM) in an individual in need thereof. The method includes administering a therapeutically effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof to a subject in need thereof, wherein the therapeutically effective amount is a total daily dose of about 2mg-50mg. In some embodiments, the total daily dose of Compound 1 is about 2mg-30mg, 10mg-20mg, 2mg-10mg, or 2mg-5mg. In some embodiments, the total daily dose of Compound 1 is 2.5mg-15mg. In some embodiments, the total daily dose of Compound 1 is 5mg-15mg. In some embodiments, the total daily dose of Compound 1 is 2mg-15mg. In some embodiments, the total daily dose of Compound 1 is 2.5mg-15mg. In some embodiments, the method of preventing or delaying the onset of HCM further comprises a dose adjustment step as described herein to achieve and maintain a desired plasma concentration.

[0148] Pharmaceutical Compositions Compound 1 can be prepared in a variety of compositions suitable for delivery to a subject. Compositions suitable for administration to a subject typically include Compound 1 or a pharma- ceutically acceptable salt thereof and a pharma-ceutically acceptable excipient.

[0149] The pharmaceutical composition for administering Compound 1 or a pharma- ceutically acceptable salt described herein may be conveniently presented in unit dosage form and may be prepared by any method known in the art of pharmacy and drug delivery. All methods include the step of associating the active ingredient with a carrier containing one or more accessory ingredients. In general, the pharmaceutical composition is prepared by uniformly and intimately associating the active ingredient with a liquid carrier or finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition, the active agent is generally included in an amount sufficient to produce the desired effect on myocardial contractility (i.e., reducing the frequent supranormal systolic contractility in HCM) and to improve diastolic left ventricular relaxation. Such improved relaxation may alleviate the symptoms of hypertrophic cardiomyopathy and the pathogenesis of other diastolic dysfunction. The pharmaceutical composition may also ameliorate the effects of diastolic dysfunction causing coronary flow impairment, improving coronary flow impairment as an adjunct agent in angina pectoris and ischemic heart disease. The pharmaceutical compositions also provide benefit against adverse left ventricular remodeling in HCM and other causes of left ventricular hypertrophy resulting from chronic volume or pressure overload (e.g., from valvular heart disease or systemic hypertension).

[0150] Pharmaceutical compositions containing Compound 1 or a pharma- ceutically acceptable salt thereof can be in a form suitable for oral use, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, elixirs, solutions, buccal patches, oral gels, chewing gums, chewable tablets, effervescent powders, and effervescent tablets. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions can contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, antioxidants, and preservatives to provide pharma- cetically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharma- cetically acceptable excipients suitable for tablet manufacture. Such excipients may be, for example, inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as PVP, cellulose, PEG, starch, gelatin, or gum arabic, and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or may be enteric-coated or otherwise coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a long period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. The tablets may also be coated to form osmotic therapeutic tablets for controlled release.

[0151] Formulations for oral use can also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil).In addition, emulsions can be prepared using water-immiscible ingredients such as oils and stabilized with surfactants such as monodiglycerides, PEG esters, etc.

[0152] Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum arabic, and dispersing or wetting agents can be natural phosphatides, such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearates, or condensation products of ethylene oxide with long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0153] Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or in a mineral oil (e.g., liquid paraffin). Oily suspensions can contain a thickening agent (e.g., beeswax, hard paraffin, or cetyl alcohol). In order to provide a palatable oral preparation, sweetening and flavoring agents such as those described above can be added. Such compositions can be preserved by the addition of an antioxidant, such as ascorbic acid.

[0154] Dispersible powders and granules suitable for preparation of an aqueous suspension by addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweetening, flavoring, and coloring agents, may also be present.

[0155] The pharmaceutical compositions described herein can also be in the form of oil-in-water emulsions. The oil phase can be a vegetable oil (e.g., olive oil or peanut oil), a mineral oil (e.g., liquid paraffin), or a mixture thereof. Suitable emulsifiers can be natural gums (e.g., gum arabic or gum tragacanth), natural phosphatides (e.g., soybean, lecithin), and esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensation products of said partial esters with ethylene oxide (e.g., polyoxyethylenesorbitan monooleate). Emulsions can also contain sweetening and flavoring agents.

[0156] Syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol, or sucrose. Such formulations can also contain a demulcent, a preservative, and flavoring and coloring agents. Oral solutions can be prepared in combination with, for example, cyclodextrin, PEG, and surfactants.

[0157] Pharmaceutical dosage form The present disclosure includes novel pharmaceutical dosage forms of Compound 1 and its pharma- ceutical acceptable salts. The dosage forms described herein are suitable for oral administration to subjects. The dosage forms can take any form suitable for oral administration, including, but not limited to, capsules or tablets.

[0158] In some embodiments, the disclosure provides a single unit dose capsule or tablet form containing 2-10 mg or 2-15 mg of Compound 1 having the formula: [ka]

[0159] In some embodiments, the amount of Compound 1 is about 2 mg-5 mg. In some embodiments, the amount of Compound 1 is about 5 mg-10 mg. In some embodiments, the amount of Compound 1 is about 2.5 mg. In some embodiments, the amount of Compound 1 is about 5 mg. In some embodiments, the amount of Compound 1 is about 7.5 mg. In some embodiments, the amount of Compound 1 is about 10 mg.

[0160] In some embodiments, the unit dosage form of Compound 1 is a capsule. In some embodiments, the unit dosage form of Compound 1 is a tablet.

[0161] In some embodiments, the unit dosage form is a size 0, 1, 2, 3, 4, or 5 capsule. In some embodiments, the unit dosage form is a size 4 capsule. In some embodiments, the unit dosage form is a size 5 capsule.

[0162] kit The present disclosure also encompasses kits that include the pharmaceutical compositions and dosage forms of the invention.

[0163] In some aspects, the present invention provides kits comprising Compound 1. Some of the kits described herein include a label describing a method for administering Compound 1. Some of the kits described herein include a label describing a method for treating hypertrophic cardiomyopathy (HCM). In some embodiments, the kits described herein include a label describing a method for treating obstructive HCM (oHCM). In some embodiments, the kits described herein include a label describing a method for reducing a left ventricular outflow tract (LVOT) gradient in a subject. In some embodiments, the kits described herein include a label describing a method for reducing a resting left ventricular outflow tract (LVOT) pressure gradient in a subject. In some embodiments, the kits described herein include a label describing a method for reducing a stressed left ventricular outflow tract (LVOT) gradient in a subject.

[0164] Compositions of the invention include, but are not limited to, compositions comprising Compound 1 in a bottle, jar, vial, ampoule, tube, or other container closure system approved by the U.S. Food and Drug Administration (FDA) or other regulatory agency, and can provide one or more dosages containing the compound. The package or dispenser may also include a notice associated with the container in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, the notice indicating approval by the agency. In certain embodiments, the kit can include a formulation or composition described herein, a container closure system including the formulation or dosage unit form including the formulation, and a notice or instructions describing the method of use described herein. EXAMPLES

[0165] Example 1. Preparation of (S)-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione. [ka] Compound 1.1. Isopropylurea. To a stirred solution of isopropylamine (15.3 g, 0.258 mol, 1.0 equiv.) in CH2Cl2 (200 mL) at 0° C. under argon was added trimethylsilyl isocyanate (30 g, 0.26 mol, 1.0 equiv.) dropwise. The resulting mixture was allowed to reach ambient temperature and stirred overnight. After cooling to 0° C., CH3OH (100 mL) was added dropwise. The resulting solution was stirred at room temperature for 2 hours (h) and then concentrated under reduced pressure. The crude residue was recrystallized from CH3OH:Et2O (1:20) to give 15.4 g (58%) of the title compound as a white solid. LC / MS: m / z (ES+) 103 (M+H) + .

[0166] [ka] Compound 1.2. 1-Isopropyl barbiturate. To a stirred solution of 1.1 (14.4 g, 0.14 mol, 1.00 equiv.) in CH3OH (500 mL) was added dimethyl malonate (19.55 g, 0.148 mol, 1.05 equiv.) and sodium methoxide (18.9 g, 0.35 mol, 2.50 equiv.). The resulting mixture was stirred at 65° C. overnight. After cooling to ambient temperature and then to 0° C., the pH was carefully adjusted to 3 with concentrated aqueous HCl. The resulting mixture was concentrated under reduced pressure. The residue was taken up in EtOH (200 mL) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using CH2Cl2 / CH3OH (20:1) as eluent to give 16.8 g (50%) of the title compound as a white solid. LC / MS: m / z (ES+) 171 (M+H) + . 1 1 H-NMR (300 MHz, d6-DMSO): δ 11.19 (s, 1H), 4.83 (m, 1H), 3.58 (s, 2H), 1.32 (d, J = 6.0 Hz, 6H).

[0167] [ka] Compound 1.3.6-Chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione. To a 100 mL round bottom flask containing compound 1.2 (11.4 g, 66.99 mmol, 1.00 equiv.) under argon was added triethylbenzylammonium chloride (21.3 g, 93.51 mmol, 1.40 equiv.) and POCl3 (30 mL). The resulting mixture was stirred at 50° C. overnight. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in CHCl (150 mL) followed by slow addition of HO (100 mL). The phases were separated and the organic layer was washed with HO (100 mL), dried over anhydrous NaSO4 and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using EtOAc / petroleum ether (1:1) as eluent to afford 5.12 g (40%) of the title compound as a pale yellow solid. 1 H-NMR (300 MHz, d6-DMSO): δ 12.22 (s, 1H), 5.88 (s, 1H), 4.95 (m, 1H), 1.34 (d, J = 6.0 Hz, 6H).

[0168] [ka] Compound 1. (S)-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione. To a solution of 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (1.3, 1.0 g, 5.31 mmol) in 1,4-dioxane (20 mL) was added (S)-α-methylbenzylamine (Sigma-Aldrich, 1.43 g, 11.7 mmol, 2.2 equiv). The reaction mixture was stirred at 80° C. for 24 h. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residue was taken up in EtOAc (70 mL) and washed with aqueous 1N HCl (2×50 mL) and brine (40 mL). The organic layer was dried over anhydrous Na2SO4 and then concentrated under reduced pressure to half the original volume to give a precipitate. Hexane (20 mL) was added and the mixture was stirred at room temperature. The resulting solid was collected by filtration, washed with hexanes (20 mL), and dried to give 1.0 g (69%) of the title compound as a white solid. LC / MS: m / z (ES+) 274 (M+H). + . 1 H-NMR (400 MHz, d6-DMSO): δ 9.77 (s, 1H), 7.32 (m, 4H), 7.24 (m, 1H), 6.50 (d, J = 6.8 Hz, 1H), 4.87 (m, 1H), 4.52 (m, 1H), 4.31 (d, J=6.8 Hz, 1H), 1.37 (m, 3H), 1.24 (m, 6H). 1 H NMR (400 MHz, CD3OD) δ ppm 7.39-7.20 (m, 5H), 5.01 (m, 1H), 4.48 (m, 1H), 1.49 (d, J = 6.7 Hz, 3H), 1.36 (m, 6H).

[0169] Example 2. Phase I Clinical Trial To date, three clinical trials have examined the safety and tolerability of Compound 1. Two studies have been completed and one is ongoing. A double-blind, placebo-controlled, single ascending dose (SAD) study (Compound 1-002) has been conducted in healthy men. Subjects were administered single doses ranging from 1 mg to 48 mg. An open-label, group-sequential SAD study (Compound 1-001) has also been completed in subjects with clinically stable HCM, administering single doses up to 144 mg. In addition, a double-blind, placebo-controlled, multiple ascending dose (MAD) study (Compound 1-003) is being conducted in healthy adult subjects administering multiple doses of Compound 1 up to 25 mg once daily (QD) for up to 28 days. [Table 1] (1) 48 mg cohort (n=4 patients); 96 mg cohort (n=6); 144 mg cohort (n=5). (2) Each cohort was randomized 6:2 to receive Compound 1 or matching placebo. (3) Each cohort was randomized 10:2 to receive Compound 1 or matching placebo. (4) The 25 mg cohort was administered for 25 days.

[0170] 2.1 Compound 1-002 Test In the Compound 1-002 study, healthy male subjects received a single dose of 1 mg-48 mg as an oral suspension. All dose levels were well tolerated with no serious adverse events (SAEs), deaths, or study discontinuations due to reported adverse events (AEs). The incidence of treatment-emergent AEs did not appear to increase with dose. The pharmacokinetic (PK) profile of Compound 1 showed rapid absorption followed by distribution, followed by a prolonged elimination phase with a mean elimination half-life of approximately 8 days. A single dose of Compound 1 ≥ 12 mg was associated with a detectable reduction in LV contractility from baseline as assessed by three independent echocardiographic measures (left ventricular ejection fraction [LVEF], LV fractional shortening [LVFS], and LVOT velocity time integral [VTI]). At the highest dose (48 mg) tested in healthy subjects, the mean reduction in LVEF at any time point relative to baseline was -6%. No changes in systolic blood pressure (BP) or heart rate (HR) were detected at any of the dose levels tested in this study.

[0171] 2.2 Compound 1-001 Test In the MYK-461-001 study, 15 subjects with HCM received single doses up to 144 mg. All dose levels were well tolerated with no deaths, discontinuations due to AEs, or dose-related treatment-emergent AEs, except for one of five subjects who received the 144 mg dose. This subject experienced an SAE described as a vasovagal reaction characterized by a period of asystole and hypotension, but recovered spontaneously without sequelae. With regard to the assessment of causality, there are no preclinical or other clinical data linking Compound 1 to modulation of cardiac ion channel currents, or the generation or conduction of apical beats. Compound 1 has no demonstrated vasoactive properties and is biochemically inactive against smooth muscle myosin. Other potential contributors to this event include chronic beta-blockade with metoprolol succinate 150 mg once daily and the observation that the subject inadvertently performed a Valsalva maneuver during grip strength assessment immediately prior to the event.

[0172] As shown by the results in Table 2, the LVOT obstruction in the patients was reversed after a single dose of Compound 1. Two subjects enrolled in Study 001 demonstrated an LVOT pressure gradient (upon challenge). Each subject received a single 96 mg dose of Compound 1. Both patients' gradients were reversed after dosing. [Table 2]

[0173] Preliminary PK analysis in the Compound 1-001 study revealed that the PK profile in subjects with HCM was similar to that in healthy subjects. All subjects with HCM demonstrated evidence of mechanism in terms of demonstration of reduced LV contractility by at least one of three independent echocardiographic measures. In two subjects, measurable LVOT gradients after Valsalva were reduced to less than 10 mmHg after a single 96 mg dose of Compound 1.

[0174] 2.3 Compound 1-003 Test The Compound 1-003 study is dosing four cohorts of healthy adult subjects, each of whom is scheduled to receive dosing for 28 days. Compound 1 was well tolerated at multiple doses up to 25 mg once daily. All AEs were mild or moderate in severity, with no SAEs. In cohort 3, diarrhea and / or abdominal cramps were observed in 3 of 12 subjects receiving blinded dosing (either Compound 1 12.5 mg or placebo once daily). One of these subjects discontinued due to recurrent diarrhea upon rechallenge, and the other two subjects successfully resumed study drug. The investigators considered these gastrointestinal AEs to be mild or moderate in severity and possibly related to study drug. No gastrointestinal AEs were reported in cohort 4 (Compound 1 25 mg or placebo).

[0175] Dosing in cohort 4 was discontinued by the investigator on day 25 in 5 of 12 subjects receiving blinded treatment (either Compound 1 25 mg or placebo once daily) due to reaching predefined discontinuation criteria for dose escalation (≥20% reduction in LVEF). All subjects remained asymptomatic.

[0176] PD evidence of reduced contractility was evident at the higher dose levels (12.5 mg once daily and 25 mg once daily). These data, along with PK and PD data from all subjects in all previous studies, have been incorporated into a robust PK-PD model to help inform a safe dosing strategy for the current study that is likely to be similarly effective.

[0177] Overall, a favorable safety profile was demonstrated in HCM patients and healthy volunteers, as shown in Table 3 below. [Table 3]

[0178] Clinically significant and dose-dependent responses were observed across all patient populations in the Phase 1 study. [Table 4] (1) 48 mg cohort (n=4 patients); 96 mg cohort (n=6); 144 mg cohort (n=5). (2) Each cohort was randomized 6:2 to receive Compound 1 or matching placebo. (3) Each cohort was randomized 10:2 to receive Compound 1 or matching placebo. (4) The 25 mg cohort was administered for 25 days. Table 5 below provides an overview of the three Phase 1 programs. [Table 5]

[0179] Example 3. A Phase 2, Open-Label Pilot Study to Evaluate the Efficacy, Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Compound 1 in Subjects with Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction (Pioneer-HCM-A)

[0180] Purpose of the test: Main purpose: To characterize the effect of 12 weeks of Compound 1 administration on reducing maximum left ventricular outflow tract (LVOT) gradient after exercise in subjects with symptomatic hypertrophic cardiomyopathy (HCM) and LVOT obstruction. Secondary Objectives: To evaluate the proportion of subjects with symptomatic HCM and LVOT obstruction who achieve a post-exercise LVOT gradient response with a maximum gradient of less than 30mmHg To evaluate the effect of 12 weeks of Compound 1 on dyspnea symptom score, peak oxygen consumption (pVO2), and expiratory volume (VE) / carbon dioxide production (VCO2) slope in subjects with symptomatic HCM and LVOT obstruction To evaluate the pharmacokinetics (PK) of Compound 1 in subjects with symptomatic HCM and LVOT obstruction To evaluate the pharmacodynamics (PD) of Compound 1 in subjects with symptomatic HCM and LVOT obstruction, as assessed by various echocardiographic imaging parameters in subjects with symptomatic HCM and LVOT obstruction To evaluate the safety and tolerability of Compound 1 in subjects with symptomatic HCM and LVOT obstruction To evaluate post-dose reversibility of Compound 1 effects after a 4-week drug holiday in subjects with symptomatic HCM and LVOT obstruction

[0181] Exploratory purpose: To evaluate the proportion of subjects with symptomatic HCM and LVOT obstruction who achieve a post-exercise LVOT gradient response with a maximum gradient of less than 10mmHg To evaluate the effect of 12 weeks of Compound 1 on New York Heart Association (NYHA) functional class, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, and Kansas City Cardiomyopathy Questionnaire (KCCQ) Global Summary Score (OSS) in subjects with symptomatic HCM and LVOT obstruction To evaluate the effect of Compound 1 administration on arterial pulse wave morphology, as assessed using an optical biosensor, in subjects with symptomatic HCM and LVOT obstruction To evaluate the effect of Compound 1 administration on heart rate and rhythm, as assessed using a cardiac monitoring skin patch, in subjects with symptomatic HCM and LVOT obstruction

[0182] Selection criteria: Each subject must meet the following criteria to be included in the study: 1. Able to understand and comply with study procedures, understand the risks associated with the study, and provide written consent in accordance with federal, local, and institutional guidelines prior to the first study-specific procedure. 2. Men and women aged 18-70 years at the time of the screening visit. 3. Diagnosed with HCM (hypertrophied, non-dilating left ventricle with no known systemic or other cause) with left ventricular (LV) wall thickness ≥15mm at time of initial diagnosis, or ≥13mm with a clear family history of HCM. 4. Body mass index (BMI) at the time of screening visit, calculated using the institution's standard formula, between 18 and 37 kg / m 2 (inclusive). 5. At the Screening Visit, all safety laboratory parameters (chemistry, hematology, and urinalysis) are within normal ranges (laboratory reference ranges) as assessed by a central laboratory, or if outside normal ranges, meet both of the following criteria: Deemed clinically insignificant by the investigator - Liver function test results are less than 1.5 times the upper limit of the laboratory's reference range. 6. At the screening visit, have a documented left ventricular ejection fraction (LVEF) of 55% or greater as quantified by the investigator and the study site's echocardiography facility. 7. At the screening visit, a resting LVOT gradient of 30mmHg or greater and a maximum post-exercise LVOT gradient of 50mmHg or greater as determined by the investigator and the study site's echocardiography facility. 8.NYHA functional class II or higher, determined by the investigator to be due to LVOT obstruction. 9. In the judgment of the investigator and the echocardiography laboratory at the study site, the device has a sufficient ultrasound bone window and is capable of performing an adequate transthoracic echocardiogram (TTE). 10. Female subjects must not be pregnant or lactating and, if sexually active, must use one of the following accepted methods of contraception from the Screening Visit until 3 months after the last dose of investigational medicinal product (IMP): · Double-barrier methods (e.g., men use condoms and women use diaphragms or cervical caps) Barrier and hormonal contraception (e.g., men use condoms and women use hormonal contraception) The woman had been surgically sterilized 6 months prior or was postmenopausal 2 years prior. Permanent sterilization methods include hysterectomy, bilateral oophorectomy, bilateral salpingectomy, and / or documented bilateral tubal occlusion ≥6 months prior to screening. A woman is considered postmenopausal if she has been amenorrhea for at least two years since cessation of all exogenous hormone therapy and her follicle-stimulating hormone (FSH) levels are within the postmenopausal range. 11. Male subjects with female partners (including postmenopausal partners) must agree to use highly effective contraception from the screening visit through 3 months after the final dose of study drug. Highly effective contraception methods include proven vasectomy, sexual abstinence, dual barrier methods (e.g., men using condoms and women using diaphragms or cervical caps), or barrier and hormonal contraception (e.g., men using condoms and women using hormonal contraception). Due to the risk of drug secretion in semen, male subjects with currently pregnant partners (including men who have had a vasectomy) should use barrier methods for the duration of the study and for 3 months after the final dose of study drug. In addition, male subjects with sexual partners should use condoms for the duration of the study and for 3 months after the final dose of study drug to prevent transfer of Compound 1 in semen to their partners, even if they are not pregnant or likely to become pregnant. 12. Must be able to complete the Dyspnea Numeric Rating Scale (NRS) and KCCQ according to established guidelines.

[0183] Exclusion criteria: Subjects who meet any of the following criteria will be excluded from the study: 1. Hypersensitivity to Compound 1 or any of the components of the Compound 1 formulation. 2. The presence of any medical condition that would prevent exercise stress testing. 3. History of sustained ventricular tachyarrhythmia. 4. History of syncope due to exertion within the past 6 months. 5. Active infection. 6. Persistent atrial fibrillation or atrial fibrillation at screening. 7. Have a QTc Fridericia (QTcF) >500 ms or any other electrocardiogram (ECG) abnormality deemed by the investigator to pose a risk to subject safety (e.g., type II second-degree atrioventricular block). 8. Aortic stenosis or fixed subaortic occlusion. 9. History of LV systolic dysfunction (LVEF < 45%) at any time during the clinical course. 10. History of coronary artery disease. 11. History of any type of malignancy, with the following exceptions: cervical intraepithelial neoplasia >5 years prior to screening, or surgically excised non-melanoma skin cancer >2 years prior to screening. 12. Have positive serology for human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV) at screening. 13. Test positive for alcohol or drug abuse at screening. 14. History or evidence of any other clinically significant disorder, condition, or disease (other than those outlined above) that, in the opinion of the Investigator or MyoKardia physician, would pose a risk to the subject's safety or interfere with the evaluations, procedures, or completion of the study. 15. Participated in a clinical trial (or currently using an investigational device) receiving any investigational drug within 30 days prior to screening or within at least 5 half-lives of each (whichever is longer). Participation in previous clinical trials using Compound 1 is permitted as long as these criteria are met. 16. Current use of tobacco- or nicotine-containing products exceeds 10 cigarettes or equivalent per day. 17. Subjects who, in the opinion of the investigator, require ongoing therapy with beta-blockers, calcium channel blockers, or disopyramide. Subjects receiving any of these medications, which in the opinion of the investigator can be safely discontinued, will be eligible as long as the medication is discontinued ≥14 days prior to the Screening Visit. 18. Prior treatment with cardiotoxic agents (e.g., doxorubicin or similar) or current treatment with antiarrhythmic agents with negative inotropic activity (e.g., flecainide or propafenone). 19. Unable to comply with study constraints / requirements, including the number of required visits to clinical sites. 20. Is an employee of MyoKardia or a relative of an employee, an investigator, or a staff member or family member of an investigator.

[0184] Overall study design and planning This is a Phase 2, open-label, pilot study to evaluate the efficacy, PK, PD, safety, and tolerability of Compound 1 in subjects with symptomatic HCM and LVOT obstruction. Approximately 10 adult subjects with symptomatic HCM, a resting LVOT gradient of 30 mmHg or greater, and a maximum post-exercise LVOT gradient of 50 mmHg or greater will be enrolled. The study will have a 12-week treatment period and a 4-week washout period (Figure 3).

[0185] At screening, subjects undergo a transthoracic echocardiogram (TTE) in the supine or left lateral decubitus position. In addition to a standardized full TTE, instantaneous maximum LVOT gradient at rest (baseline) and maximum induced LVOT gradient are collected. Subjects then undergo a standard symptom-limited exercise stress test (hemodynamic stress echocardiogram). Subjects are systematically evaluated for symptoms of dyspnea and / or angina. Instantaneous maximum LVOT gradient is assessed by TTE immediately after exercise.

[0186] On Day 1, a resting TTE is performed, blood samples are taken for PK, and subjects undergo assessment of pVO2, VE / VCO2, and other variables via cardiopulmonary exercise testing (CPET). Following CPET, subjects are dosed with open-label oral Compound 1 at the investigational site and observed for at least 1 hour post-dose, with vital signs and ECG assessed at 1 hour post-dose. Subjects are then provided with sufficient Compound 1 for once-daily dosing at home.

[0187] Subjects will be evaluated at the investigational site at weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, and 16. At each of these visits, a resting TTE will be performed and blood samples will be drawn for PK. On study visit days, study drug will be administered at the investigational site with blood samples drawn for PK approximately 2 hours prior to dosing. Hemodynamic stress echocardiograms will be performed at weeks 4, 12, and 16 to assess maximum LVOT gradient. CPET will be performed between weeks 10 and 12 (inclusive).

[0188] The starting dose of Compound 1 will be 10 mg for subjects weighing approximately 60 kg and 15 mg for subjects weighing more than 60 kg. At the end of week 4 (day 28), the LVEF of each subject will be evaluated, and the subject's dose may be increased, decreased, or unchanged based on the criteria set forth in Table 6, in consultation with the investigator and medical monitor. If the plasma concentration of Compound 1 exceeds 750 ng / mL at week 2, the dose will not be increased regardless of the LVEF data at week 4, but dose reduction according to LVEF is still possible. Subjects will then receive that dose from week 5 through week 12. [Table 6] LVEF (left ventricular ejection fraction); QD (once a day). a If the plasma concentration of Compound 1 in the second week exceeded 750 ng / mL, the dose was not allowed to be increased.

[0189] All subjects who provide consent will have blood drawn on Day 1 for assessment of HCM genotype and possible additional deoxyribonucleic acid (DNA) sequencing.

[0190] In addition, subjects may separately consent to the collection of a pharmacogenetic sample, which will be stored for future analysis for genetic biomarkers of efficacy, safety-related, PD, or PK parameters quantified in future studies with clinically meaningful endpoints via DNA sequencing or other genetic testing.

[0191] Blood samples will be collected from all subjects on Day 1 and Week 12 and stored for exploratory circulating biomarker analysis (e.g., proteomic analysis related to disease activity, metabolic pathways, efficacy measures, or safety measures).

[0192] The study duration is expected to be approximately 8 months (4 months recruitment and 4 months study administration). Each subject will participate in the study for 140 days or less (maximum 28 days for screening and maximum 112 days for study administration).

[0193] Compound 1, Dosing, and Schedule The study drug consisted of immediate release oral tablets of Compound 1, supplied in four strengths: 2 mg, 5 mg, 10 mg, and 20 mg. Compound 1 tablets were plain, uncoated, and white in appearance. The 2 mg and 5 mg tablets were round-convex in shape and differed in size, while the 10 mg and 20 mg tablets were oval in shape and differed in size.

[0194] Compound 1 tablets will be manufactured in accordance with current Good Manufacturing Practice (cGMP) regulations. Compound 1 tablets will be supplied in high density polyethylene bottles with induction seals and child resistant caps, 30 tablets per bottle. All study medications will be labeled in accordance with applicable local regulatory guidelines.

[0195] Compound 1 tablets must be stored in the MyoKardia supplied packaging at controlled room temperature of 20°C-25°C (68°F-77°F). Study drug at the investigational site will be stored in a secure area with access limited to authorized study personnel.

[0196] IMP will be provided to subjects at least every 4 weeks in a high-density polyethylene bottle containing 30 tablets, appropriately labeled and with instructions for daily dosing. Subjects will be instructed to store Compound 1 tablets / bottle in a cool, dry place. The drug should be taken with approximately 8 ounces of water.

[0197] Example 4. Phase 2 Results Evaluating the Efficacy, Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Compound 1 in Subjects with Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction (Pioneer-HCM-A) Generally following the procedures described in Example 3, the following results were obtained: Each subject in the following study had discontinued beta-blocker, calcium channel blocker, and / or disopyramide therapy 14 days or more prior to the screening visit.

[0198] Stress LVOT gradient and stress ejection fraction percentage were measured in subjects receiving Compound 1 therapy (10 or 15 mg) at weeks 0, 4, and 12. In both patient populations, stress LVOT gradient disappeared with minimal changes in LVEF. See Figures 4 and 5.

[0199] We also measured resting LVOT gradients in subjects receiving Compound 1 (10, 15, or 20 mg). The resting LVOT gradient disappeared in most subjects as early as the first week, and by the second week, all subjects were less exposed to Compound 1. See Figure 6.

[0200] FIG. 7 is a plot of resting LVOT gradient versus Compound 1 concentration.

[0201] 8 is a plot of resting left ventricular ejection fraction (LVEF) (%) versus concentration of Compound 1. The graph shows an exposure-dependent decrease in resting LVEF.

[0202] Figure 9 is a plot of the mean resting LVOT gradient measured each week of the study. Figure 10 is a plot of the mean resting left ventricular ejection fraction (LVEF) (%) measured each week of the study. Compound 1 administration is discontinued after week 12. The obstructive HCM (oHCM) phenotype reverts after cessation of Compound 1.

[0203] FIG. 11 illustrates the type of plot that may be obtained when measuring oxygen consumption (mL / kg / min) and arterial blood lactate (mM / L) during cardiopulmonary exercise testing.

[0204] Figure 12 shows maximum VO2 values ​​measured during CPET at baseline (week 0, solid bars) and after week 12 (hatched bars). Compound 1 improves CPET metrics.

[0205] Figure 13 shows maximum circulatory force measured during CPET at baseline (week 0, solid bars) and after week 12 (hatched bars). Compound 1 improves CPET metrics.

[0206] 14 is a plot of absolute change in pVO2 against absolute change in left ventricular ejection fraction (LVEF), showing that the increase in exercise capacity with Compound 1 therapy is greatest in patients with the smallest decline in LVEF.

[0207] Figure 15 is a plot of N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations (pg / mL) at weeks 0, 4, 8, and 12 in subjects receiving Compound 1. Figure 16 is a plot of N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations (pg / mL) versus Compound 1 concentration. These figures show that NT-proBNP levels are reduced after 4 weeks of Compound 1, but may rebound with higher exposure.

[0208] FIG. 17 shows the New York Heart Association (NYHA) functional class of subjects at baseline (week 0), 12 weeks after Compound 1 administration, and 16 weeks after Compound 1 administration (12 weeks on Compound 1, 4 weeks off Compound 1).

[0209] Figure 18 shows the mean dyspnea symptom score for each subject at the times indicated (Day 1-Week 16). Compound 1 was administered through Week 12. The Week 16 data point is 4 weeks after Compound 1 was discontinued. Overall, the data show that dyspnea improves with Compound 1 administration and returns after cessation of therapy.

[0210] Phase 2 studies show: Compound 1 is well tolerated at doses up to 20 mg once daily Compound 1 at concentrations above 225 ng / mL was associated with a subhemodynamically significant reduction in the resting gradient Two predictive CPET metrics, maximum VO2 (pVO2) and circulatory power (CP), improve in oHCM patients treated with Compound 1 The most robust improvements in pVO2 (>3mL / min / kg) were associated with minimal changes in resting LVEF Plasma concentrations of 225-600 ng / mL of compound 1 produced a positive inotropic effect and a reduced gradient on myocardial contractility. -NYHA classification and dyspnea scores improve with Compound 1 therapy.

[0211] Example 5. A Phase 2, Open-Label Pilot Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Compound 1 in Subjects with Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction (Pioneer-HCM-B) This study is similar to the study described in Example 3, but has some important differences. For example, subjects in the Phase 2-B study are not required to discontinue beta-blocker therapy, and the dose of Compound 1 is reduced to 2-5 mg. Table 7 below provides some study details compared to the Phase 2-A study described above. [Table 7]

[0212] Example 6. Phase 2 results evaluating the efficacy, pharmacokinetics, pharmacodynamics, safety, and tolerability of Compound 1 in subjects with symptomatic hypertrophic cardiomyopathy and left ventricular outflow tract obstruction (Pioneer-HCM-B) Following generally the procedures described in Examples 3 and 5, the following results were obtained.

[0213] FIG. 19 is a plot of the mean post-exercise resting LVOT gradient (mmHg) at weeks 4, 12, and 16 of the study (12 weeks on Compound 1, 4 weeks off).

[0214] FIG. 20 is a plot of the change in resting LVEF (%) over weeks 1-8, 12, and 16 of the study (12 weeks on Compound 1, 4 weeks off).

[0215] FIG. 21 illustrates the improvement in NYHA functional class in individuals after 12 weeks, with reversal of improvement after 4 weeks off Compound 1.

[0216] Figure 22 illustrates the rapid improvement in peak dyspnea throughout the study, and also shows that improvement is reversed after a 4-week withdrawal of Compound 1.

[0217] FIG. 23 illustrates the change in max VO2 by week 12 during the study.

[0218] Figure 24 is a plot of resting LVOT (mmHg) as a function of Compound 1 concentration. Cohort B is open squares and Cohort A is closed squares.

[0219] The results for Cohort B (2-5 mg daily dose) are shown below in Table 8. Of note, four subjects experienced an improvement in peak VO2 of 2.9 mL / kg / min or more. Table 8: Cohort B Overview [Table 8]

[0220] Of note, 5 of 10 patients had an improvement in pVO2 of >1.5 mL / kg / min, and 8 of 10 patients had an improvement in NYHA class.

[0221] Phase 2 Parts A and B show: Plasma concentrations of Compound 1 between 350-700ng / mL were associated with a reduction in LVOT gradient below the 30mmHg level The reduction in gradient was accompanied by improvement in symptoms, reductions in pVO2 and NT-proBNP during exercise, and improvements in echocardiographic measures of diastolic function Plasma concentrations of Compound 1 of 350-700ng / mL resulted in clinical improvement of oHCM (improvement of symptoms and maximum VO2) while maintaining LVEF ≥ 55% The therapeutic range was well tolerated and was associated with limited reductions in LVEF, often corresponding to normalization of the hypercontractile state present at baseline Concentrations above 1000ng / mL were associated with excessive pharmacological effects

[0222] Parts A and B of the Phase 2 study also show extended improvement with Compound 1 (see Tables 9 and 10). Table 9: Cohort A: e' and E / e' at baseline and week 12 [Table 9] Table 10: Cohort B: e' and E / e' at baseline and week 12 [Table 10]

[0223] Example 7. Pivotal study to confirm safety and efficacy in patients with oHCM (Explorer-HCM) The study will be 24 weeks long and will include approximately 220 participants. The primary metric to be measured in this study will be VO2 max. Figure 25 shows the study design.

[0224] The study is a phase 3, double-blind, randomized, placebo-controlled, multicenter, international, parallel-group study evaluating the safety, tolerability, and efficacy of mavacamten compared to placebo (1:1) in participants with symptomatic oHCM. Approximately 220 participants will be enrolled, including approximately 80 participants (approximately 40 per treatment group) who consent to participate in the CMR substudy at selected centers. Randomization will be stratified according to NYHA functional class (II or III), current treatment with beta-blockers (yes or no), type of ergometer (treadmill or exercise bike) to be used during the study, and consent to the CMR substudy (yes or no).

[0225] The study included three periods and is summarized in FIG.

[0226] Screening Period (Days -28 to -1): Participants will undergo a variety of physical, laboratory, symptom, and PRO assessments over 1-2 days to evaluate eligibility criteria including the presence of HCM and the presence of obstruction (at rest or induced). Investigators should also ensure that participants can adequately perform a Valsalva maneuver. Key screening tests include ECG; TTE at rest, during Valsalva maneuver, and after exercise; and CPET. Screening test results reported by core laboratories (echocardiogram core laboratory, echocardiography core laboratory, and CPET core laboratory) will be used to confirm eligibility for randomization. A minimum of 14 days will be required to perform the screening procedures.

[0227] CPET and post-exercise TTE can be performed on the same day or on different days during the screening period. If CPET and post-exercise TTE are performed on the same day, participants must exercise only once for both procedures and participants will undergo CPET followed by post-exercise TTE. If participants undergo CPET and post-exercise TTE on different days, participants will first undergo rest, Valsalva, and post-exercise TTE (and send echocardiograms to a core laboratory to quantify the respective LVOT gradients) and then CPET at a later date.

[0228] oParticipants receiving treatment for their HCM condition should receive medical therapy as determined by the investigator to be optimal for their condition and as informed by HCM treatment guidelines (e.g., beta-blockers, verapamil, or diltiazem). This treatment should be stable and well tolerated for at least 2 weeks prior to screening. Concomitant medications at the time of screening should be maintained at stable doses unless safety or tolerability concerns arise.

[0229] Participants may also be considered for enrollment if the investigator determines that not receiving treatment for the underlying oHCM condition is a reasonable option (e.g., prior intolerance to or contraindication to beta-blockers). In such cases, no plans should be made to initiate treatment (with beta-blockers, verapamil, or diltiazem) after study randomization.

[0230] Double-blind treatment period (Day 1 [randomization] through Week 30 / EOT): Participants who meet all eligibility criteria will be initially randomized in a 1:1 ratio via an interactive response system (IXRS) to receive a starting dose of mavacamten 5 mg once daily or matching placebo.

[0231] Overall, the 30-week double-blind treatment period will include a total of 10 scheduled visits, allowing for maintaining participant contact every 2-4 weeks. All visits will include, but are not limited to, clinical assessments (symptoms, PRO assessments, AE / SAE assessments, concomitant medications). ECG, TTE, and laboratory assessments will also be performed at all visits except Week 8 and Week 14. Blood for PK (trough plasma concentrations) will be drawn at all visits except Week 14. The results of the TTE performed at each scheduled visit after randomization should be blinded to the investigator and study site personnel. Exceptions may occur if a site measures LVEF ≤ 30%, in which case the investigator will be notified and study drug will be permanently discontinued.

[0232] After randomization, participants will have their first visit for initial assessment of clinical tolerability and safety at Week 4. At this visit, PK sample collection and blinded TTE will be performed. Should results from Week 4 exceed PK / PD criteria (700ng / mL<trough PK<1000ng / mL), the dose will be reduced to 2.5mg via IXRS at Week 6.

[0233] Participants are subsequently seen for reassessment at weeks 6 and 12. Blinded assessments, including trough PK and TTE measures of LVEF and LVOT slope by Valsalva, are performed to guide dose adjustments via the IXRS. At weeks 8 and 14, dose adjustments (dose escalation, dose reduction, no dose change) are made based on the results of the week 6 and week 12 assessments.

[0234] For additional safety, blood samples will be collected at week 8 to determine trough plasma PK. If PK is >700 but <1000ng / mL, an unscheduled visit will be scheduled 2 weeks later for dose reduction. Study drug will be temporarily discontinued any time PK plasma levels ≥1000ng / mL.

[0235] No further titrations are scheduled after Week 14. Blinded assessments at Weeks 18, 22, and 26 may inform dose reductions or temporary discontinuation of study drug. Whenever the mavacamten dose is reduced, participants will continue on the reduced dose until EOT (Week 30) unless further safety concerns or intolerance arise.

[0236] At Week 30 / EOT, participants will complete a post-exercise TTE (between Weeks 26 and 30) and a CPET (Week 30). Any participant who permanently discontinues treatment before Week 30 should have an Early Discontinuation (ET) visit, including a CPET and post-exercise TTE, as soon as possible. ET participants will also be encouraged to complete all remaining study visits and assessments, including Week 30.

[0237] Post-treatment follow-up period (Week 30 / EOT to Week 38 / End of Study [EOS]): After the end of the double-blind treatment period (Week 30), participants will be contacted by phone at Week 34 and will return for an EOS visit at Week 38. At the EOS visit, baseline resting assessments will be repeated. This post-treatment follow-up period applies only to participants who receive study medication after Week 22.

[0238] Selection Criteria Each participant must meet the following criteria to be included in the study: 1. Able to understand and comply with study procedures, understand the risks associated with the study, and provide written consent in accordance with federal, local, and institutional guidelines prior to the first study-specific procedure. 2. Age 18 or older at the time of screening 3.Weight >45kg at screening 4.Having a sufficient ultrasound bone window to enable accurate TTE 5. Diagnosed with oHCM consistent with current American College of Cardiology Foundation / American Heart Association and European Society of Cardiology guidelines, i.e., meets the following criteria for therapy (as documented by echocardiographic core laboratory): a. Has non-dilating ventricles in the absence of other cardiac (e.g., hypertension, aortic stenosis) or systemic disease and a maximal LV wall of ≥15 mm (or ≥13 mm with a clear family history of HCM) or unexplained LV hypertrophy; and b. Have a peak LVOT gradient of 50 mmHg or greater during screening as assessed by echocardiography at rest, after a Valsalva maneuver, or after exercise (confirmed by echocardiographic core laboratory interpretation) 6. LVEF ≥ 55% documented by screening TTE reading at echocardiographic core laboratory 7.Having NYHA class II or III symptoms at screening 8. Demonstrated resting oxygen saturation of 90% or greater at screening 9. Ability to perform CPET in an upright position and have a gas exchange ratio (RER) of 1.0 or greater on a central reading; if the RER is between 0.91 and 1.0, participants may be enrolled only if the central CPET laboratory determines that maximal exercise has been achieved in the subject (the only acceptable evidence for subpeak performance is [1] a decrease in systolic blood pressure (SBP) or [2] severe angina as documented in the CPET Laboratory Manual). 10. Female participants must not be pregnant or breastfeeding and, if sexually active, must use one of the following accepted methods of contraception from the screening visit until 3 months after the last dose of investigational medicinal product (IMP): Hormonal contraceptives are not considered highly effective methods of contraception in this study because mavacamten may reduce the effectiveness of hormonal contraceptives. · Double-barrier methods (e.g., vasectomy, or condom use by the man and diaphragm or cervical cap by the woman) In addition to a barrier (e.g., male condom use), women should use a non-hormonal intrauterine device (IUD) or intrauterine system (IUS). · The woman has been surgically sterilized for 6 months or has been postmenopausal for 2 years. Permanent sterilization methods include hysterectomy, bilateral oophorectomy, bilateral salpingectomy, and / or documented bilateral tubal occlusion 6 months or more prior to screening. A woman is considered postmenopausal if she has been amenorrhea for at least 2 years since cessation of all exogenous hormone therapy and has follicle-stimulating hormone (FSH) levels within the postmenopausal range 11. Male participants with sexual partners must agree to use condoms during the study and for 3 months after the final dose of IMP to prevent transfer of mavacamten in semen to their partners.

[0239] Exclusion criteria Participants who meet any of the following criteria will be excluded from the study: 1. Previously participated in clinical trials using mavacamten 2. Hypersensitivity to any of the components of the mavacamten formulation 3. Participated in a clinical trial (or currently using an investigational device) receiving any investigational drug within 30 days prior to screening or within at least 5 half-lives of the respective investigational drug (whichever is longer). 4. Known infiltrative or storage disorders causing cardiac hypertrophy similar to oHCM (e.g., Fabry disease, amyloidosis, or Noonan syndrome with LV hypertrophy) 5. Have any medical condition that would prevent standing exercise testing 6. History of exercise-induced syncope or sustained ventricular tachyarrhythmia within 6 months prior to screening 7. History of resuscitated sudden cardiac arrest (at any time) or known history of appropriate implantable cardioverter defibrillator (ICD) discharge for life-threatening ventricular arrhythmia within 6 months prior to screening 8.Has paroxysmal intermittent atrial fibrillation and atrial fibrillation is present based on the investigator's assessment of the participant's ECG at screening 9. Persistent or permanent atrial fibrillation, not taking anticoagulants for ≥4 weeks prior to screening, and / or not having adequate heart rate control within 6 months of screening (Note: Patients with persistent or permanent atrial fibrillation who are anticoagulated and have adequate heart rate control are permitted) 10. Current treatment (within 14 days prior to screening) or planned treatment during the study with disopyramide or ranolazine 11. Current treatment (within 14 days prior to screening) or planned treatment during the study with a combination of a beta-blocker and verapamil or a combination of a beta-blocker and diltiazem 12.Individuals taking beta-blockers, verapamil, or diltiazem have had any dose adjustments in these medications within 14 days prior to screening, or anticipated changes in treatment regimen with these medications during the study 13. LVOT gradient with Valsalva maneuver (Valsalva gradient) less than 30mmHg in screening TTE 14. Has been successfully treated with invasive septal reduction (surgical myectomy or percutaneous ASA) within 6 months prior to screening or plans to undergo either of these treatments during the study (Note: individuals who have not had successful myectomy or percutaneous ASA performed more than 6 months prior to screening may be enrolled if study eligibility criteria for LVOT gradient criteria are met) 15.Has had an ICD placed within 6 months prior to screening or is planning to have an ICD placed during the study 16. Have a QT interval by Fridericia correction (QTcF) >480 ms or any other ECG abnormality deemed by the investigator to pose a risk to the participant's safety (e.g., type II second-degree atrioventricular block) 17. Have documented obstructive coronary artery disease (>70% stenosis of one or more epicardial coronary arteries) or a history of myocardial infarction 18. Known moderate or severe (as determined by the investigator) aortic stenosis at screening 19.Any acute or serious comorbid condition (e.g., significant infection or hematologic, renal, metabolic, gastrointestinal, or endocrine dysfunction) that, in the opinion of the investigator, may lead to premature termination of study participation or may interfere with the measurement or interpretation of efficacy and safety evaluations in the study. 20.Having pulmonary disease that limits exercise capacity or systemic arterial oxygen saturation 21. History of clinically significant malignancy within 10 years of screening: Participants were eligible for inclusion in the study if they had successfully treated non-metastatic squamous or basal cell carcinoma of the skin or adequately treated cervical intraepithelial neoplasia Participants with other malignancies who have been cancer-free for more than 10 years prior to screening may be included in the study 22. At screening, safety laboratory parameters (chemistry, hematology, coagulation, and urinalysis) outside the normal range (based on central laboratory reference ranges) as assessed by a central laboratory; however, participants with safety laboratory parameters outside the normal range may be included in the study if they meet all of the following criteria: - Safety laboratory parameters outside the normal range are deemed by the investigator to be of no clinical importance Alanine aminotransferase or aspartate aminotransferase results, if available, must be less than 3 times the upper limit of the laboratory reference range - Estimated glomerular filtration rate adjusted for body size is 30mL / min / 1.73m2 or more 23. Positive serology for human immunodeficiency virus, hepatitis C virus, or hepatitis B virus at screening 24.Has a history or evidence of any other clinically significant disorder, condition, or disease that, in the opinion of the investigator, would pose a risk to the participant's safety or interfere with the evaluations, procedures, or completion of the study. 25. Currently taking, or has taken within 14 days prior to screening, any prohibited medications, such as CYP 2C19 inhibitors (e.g., omeprazole), strong CYP 3A4 inhibitors, or St. John's wort 26. Prior treatment with cardiotoxic drugs such as doxorubicin or similar drugs 27. Unable to comply with study requirements, including the required number of clinical site visits 28.A first degree relative of a clinical trial site personnel directly involved in the study, any study vendor, or a sponsor

[0240] Mavacamten and matching placebo, dosing, and schedule The mavacamten capsules and matching placebo have the same appearance. The study medication is presented as a size 2 blue opaque capsule with a yellow band printed on the body and a black band printed on the cap. Each capsule contains a white to off-white powder. The active capsules are supplied in four strengths: 2.5 mg, 5 mg, 10 mg, and 15 mg.

[0241] Active mavacamten and placebo capsules will be manufactured according to current Good Manufacturing Practice (cGMP) regulations. The capsules will be supplied in high-density polyethylene bottles with induction seals and child-resistant caps, 30 tablets per bottle. All study medications will be labeled in accordance with applicable local regulatory guidelines.

[0242] Active mavacamten and placebo capsules must be stored in the packaging provided by MyoKardia at 2°C-25°C (36°F-77°F). Study drug at the investigational site will be stored in a secure area with access limited to authorized study personnel.

[0243] Study medication will be provided to participants in appropriately labeled high-density polyethylene bottles containing 30 tablets. Participants will take study medication as directed by the investigator. Participants will be instructed to store study medication capsules and bottles in a cool, dry place. Study medication should be taken with approximately 8 ounces (48 teaspoons or approximately 235 mL) of water.

[0244] Dose adjustment Dose titration period (weeks 1 to 14) The double-blind dosing period included a two-tiered titration scheme at weeks 8 and 14 designed to achieve safe and effective dosing based on each participant's PK / PD response parameters (Figure 25 and Table 11).

[0245] In this study, the starting dose of study medication was mavacamten 5 mg or matching placebo once daily, and each participant received this dose of study medication from days 1 to 8 unless PK / PD criteria were met at week 4, in which case the dose was reduced at week 6 (Table 11).

[0246] Participants will receive dose adjustments (dose escalation, dose reduction, or no dose change) at weeks 8 and 14 based on the results from PK / PD assessments at weeks 6 and 12, respectively (Table 11). Note that Table 11 is provided for IXRS programming. No active dose adjustments will be made by study sites or investigators. All dose adjustments will occur in a double-blind manner via the IXRS, and all participants, whether receiving mavacamten or matching placebo, will undergo evaluations that may lead to blinded dose adjustments. However, participants on placebo will remain on placebo (in a blinded manner) unless temporarily or permanently discontinued.

[0247] For additional safety, blood samples will be taken at week 8 to quantify trough plasma PK. If PK is greater than 700 and less than 1000 ng / mL, an unscheduled visit will be scheduled 2 weeks later for dose reduction (see Table 11). Dose reduction will occur via the IXRS, which will randomly select participants from the placebo group for an unscheduled follow-up visit to avoid potential bias.

[0248] If the mavacamten dose is reduced at any time during the study, participants will continue on the reduced dose until EOT (week 30) unless safety concerns or intolerance arise that require further dose reduction or dose discontinuation.

[0249] Based on PK modeling informed by previous mavacamten clinical trials, and depending on the demographic characteristics of patients enrolled, it is estimated that the following percentages of participants will achieve target steady-state concentrations at the following doses: 2.5 mg (<1%), 5 mg (5-20%), 10 mg (40-50%), and 15 mg (30-55%).

[0250] If the PK / PD criteria for dose reduction are met, execute the dose reduction as follows: Table 11: Blinded Dose Titration Schedule (Day 1 - Week 14) PK / PD criteria for dose reduction (LVEF ≥ 50% required) a [Table 11] a LVEF and trough PK will be communicated directly from the core laboratory to IXRS based on their assessment and will therefore be blinded to the investigator, study site personnel, and sponsor. b Dose reductions will be applied if PK criteria are met. c Assessment of dose reduction at week 8 is based solely on plasma PK values. As no TTE is performed at week 8, LVEF results are not available. Weeks 6 and 12: If the PK / PD criteria for dose reduction are not met, potential dose escalation may proceed as follows: Dose setting (LVEF ≥ 50% required) TIFF2025020292000019.tif92170 a Setting adjustments will also be communicated directly to the IXRS based on Weeks 6 and 12, including maximum Valsalva slope measures reported by the core laboratory, thus maintaining blinding. If LVEF <50%, see Temporary Discontinuation section.

[0251] Medication period (Weeks 14-30) After the second titration at Week 14, there will be no further titrations. The dose is intended to remain unchanged unless there are other reasons for safety or early discontinuation. After Week 14, participants will return to the clinical site for monitoring at scheduled 4-week intervals (Weeks 18, 22, 26, and 30 [± 7 days]). AEs, concomitant medications, and symptoms will be assessed at each visit, and ECG, plasma PK, and TTE will also be performed for ongoing safety monitoring. Compliance with study drug will also be monitored by capsule count at each visit. If PK / PD criteria are met, an unscheduled visit 2 weeks later will be required to reduce the dose as shown in Table 12. [Table 12] a LVEF and trough PK will be communicated directly from the core laboratory to IXRS based on assessment and will therefore be blinded to the investigator, study site personnel, and sponsor. If LVEF <50%, see Temporary Discontinuation section. b Dose reductions will be applied if PK criteria are met.

[0252] Blinded dose adjustment leading to temporary discontinuation In addition to the blinded dose adjustments described above (not preceded by dose discontinuation), at any time during the treatment period (T), dosing may be temporarily discontinued for excessive pharmacologic effect (systolic dysfunction), higher than expected plasma concentrations, or excessive QTcF prolongation as described below.

[0253] If a participant has a resting LVEF < 50%, plasma drug concentration ≥ 1000ng / mL, or QTcF ≥ 500msec (quantified by echocardiographic central laboratory, PK analysis laboratory, or ECG core laboratory, respectively), the investigator and sponsor will be informed that they meet the criteria for temporary discontinuation. Upon receiving this information, the study site / investigator will call the participant and instruct them to discontinue study drug and return for an on-site consultation within 2-4 weeks (T+2-4 weeks). This may correspond to a scheduled or unscheduled visit. Please note that to avoid potential bias, for each participant with an unscheduled follow-up visit due to a safety signal, the IXRS will also randomly select a participant from the placebo group for an unscheduled follow-up visit.

[0254] At the follow-up visit (T+2-4 weeks), ECG, plasma PK, and TTE will be repeated, and another unscheduled visit will be scheduled 2 weeks later (T+4-6 weeks).If LVEF ≥ 50% and plasma drug concentration < 1000ng / mL and QTcF < 500msec, study drug will be resumed (at T+6 weeks) at a lower dose for the remainder of the study as follows (previous dose → resumed dose): Placebo → Placebo 2.5mg → placebo 5mg → 2.5mg 10mg → 5mg 15mg → 10mg

[0255] If LVEF, plasma drug concentrations, and / or QTcF remain out of range at the follow-up visits, study drug will be permanently switched to placebo.

[0256] Test evaluation For assessments that require the participant to be in a semi-recumbent or supine position, assessments should be performed with the participant in the same position at all time points. When multiple assessments are performed at the same time point, the preferred sequence of assessments is ECG, vital signs, PK, and TTE, all prior to dosing of study drug. The sequence of assessments may vary slightly at certain time points (e.g., additional PK sampling 1 hour post-dose on Day 1 and Week 30 / EOT) to facilitate performing the required assessments as simultaneously as possible. Unscheduled or additional safety assessments may be performed if necessary in the opinion of the investigator. Consultation with the medical monitor is encouraged whenever possible.

[0257] Echocardiogram and cardiopulmonary exercise testing All echocardiographic data will be sent to a central imaging laboratory, CPET data will be sent to a central laboratory, and pre-specified echocardiographic results from multiple visits and CPET results from the screening visit will be sent exclusively to IXRS for confirmation of eligibility and maintenance of blinding.

[0258] Resting transthoracic echocardiography Rest TTE will be assessed prior to dosing during the on-site visit. Instantaneous maximum LVOT gradient at rest and maximum induced LVOT gradient (Valsalva maneuver) will be assessed. The investigator should ensure that the participant is able to perform the Valsalva maneuver adequately during screening. Care should be taken to select the best window and angle when acquiring the Doppler signal to assess the LVOT gradient and to avoid contamination by the mitral regurgitation (MR) jet, if present. Left ventricular ejection fraction (2-dimensional LVEF) and fractional shortening will also be analyzed along with various other echocardiographic measures (see Study Reference Manual). Results of all TTEs performed at each scheduled post-randomization visit should be blinded to the investigator and the on-site study team, except for the unblinded sonographer. Rest TTE should be performed prior to exercise afterstress echocardiography and / or CPET at screening and EOT.

[0259] Postexercise echocardiography Participants will undergo standard symptom-limited exercise stress testing (post-exercise stress echocardiography) at screening and before dosing with study medication between weeks 26 and 30. This test may be performed on a different day than the CPET. However, if both procedures are performed on the same day, participants must exercise only once for both procedures, and participants will first undergo the CPET and then the post-exercise stress echocardiography. The instantaneous maximum LVOT gradient will be assessed by TTE immediately after exercise. When acquiring the Doppler signal to assess the LVOT gradient, care should be taken to select the best window and angle and to avoid contamination by the MR jet, if present. Participants receiving standard cardiomyopathic therapy (e.g., beta-blockers or calcium channel blockers) should always be on the same dose at baseline and at EOT stress echocardiography whenever possible, and this medication should be administered before the exercise stress test.

[0260] Cardiopulmonary Exercise Testing CPET will be performed using a standardized treadmill or bicycle ergometer at screening and prior to dosing of study medication at Week 30. The same modality (treadmill or standing bicycle) must be used for all CPETs performed on a given participant. Supine testing (i.e., use of a recumbent bicycle) is not permitted during CPET. Symptom-limited exercise testing will be performed after a 4-hour fast (water is permitted). Participants will be encouraged to perform maximally to achieve their expected maximum exercise heart rate (HR) and exertion level. At rest and during maximal exercise, cardiovascular and multiple other performance parameters will be assessed, including but not limited to: oxygen consumption (VO2), age-predicted VO2 percent, carbon dioxide production (VCO2), expiratory ventilation (VE), VE / VO2 ratio, ventilatory efficiency (VE / VCO2 slope), RER, circulatory power (maxVO2 / maxSBP), metabolic equivalents achieved (METS), O2 pulse at maximal exercise, and end-tidal CO2. Participants receiving standard cardiomyopathic therapy (e.g., beta-blockers or calcium channel blockers) should be on the same dose at screening and EOT CPET whenever possible, and this medication should be administered prior to exercise testing.

[0261] New York Heart Association Classification The NYHA functional classification of heart failure will assign participants to one of four categories based on their symptoms. Heart failure classification will be assessed by the investigator at each study visit and recorded as indicated in the clinical database. New York Heart Association Functional Classification of Heart Failure Classification Patient Symptoms Class I: No limitations on physical activity. Ordinary physical activity does not cause excessive fatigue, palpitations, or dyspnea (shortness of breath). Grade II: Mild limitations in physical activity. No symptoms at rest. Ordinary physical activity causes fatigue, palpitations, and dyspnea (shortness of breath). Grade III: Significant limitations in physical activity. No symptoms at rest. Fatigue, palpitations, or shortness of breath with less than normal activity. Grade IV: Symptoms are present with any physical activity. Symptoms of heart failure at rest. Symptoms worsen with any attempt at physical activity. Source: http: / / www.heart.org / HEARTORG / Conditions / HeartFailure / AboutHeartFailure / Classes-of-Heart-Failure_UCM_306328_Article.jsp#.VrtuzPkrKUl

[0262] Hypertrophic cardiomyopathy symptom questionnaire The HCM Symptoms Questionnaire (HCMSQ) is a self-administered 11-item questionnaire assessing the core symptoms of HCM (fatigue / tiredness, heart palpitations, chest pain, dizziness, and shortness of breath). Participants complete the HCMSQ once daily in the evening. The HCMSQ is completed on a handheld electronic device. Participants are trained to use the electronic device at the screening visit. During the screening period, participants complete the HCMSQ for a minimum of 7 consecutive days. From weeks 1 to 6, participants complete the HCMSQ daily. For the remainder of the treatment period (through week 30 / EOT), participants complete the HCMSQ for 7 consecutive days every 4 weeks and again at week 38 / EOS for 7 consecutive days. Reminder alarms on the electronic device and clinic reminders from site staff are used to ensure on-schedule completion of the HCMSQ.

[0263] Exploratory evaluation Patient's Global Impression of Severity and Patient's Global Impression of Change The Patient Global Impression of Severity (PGIS) is a single-item questionnaire that asks participants to rate their overall symptom severity over the past week on a 5-point categorical rating scale (none, mild, moderate, severe, very severe). The Patient Global Impression of Change (PGIC) is a single-item questionnaire that asks participants to rate the overall change in symptom severity over time on a 7-point categorical rating scale (much better to much worse). The PGIC and other PRO assessments completed at the visit should be completed, whenever possible, before any other study procedures and before any meaningful discussion of the study or study administration with site staff.

[0264] Work Productivity and Activity Impairment Questionnaire The Work Productivity and Activity Impairment (WPAI-SHP) questionnaire was designed as a patient-reported quantitative assessment of the ability to work and perform usual activities. Specifically, the WPAI-SHP asks about the impact of a specific health problem (in this case HCM) on absenteeism, presenteeism, and daily activity impairment. The WPAI-SHP and other PRO assessments completed at the clinic visit should be completed, whenever possible, before any other study procedures and before any meaningful discussion of the study or study administration with clinical site staff.

[0265] EuroQol 5-dimensional questionnaire (5 levels) The EuroQol 5 Dimensions 5 Levels Questionnaire (EQ-5D-5L) is a comprehensive PRO instrument measuring health status and health-related quality of life. The EQ-5D-5L has two components: (1) a health utility index score derived from five items addressing "today" mobility, self-care, usual activities, pain / discomfort, and anxiety / depression, and (2) a current ("just now") general health status score derived from a single visual analog scale (VAS) ranging from 0 to 100. Items contributing to the EQ-5D-5L health utility index score each have the same 5-point response scale (1=no problems, 2=a little problem, 3=moderate problems, 4=a lot of problems, 5=extreme problems). The VAS is anchored at the "best possible health state" and "worst possible health state" endpoints. The EQ-5D-5L is essential for acceptance by many health technology assessment bodies for coverage decisions. The EQ-5D-5L and other PRO assessments completed at the visit should, where possible, be completed before any other study procedures and before any meaningful discussion of the study or study administration with site staff.

[0266] Kansas City Cardiomyopathy Questionnaire (23-item version) The Kansas City Cardiomyopathy Questionnaire (23-item version) (KCCQ-23) is a patient-reported questionnaire that measures the impact of a patient's cardiovascular disease or its treatment on six different domains: symptoms / signs, physical limitations, quality of life, social limitations, self-efficacy, and symptom stability using a 2-week recall. In addition to the personal domains, two summary scores can be calculated from the KCCQ-23: an overall summary score (including a total score of symptoms, physical limitations, and quality of life) and a clinical summary score (the sum of the symptom and physical limitations scales). Score range is 0-100, with higher scores reflecting a better health status. When possible, before performing any other study procedures and before having any meaningful discussion about the study or study administration with the site staff.

[0267] Wrist-worn accelerometer Participants will be issued with a wrist-worn accelerometer (GT9X ActiGraph Link) at two time points during the study to collect activity data. The device has sufficient battery life to store activity data for up to 11 days. After the data collection period, the accelerometer will be returned for data upload and analysis. The analysis will account for daily step counts. These data will be used to explore the amount and type of physical activity performed before and during dosing with study medication. Accelerometers will be issued at screening (≥11 days prior to Day 1) and at Week 26.

[0268] Pharmacokinetic, Pharmacogenetic, and Biomarker Assessment Pharmacokinetic evaluation At all site visits after Day 1, blood samples will be collected prior to dosing for mavacamten plasma concentration assessment. Additionally, at Week 30 (final dose), PK blood samples will also be collected within 1-2 hours post-dose for PK modeling. Unscheduled or additional PK samples may be collected if appropriate in the opinion of the investigator and / or sponsor.

[0269] At all visits from Day 1 through Week 30, study drug will be administered at the study site to facilitate collection of PK samples. Dates and times of dosing will be recorded. All trough PK samples will be sent to a core laboratory for processing and results will be transmitted to the IXRS.

[0270] Genotype / pharmacogenetic / biomarker evaluation HCM genotyping For participants who provide consent, blood will be drawn pre-dose on Day 1 for assessment of HCM genotype and possible additional DNA sequencing. If participants with previous genotype testing positive for an HCM-associated genetic mutation agree to provide their results, no further genotype evaluation will be performed.

[0271] Pharmacogenetic evaluation Blood will be collected at screening for CYP 2C19 genotyping. Residuals from this pharmacogenetic sample will also be stored for potential future analysis for genetic biomarkers of efficacy, safety-related, PD, or PK parameters quantified in future studies with clinically meaningful endpoints through DNA sequencing or other genetic testing. Samples from individuals who fail screening must be discarded.

[0272] Exploratory Biomarker Evaluation Blood samples will be collected on Day 1 and Week 30 and stored for relevant exploratory disease markers (including but not limited to proteomic analyses related to disease activity, metabolic pathways, efficacy measures, or safety measures).

[0273] NT-proBNP Blood samples for NT-proBNP concentrations will be collected at all post-screening site visits. All NT-proBNP blood draws should be taken at rest and before any exercise. Serum NT-proBNP concentrations will be included in the data package established at the regular IDMC meeting. Unscheduled or additional blood samples may be collected if appropriate in the opinion of the Investigator (e.g., responsible for medical management of heart failure) and / or Sponsor. Consultation with the medical monitor is encouraged whenever possible.

[0274] Safety assessment Safety will be assessed throughout the study. Safety assessments include medical history, physical examination, ECG, vital signs, observed or participant-reported AEs, pregnancy testing, and safety laboratory results. Any abnormal finding judged clinically significant by the investigator will be recorded as an AE.

[0275] The following safety endpoints will be adjudicated by the CEAC: death, stroke, acute myocardial infarction, total hospitalizations (CV and non-CV), heart failure (HF) events (including HF hospitalizations and emergency emergency room (ER) / outpatient (OP) HF visits), atrial fibrillation / flutter (new from screening), ICD therapy, resuscitated cardiac arrest, ventricular tachyarrhythmias (ventricular tachycardia (VT) and ventricular fibrillation (VF); also including any torsades de pointes identified during the CEAC review).

[0276] Medical history A complete medical history will be taken at the screening visit and will include evaluation (past or current) of the following: general, head and neck, eyes, ears, nose, throat, chest / respiratory, heart / cardiovascular, gastrointestinal / hepatic, gynecological / genitourinary, musculoskeletal / extremities, skin, neurological / psychiatric, endocrine / metabolic, hematological / lymphatic, allergy / drug sensitivity, previous surgery, substance abuse, or any other disease or injury, as well as participation in a clinical trial (investigational drugs and / or devices or other therapies).

[0277] Physical Examination At selected visits, a complete physical examination will be performed, including neurological examination (gross motor and deep tendon reflexes), height (at screening only) and weight, as well as evaluation of the following: general appearance, skin, head and neck, oral cavity, lymph nodes, thyroid, abdominal, musculoskeletal, cardiovascular, and respiratory systems. At all other visits, a brief cardiopulmonary physical will be performed, and other systems will be evaluated as indicated in the interval history.

[0278] At screening, height (cm) and weight (kg) will be measured and body mass index (kg / m2) will be calculated. Participants will be required to remove their shoes and wear clothing designated by the clinical site.

[0279] Body weights are recorded on-site at screening and at 30 weeks.

[0280] 12 lead ECG A 12-lead ECG assessment will be performed after 10 minutes of rest at screening and at all on-site study visits except visits at weeks 8 and 14. All ECG data will be sent to a central cardiac laboratory and transmitted to IXRS.

[0281] On Day 1, an ECG will be performed within 2 hours prior to the dose. At all other visits, an ECG will be taken prior to dosing.

[0282] The Investigator may perform a 12-lead ECG safety assessment if deemed necessary for any other safety reason, which should be recorded as an unscheduled assessment.

[0283] Cardiac monitoring skin patch At two time points during the study, participants wear a small device to collect continuous HR and rhythm data for up to 14 days. The self-contained device is attached to the skin with a medical adhesive and contains surface electrodes, internal electronics to capture continuous ECG waveforms, an accelerometer to capture physical activity, sufficient solid-state memory to store data over multiple days, and a battery to power the device. After a period of data collection, the device is transported to a core testing site where the continuous ECG waveforms and activity records stored on the device are uploaded for analysis. The analysis provides a full disclosure of HR, cardiac rhythm, and physical activity over the period when the device was properly applied and functioning. The device is used to explore HR and cardiac rhythm patterns before and during administration of the study drug.

[0284] Vital signs Vital signs will be assessed at each on-site study visit except for visits at weeks 8 and 14. Complete vital signs will be obtained, including temperature, HR, respiratory rate, and blood pressure (BP), at screening, ET, Week 30 / EOT, and Week 38. At all other visits, only HR and BP will be required.

[0285] Vital signs are obtained with participants in the same position and BP is measured via an automated recorder after at least 5 minutes of rest.

[0286] Vital signs will be measured prior to dosing at all visits. Alert values ​​will be flagged. See the Study Laboratory Manual for further details.

[0287] Other safety assessments At screening, a serum pregnancy test will be performed in all women of childbearing potential. In addition, on-site or home urine pregnancy tests will be performed every 4-6 weeks throughout the study. If any urine test is positive, a confirmatory serum test will be performed.

[0288] Cardiac magnetic resonance imaging substudy For qualified participating sites, participants will have the option to participate in the CMR substudy. Approximately 80 participants will be enrolled (approximately 40 per dose group). Participants will undergo CMR on Day 1 and Week 30. Please refer to the CMR Substudy Reference Manual for further details.

[0289] Restrictions for participants during this study The following restrictions will be applied when specified during the study. Participants may be subject to exclusion or withdrawal from the study if they do not adhere to these restrictions or if they test positive for any laboratory test (e.g., drugs, alcohol, pregnancy). From 72 hours prior to the first dose until the final follow-up visit, participants should not engage in unaccustomed strenuous exercise, except during protocol-specified exercise testing. Participants will be required to refrain from donating blood or plasma from the time of screening until 3 months after the final study visit. From Day 1 until the final follow-up visit, participants are asked to refrain from grapefruit or grapefruit juice, Seville oranges, and quinine (e.g., tonic water).

[0290] Example 8. Lusitropic properties of compound 1 Compound 1 stabilizes myosin away from actin, thereby reducing the number of myosin heads that can participate in contraction. This reduction can directly reduce contractile function and improve diastolic compliance by requiring fewer heads to dissociate during diastole. This additional activity by Compound 1 and related compounds indicates that physicians can independently select agents that optimize contractile and diastolic effects through the selection of different agents and doses of these agents to provide greater lusitropic benefits for less negative inotropic costs. The ability to optimize these effects allows Compound 1 and related compounds to be used to treat diseases of diastolic dysfunction, including RCM, with minimal perturbation of contractile function.

[0291] Preclinically, Compound 1 reduces contractility with a profile distinct from other negative inotropes. Acute or chronic administration of Compound 1 reduced myocardial contractility and increased LV end-diastolic dimension while preserving systemic arterial pressure and LV end-diastolic pressure, suggesting improved compliance. In contrast to the acute effects of other negative inotropes, Compound 1 preserved end-diastolic pressure and estimated (linear) end-diastolic stiffness despite a marked increase in preload (EDV), consistent with a beneficial downward / rightward shift in the pressure-volume relationship.

[0292] Emerging data from the PIONEER trial in obstructive HCM (Table 13: Cohort A; Table 14: Cohort B) further suggest that Compound 1 improves left ventricular compliance in the context of diastolic dysfunction, as evidenced by increased LVEDV with reduced LV filling pressures (as assessed by E / e'). [Table 13] [Table 14]

[0293] Compound 1 (15 mg / day) abolishes the LVOT gradient and reduces resting LV systolic function in patients with oHCM. This is accompanied by improved LV filling pressures (reduced E / e'), improved diastolic wall load (reduced NT-proBNP), and increased peak diastolic mitral annular velocity with an increase in LVEDV that is not consistent with improved LV diastolic function. An effect of reduced LV afterload on mitral annular velocity cannot be excluded.

[0294] Preliminarily, Compound 1 (2 mg / day for 4 weeks) has a consistent effect on LVOT resting and exercise gradients in patients analyzed so far. At this dosage level, LV systolic function at rest and immediately after exercise is not affected by Compound 1. However, beneficial effects in the absence of afterload changes are observed on LV filling pressure (↓E / e' and NT-proBNP) and peak diastolic mitral annular motion velocity (e'). This is consistent with a beneficial effect on diastolic function.

[0295] The most important indications for positive lusitropic agents are considered to be (in ascending order based on complexity): Symptomatic non-obstructive HCM Hereditary restrictive noninvasive restrictive cardiomyopathy (e.g., troponin I, T; desmin-related) Symptomatic active relaxation disorder (present in approximately 75% of HFpEF cases) (excluding infiltrative diseases (amyloid) and fibrosis (scleroderma, radiotherapy-induced cardiomyopathy, idiopathic fibrosis)) After symptomatic aortic valve replacement (surgical or transcatheter)

[0296] Potential indications with the highest likelihood of technical success are those in which there is demonstrable evidence of impaired active relaxation. The most homogeneous population may be patients with symptomatic nonobstructive HCM. For the broader HFpEF population, eligible patients would be selected according to the ESC 2016 guidelines, which define a normal ejection fraction (≥50%) with direct evidence of abnormal diastolic function, including: abnormal LV relaxation, filling, diastolic distensibility, or stiffness as measured by echocardiography (mitral E / A ratio >0.8; E / e' ≥14; septal e' <7 cm / sec; lateral wall e' <10 cm / sec) or cardiac magnetic resonance (abnormal peak filling rate, time to peak filling rate, peak diastolic strain rate) in conjunction with high levels of BNP (>35 pg / mL) or NT-proBNP (>125 pg / mL).

[0297] Example 9. Quantitation of Compound 1 Plasma Concentration High pressure liquid chromatography (HPLC) coupled to tandem mass spectrometry (MS / MS) was used to measure the concentration of Compound 1 in human plasma. This method has been used for the bioanalysis of Compound 1 in all clinical trials to date, and all clinical data was collected using plasma. A brief description of the method is provided below.

[0298] The concentration of compound 1 in human plasma was quantified using liquid-liquid extraction and HPLC / MS / MS. An aliquot of the extract was injected into an HPLC system coupled to a triple quadrupole mass spectrometer (Sciex API5500). A Lux 3u Cellulose-4 HPLC column (150×2.0 mm) (Supelco) was used to separate compound 1 from interfering compounds that may be present in the sample extract. The internal standard was a multiply deuterated analog of compound 1 to ensure that it had similar chemical properties to the analyte but a different mass for selective detection. To quantify the concentration, the peak area of ​​the product ion of compound 1 was measured against that of the internal standard.

[0299] [Aspect 1] 1. A method of treating hypertrophic cardiomyopathy (HCM) in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein the therapeutically effective amount is a total daily dose of about 1 mg-50 mg. [Aspect 2] The method of embodiment 1, wherein said therapeutically effective amount is a total daily dosage of about 2 mg-30 mg. [Aspect 3] The method of embodiment 1, wherein said therapeutically effective amount is a total daily dosage of about 10 mg-20 mg. [Aspect 4] The method of embodiment 1, wherein said therapeutically effective amount is a total daily dosage of about 5 mg-15 mg. [Aspect 5] The method of embodiment 1, wherein said therapeutically effective amount is a total daily dosage of about 2 mg-10 mg. [Aspect 6] The method of embodiment 1, wherein said therapeutically effective amount is a total daily dosage of about 2 mg-5 mg. [Aspect 7] The method of embodiment 1, wherein the therapeutically effective amount is a total daily dosage of about 2 mg-15 mg. [Aspect 8] The method of any one of aspects 1-6, wherein the subject has not received beta-blocker therapy for a period of at least two weeks prior to initiating treatment with Compound 1. [Aspect 9] The method of any one of aspects 1-6, wherein compound 1 is administered in combination with beta-blocker therapy. [Aspect 10] The method of any one of aspects 1-9, wherein the total daily dose is administered for a period of 8-12 weeks. [Aspect 11] The method of any one of aspects 1-10, wherein administration of a therapeutically effective amount of Compound 1 improves, stabilizes, or delays deterioration of the subject's New York Heart Association (NYHA) functional class. [Aspect 12] The method of embodiment 11, wherein administration of a therapeutically effective amount of Compound 1 reduces the New York Heart Association (NYHA) functional class of the subject. [Aspect 13] The method of embodiment 12, wherein the NYHA functional class is reduced from IV to III, from IV to II, or from IV to I. [Aspect 14] The method of embodiment 12, wherein the NYHA functional class is reduced from class III to class II. [Aspect 15] The method of embodiment 12, wherein the NYHA functional class is reduced from class III to class I. [Aspect 16] The method of embodiment 12, wherein the NYHA functional class is reduced from II to I. [Aspect 17] The method of any one of embodiments 1-10, wherein the total daily dose is adjusted according to the needs of the individual patient. [Aspect 18] The method of embodiment 17, wherein the total daily dose is adjusted 1-8 weeks after administration of Compound 1. [Aspect 19] The method of embodiment 18, wherein the total daily dose is adjusted after two weeks. [Aspect 20] The method of embodiment 18, wherein the total daily dose is adjusted after 4 weeks. [Aspect 21] The method of embodiment 18, wherein the total daily dose is adjusted after 6 weeks. [Aspect 22] The method of embodiment 18, wherein the total daily dose is adjusted after 8 weeks. [Aspect 23] The method of any one of aspects 17-22, wherein the total daily dose is reduced when the subject's New York Heart Association (NYHA) functional class is reduced. [Aspect 24] The method of embodiment 23, wherein the total daily dose is reduced from 5 mg to 2.5 mg when the subject's NYHA functional class is reduced from III to I, III to II, or II to I. [Aspect 25] The method of any one of aspects 17-22, wherein the total daily dose is increased when the subject's New York Heart Association (NYHA) functional class is not reduced or worsens. [Aspect 26] The method of embodiment 25, wherein the total daily dose is increased from 5 mg to 7.5 mg, 10 mg, or 15 mg. [Aspect 27] The method of any one of aspects 17-22, wherein the total daily dose is 5 mg and the dose is increased when the subject has a resting left ventricular ejection fraction (LVEF) of 55% or greater and a resting left ventricular outflow tract (LVOT) peak gradient of 30 mmHg or greater. [Aspect 28] The method of embodiment 27, wherein the total daily dose is increased to 7.5 mg when the subject's resting LVEF is greater than or equal to 55% and the maximum resting LVOT gradient is greater than or equal to 30 mmHg and less than 50 mmHg. [Aspect 29] The method of embodiment 27, wherein the total daily dose is increased to 10 mg when the subject's resting LVEF is 55% or greater and resting LVOT maximum gradient is 50 mmHg or greater. [Aspect 30] The method of any one of aspects 17-22, wherein the total daily dose is 5 mg, and when the subject has a resting left ventricular ejection fraction (LVEF) of 54-46% and a resting left ventricular outflow tract (LVOT) maximum gradient of 50 mmHg or greater, the dose is increased to 7.5 mg. [Aspect 31] The method of any one of aspects 1-30, wherein the HCM is obstructive HCM (oHCM). [Aspect 32] The method of embodiment 1, wherein the subject has a pressure gradient of at least 30 mmHg in the subject's left ventricular outflow tract (LVOT) prior to initiation of treatment. [Aspect 33] The method of embodiment 1, wherein the therapeutically effective amount is sufficient to reduce post-exercise maximum gradient LVOT in the subject to 30 mmHg or less. [Aspect 34] The method of embodiment 1, wherein the therapeutically effective amount is sufficient to reduce post-exercise maximum gradient LVOT in the subject to 20 mmHg or less. [Aspect 35] The method of embodiment 1, wherein the therapeutically effective amount is sufficient to reduce post-exercise maximum gradient LVOT in said subject to less than 10 mmHg. [Aspect 36] The method of embodiment 1, wherein the therapeutically effective amount is sufficient to result in a change in maximum post-exercise LVOT gradient from baseline to week 12 of -100 mmHg or greater in said subject. [Aspect 37] The method of embodiment 1, wherein the therapeutically effective amount is sufficient to increase max VO2 (mL / kg / min) in said subject by +3.0 or more. [Aspect 38] The method of embodiment 1, wherein the therapeutically effective amount is sufficient to increase max VO2 (mL / kg / min) in said subject by +2.0 or more. [Aspect 39] The method of embodiment 1, wherein the therapeutically effective amount is sufficient to increase max VO2 (mL / kg / min) in said subject by +1.5 or more. [Aspect 40] The method of embodiment 1, wherein said compound 1 is administered orally. [Aspect 41] The method of embodiment 1, wherein said compound 1 is administered once daily. [Aspect 42] The method of embodiment 1, wherein said compound 1 is administered twice daily. [Aspect 43] The method of embodiment 1, wherein said compound 1 is administered daily for at least 12 weeks. [Aspect 44] The method of embodiment 1, wherein said compound 1 is administered daily for at least four weeks. [Aspect 45] The method of embodiment 1, wherein said compound 1 is administered in a unit dosage form containing 2.5 mg, 5 mg, 7.5 mg, 10 mg, or 20 mg of compound 1. [Aspect 46] The method of embodiment 1, wherein the therapeutically effective amount is a total daily dosage of about 10 mg to about 25 mg. [Aspect 47] The method of embodiment 1, wherein the therapeutically effective amount is a total daily dosage of about 15 mg to about 20 mg. [Aspect 48] The method of embodiment 1, wherein the therapeutically effective amount is about 2.5 mg total daily dose. [Aspect 49] The method of embodiment 1, wherein the therapeutically effective amount is a total daily dosage of about 5 mg. [Aspect 50] The method of embodiment 1, wherein the therapeutically effective amount is about 7.5 mg total daily dose. [Aspect 51] The method of embodiment 1, wherein the therapeutically effective amount is a total daily dosage of about 10 mg. [Aspect 52] The method of embodiment 1, wherein the therapeutically effective amount is a total daily dosage of about 15 mg. [Aspect 53] The method of embodiment 1, wherein the therapeutically effective amount is a total daily dosage of about 20 mg. [Aspect 54] The method of embodiment 1, wherein the therapeutically effective amount is a total daily dosage of about 25 mg. [Aspect 55] The method of embodiment 1, wherein the therapeutically effective amount is a dosage administered once daily selected from the group consisting of 10, 15, 20, and 25 mg. [Aspect 56] The method of embodiment 1, further comprising, prior to said administering, measuring said left ventricular ejection fraction (LVEF) in said subject to obtain a first LVEF value. [Aspect 57] 2. The method of embodiment 1, further comprising measuring the LVEF in the subject 4 weeks after said administering to obtain a second LVEF value, and calculating a percentage change of said second LVEF value compared to the first LVEF value. [Aspect 58] 58. The method of embodiment 57, wherein the total daily dosage is adjusted according to the percentage change. [Aspect 59] 58. The method of embodiment 57, wherein the total daily dose is increased by 10 mg when the percentage change is less than 10%. [Aspect 60] 58. The method of embodiment 57, wherein the total daily dose is increased by 5 mg when the percentage change is greater than or equal to 10% but less than 15%. [Aspect 61] 58. The method of embodiment 57, wherein when the percentage change is greater than or equal to 15% and less than 20%, the total daily dose remains the same. [Aspect 62] 58. The method of embodiment 57, wherein the total daily dose is reduced by 5 mg when the percentage change is 20% or greater. [Aspect 63] The method of embodiment 1, further comprising measuring the body weight of said subject prior to said administration of said Compound 1. [Aspect 64] 64. The method of embodiment 63, wherein said daily dosage is about 10 mg for the first 4 weeks of treatment when said subject weighs 60 kg or less. [Aspect 65] The method of embodiment 63, wherein the daily dosage is about 15 mg for the first 4 weeks of treatment when the subject weighs more than 60 kg. [Aspect 66] The method of embodiment 1, further comprising measuring the plasma concentration of said compound 1 two weeks after said administering. [Aspect 67] The method of embodiment 66, wherein when the plasma concentration of compound 1 is greater than 750 ng / mL, the daily dosage remains the same for the remainder of the treatment period. [Aspect 68] The method of embodiment 1, wherein the subject has a left ventricular wall thickness of 15 mm or greater prior to treatment. [Aspect 69] Prior to treatment, the subject has a body mass index (BMI) of about 18 to about 37 kg / m 2 2. The method of embodiment 1, wherein [Aspect 70] The method of embodiment 1, wherein the subject has an LVEF of greater than or equal to 55% prior to treatment. [Aspect 71] The method of embodiment 1, wherein the subject has a maximum post-exercise LVOT gradient of 50 mmHg or greater prior to treatment. [Aspect 72] The following formula: [ka] A single unit dose capsule containing 2-15 mg of compound 1 having the formula: [Aspect 73] 73. The single unit dose capsule of embodiment 72, wherein the capsule comprises about 2.5 mg of Compound 1. [Aspect 74] 73. The single unit dose capsule of embodiment 72, wherein the capsule comprises about 5 mg of compound 1. [Aspect 75] 73. The single unit dose capsule of embodiment 72, wherein the capsule comprises about 7.5 mg of Compound 1. [Aspect 76] 73. The single unit dose capsule of embodiment 72, wherein the capsule comprises about 10 mg of Compound 1. [Aspect 77] 73. The single unit dose capsule of embodiment 72, wherein the capsule comprises about 15 mg of Compound 1. [Aspect 78] The following formula: [ka] A single unit dose tablet containing 2-15 mg of compound 1 having the formula: [Aspect 79] 79. The single unit dose tablet of embodiment 78, wherein the tablet comprises about 2.5 mg of Compound 1. [Aspect 80] 79. The single unit dose tablet of embodiment 78, wherein the tablet comprises about 5 mg of compound 1. [Aspect 81] 79. The single unit dose tablet of embodiment 78, wherein the tablet comprises about 7.5 mg of Compound 1. [Aspect 82] 79. The single unit dose tablet of embodiment 78, wherein the tablet comprises about 10 mg of Compound 1. [Aspect 83] The single unit dose tablet of embodiment 78, wherein the tablet comprises about 15 mg of Compound 1. [Aspect 84] The following formula: [ka] A pharmaceutical composition comprising 2-15 mg of compound 1 having the formula: [Aspect 85] 85. The pharmaceutical composition of embodiment 84, comprising about 2.5 mg of compound 1. [Aspect 86] 85. The pharmaceutical composition according to embodiment 84, comprising about 5 mg of compound 1. [Aspect 87] 85. The pharmaceutical composition of embodiment 84, comprising about 7.5 mg of compound 1. [Aspect 88] 85. The pharmaceutical composition according to embodiment 84, comprising about 10 mg of compound 1. [Aspect 89] 85. The pharmaceutical composition of embodiment 84, comprising about 15 mg of compound 1. [Aspect 90] A kit comprising the unit dose of any one of embodiments 72-76. [Aspect 91] The kit of embodiment 90, further comprising a label having instructions for administering Compound 1. [Aspect 92] 1. A method for treating myocardial diastolic dysfunction in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein the therapeutically effective amount is a total daily dose of about 2 mg-50 mg. [Aspect 93] 93. The method of embodiment 92, wherein said therapeutically effective amount is a total daily dosage of about 2 mg-30 mg. [Aspect 94] 93. The method of embodiment 92, wherein said therapeutically effective amount is a total daily dose of about 2 mg. [Aspect 95] 93. The method of embodiment 92, wherein said therapeutically effective amount is a total daily dosage of about 10 mg-15 mg. [Aspect 96] 93. The method of embodiment 92, wherein said therapeutically effective amount is a total daily dosage of about 2 mg-15 mg. [Aspect 97] The method of any of aspects 92-95, wherein the subject in need of treatment of myocardial diastolic function dysfunction is from a patient population characterized by non-obstructive hypertrophic cardiomyopathy (non-oHCM) or heart failure with preserved ejection fraction (HFpEF); or, the subject in need of treatment of myocardial diastolic function dysfunction exhibits abnormal left ventricular stiffness as measured by echocardiography, or left ventricular stiffness as measured by cardiac magnetic resonance or other diagnostic technique. [Aspect 98] The method of embodiment 97, wherein said subject in need of treatment of myocardial diastolic dysfunction is a subject from a patient population characterized by non-obstructive hypertrophic cardiomyopathy. [Aspect 99] The method of embodiment 97, wherein said subject in need of treatment for myocardial diastolic dysfunction is a subject from a patient population characterized by HFpEF. [Aspect 100] The method of embodiment 97 or embodiment 99, wherein said patient with HFpEF has an ejection fraction of greater than or equal to 50% and has evidence of abnormal diastolic function. [Aspect 101] 98. The method of embodiment 97, wherein the subject in need of treatment for myocardial diastolic dysfunction exhibits left ventricular stiffness as measured by echocardiography. [Aspect 102] The method of embodiment 97 or embodiment 101, wherein the subject has left ventricular stiffness measured by echocardiography when at least one of the following characteristics is met: mitral valve E / A ratio > 0.8; E / e' ≧ 14; septal e' < 7 cm / sec; lateral wall e' < 10 cm / sec. [Aspect 103] 98. The method of embodiment 97, wherein the subject in need of treatment for myocardial diastolic dysfunction exhibits left ventricular stiffness as measured by cardiac magnetic resonance. [Aspect 104] The method of embodiment 97 or embodiment 103, wherein the subject has left ventricular stiffness as measured by cardiac magnetic resonance when at least one of the following characteristics: abnormal maximum filling rate, time to maximum filling rate, or maximum diastolic strain rate is met. [Aspect 105] The method of any one of embodiment 97 or embodiments 101-104, wherein said subject further exhibits elevated serum blood levels of brain natriuretic peptide (BNP) or N-terminal pro-brain natriuretic peptide (NT-proBNP). [Aspect 106] The method of embodiment 105, wherein serum blood levels are elevated when at least 35 pg / mL BNP or 125 pg / mL NT-proBNP is present. [Aspect 107] A method for treating hypertrophic cardiomyopathy in an individual in need of such treatment, comprising administering to the individual an amount of Compound 1 effective to achieve and maintain a plasma concentration of Compound 1 of 200-750 ng / mL. [Aspect 108] The method of embodiment 107, wherein 2-15 mg of Compound 1 achieves and maintains a plasma concentration of Compound 1 of 200-750 ng / mL. [Aspect 109] The method of embodiment 107, wherein 5-15 mg of Compound 1 achieves and maintains a plasma concentration of Compound 1 of 200-750 ng / mL. [Aspect 110] The method of embodiment 107, wherein about 2.5 mg of Compound 1 achieves and maintains a plasma concentration of Compound 1 of 200-750 ng / mL. [Aspect 111] The method of embodiment 107, wherein about 5 mg of Compound 1 achieves and maintains a plasma concentration of Compound 1 of 200-750 ng / mL. [Aspect 112] The method of embodiment 107, wherein about 10 mg of Compound 1 achieves and maintains a plasma concentration of Compound 1 of 200-750 ng / mL. [Aspect 113] The method of embodiment 107, wherein about 15 mg of Compound 1 achieves and maintains a plasma concentration of Compound 1 of 200-750 ng / mL. [Aspect 114] The method of any one of aspects 107-113, wherein said plasma concentration of Compound 1 is 350-700 ng / mL. [Aspect 115] The method of any one of aspects 107-114, wherein the HCM is obstructive HCM (oHCM). [Aspect 116] The method of any one of aspects 107-114, wherein the HCM is non-obstructive HCM. [Aspect 117] 1. A method for treating hypertrophic cardiomyopathy (HCM) in an individual in need thereof, comprising administering a daily dose of 5 mg of Compound 1 for at least one week; increasing said daily dose to 10 mg when said individual has a plasma concentration of Compound 1 below 200 ng / mL; or reducing the daily dose to 2.5 mg when the plasma concentration of Compound 1 in the individual is greater than 750 ng / mL; or maintaining the daily dose at 5 mg when the plasma concentration of Compound 1 in the individual is between 200-750 ng / mL. The method comprising: [Aspect 118] when the plasma concentration of Compound 1 in the individual falls below 350 ng / mL, the daily dose is increased to 10 mg; when the plasma concentration of Compound 1 in the individual is greater than 700 ng / mL, the daily dose is reduced to 2.5 mg; When the plasma concentration of Compound 1 in the individual is between 350 ng / mL and 700 ng / mL, the daily dose is maintained at 5 mg. The method according to embodiment 117. [Aspect 119] when the individual's Valsalva gradient is 30 mmHg or greater and the plasma concentration of Compound 1 in the individual is below the recited amount, the daily dose is increased; said daily dose is maintained when said individual's Valsalva gradient is less than 30 mmHg and said plasma concentration of Compound 1 in said individual is below the recited amount; 119. The method according to embodiment 117 or 118. [Aspect 120] 120. The method of any one of embodiments 117 or 119, wherein said individual is administered 5 mg of Compound 1 for at least two weeks. [Aspect 121] 120. The method of any one of embodiments 117 or 119, wherein said individual is administered 5 mg of Compound 1 for at least 4 weeks. [Aspect 122] The method of any one of embodiments 117 or 119, wherein said individual is administered 5 mg of Compound 1 for at least 6 weeks. [Aspect 123] The method of any one of embodiments 117 or 119, wherein said individual is administered 5 mg of Compound 1 for at least 8 weeks. [Aspect 124] the daily dose is increased to 10 mg and Compound 1 is administered for at least one week, and the method comprises: increasing the daily dose to 15 mg when the plasma concentration of Compound 1 in the individual is below 200 ng / mL; or reducing the daily dose to 5 mg when the plasma concentration of Compound 1 in the individual is greater than 750 ng / mL; or maintaining the daily dose at 10 mg when the plasma concentration of Compound 1 in the individual is between 200-750 ng / mL The method of any one of embodiments 117-121, further comprising: [Aspect 125] when the plasma concentration of Compound 1 in the individual falls below 350 ng / mL, the daily dose is increased to 15 mg; when the plasma concentration of Compound 1 in the individual is greater than 700 ng / mL, the daily dose is reduced to 5 mg; When the plasma concentration of Compound 1 in the individual is between 350 ng / mL and 700 ng / mL, the daily dose is maintained at 10 mg. The method according to embodiment 124. [Aspect 126] when the individual's Valsalva gradient is 30 mmHg or greater and the plasma concentration of Compound 1 in the individual is below the recited amount, the daily dose is increased; said daily dose is maintained when said individual's Valsalva gradient is less than 30 mmHg and said plasma concentration of Compound 1 in said individual is below the recited amount; 126. The method of embodiment 124 or 125. [Aspect 127] The method of any one of embodiments 124-126, wherein the individual is administered 10 mg of Compound 1 for at least two weeks. [Aspect 128] The method of any one of embodiments 124-126, wherein the individual is administered 10 mg of Compound 1 for at least 4 weeks. [Aspect 129] The method of any one of embodiments 124-126, wherein the individual is administered 10 mg of Compound 1 for at least 6 weeks. [Aspect 130] The method of any one of embodiments 124-126, wherein the individual is administered 10 mg of Compound 1 for at least 8 weeks. [Aspect 131] the daily dose is reduced to 2.5 mg and Compound 1 is administered for at least an additional week, and the method comprises: increasing the daily dose to 5 mg when the plasma concentration of Compound 1 in the individual is below 200 ng / mL; or maintaining the daily dose at 2.5 mg when the plasma concentration of Compound 1 in the individual is between 200-750 ng / mL; The method of any one of embodiments 117-121, further comprising: [Aspect 132] when the plasma concentration of Compound 1 in the individual falls below 350 ng / mL, the daily dose is increased to 5 mg; When the plasma concentration of Compound 1 in the individual is between 350 ng / mL and 700 ng / mL, the daily dose is maintained at 2.5 mg. The method according to embodiment 131. [Aspect 133] when the individual's Valsalva gradient is 30 mmHg or greater and the plasma concentration of Compound 1 in the individual is below the recited amount, the daily dose is increased; said daily dose is maintained when said individual's Valsalva gradient is less than 30 mmHg and said plasma concentration of Compound 1 in said individual is below the recited amount; 133. The method of embodiment 131 or 132. [Aspect 134] The method of any one of embodiments 131-133, wherein the individual is administered 2.5 mg of Compound 1 for at least two weeks. [Aspect 135] The method of any one of embodiments 131 or 133, wherein said individual is administered 2.5 mg of Compound 1 for at least 4 weeks. [Aspect 136] The method of any one of aspects 117-135, wherein the HCM is obstructive HCM (oHCM). [Aspect 137] The method of any one of aspects 117-135, wherein the HCM is non-obstructive HCM. [Aspect 138] 1. A method for treating hypertrophic cardiomyopathy (HCM) in an individual in need thereof by achieving and maintaining a plasma concentration of 200-750 ng / mL of Compound 1, comprising: a) administering to the individual a daily dose of Compound 1 selected from the group consisting of 2.5, 5, 10, and 15 mg. The method comprising: [Aspect 139] The method of embodiment 138, wherein the plasma concentration of Compound 1 is 350-700 ng / mL. [Aspect 140] bi) increasing the daily dose to the next higher dose when the plasma concentration of Compound 1 in the individual falls below 200 ng / mL; or b-ii) reducing the daily dose to the next lower dose when the plasma concentration of Compound 1 in the individual exceeds 750 ng / mL; or b-iii) maintaining said daily dose of Compound 1 when said plasma concentration of Compound 1 in said individual is between 200-750 ng / mL. The method of embodiment 138, further comprising: [Aspect 141] bi) increasing the daily dose to the next higher dose when the plasma concentration of Compound 1 in the individual falls below 350 ng / mL; or b-ii) reducing the daily dose to the next lower dose when the plasma concentration of Compound 1 in the individual is greater than 700 ng / mL; or b-iii) maintaining said daily dose of Compound 1 when said plasma concentration of Compound 1 is 350-700 ng / mL. The method of embodiment 139, further comprising: [Aspect 142] The method of embodiment 140 or 141, wherein increasing the daily dose in step bi) is performed when the individual's Valsalva slope is greater than or equal to 30 mmHg and the plasma concentration of Compound 1 in the individual is below the recited amount, and the daily dose of Compound 1 is maintained when the individual's Valsalva slope is less than 30 mmHg and the plasma concentration of Compound 1 in the individual is below the recited amount. [Aspect 143] c) Repeat step b) every 2-4 weeks. The method of any one of embodiments 140-142, further comprising: [Aspect 144] c) Repeat step b) every 4-6 weeks. The method of any one of embodiments 140-142, further comprising: [Aspect 145] c) Repeat step b) every 4-8 weeks. The method of any one of embodiments 140-142, further comprising: [Aspect 146] The method of any one of aspects 138-145, wherein the HCM is obstructive HCM (oHCM). [Aspect 147] The method of any one of aspects 138-145, wherein the HCM is non-obstructive HCM. [Aspect 148] 1. A method for treating hypertrophic cardiomyopathy (HCM) in an individual in need thereof by achieving and maintaining a plasma concentration of Compound 1 of 200-750 ng / mL in the individual, comprising administering a daily dose of 2.5-15 mg of Compound 1, increasing the daily dose when the plasma concentration of Compound 1 in the individual is less than 200 ng / mL, or decreasing the daily dose when the plasma concentration of Compound 1 in the individual is greater than 750 ng / mL. [Aspect 149] The method of embodiment 148, wherein the plasma concentration of Compound 1 in the individual is achieved and maintained at 350-700 ng / mL, and the daily dose of Compound 1 is increased when the plasma concentration of Compound 1 in the individual is less than 350 ng / mL, or the plasma concentration of Compound 1 is decreased when the plasma concentration of Compound 1 in the individual is less than 700 ng / mL. [Aspect 150] when the individual's Valsalva gradient is 30 mmHg or greater and the plasma concentration of Compound 1 in the individual is below a recited amount, the daily dose of Compound 1 is increased; said daily dose is maintained when said individual's Valsalva gradient is less than 30 mmHg and said plasma concentration of Compound 1 in said individual is below the recited amount; 150. The method of embodiment 148 or 149. [Aspect 151] The method of any one of aspects 148-150, wherein the HCM is obstructive HCM (oHCM). [Aspect 152] The method of any one of aspects 148-150, wherein the HCM is non-obstructive HCM. [Aspect 153] 1. A method for treating hypertrophic cardiomyopathy in an individual in need thereof by achieving and maintaining a plasma concentration of Compound 1 of 200-750 ng / mL in said individual, comprising: a) administering a daily dose of 2.5-15 mg of Compound 1 for at least one week; b) measuring the plasma concentration of Compound 1 in said individual; c) increasing the daily dose of Compound 1 when the plasma concentration of Compound 1 in the individual is less than 200 ng / mL; or reducing the daily dose of Compound 1 when the plasma concentration of Compound 1 in the individual exceeds 750 ng / mL; or continuing the same daily dose of Compound 1 when the plasma concentration of Compound 1 in the individual is 200-750 ng / mL. The method comprising: [Aspect 154] wherein the plasma concentration of compound 1 in the individual is achieved and maintained at 350 ng / mL-700 ng / mL, and step c) increasing the daily dose of Compound 1 when the plasma concentration of Compound 1 in the individual is less than 350 ng / mL; or reducing the daily dose of Compound 1 when the plasma concentration of Compound 1 in the individual exceeds 700 ng / mL; or continuing the same daily dose of Compound 1 when the plasma concentration of Compound 1 in the individual is 350-700 ng / mL. The method of embodiment 153, comprising: [Aspect 155] When the individual's Valsalva gradient is 30 mmHg or greater and the plasma concentration of Compound 1 in the individual is below the recited amount, the daily dose of Compound 1 is increased; or said daily dose is maintained when said individual's Valsalva gradient is less than 30 mmHg and said plasma concentration of Compound 1 in said individual is below the recited amount; The method according to embodiment 153 or 154. [Aspect 156] d) Repeat steps a)-c) every 1-12 weeks. 155. The method of embodiment 153 or 154, further comprising: [Aspect 157] The method of embodiment 156, wherein steps a)-c) are repeated every two weeks. [Aspect 158] The method of embodiment 156, wherein steps a)-c) are repeated every four weeks. [Aspect 159] The method of embodiment 156, wherein steps a)-c) are repeated every 6 weeks. [Aspect 160] The method of embodiment 156, wherein steps a)-c) are repeated every 8 weeks. [Aspect 161] The method of embodiment 156, wherein steps a)-c) are repeated every 10 weeks. [Aspect 162] The method of embodiment 156, wherein steps a)-c) are repeated every 12 weeks. [Aspect 163] The method of any one of embodiments 153-162, wherein the initial daily dose of compound 1 in step a) is 5 mg. [Aspect 164] The method of any one of aspects 153-162, wherein the daily dose of compound 1 is selected from the group consisting of 2, 2.5, 5, 10, and 15 mg, and in step c) the daily dose of compound 1 is increased or decreased to the next higher amount of compound 1 or the next lower amount of compound 1. [Aspect 165] The method of any one of aspects 153-164, wherein the HCM is obstructive HCM (oHCM). [Aspect 166] The method of any one of aspects 153-164, wherein the HCM is non-obstructive HCM. [Aspect 167] 1. A method for treating hypertrophic cardiomyopathy in an individual in need thereof, comprising administering to the individual a total daily dose of an amount selected from the group consisting of 2.5 mg, 5 mg, 10 mg, and 15 mg. [Aspect 168] The method of embodiment 167, wherein said total daily dose of Compound 1 is 2.5 mg. [Aspect 169] The method of embodiment 167, wherein said total daily dose of Compound 1 is 5 mg. [Aspect 170] The method of embodiment 167, wherein said total daily dose of Compound 1 is 10 mg. [Aspect 171] The method of embodiment 167, wherein said total daily dose of Compound 1 is 15 mg. [Aspect 172] The method of any one of aspects 167-171, wherein the HCM is obstructive HCM (oHCM). [Aspect 173] The method of any one of aspects 167-171, wherein the HCM is non-obstructive HCM. [Aspect 174] 1. A method for treating hypertrophic cardiomyopathy in an individual in need thereof, comprising: a) administering to said individual a daily dose of 2-15 mg of Compound 1 for at least one week; b) monitoring said individual; c) adjusting the daily dose of Compound 1 based on pharmacokinetic and / or pharmacodynamic measures. The method comprising: [Aspect 175] The method of embodiment 174, wherein said monitoring is a non-invasive monitoring technique. [Aspect 176] The method of embodiment 175, wherein the non-invasive monitoring technique is selected from the group consisting of measuring maximum VO2 level, assessing NYHA functional class, measuring Valsalva gradient, measuring cardiac activity using an electrocardiogram or an echocardiogram, and combinations thereof. [Aspect 177] The adjusting step includes: increasing said daily dose of Compound 1 when said individual does not demonstrate clinical improvement in one or more of said non-invasive monitoring techniques; or reducing said daily dose of Compound 1 when said individual shows clinical regression in one or more of said non-invasive monitoring techniques; or continuing the same daily dose of Compound 1 when the individual shows clinical improvement in one or more of the non-invasive monitoring techniques. The method of embodiment 176, comprising: [Aspect 178] The method of embodiment 174, wherein the monitoring step comprises measuring a plasma concentration of Compound 1 in the individual, and / or the monitoring step comprises measuring a plasma concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP) in the individual. [Aspect 179] The adjusting step includes: increasing the daily dose of Compound 1 when the plasma concentration of Compound 1 in the individual is less than 200 ng / mL; or reducing the daily dose of Compound 1 when the plasma concentration of Compound 1 in the individual exceeds 750 ng / mL; or continuing the same daily dose of Compound 1 when the plasma concentration of Compound 1 in the individual is 200-750 ng / mL. The method of embodiment 178, comprising: [Aspect 180] The adjusting step includes: increasing the daily dose of Compound 1 when the plasma concentration of Compound 1 in the individual is less than 350 ng / mL; or reducing the daily dose of Compound 1 when the plasma concentration of Compound 1 in the individual exceeds 700 ng / mL; or continuing the same daily dose of Compound 1 when the plasma concentration of Compound 1 in the individual is 350-700 ng / mL. The method of embodiment 178, comprising: [Aspect 181] when the individual's Valsalva gradient is 30 mmHg or greater and the plasma concentration of Compound 1 in the individual is below the recited amount, the daily dose of Compound 1 is increased; or said daily dose is maintained when said individual's Valsalva gradient is less than 30 mmHg and said plasma concentration of Compound 1 in said individual is below the recited amount; 181. The method of embodiment 179 or 180. [Aspect 182] d) Repeat steps a)-c) every 1-12 weeks. The method of any one of embodiments 174-181, further comprising: [Aspect 183] The method of embodiment 182, wherein steps a)-c) are repeated every two weeks. [Aspect 184] The method of embodiment 182, wherein steps a)-c) are repeated every four weeks. [Aspect 185] The method of embodiment 182, wherein steps a)-c) are repeated every 6 weeks. [Aspect 186] The method of embodiment 182, wherein steps a)-c) are repeated every 8 weeks. [Aspect 187] The method of embodiment 182, wherein steps a)-c) are repeated every 10 weeks. [Aspect 188] The method of embodiment 182, wherein steps a)-c) are repeated every 12 weeks. [Aspect 189] The method of any one of embodiments 174-188, wherein the initial daily dose of compound 1 in step a) is 5 mg. [Aspect 190] The method of any one of aspects 174-189, wherein the daily dose of compound 1 is selected from the group consisting of 2, 2.5, 5, 10, and 15 mg, and in step c) the daily dose of compound 1 is increased to the next higher amount of compound 1 or decreased to the next lower amount of compound 1. [Aspect 191] The method of any one of aspects 174-189, wherein the daily dose of compound 1 is selected from the group consisting of 2.5, 5, 7.5, 10, 12.5, and 15 mg, and in step c) the daily dose of compound 1 is increased to the next higher amount of compound 1 or decreased to the next lower amount of compound 1. [Aspect 192] The method of any one of aspects 174-189, wherein the HCM is obstructive HCM (oHCM). [Aspect 193] The method of any one of aspects 174-189, wherein the HCM is non-obstructive HCM.

Claims

[Claim 1] The invention described herein and in the drawings.

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