Treatment methods using myosin modulators

Abstract

Disclosed herein are therapeutic methods comprising administering to a subject in need thereof a therapeutically effective amount of a myosin modulator, or a pharmaceutically acceptable salt thereof, and diagnostic methods useful in connection with those treatments. Findings uncovered in clinical trials with mavacamten and using mavacamten with other myosin inhibitors in preclinical settings provide new insights into how myosin inhibitors can be beneficially used to affect the pathology of HCM and other diseases.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application is a compilation of U.S. Provisional Patent Applications No. 62 / 933,517 filed November 10, 2019, No. 62 / 933,970 filed November 11, 2019, No. 62 / 935,922 filed November 15, 2019, No. 63 / 001,473 filed March 29, 2020, and No. 63 / 002,302 filed March 30, 2020. This application claims priority to the same Nos. 63 / 006,701 filed on 7 April 2020, Nos. 63 / 022,573 filed on 10 May 2020, Nos. 63 / 059,143 filed on 30 July 2020, and Nos. 63 / 064,450 filed on 12 August 2020, each of which is incorporated herein by reference.

[0002] This disclosure relates to a therapeutic method comprising administering a therapeutically effective amount of a myosin modulator or a pharmaceutically acceptable salt thereof to a subject in need thereof, and a diagnostic method useful in connection with such therapeutic methods. [Background technology]

[0003] Hypertrophic cardiomyopathy (HCM) is a chronic, progressive disease that can lead to debilitating symptoms and cardiac dysfunction due to excessive contraction of the heart muscle and reduced left ventricular filling capacity. It is estimated that 1 in 500 people will have HCM. The most common cause of HCM is mutations in the myocardial ganglia proteins. In approximately two-thirds of HCM cases, the pathway through which blood leaves the heart, known as the left ventricular outflow tract (LVOT), is obstructed by hypertrophied, affected muscle, limiting blood flow from the heart to the rest of the body (obstructive HCM). In other cases, the thickened myocardium does not obstruct the LVOT, and the disease is caused by diastolic dysfunction due to hypertrophied and hardened myocardium (non-obstructive HCM). In both obstructive and non-obstructive HCM cases, exertion can cause fatigue or shortness of breath, potentially impairing the ability to perform daily living activities. HCM is also associated with an increased risk of atrial fibrillation, stroke, heart failure, and sudden cardiac death.

[0004] Mavacamten is a novel oral allosteric modulator of cardiac myosin being developed for the treatment of hypertrophic cardiomyopathy (HCM). This therapy aims to reduce myocardial contractility by inhibiting the excessive formation of myosin-actin crosslinks, which underlie the hypercontractility, left ventricular hypertrophy, and reduced compliance characteristics of HCM. Mavacamten is currently being evaluated in multiple clinical trials for the treatment of obstructive and non-obstructive HCM. A pivotal Phase 3 clinical trial known as EXPLORER-HCM is being conducted in patients with symptomatic obstructive HCM, and a Phase 2 clinical trial known as MAVERICK-HCM is being conducted in patients with symptomatic non-obstructive HCM (nHCM). In addition, two long-term follow-up trials are underway: the PIONEER open-label continuation trial for patients with obstructive HCM from the Phase 2 PIONEER trial, and MAVA-LTE, a continuation trial for patients who have completed either EXPLORER-HCM or MAVERICK-HCM. Mabacamten is the first myosin inhibitor to progress to clinical trials.

[0005] Findings from clinical trials using mabacamten and from the use of mabacamten with other myosin inhibitors in preclinical settings provide new insights into how myosin inhibitors can be beneficially used to influence the pathogenesis of HCM and other diseases. [Overview of the Initiative]

[0006] In some embodiments, the Disclosure provides a method for treating a disease of interest, comprising administering a therapeutically effective dose of a myosin modulator to a subject in need thereof, wherein the subject has (1) elevated cardiac troponin levels and / or (2) elevated BNP or proBNP levels. In further embodiments, such a subject has normal contractility or systolic hypercontractility. In some embodiments, such a subject has a left ventricular ejection fraction (LVEF) of 52% or greater or 50% or greater. In some embodiments, the disease is a heart disease.

[0007] In some embodiments, subjects treated with myosin inhibitors have (1) elevated cardiac troponin levels and / or (2) elevated BNP or proBNP levels, and such subjects have normal contractility or systolic hypercontractility, as well as (A) diastolic dysfunction or elevated filling pressure and / or (B) left ventricular hypertrophy or left atrial enlargement.

[0008] In some embodiments, such subjects have a left ventricular ejection fraction (LVEF) of 52% or greater, or 50% or greater. In some embodiments, subjects have any of the following: (1) diastolic dysfunction, (2) elevated left ventricular filling pressure, or (3) left ventricular hypertrophy and / or left atrial enlargement.

[0009] In some embodiments, the myosin modulator is a myosin inhibitor. In some embodiments, the myosin inhibitor is a myosin inhibitor specifically identified in this application. In some embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, the Disclosure provides a method for treating a disease of interest, comprising administering a therapeutically effective amount of a myosin modulator or inhibitor to a subject in need thereof, wherein the subject has elevated cardiac troponin I (cTnI) or cardiac troponin T (cTnT). In some embodiments, cardiac troponin is cTnI. In some embodiments, cardiac troponin is cTnT. In some embodiments, cardiac troponin is high-sensitivity cTnI (hs-cTnI). In some embodiments, cardiac troponin is high-sensitivity cTnT (hs-cTnT). In some embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof. In some embodiments, the disease is a heart disease.

[0011] In some embodiments, the present disclosure provides a method for treating a subject disease in which the subject is suffering from symptoms of a cardiovascular disease.

[0012] In some embodiments, the disclosure provides a method for treating a subject disease in which the subject suffers from symptoms selected from shortness of breath, dizziness, chest pain, syncope, or limitations in daily living activities. In some embodiments, limitations in daily living activities are selected from the group consisting of restrictions on personal care, movement, or eating. In some embodiments, the disease is a heart disease.

[0013] In some embodiments, the present disclosure provides a method for treating a disease of interest, comprising administering a therapeutically effective amount of a myosin modulator or inhibitor to a subject in need thereof, the subject having elevated pro-BNP or BNP levels. In some embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof. In some embodiments, the disease is a heart disease.

[0014] In some embodiments, the Disclosure provides a method for treating a disease of interest, comprising administering a therapeutically effective amount of a myosin modulator or inhibitor to a subject in need thereof, wherein the subject has (1) elevated cardiac troponin I (cTnI) or cardiac troponin T (cTnT) levels, and (2) elevated pro-BNP levels. In some embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof. In some embodiments, the disease is a heart disease.

[0015] In some embodiments, the present disclosure provides a method for treating a disease of interest, comprising administering a therapeutically effective amount of a myosin modulator or inhibitor to a subject in need thereof, the subject having an elevated E / e'. In some embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof. In some embodiments, the disease is a heart disease.

[0016] In some embodiments, the Disclosure provides a method for treating a disease of interest, comprising administering a therapeutically effective amount of a myosin modulator or inhibitor to a subject in need thereof, the subject having elevated cardiac troponin levels and an elevated E / e'. In some embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof. In some embodiments, the disease is a heart disease.

[0017] In some embodiments, the Disclosure provides a method for treating a disease of interest, comprising administering a therapeutically effective amount of a myosin modulator or inhibitor to a subject in need thereof, wherein the subject has elevated cardiac troponin I (cTnI) and / or elevated cardiac troponin T (cTnT), and / or elevated pro-BNP levels, and / or elevated E / e'. In some embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof. In some embodiments, the disease is a heart disease.

[0018] In some embodiments, the present disclosure provides a method for treating a disease of interest, comprising administering a therapeutically effective amount of a myosin modulator or inhibitor to a subject in need thereof, the subject having a normal or hypersystolic left ventricular ejection fraction (LVEF). In some embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof. In some embodiments, the disease is a heart disease.

[0019] In some embodiments, the Disclosure provides a method for treating a disease of interest, comprising administering a therapeutically effective amount of a myosin modulator or inhibitor to a subject in need thereof, wherein the subject has (1) elevated cardiac troponin I (cTnI) or cardiac troponin T (cTnT) levels, and / or (2) elevated pro-BNP levels, and / or (3) elevated E / e', and / or (4) normal or hyperconstrictive left ventricular ejection fraction (LVEF). In some embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof. In some embodiments, the disease is a heart disease.

[0020] In some embodiments, the Disclosure provides a method for treating a disease of interest, comprising administering a therapeutically effective amount of a myosin modulator or inhibitor to a subject in need thereof, wherein the subject suffers from diastolic dysfunction, left ventricular hypertrophy (LVH), angina pectoris, ischemia, hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), or heart failure with preserved ejection fraction (HFpEF); or the subject suffers from valvular aortic stenosis, a combination of LV systolic and diastolic dysfunction, idiopathic RV hypertrophy, chronic kidney disease, aortic regurgitation, Tetralogy of Fallot, mitral stenosis, or acute coronary syndrome. In some embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof. In some embodiments, angina pectoris is microvascular angina. In some embodiments, LVH is malignant LVH.

[0021] In some embodiments, the Disclosure provides a method for treating a disease of interest, comprising administering a therapeutically effective amount of a myosin modulator or inhibitor to a subject in need thereof, who has been diagnosed with HCM. In some embodiments, the HCM is obstructive HCM. In some embodiments, the HCM is non-obstructive HCM. In some embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the present disclosure provides a method for treating a disease of interest, comprising administering a therapeutically effective amount of a myosin modulator or inhibitor to a subject in need thereof, who has been diagnosed with HFpEF. In some embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, the present disclosure provides a method for treating a disease of interest, comprising administering a therapeutically effective amount of a myosin modulator or inhibitor to a subject in need thereof, wherein the subject suffers from a disease including oHCM, nHCM, HFpEF, left ventricular hypertrophy (LVH), or angina pectoris, and the method is as follows: The procedure includes the steps of recommending that the subject be tested for elevated cardiac troponin levels, and administering a therapeutically effective dose of a myosin modulator or inhibitor to the subject if the subject has elevated cardiac troponin levels. In some embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, the cardiac troponin measured is cTnI, cTnT, hs-cTnI, or hs-cTnT.

[0025] In some embodiments, the method recommends testing the subject for elevated NT-proBNP or BNP levels, and further includes the step of administering a myosin modulator or inhibitor if elevated cardiac troponin levels and elevated NT-proBNP or BNP levels are observed.

[0026] In some embodiments, the method recommends evaluating the subject for elevated E / e', and then further includes the step of administering a myosin modulator or inhibitor if elevated cardiac troponin levels and elevated E / e' are observed.

[0027] In some embodiments, the increased E / e' exceeds 10. In some embodiments, the increased E / e' exceeds 13. In some embodiments, the increased E / e' exceeds 14.

[0028] In some embodiments, the method recommends testing the subject for elevated NT-proBNP or BNP levels, and further includes the step of administering a modulator or myosin inhibitor if (1) elevated NT-proBNP or BNP levels and (2) elevated E / e' are observed.

[0029] In some embodiments, the method recommends testing the subject for elevated cardiac troponin levels (i.e., cTnI or cTnT), and / or elevated NT-proBNP or BNP levels, and / or elevated E / e', and further includes the step of administering a myosin modulator or inhibitor if elevated cardiac troponin, elevated NT-proBNP or BNP levels, and / or elevated E / e' are observed.

[0030] In some embodiments, the disease in question is diagnosed according to the New York Heart Association (NYHA) classification. In some embodiments, treatment includes the step of evaluating the subject's NYHA classification score before and after administration of a therapeutically effective dose of a myosin modulator or inhibitor, where a decrease in the NYHA score after administration of the myosin modulator or inhibitor indicates a reduction in the severity of the disease in question.

[0031] In some embodiments, treatment includes administering a myosin modulator or inhibitor until the subject progresses from NYHA class III to class II, or from class II to class I. In some embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, the NYHA classification score of a subject decreases from grade III to grade II, or from grade II to grade I, after administration of a therapeutically effective dose of a myosin modulator or inhibitor.

[0033] In some embodiments, the disease in question is diagnosed according to the Kansas City Cardiomyopathy Questionnaire (KCCQ) score.

[0034] In some embodiments, the treatment includes the step of determining the subject's KCCQ score before and after administration of a therapeutically effective dose of a myosin modulator or inhibitor, wherein an increase in the KCCQ score after administration of the myosin modulator or inhibitor indicates a reduction in the severity of the subject's disease.

[0035] In some embodiments, subjects are evaluated for their maximal exercise oxygen consumption (VO2) before and after administration of a therapeutically effective dose of a myosin modulator or inhibitor, and an increase in maximal exercise oxygen consumption in a subject after administration of the myosin modulator or inhibitor indicates a reduction in the degree of the subject's HCM or at least one symptomatic component or condition. In some embodiments, subjects are evaluated for their VE / VCO2 or VE / VCO2 slope during exercise before and after administration of a therapeutically effective dose of a myosin modulator or inhibitor. In some embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, after administration of a therapeutically effective dose of myosin modulator or inhibitor, the subject experiences an improvement in pVO2. In some embodiments, the subject experiences an improvement in NYHA classification. In some embodiments, the subject experiences (i) an improvement of at least 1.5 mL / kg / min in pVO2 and a reduction of 1 or more degrees in NYHA classification, or (ii) an improvement of at least 3.0 mL / kg / min in pVO2 without deterioration of NYHA classification. In some embodiments, the subject experiences an improvement in VE / VCO2 or VE / VCO2 slope.

[0037] In some embodiments, subjects experience a reduction in the risk of major cardiovascular events. In some embodiments, major cardiovascular events are selected from a group consisting of death, hospitalization due to disease progression, and myocardial infarction. In some embodiments, subjects experience a statistically significant reduction in cardiac troponin and / or NT-proBNP or BNP levels.

[0038] In some embodiments, the patient has been diagnosed with HCM and is eligible for surgical intervention or percutaneous ablation to treat the disease. In some embodiments, the HCM is occlusive HCM. In some embodiments, the HCM is non-occlusive HCM.

[0039] In some embodiments, the patient is diagnosed with HFpEF.

[0040] In some embodiments, the subjects being treated are children, adolescents, or adults. In some embodiments, adolescents are 12 to 17 years old. In some embodiments, children are 5 to 11 years old.

[0041] In some embodiments, the present disclosure provides a method for reducing mortality in subjects suffering from conditions resulting from cardiovascular disease, the method comprising administering a therapeutically effective initiating dose of a myosin modulator or inhibitor to a subject to achieve a stable, desired clinical state, and subsequently administering a tapering regimen of the myosin modulator or inhibitor to maintain or improve the desired clinical state. In some embodiments, the method is a method for treating cardiovascular disease resulting in a reduction in mortality.

[0042] In some embodiments, symptoms resulting from cardiovascular disease include shortness of breath, dizziness, chest pain, syncope, fatigue, or limitation of daily living activities. In some embodiments, limitation of daily living activities is selected from the group consisting of restrictions on personal care, movement, or diet. In some embodiments, cardiovascular disease is selected from the group consisting of oHCM, nHCM, HFpEF, LVH, or angina pectoris. In some embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the major cardiovascular event is selected from the group consisting of death, hospitalization due to disease progression, and myocardial infarction.

[0044] In some embodiments, the reduced daily dosage regimen is about one-third, one-fourth, or one-fifth of the amount of mavacamten required to maintain the target plasma level of mavacamten. In some embodiments, the plasma level of mavacamten is 200–750 ng / mL.

[0045] In some embodiments, the dose reduction regimen is less than 5 mg per day, 4 mg or less per day, 3 mg or less per day, 2 mg or less per day, or 1 mg or less per day. In some embodiments, the therapeutically effective starting dose of mabacamten is about 5 mg to about 15 mg, and the dose reduction regimen is less than 5 mg of mabacamten per day.

[0046] In some embodiments, the dose reduction regimen is administered to the subject over a long period of time.

[0047] In some embodiments, the present disclosure provides a method for treating a subject after septal reduction therapy (SRT), comprising administering a tapering regimen of myosin modulator or inhibitor to the subject to maintain a stable and desired clinical state after septal reduction therapy. In some embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof.

[0048] In some embodiments, the dose reduction regimen is a daily dose of mabacamten to achieve a plasma concentration of 50–350 ng / ml, or less than 5 mg per day, 4 mg or less per day, 3 mg or less per day, 2.5 mg or less per day, or 1 mg or less per day.

[0049] In some embodiments, the disclosure provides a method for preventing HCM or LVH in subjects at risk of developing HCM or LVH, comprising the step of administering a myosin modulator or inhibitor to a subject at risk and in need thereof, the subject having elevated cardiac troponin levels. In some embodiments, the subject at risk further has elevated pro-BNP levels. In some embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, the Disclosure provides a method for preventing HCM or LVH in subjects at risk of developing HCM or LVH, comprising the step of administering a low dose of a myosin modulator or inhibitor to a subject in need to completely or partially prevent the development of HCM or LVH. In some embodiments, the myosin modulator or inhibitor is administered over a long period of time. In some embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof. In some embodiments, the subject being treated is a child, adolescent, or adult. In some embodiments, the subject has symptoms of HCM or LVH, including shortness of breath, dizziness, chest pain, syncope, fatigue, and limitation of daily living activities.

[0051] In some embodiments, restrictions on daily living activities are selected from a group consisting of restrictions on personal care, movement, or diet. In some embodiments, the low dose of myosin modulator or inhibitor is one-third to one-fifth of the amount required for such myosin inhibitor to reduce the LVOT gradient in oHCM patients. In some embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof.

[0052] In some embodiments, a low dose of mavacamten is less than 5 mg per day, or an amount sufficient to maintain a plasma concentration of mavacamten between 50 and 350 ng / mL. In some embodiments, a low dose of mavacamten is 1 mg, 2 mg, 2.5 mg, or 3 mg per day. In some embodiments, a myosin modulator or inhibitor dosing regimen is administered to the subject in the early stages of HCM or LVH development.

[0053] In some embodiments, the present disclosure provides a method for reducing adverse events in a subject associated with reduced cardiac output after treatment involving a myosin modulator or inhibitor, the method comprising the step of administering a therapeutic dose of a beta-adrenergic agonist to the subject. In some embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments, the beta-adrenergic agonist is dobutamine or levocimendan. In some embodiments, the therapeutic dose of the beta-adrenergic agonist is a dobutamine infusion of about 5 μg / kg / min to about 10 μg / kg / min. In some embodiments, the therapeutic dose of the beta-adrenergic agonist is a levocimendan infusion of about 0.2 to about 0.4 μmol / kg over a period of about 30 minutes.

[0055] In some embodiments, the method further includes an additional step of administering intravenous volume supplementation and / or an arterial vasoconstrictor to the target. In some embodiments, the arterial vasoconstrictor is an adrenergic agonist.

[0056] In some embodiments, the method further includes monitoring the plasma concentration of mabacamten in the subject and determining, based on the measured plasma concentration, that the subject has been administered an amount exceeding the therapeutic dose of mabacamten. In some embodiments, the method further includes monitoring LVEF and / or NT-proBNP and determining, based on the measured LVEF and / or NT-proBNP, that the subject has been administered (or may have been administered) an amount exceeding the therapeutic dose of mabacamten. In some embodiments, an amount exceeding the therapeutic dose of mabacamten is a dose of mabacamten that results in a plasma concentration of mabacamten greater than approximately 1000 ng / mL in the subject.

[0057] In some embodiments, the present disclosure provides methods for treating a subject with mabacamten for more than 28 weeks or more than 48 weeks (i.e., may include long-term medication).

[0058] In some embodiments, the present disclosure provides a method for treating a disease of interest, comprising administering a therapeutically effective amount of a myosin modulator or inhibitor to a subject in need thereof, wherein the subject has elevated cardiac troponin and / or elevated E / e', where the cardiac troponin is cardiac troponin I (cTnI) or cardiac troponin T (cTnT). In some embodiments, the subject further has elevated NT-proBNP or BNP levels. In some embodiments, the subject further has elevated E / e'.

[0059] In some embodiments, the subjects have a normal or hypersystolic left ventricular ejection fraction (LVEF). In some embodiments, the normal LVEF is between 52 and 74%, or in some embodiments, between 50 and 74%.

[0060] In some embodiments, the subjects suffer from diastolic dysfunction, left ventricular hypertrophy (LVH), malignant LVH, angina pectoris, ischemia, hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), or heart failure with preserved ejection fraction (HFpEF).

[0061] In some embodiments, the subjects have valvular aortic stenosis, a combination of LV systolic and diastolic dysfunction, idiopathic RV hypertrophy, chronic kidney disease, aortic regurgitation, Tetralogy of Fallot, mitral stenosis, or acute coronary syndrome.

[0062] In some embodiments, the myosin modulator is a myosin inhibitor. In further embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, subjects experience a reduction in the risk of major cardiovascular events, which are selected from a group consisting of death, hospitalization due to disease progression, and myocardial infarction.

[0064] In some embodiments, subjects experience a statistically significant reduction in (a) cardiac troponin and / or (b) NT-proBNP or BNP levels.

[0065] In some embodiments, the Disclosure provides a method for treating a disease of interest, comprising administering a therapeutically effective dose of a myosin modulator or inhibitor to a subject in need thereof, wherein the subject suffers from a disease including oHCM, nHCM, HFpEF, diastolic dysfunction, left ventricular hypertrophy (LVH), malignant LVH, ischemia, or angina pectoris, and the Method comprises the steps of recommending that the subject be tested for elevated cardiac troponin levels and / or elevated E / e'; and administering a therapeutically effective dose of a myosin modulator or inhibitor to the subject if the subject has elevated cardiac troponin levels and / or elevated E / e'.

[0066] In some embodiments, the cardiac troponin measured is cTnI or cTnT. In some embodiments, the method recommends testing the subject for elevated E / e', and then further includes the step of administering a myosin modulator or inhibitor if elevated cardiac troponin levels and elevated E / e' are observed.

[0067] In some embodiments, the method recommends evaluating the subject for elevated NT-proBNP or BNP, and further includes the step of administering a myosin modulator or inhibitor if elevated cardiac troponin levels, elevated NT-proBNP or BNP levels, and elevated E / e' are observed.

[0068] In some embodiments, the method further includes evaluating the maximal oxygen consumption (pVO2) and / or VE / VCO2 or VE / VCO2 slope in a subject during exercise before and after administration of a therapeutically effective dose of a myosin modulator or inhibitor. In some embodiments, the subject's maximal oxygen consumption (pVO2) increases. In some embodiments, the subject's VE / VCO2 or VE / VCO2 slope improves. In some embodiments, the disease is HFpEF, obstructive HCM, or non-obstructive HCM.

[0069] In some embodiments, subjects experience a reduction in the risk of major cardiovascular events, which are selected from a group consisting of death, hospitalization due to disease progression, and myocardial infarction. In some embodiments, subjects experience a statistically significant reduction in cardiac troponin and / or NT-proBNP or BNP levels.

[0070] In some embodiments, the Disclosure provides that after administration of a therapeutically effective dose of a myosin modulator or inhibitor, a subject experiences an improvement in pVO2 and, optionally, an improvement in NYHA classification, for example, (i) an improvement of at least 1.5 mL / kg / min in pVO2 and a reduction of 1 or more degrees in NYHA classification, or (ii) an improvement of at least 3.0 mL / kg / min in pVO2 without deterioration of NYHA classification.

[0071] In some embodiments, the present disclosure provides a method for administering mabacamten or a pharmaceutically acceptable salt thereof to a subject suffering from HFpEF, comprising: measuring the subject's first NT-proBNP or BNP level; administering a first dose of mabacamten or a pharmaceutically acceptable salt thereof to the subject during a first treatment period; measuring the subject's second NT-proBNP or BNP level; administering a second dose of mabacamten or a pharmaceutically acceptable salt thereof exceeding the first dose during a second treatment period if the second NT-proBNP or BNP level is not at least 15-75% lower than the first NT-proBNP or BNP level; and administering a first dose of mabacamten or a pharmaceutically acceptable salt thereof during a second treatment period if the second NT-proBNP or BNP level is at least 15-75% lower than the first NT-proBNP or BNP level.

[0072] In some embodiments, the method involves administering a second dose exceeding the first dose of mabacamtene or a pharmaceutically acceptable salt thereof during the second treatment period if the second NT-proBNP or BNP level is not at least 40-60% lower than the first NT-proBNP or BNP level; and administering a first dose of mabacamtene or a pharmaceutically acceptable salt thereof during the second treatment period if the second NT-proBNP or BNP level is at least 40-60% lower than the first NT-proBNP or BNP level; or The following are further included: if the second NT-proBNP or BNP level is not at least 50% lower than the first NT-proBNP or BNP level, administer a second dose exceeding the first dose of mabacamtene or a pharmaceutically acceptable salt thereof during the second treatment period; and if the second NT-proBNP or BNP level is at least 50% lower than the first NT-proBNP or BNP level, administer a first dose of mabacamtene or a pharmaceutically acceptable salt thereof during the second treatment period. In some embodiments, the first NT-proBNP or BNP level is an elevated level. In some embodiments, the method further includes measuring a first LVEF of the subject and measuring a second LVEF of the subject after the first LVEF and after the start of the first treatment period. In some embodiments, the method further includes measuring a second LVEF at the end of the first treatment period, after its completion, or within four weeks prior to its completion.

[0073] In some embodiments, if the second NT-proBNP or BNP level is not at least 15-75% lower than the first NT-proBNP or BNP level, and the second LVEF is not at least 10-20% lower than the first LVEF, a second dose greater than the first dose of mabacamten or a pharmaceutically acceptable salt is administered during the second treatment period; if the second NT-proBNP or BNP level is at least 15-75% lower than the first NT-proBNP or BNP level, or if the second LVEF is at least 10-20% lower than the second LVEF, a first dose of mabacamten or a pharmaceutically acceptable salt is administered during the second treatment period; or If the second NT-proBNP or BNP level is not at least 40-60% lower than the first NT-proBNP or BNP level, and the second LVEF is not at least 10-20% lower than the first LVEF, a second dose greater than the first dose of mabacamtene or a pharmaceutically acceptable salt is administered during the second treatment period; if the second NT-proBNP or BNP level is at least 40-60% lower than the first NT-proBNP or BNP level, or if the second LVEF is at least 10-20% lower than the second LVEF, the first dose of mabacamtene or a pharmaceutically acceptable salt is administered during the second treatment period; or If the second NT-proBNP or BNP level is not at least 50% lower than the first NT-proBNP or BNP level, and the second LVEF is not at least 15% lower than the first LVEF, a second dose greater than the first dose of mabacamtene or a pharmaceutically acceptable salt thereof is administered during the second treatment period; if the second NT-proBNP or BNP level is at least 50% lower than the first NT-proBNP or BNP level, or if the second LVEF is at least 15% lower than the second LVEF, the first dose of mabacamtene or a pharmaceutically acceptable salt thereof is administered during the second treatment period.

[0074] In some embodiments, the first NT-proBNP or BNP level is measured before the first treatment period. In some embodiments, the first NT-proBNP or BNP level is measured immediately before or within two weeks before the first treatment period. In some embodiments, the second NT-proBNP or BNP level is measured during the first treatment period. In some embodiments, the second NT-proBNP or BNP level is measured at the end of the first treatment period or within four weeks of its end.

[0075] In some embodiments, the present disclosure relates to a method for administering mabacamten or a pharmaceutically acceptable salt thereof to a subject suffering from HFpEF, Measure the troponin level of the target cardiac muscle; During the first treatment period, administer a first dose of mabacamten or a pharmaceutically acceptable salt thereof to the target area; Measure the troponin level of the second cardiac muscle in the target patient; If the second cardiac troponin level is not at least 10-50% lower than the first cardiac troponin level, administer a second dose of mabacamten or a pharmaceutically acceptable salt thereof exceeding the first dose during the second treatment period; and The present invention provides a method comprising administering a first dose of mabacamten or a pharmaceutically acceptable salt thereof during a second treatment period if the second cardiac troponin level is at least 10–50% lower than the first cardiac troponin level.

[0076] In some embodiments, this method If the second cardiac troponin level is not at least 20-40% lower than the first cardiac troponin level, administer a second dose of mabacamten or a pharmaceutically acceptable salt thereof exceeding the first dose during the second treatment period; and If the second cardiac troponin level is at least 20–40% lower than the first cardiac troponin level, the treatment further includes administering a first dose of mabacamten or a pharmaceutically acceptable salt thereof during the second treatment period.

[0077] In some embodiments, this method If the second cardiac troponin level is not at least 30% lower than the first cardiac troponin level, administer a second dose of mabacamten or a pharmaceutically acceptable salt thereof exceeding the first dose during the second treatment period; and If the second cardiac troponin level is at least 30% lower than the first cardiac troponin level, the treatment further includes administering a first dose of mabacamten or a pharmaceutically acceptable salt thereof during the second treatment period.

[0078] In some embodiments, the method further includes measuring a first LVEF of the subject and measuring a second LVEF of the subject after the first LVEF and after the start of the first treatment period. In some embodiments, the method further includes measuring a second LVEF at the end of the first treatment period, after its completion, or within two weeks prior to its completion.

[0079] In some embodiments, if the second cardiac troponin level is not at least 10-50% lower than the first cardiac troponin level and the second LVEF is not at least 10-20% lower than the first LVEF, a second dose exceeding the first dose of mabacamtene or a pharmaceutically acceptable salt thereof is administered during the second treatment period; if the second cardiac troponin level is at least 10-50% lower than the first cardiac troponin level, or if the second LVEF is at least 10-20% lower than the second LVEF, the first dose of mabacamtene or a pharmaceutically acceptable salt thereof is administered during the second treatment period, or If the second cardiac troponin level is not at least 20-40% lower than the first cardiac troponin level, and the second LVEF is not at least 10-20% lower than the first LVEF, a second dose exceeding the first dose of mabacamtene or a pharmaceutically acceptable salt thereof is administered during the second treatment period; if the second cardiac troponin level is at least 20-40% lower than the first cardiac troponin level, or if the second LVEF is at least 10-20% lower than the second LVEF, the first dose of mabacamtene or a pharmaceutically acceptable salt thereof is administered during the second treatment period, or If the second cardiac troponin level is not at least 30% lower than the first cardiac troponin level and the second LVEF is not at least 15% lower than the first LVEF, a second dose exceeding the first dose of mabacamtene or a pharmaceutically acceptable salt thereof is administered during the second treatment period; if the second cardiac troponin level is at least 30% lower than the first cardiac troponin level, or if the second LVEF is at least 15% lower than the second LVEF, the first dose of mabacamtene or a pharmaceutically acceptable salt thereof is administered during the second treatment period.

[0080] In some embodiments, the method further includes measuring a first NT-proBNP or BNP level of the subject, and measuring a second NT-proBNP or BNP level of the subject after the first NT-proBNP or BNP level and after the start of the first treatment period. In some embodiments, the second NT-proBNP or BNP level is measured at the end of the first treatment period, after its completion, or within four weeks prior to its completion.

[0081] In some embodiments, the method involves administering a second dose exceeding the first dose of mabacamtene or a pharmaceutically acceptable salt during the second treatment period if the second cardiac troponin level is not at least 10-50% lower than the first cardiac troponin level, and the second NT-proBNP or BNP level is not more than 20-60% higher than the first NT-proBNP or BNP level; or administering a first dose of mabacamtene or a pharmaceutically acceptable salt during the second treatment period if the second cardiac troponin level is at least 10-50% lower than the first cardiac troponin level, or if the second NT-proBNP or BNP level is more than 20-60% higher than the first NT-proBNP or BNP level, or If the second cardiac troponin level is not at least 20-40% lower than the first cardiac troponin level, and the second NT-proBNP or BNP level is not more than 40-55% higher than the first NT-proBNP or BNP level, then during the second treatment period, administer a second dose exceeding the first dose of mabacamtene or a pharmaceutically acceptable salt thereof; or if the second cardiac troponin level is at least 20-40% lower than the first cardiac troponin level, or if the second NT-proBNP or BNP level is more than 40-55% higher than the first NT-proBNP or BNP level, then during the second treatment period, administer the first dose of mabacamtene or a pharmaceutically acceptable salt thereof, or If the second cardiac troponin level is not at least 30% lower than the first cardiac troponin level, and the second NT-proBNP or BNP level is not more than 50% higher than the first NT-proBNP or BNP level, then during the second treatment period, a second dose exceeding the first dose of mabacamten or a pharmaceutically acceptable salt thereof should be administered, and If the second cardiac troponin level is at least 30% lower than the first cardiac troponin level, or if the second NT-proBNP or BNP level is more than 50% higher than the first NT-proBNP or BNP level, the treatment further includes administering a first dose of mabacamten or a pharmaceutically acceptable salt thereof during the second treatment period.

[0082] In some embodiments, the first cardiac troponin level is measured before the first treatment period. In some embodiments, the first cardiac troponin level is measured immediately before or within two weeks before the first treatment period. In some embodiments, the second cardiac troponin level is measured during the first treatment period. In some embodiments, the second cardiac troponin level is measured at the end of the first treatment period or within four weeks of its end.

[0083] In some embodiments, the first dose is about 1 mg to about 5 mg. In some embodiments, the first dose is about 2.5 mg. In some embodiments, the second dose is about 2.5 mg to about 10 mg. In some embodiments, the second dose is about 5 mg. In some embodiments, the second dose is about 1.5 to about 3 times the first dose. In some embodiments, the second dose is about 2 times the first dose.

[0084] In some embodiments, the first dose is administered daily during the first treatment period. In some embodiments, the first treatment period is at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, 4 to 20 weeks, 10 to 16 weeks, or about 14 weeks. In some embodiments, the second dose is administered daily during the second treatment period. In some embodiments, the second treatment period is at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, or at least 12 weeks.

[0085] In some embodiments, the subject has prior objective evidence of heart failure, as indicated by one or more of the following: Previous hospitalization for heart failure accompanied by X-ray evidence of pulmonary congestion; Elevated left ventricular end-diastolic pressure or pulmonary capillary wedge pressure at rest or during exercise; Elevated NT-ProBNP or BNP levels; and Echocardiographic evidence of a medial E / e' ratio ≥ 15 or left atrial enlargement accompanied by long-term treatment with loop diuretics.

[0086] In some embodiments, cardiac troponin is cardiac troponin I (cTnI) or cardiac troponin T (cTnT), or high-sensitivity cTnI (hs-cTnI). In some embodiments, the elevated troponin level is above the upper limit of normal (ULN). In some embodiments, the ULN for cTnT is approximately 0.014 ng / mL. In some embodiments, the ULN for cTnI is approximately 47 pg / mL.

[0087] In some embodiments, the increased E / e' is greater than 10. In some embodiments, E / e' is the average E / e'. In some embodiments, the increased E / e' is greater than 13. In some embodiments, the increased E / e' is greater than 14.

[0088] In some embodiments, elevated BNP exceeds 35 pg / mL. In some embodiments, elevated NT-proBNP exceeds 125 pg / mL. In some embodiments, elevated NT-proBNP exceeds 250 pg / mL. In some embodiments, elevated NT-proBNP exceeds 300 pg / mL. In some embodiments, elevated T-proBNP exceeds 450 pg / mL. In some embodiments, the subjects are 74 years of age or younger with NT-proBNP exceeding 125 pg / mL. In some embodiments, the subjects are 75 years of age or older with NT-proBNP exceeding 125 pg / mL.

[0089] In some embodiments, the subjects suffer from diastolic dysfunction, elevated filling pressure, elevated left ventricular filling pressure, left atrial enlargement, maintenance of systolic function, or systolic hypercontractility.

[0090] In some embodiments, the subjects suffer from left ventricular hypertrophy (LVH), malignant LVH, angina pectoris, ischemia, hypertrophic cardiomyopathy (HCM), or restrictive cardiomyopathy (RCM).

[0091] In some embodiments, the subjects suffer from heart failure with preserved ejection fraction (HFpEF).

[0092] In some embodiments, the subject suffers from shortness of breath, fatigue, palpitations (atrial fibrillation), chest pain and discomfort, dizziness, fainting, palpitations, limitation of daily living activities, or edema.

[0093] In some embodiments, the subjects suffer from myocardial diastolic dysfunction, elevated LV filling pressure, left ventricular wall hypertrophy, left atrial enlargement, normal or hypercontractility, myocardial injury and fibrosis, or abnormal myocardial energy characteristics.

[0094] In some embodiments, the subjects suffer from reduced exercise tolerance, fatigue, malaise, increased recovery time after exercise, and ankle swelling.

[0095] In some embodiments, the subjects have a normal or hypersystolic left ventricular ejection fraction (LVEF). In some embodiments, a normal LVEF is between 50–74% or 52–74%.

[0096] In some embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments, subjects experience a reduction in the risk of major cardiovascular events, which are selected from a group consisting of death, hospitalization due to disease progression, and myocardial infarction.

[0098] In some embodiments, the Disclosure provides a method for treating a disease of interest, comprising administering a therapeutically effective dose of a myosin inhibitor to a subject in need thereof, the subject having an LVEF greater than 52, as well as one or more of the following: elevated cardiac troponin, elevated NT-proBNP or BNP, and elevated E / e'. In some embodiments, the disease is a heart disease.

[0099] In some embodiments, the subject maintains contractile function or has normal contractility or systolic hypercontractility. In some embodiments, by treating the disease with a myosin modulator or inhibitor, the subject experiences a reduction in longitudinal global strain. In some embodiments, the subject has diastolic dysfunction.

[0100] In some embodiments, by treating the disease with a myosin modulator or inhibitor, the subject experiences a reduction in left ventricular filling pressure. In some embodiments, this reduction is characterized by an improvement in mean E / e'. In some embodiments, the subject has left ventricular hypertrophy or left atrial enlargement. In some embodiments, the subject has mild left ventricular hypertrophy.

[0101] In some embodiments, by treating the disease with a myosin modulator or inhibitor, the subject experiences a reduction in left ventricular myocardial mass, left ventricular wall thickness, ventricular septal thickness, or left ventricular septal thickness. In some embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic effective dose is about 2.5 mg to about 15 mg. In some embodiments, the therapeutic effective dose is about 2.5 mg to about 5 mg per day. In some embodiments, the therapeutic effective dose is about 5 mg to about 7.5 mg per day. In some embodiments, the therapeutic effective dose is about 7.5 mg to about 15 mg per day.

[0102] In some embodiments, subjects have a LVEF greater than 50%, and one or more of the following: elevated cardiac troponin, elevated NT-proBNP or BNP, and elevated E / e', where cardiac troponin is cardiac troponin T (cTnT) and / or cardiac cTnI and / or high-sensitivity cTnI (hs-cTnI), elevated E / e' is greater than 10 or 13, or E / e' is mean E / e', BNP is greater than 35 pg / mL, NT-proBNP is greater than 125 pg / mL, or NT-proBNP is greater than 200 or 300 pg / mL.

[0103] In some embodiments, the Disclosure provides methods for measuring cardiac disease by echocardiography (ECHO), magnetic resonance imaging (MRI), computed tomography (CT) scan, or cardiac catheterization.

[0104] Also disclosed herein are methods for treating subjects suffering from oHCM, including administering a myosin modulator to the subject, who is eligible for septal reduction therapy (SRT).

[0105] In some embodiments, the treatment involves administering a therapeutically effective dose of a myosin modulator to the target.

[0106] In some embodiments, the treatment reduces the likelihood of the subject receiving SRT. In some embodiments, the treatment reduces the short-term likelihood of the subject receiving SRT. In some embodiments, the treatment eliminates the need for the subject to receive SRT.

[0107] In some embodiments, the treatment reduces the thickness of the interventricular septum (IVS). In some embodiments, the treatment reduces the IVS thickness by at least 1 mm, at least 2 mm, at least 3 mm, at least 4 mm, or at least 5 mm. In some embodiments, the treatment reduces the interventricular septum (IVS) thickness compared to the IVS thickness before treatment. In some embodiments, before administration of the myosin modulator, the subject has an interventricular septum (IVS) thickness of 13 mm or more and a family history of HCM. In some embodiments, before administration of the myosin modulator, the subject has an interventricular septum (IVS) thickness of 15 mm or more.

[0108] In some embodiments, the subject has severe dyspnea or chest pain prior to treatment.

[0109] In some embodiments, the subjects are diagnosed with NYHA Class III or IV, or NYHA Class II with exertional symptoms, prior to treatment. In some embodiments, the exertional symptoms are exertional syncope or a presyncope state.

[0110] In some embodiments, the subject has a dynamic LVOT gradient of 50 mmHg or greater at rest or induced, accompanied by septal hypertrophy, prior to treatment. In some embodiments, induction is determined during the Valsalva maneuver or exercise.

[0111] In some embodiments, the subjects have a LVEF of 60% or more before treatment.

[0112] In some embodiments, the treatment improves the NYHA classification, specifically from NYHA Class III to Class II, or from NYHA Class II to Class I. In some embodiments, the treatment improves the KCCQ.

[0113] In some embodiments, the myosin modulator is a myosin inhibitor.

[0114] In some embodiments, the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments, the therapeutically effective dose of mabacamtene or a pharmaceutically acceptable salt thereof is about 2.5 mg to about 15 mg. In some embodiments, the therapeutically effective dose is about 5 mg to about 7.5 mg per day, or about 7.5 mg to about 15 mg per day. In some embodiments, the therapeutically effective dose is about 5 mg per day. In some embodiments, the therapeutically effective dose is administered once daily for 16 weeks or more. In some embodiments, the therapeutically effective dose is administered once daily for 32 weeks or more. In some embodiments, the therapeutically effective dose is administered once daily for 96 weeks or more. In some embodiments, the therapeutically effective dose of mabacamtene or a pharmaceutically acceptable salt thereof is 5 mg per day for 16 weeks or more.

[0116] In some embodiments, subjects are optionally evaluated for dose adjustment at weeks 4, 8, 12, or 16. In some embodiments, the therapeutically effective dose of mabacamten or a pharmaceutically acceptable salt thereof is 5 mg per day for 32 weeks or longer. In some embodiments, subjects are optionally evaluated for dose adjustment at weeks 4, 8, 12, or 16, 20, 24, 28, or 32.

[0117] In some embodiments, a therapeutically effective dose of mabacamten or a pharmaceutically acceptable salt thereof is 5 mg per day for at least 96 weeks. In some embodiments, subjects are optionally evaluated for dose adjustment at weeks 4, 8, 12, or 16, 20, 24, 28, or 32, 44, 56, 68, 80, 92, 104, 116, or 128.

[0118] In some embodiments, each dose adjustment includes reducing the dose to 2.5 mg or 1 mg per day. In some embodiments, each dose adjustment includes increasing the dose to 7.5 mg or 15 mg per day.

[0119] In some embodiments, the evaluation of dose adjustments includes the assessment of one or more of the following: vital signs, body weight, NYHA functional classification, adverse events, concomitant medications, physical examination, KCCQ, resting Valsalva test, transthoracic echocardiography, transthoracic echocardiography, post-exercise, accelerometer, Holter monitor application, single 12-lead ECG, PK sample, blood chemistry and coagulation, cardiac biomarkers, or exploratory biomarkers.

[0120] In some embodiments, the evaluation includes the evaluation of one or more cardiac biomarkers. In some embodiments, the one or more cardiac biomarkers include NT-proBNP or BNP. In some embodiments, the one or more cardiac biomarkers include cardiac troponin. In some embodiments, the cardiac troponin is cardiac troponin I (cTnI) or high-sensitivity cTnI (hs-cTnI). In some embodiments, the cardiac troponin is cardiac troponin T (cTnT) or high-sensitivity cTnT (hs-cTnT).

[0121] In some embodiments, vital signs include body temperature, heart rate (HR), respiratory rate, or blood pressure.

[0122] In some embodiments, the assessment includes an analysis of the LVOT gradient, left ventricular ejection fraction (LVEF), left ventricular (LV) filling pressure, or left atrial size.

[0123] In some embodiments, the evaluation includes assessing the change from baseline to week 16 in subjects treated with mabacamtene compared to subjects treated with placebo. In some embodiments, the evaluation includes assessing the change from baseline to week 16 in subjects treated with mabacamtene compared to the change from baseline to week 32 in subjects treated with mabacamtene. In some embodiments, the evaluation includes assessing the change from baseline to week 32 in subjects treated with mabacamtene compared to subjects treated with placebo from week 1 to week 16 and then treated with mabacamtene from week 17 to week 32.

[0124] In some embodiments, the evaluation involves assessing the change in the subject's NYHA functional classification, KCCQ-23 score, NT-proBNP or BNP, cardiac troponin, or LVOT gradient. In some embodiments, cardiac troponin is cardiac troponin I (cTnI) or high-sensitivity cTnI (hs-cTnI). In some embodiments, cardiac troponin is cardiac troponin T (cTnT) or high-sensitivity cTnT (hs-cTnT).

[0125] In some embodiments, the evaluation includes an analysis of the LVOT gradient and / or LVEF. In some embodiments, the method includes increasing the dose of mabacamten if the LVOT gradient of the subject exceeds 30 mmHg and the LVEF of the subject is 50% or greater.

[0126] In some embodiments, the subject is re-evaluated for SRT eligibility at weeks 16, 32, 80, and / or 128. In some embodiments, the evaluation shows that the method according to any one of claims 1 to 33 reduces the need for SRT for the subject. In some embodiments, the evaluation shows that the method according to any one of claims 1 to 33 eliminates the need for SRT for the subject.

[0127] In some embodiments, the subject is resistant to treatment with standard treatment for oHCM. "Resistant" refers to the subject's disease (in this case, oHCM) not responding to treatment. In one embodiment, the subject is resistant if the subject remains symptomatic after treatment (e.g., NYHA class III or IV) and has an LVOT gradient of 50 mmHg or greater. "Standard treatment" refers to the treatment of a disease (in this case, oHCM) that is commonly used and accepted by medical professionals in the pharmaceutical field. In one embodiment, standard treatment for oHCM includes the administration of beta-blockers, calcium channel blockers, disopyramide, or any combination thereof. In some embodiments, the subject is resistant to treatment of oHCM with beta-blockers, calcium channel blockers, disopyramide, or any combination thereof. In some embodiments, the subjects have reached maximally tolerable medical treatment with standard oHCM therapy prior to treatment with a myosin inhibitor or mabacamten or a pharmaceutically acceptable salt thereof, remain symptomatic NYHA class III or IV, and have an LVOT gradient of 50 mmHg or higher. In some embodiments, the subjects have reached maximally tolerable medical treatment with a beta-blocker, calcium channel blocker, and / or disopyramide prior to treatment with a myosin inhibitor or mabacamten or a pharmaceutically acceptable salt thereof, remain symptomatic NYHA class III or IV, and have an LVOT gradient of 50 mmHg or higher.

[0128] In some embodiments, the subject receives adjunctive therapy, including treatment with standard treatment for oHCM, in the course of treatment with a myosin inhibitor or mabacamtene or a pharmaceutically acceptable salt thereof. In some embodiments, the subject receives adjunctive therapy, including beta-blockers, calcium channel blockers, disopyramide, or any combination thereof, in the course of treatment with a myosin inhibitor or mabacamtene or a pharmaceutically acceptable salt thereof.

[0129] In some embodiments, subjects with oHCM to be treated to reduce the likelihood of SRT are classified as NYHA class IV. In some embodiments, the oHCM is symptomatic oHCM. In some embodiments, subjects with HCM to be treated to reduce the likelihood of SRT meet the selection and exclusion criteria of Example 6.

[0130] In some embodiments, this specification provides a method for treating or alleviating shortness of breath in patients diagnosed with symptomatic obstructive HCM, the method comprising administering a therapeutically effective dose of mabacamten or a pharmaceutically acceptable salt thereof to the patient once daily for more than 21 weeks.

[0131] In some embodiments, shortness of breath is determined by a patient-reported questionnaire.

[0132] In some embodiments, the questionnaire consists of two or more questions regarding the patient's shortness of breath symptoms.

[0133] In some embodiments, the questionnaire is HCMSQ-SoB.

[0134] In some embodiments, the therapeutically effective dose is approximately 2.5 mg to 15 mg per day.

[0135] In some embodiments, mabacamten is administered for at least 30 weeks.

[0136] In some embodiments, the patient has an LVEF of more than 50%.

[0137] In some embodiments, the therapeutically effective dose is such that the trough plasma concentration of mabacamten in the patient is approximately 350 to approximately 700 ng / mL.

[0138] In some embodiments, the therapeutically effective dose is such that the patient's post-exercise LVOT gradient is less than approximately 50 mmHg or less than approximately 30 mmHg.

[0139] In some embodiments, this specification provides a method for improving the quality of life of patients diagnosed with symptomatic obstructive HCM, the method comprising administering a therapeutically effective dose of mabacamtene or a pharmaceutically acceptable salt thereof to the patient for at least 30 weeks, the improvement in the patient's quality of life being measured by an improvement of at least 6 points in the patient's KCCQ score compared to before treatment with mabacamtene or a pharmaceutically acceptable salt thereof.

[0140] In some embodiments, the KCCQ score is based on using one or all of KCCQ-CSS, KCCQ-OSS, or KCCQ-TSS.

[0141] In some embodiments, improvement in quality of life is further judged by improvement in shortness of breath.

[0142] In some embodiments, improvement in shortness of breath is determined by a questionnaire consisting of two or more questions.

[0143] In some embodiments, improvement in shortness of breath is determined by the HCMSQ-SoB score.

[0144] In some embodiments, patients achieve a 6-point improvement in their KCCQ score.

[0145] In some embodiments, the therapeutically effective dose is approximately 2.5 mg to 15 mg per day.

[0146] In some embodiments, the patient has an LVEF of more than 50%.

[0147] In some embodiments, the therapeutically effective dose is such that the trough plasma concentration of mabacamten in the patient is approximately 350 to approximately 700 ng / mL.

[0148] In some embodiments, the therapeutically effective dose is such that the patient's post-exercise LVOT gradient is less than approximately 30 mmHg or less than approximately 50 mmHg.

[0149] In some embodiments, the foregoing describes a method for treating symptomatic obstructive HCM in patients who require treatment for it, Administer mabacamten or a pharmaceutically acceptable salt thereof to the patient at an initial dose of approximately 2.5 to 5 mg per day; and This includes setting the starting dose to a second dose of approximately 2.5 to 15 mg per day, The patient said: • Improvement of at least 1.5 mL / kg / min in maximum oxygen consumption (pVO2) and a reduction of 1 degree or more in the NYHA functional classification; • Improvement in pVO2 of 3.0 mL / kg / min or more without deterioration of NYHA functional classification; • Improvement of the maximum LVOT gradient after exercise; • At least one improvement in NYHA functional classification; • Improvement of pVO2; • Improvement of KCCQ score; • Improvement in HCMSQ score; • Maximum LVOT gradient after exercise is <50mmHg; • Maximum LVOT gradient after exercise is <30mmHg; ·Improvement of NT-proBNP levels; and Provides a method to achieve one or more of the following improvements: hs-cTnI level improvement.

[0150] In some embodiments, the patient is: • Improvement in EuroQol 5-D 5-Level Questionnaire scores; • Improvement in questionnaire scores regarding work productivity and activity impairment; • Improvement in the overall patient impression score and the overall patient impression-severity score; Achieve one or more of the following: improved daily step count and / or other accelerometer parameters.

[0151] In some embodiments, the starting dose is dose-set so that the patient's trough plasma concentration of mavacamten reaches approximately 350 to approximately 700 ng / mL.

[0152] In some embodiments, the starting dose is dose-set such that the patient's trough plasma concentration of mavacamten reaches approximately 350 to approximately 700 ng / mL and the patient's Valsalva LVOT gradient reaches less than approximately 30 mmHg.

[0153] In some embodiments, the starting dose is 2.5 or 5 mg per day.

[0154] In some embodiments, the second dose is 2.5, 5, 10, or 15 mg per day.

[0155] In some embodiments, mabacamten is administered daily for at least about 30 weeks.

[0156] In some embodiments, the patient being treated has (a) oHCM classified as NYHA II or NYHA III, (b) a maximum LVOT gradient greater than 50 mmHG as assessed by echocardiography at rest, after the Valsalva maneuver, or after exercise, and (c) an LVEF greater than 55%.

[0157] In some embodiments, the patient meets the selection and / or exclusion criteria described in Table 7.0 of Example 7.

[0158] In some embodiments, setting the starting dose to a second dose of approximately 2.5 to 15 mg per day includes setting the starting dose to a second dose of 2.5 mg per day when the patient's Valsalva LVOT gradient is less than 20 mmHg.

[0159] In some embodiments, the foregoing describes a method for treating symptomatic obstructive HCM in patients who require treatment for it, Administer mabacamten or a pharmaceutically acceptable salt thereof to the patient at a starting dose of approximately 2.5 to 5 mg per day; This includes setting the starting dose to a second dose of approximately 2.5 to 15 mg per day so that the patient's Valsalva LVOT gradient reaches less than approximately 30 mmHg. The patient said: • Improvement of at least 1.5 mL / kg / min in maximum oxygen consumption (pVO2) and a reduction of 1 degree or more in the NYHA functional classification; • Improvement in pVO2 of 3.0 mL / kg / min or more without deterioration of NYHA functional classification; • Improvement of the maximum LVOT gradient after exercise; • At least one improvement in NYHA functional classification; • Improvement of pVO2; • Improvement of KCCQ score; • Improvement in HCMSQ score; • Maximum LVOT gradient after exercise is <50mmHg; • Maximum LVOT gradient after exercise is <30mmHg; • Improvement in NT-proBNP levels; Provides a method to achieve one or more of the following improvements: hs-cTnI level improvement.

[0160] In some embodiments, the patient is: • Improvement in EuroQol 5-D 5-Level Questionnaire scores; • Improvement in questionnaire scores regarding work productivity and activity impairment; • Improvement in the overall patient impression score and the overall patient impression-severity score; Achieve one or more of the following: improved daily step count and / or other accelerometer parameters.

[0161] In some embodiments, the starting dose is dose-set such that the patient's Valsalva LVOT gradient reaches less than approximately 30 mmHg and the patient's trough plasma concentration of mavacamten reaches approximately 350 to approximately 700 ng / mL.

[0162] In some embodiments, the starting dose is 2.5 or 5 mg per day.

[0163] In some embodiments, the second dose is 2.5, 5, 10, or 15 mg per day.

[0164] In some embodiments, mabacamten is administered daily for at least about 30 weeks.

[0165] In some embodiments, the patient to be treated meets the selection criteria in Table 7.0 of Example 7. In some embodiments, the patient to be treated meets the exclusion criteria in Table 7.0 of Example 7.

[0166] In some embodiments, setting the starting dose to a second dose of approximately 2.5 to 15 mg per day includes setting the starting dose to a second dose of 2.5 mg per day when the patient's Valsalva LVOT gradient is less than 20 mmHg.

[0167] In some embodiments, this specification provides a method for treating HCM in patients who require treatment, (a) The step of administering a therapeutically effective dose of mabacamten or a pharmaceutically acceptable salt thereof to the patient once daily; (b) If the patient's ejection fraction falls below the threshold ejection fraction, temporarily discontinue administration of mabacamten or a pharmaceutically acceptable salt thereof; and (c) The step of resuming administration to the patient once daily of a therapeutically effective dose of mabacamten or a pharmaceutically acceptable salt thereof. This provides a method that includes [something].

[0168] In some embodiments, the threshold ejection fraction is 50%, 52%, or 55%. In some embodiments, the threshold ejection fraction is 50%.

[0169] In some embodiments, step (b) of the method further includes temporarily discontinuing the administration of mabacamtene or a pharmaceutically acceptable salt thereof for about 1 to about 8 weeks if the patient's ejection fraction falls below the threshold ejection fraction. In some embodiments, step (b) of the method further includes temporarily discontinuing the administration of mabacamtene or a pharmaceutically acceptable salt thereof for about 4 to about 6 weeks if the patient's ejection fraction falls below the threshold ejection fraction. In some embodiments, step (b) of the method further includes temporarily discontinuing the administration of mabacamtene or a pharmaceutically acceptable salt thereof until the LVEF returns to the normal range, for example, above 50%.

[0170] In some embodiments, step (c) of the method includes restarting administration of a therapeutically effective dose of mabacamten or a pharmaceutically acceptable salt thereof to the patient once daily for at least about four weeks. In some embodiments, administration is restarted at a lower dose. In some embodiments, HCM patients who have not achieved the desired clinical improvement after at least 12 weeks of administration of a daily dose of 10 mg are given a dose increased to 15 mg per day if their LVEF is greater than 60%.

[0171] In some embodiments, the therapeutically effective dose is approximately 2.5 mg to 15 mg per day.

[0172] In some embodiments, the therapeutically effective dose is such that the trough plasma concentration of mabacamten in the patient is approximately 350 to approximately 700 ng / mL.

[0173] In some embodiments, the therapeutically effective dose is such that the patient's Valsalva-LVOT gradient is less than approximately 30 mmHg.

[0174] In some embodiments, after resuming administration according to step (c), the patient: • Improvement of at least 1.5 mL / kg / min in maximum oxygen consumption (pVO2) and a reduction of 1 degree or more in the NYHA functional classification; • Improvement in pVO2 of 3.0 mL / kg / min or more without deterioration of NYHA functional classification; • Improvement of the maximum LVOT gradient after exercise; • At least one improvement in NYHA functional classification; • Improvement of pVO2; • Improvement of KCCQ score; • Improvement in HCMSQ score; • Maximum LVOT gradient after exercise is <50mmHg; • Maximum LVOT gradient after exercise is <30mmHg; • Improvement in NT-proBNP levels; Achieve one or more of the following improvements: hs-cTnI level.

[0175] In some embodiments, the patient is: • Improvement in EuroQol 5-D 5-Level Questionnaire scores; • Improvement in questionnaire scores regarding work productivity and activity impairment; • Improvement in the overall patient impression score and the overall patient impression-severity score; Achieve one or more of the following: improved daily step count and / or other accelerometer parameters.

[0176] In some embodiments, patients achieve improvements in the maximum LVOT gradient after exercise and at least a 1-degree improvement in their NYHA functional classification.

[0177] In some embodiments, patients achieve a maximum LVOT gradient of less than 50 mmHg post-exercise LVOT and an improvement of at least 1 degree in NYHA functional classification.

[0178] In some embodiments, patients achieve a maximum LVOT gradient of less than 30 mmHg post-exercise LVOT and an improvement of at least 1 degree in NYHA functional classification.

[0179] This specification also describes a method for treating symptomatic oHCM in patients requiring treatment for symptomatic oHCM, Administer the patient an initial dose of 5 mg of mabacamten or a pharmaceutically acceptable salt thereof per day for at least 4 weeks; To determine the first Valsalva maneuver gradient by evaluating the patient's LVOT gradient after the Valsalva maneuver; If the first Valsalva gradient is less than 20 mmHg, reduce the dose of mabacamten or a pharmaceutically acceptable salt thereof to 2.5 mg per day; Continue administration of mabacamten or a pharmaceutically acceptable salt thereof; To evaluate the LVOT gradient in the patient after the Valsalva maneuver and determine a second Valsalva gradient; and A method is disclosed which includes increasing the dose from 2.5 mg to 5 mg per day, or from 5 mg to 10 mg per day, if the second Valsalva gradient exceeds 30 mmHg.

[0180] In some embodiments, the first Valsalva gradient is measured approximately 4–6 weeks after administration. In some embodiments, the second Valsalva gradient is measured approximately 12 weeks after administration.

[0181] In some embodiments, the method further includes evaluating the patient's LVEF before administration, and the administration of the starting dose is initiated when the LVEF is 55% or higher.

[0182] In some embodiments, the method further includes evaluating the patient's LVEF during administration and temporarily discontinuing administration if the patient's LVEF is less than 50%.

[0183] In some embodiments, administration is discontinued after 4–6 weeks, or until the LVEF returns to 50% or higher.

[0184] In some embodiments, if the second Valsalva gradient exceeds 30 mmHg and the patient has an LVEF of 55% or more, the dose is increased from 2.5 mg to 5 mg per day, or from 5 mg to 10 mg per day.

[0185] In some embodiments, the method further includes evaluating the patient for the LVOT gradient obtained by the Valsalva maneuver to determine a third Valsalva gradient, and if the third Valsalva gradient exceeds 30 mmHg, increasing the dose from 2.5 mg to 5 mg per day, from 5 mg to 10 mg per day, or from 10 mg to 15 mg per day.

[0186] In some embodiments, if the third Valsalva gradient exceeds 30 mmHg and the patient has an LVEF of 55% or more, the dose is increased from 2.5 mg to 5 mg per day, from 5 mg to 10 mg per day, or from 10 mg to 15 mg per day. [Brief explanation of the drawing]

[0187] [Figure 1A] This is a plot of the average LVOT gradient (at rest) of the subjects in Example 1. [Figure 1B] This is a plot of the average LVOT gradient (Valsalva curve) for the subjects in Example 1. [Figure 1C] This is a plot of the average LVOT gradient (after exercise) for the subjects in Example 1. [Figure 1D] This is a plot of the mean LVEF of the subjects in Example 1. [Figure 2A] This chart shows the changes in NYHA functional classification after 48 weeks in the study of Example 1. [Figure 2B] This is a plot of the change in the overall KCCQ summary score after 48 weeks in the trial of Example 1. [Figure 3A] This is a plot of septal wall thickness measurements over 48 weeks in the experiment of Example 1. [Figure 3B] This is a plot of the posterior wall thickness measurements over 48 weeks in the experiment of Example 1. [Figure 4] This is the test scheme for Example 2. [Figure 5A] This is a plot of EDP (end-diastolic pressure) for MYK-581 versus control. [Figure 5B]Plot of MYK-581 vs. control Eed (stiffness). [Figure 5C] Parallel plots of MYK-581 vs. control tauW and dP / dt are shown, indicating improved compliance and early relaxation. [Figure 6A] Plot of ejection fraction (EF) in the test of Example 2. [Figure 6B] Plot of left atrial (LA) volume in the test of Example 2. [Figure 6C] Plot of WTd (end-diastolic wall thickness of the entire left ventricle) in the test of Example 2. [Figure 6D] Plot of T1pre in the test of Example 2. [Figure 6E] Plot of extracellular volume (ECV) in the test of Example 2. [Figure 6F] Plot of cardiac output (CO) in the test of Example 2. [Figure 6G] Plot of PV aorta in the test of Example 2. [Figure 6H] Plot of left ventricular (LV) mass in the test of Example 2. [Figure 6I] Plot of ejection fraction (EF) in the test of Example 2. [Figure 7] Test scheme of Example 3. [Figure 8] Plot of geometric mean of NT-proBNP up to week 24 in Example 3. [Figure 9] Plot of geometric mean of cTnI up to week 24 in the subpopulation with elevated cTnI in Example 3. [Figure 10] Bar graph of the rate of change of cTnI from baseline at week 16 in the subpopulation with elevated cTnI in Example 3. [Figure 11A] Bar graph of the rate of change of hs-cTnI by participants in Example 3. [Figure 11B] Bar graph of the rate of change of hs-cTnT by participants in Example 3. [Figure 12]A plot showing the relationship between the change in NT-proBNP from the baseline at the 4th week and cTnI is shown. [Figure 13] It is a bar graph of the exploratory functional composite evaluation items of Example 3. [Figure 14] It is a bar graph showing the correlation between NT-proBNP levels and pVO2 in various tests and various treatment groups. [Figure 15] It is the test scheme of Example 6. [Figure 16] It is the test scheme of Example 7. [Figure 17] It is a plot of the half-life in the subjects of Example 9 grouped by metabolic phenotype. [Figure 18] It is a plot of the clearance rate in the subjects of Example 9 grouped by metabolic phenotype. [Figure 19A] It is a scatter plot of the average measured plasma concentration of a single-dose according to Example 10. [Figure 19B] It is a scatter plot of the average measured plasma concentration of multiple doses according to Example 10. [Figure 19C] It is a scatter plot of the average measured plasma concentration of multiple doses over time according to Example 10. [Figure 20] It is a plot of the trough concentration over time based on the model of Example 10. [Figure 21] It is the test scheme of Example 1 showing the transition to an open-label continuous study. [Figure 22] It is the test scheme of Example 1, showing the dosing protocol of the test. [Figure 23A] Provide the X-ray powder diffraction (XRPD) spectrum of the A-form crystal of mavacamten (MYK-461). [Figure 23B] Provide the XRPD spectra of lots 4, 5, and 6 of Example 13. [Figure 24] Provide the thermogravimetric analysis (TGA) trace of the A-form crystal of mavacamten. [Figure 25] Provide the differential scanning calorimetry (DSC) thermogram of the A-form crystal of mavacamten. [Figure 26A] This is a chart showing the SRX (Single Rate of Return) versus concentration of mabacamten (MYK-461) and MYK-581. [Figure 26B] This is a graph showing the ATPase rate versus concentration of DRX. [Figure 26C] This is a graph showing the ATPase rate versus concentration of SRX. [Modes for carrying out the invention]

[0188] definition While various embodiments and aspects of the present invention are shown and described herein, it will be apparent to those skilled in the art that such embodiments and aspects are provided merely as examples. Those skilled in the art will likely conceive of numerous variations, alterations, and substitutions without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be employed in the practice of the present invention.

[0189] Section headings used herein are for structural purposes only and should not be construed as limiting the subject matter described herein. All documents or parts of documents cited herein (including, but not limited to, patents, patent applications, articles, books, manuals and professional works) are expressly incorporated herein by reference in their entirety for any purpose.

[0190] The following document is incorporated entirely by reference: ·The American Society of Echocardiography,Recommendations for Cardiac Chamber Quantification in Adults:A Quick Reference Guide from the ASE Workflow and Lab Management Task Force,July 2018 ·Lang et al.,Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults:An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging,Journal of the American Society of Echocardiography,January 2015 ·Nagueh et al.,Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography:An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging,Journal of the American Society of Echocardiography,2016;29:277-314 ·Caballero et al.,Echocardiographic reference ranges for normal cardiac Doppler data:results form the NORRE Study,European Heart Journal - Cardiovascular Imaging(2015)16,1031-1041 ·Jozine M.ter Maaten et al.,Connectin heart failure with preserved ejection fraction and renal dysfunction:the role of endothelial dysfunction and inflammation,European Journal of Heart Failure(2016)18,588-598 ·《美国胸科学会 / 美国胸科医师学会关于心肺运动试验的声明》,美国胸科学会 / 美国胸科医师学会,2001年11月1日 ·扎伊德等人,《心脏瓣膜病患者术前和术后舒张功能障碍》,《美国心脏病学会杂志》,2013年,62(21),1922 - 1930 ·古普塔等人,《循环利钠肽水平的种族差异:社区动脉粥样硬化风险研究》,《美国心脏协会杂志》,2015年;4:e001831 ·尤金·布劳纳沃德,《心肌病概述》,《循环研究》。2017年;121:711 - 721 ·托宾和杰弗里斯,《左心室致密化不全、线粒体和储存疾病以及先天性代谢缺陷所致心肌病》,《循环研究》。2017年;121:838 - 854 ·西里诺和何,《肥厚型心肌病概述》。2008年。载于亚当等人编著的《基因评论》(注册商标),西雅图(华盛顿州):华盛顿大学,西雅图;1993 - 2020。

[0191] Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For example, see Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY, 2nd ed., J. Wiley & Sons (New York, NY 1994), and 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 certain terms frequently used herein and are not intended to limit the scope of the present disclosure.

[0192] As used herein, the terms "a" or "an" mean one or more.

[0193] The terms "comprise," "include," and "have," and derivatives thereof, are used interchangeably herein as inclusive and open-ended terms. For example, the use of "comprising," "including," or "having" means that any element comprised, had, or included is not the only element encompassed by the clause containing that verb.

[0194] As used herein, the term "about" means a range of values that includes the specified value, as would be readily understood by one of ordinary skill in the art. In some embodiments, the term "about" means within one standard deviation using measurements generally accepted in the art. In some embodiments, "about" means within a range of ±10% of the specified value. In some embodiments, "about" means the specified value.

[0195] As used herein, “treatment” or “to treat,” or “to temporarily relieve,” “to alleviate,” or “to reduce” are interchangeable herein. These terms refer to an approach to obtain a beneficial or desired outcome, including but not limited to therapeutic benefits. Therapeutic benefits mean the elimination or alleviation of the underlying disorder being treated. Therapeutic benefits are also achieved by the elimination or alleviation of one or more physiological symptoms associated with the underlying disorder, such that improvement is observed in the subject, even if the subject still suffers from the underlying disorder. Treatment includes delaying the onset of clinical symptoms of a disease by administration of a composition; suppressing the disease, i.e., causing a reduction in the clinical symptoms of the disease; inhibiting the disease, i.e., preventing the onset of clinical symptoms by administration of a composition after the appearance of the initial symptoms; and / or mitigating the disease, i.e., causing regression of clinical symptoms by administration of a composition after the appearance of the initial symptoms. For example, certain methods described herein treat hypertrophic cardiomyopathy (HCM) by reducing or mitigating the incidence or progression of HCM, or by reducing the symptoms of HCM. Symptoms of HCM, or test results indicating HCM, are known to those skilled in the art or can be determined by those skilled in the art, and may include, but are not limited to, shortness of breath (especially during exercise), chest pain (especially during exercise), fainting (especially during or immediately after exercise), perception of a rapid, pounding, or violent heartbeat, atrial and ventricular arrhythmias, heart murmurs, hypertrophic non-diastolic left ventricle, myocardial thickening, left ventricular wall thickening, increased pressure gradient throughout the left ventricular outflow tract (LVOT), and increased post-exercise LVOT gradient.

[0196] "Patient," "subject," or "subject requiring such treatment" refers to an organism that is suffering from or susceptible to a disease or condition that can be treated by using the methods provided herein. The term does not necessarily imply that the subject has been diagnosed with a specific disease, and typically refers to an individual under medical supervision. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, cats, monkeys, goats, sheep, cows, deer, and other non-mammalian animals. In some embodiments, the patient, subject, or subject requiring such treatment is a human.

[0197] As used herein, “administration” of a compound in this disclosure includes delivery to a subject of the compound described herein or its prodrug or other pharmaceutically acceptable derivative using any suitable formulation or route of administration (e.g., those described herein).

[0198] "Pharmacologically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other materials that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0199] An "effective dose" is a quantity sufficient to achieve the stated objective (e.g., achieving an effect on the administered substance, treating a disease, reducing enzyme activity, reducing one or more symptoms of a disease or condition, or reducing intracellular viral replication). An example of an "effective dose" is a quantity sufficient to contribute to the treatment or reduction of the symptoms(s) of a disease, which may also be called a "therapeutic effective dose." Reduction(s) of symptoms(s) (and their grammatical equivalents) means a decrease in the severity or frequency of symptoms(s), or the elimination of symptoms(s). Effectiveness can also be expressed as a "multiple" increase or decrease. For example, a therapeutic effective dose may have at least 1.2 times, 1.5 times, 2 times, 5 times, or more of an effect compared to a control.

[0200] "Elevated troponin" or "suppressed troponin level" refers to a concentration of cardiac troponin (cTn) complex protein in a blood sample that exceeds the 99th percentile of the concentration in the healthy reference population. The upper limit of normal (ULN) is usually most accurately determined by individual assays or detection approaches. Cardiac troponin forms a trimer complex (T:I:C) bound to thin filaments. According to the present invention, the cardiac troponin complex or its variants in the protein components constituting the complex measured in a blood sample is preferably detected by the detection of cardiac troponin I (cTnI) or cardiac troponin T (cTnT). In one embodiment, the blood sample is a plasma sample or a serum sample. In one embodiment, the elevated troponin level is detected by an immunoassay.

[0201] In another embodiment, the elevated cTnI concentration is greater than 0.01 ng / ml, greater than 0.03 ng / ml, or greater than 0.4 ng / ml. In another embodiment, the immunoassay has a limit of quantification (LoQ) of less than 10 pg / ml or 10 pg / ml. LoQ refers to the smallest amount of analyte in the sample that can be accurately quantified with a CV of bias ≤ 10% and inaccuracy ≤ 10%. In another embodiment, the immunoassay has a limit of detection (LOD) of ≤ 0.010 ng / ml and a coefficient of variation (CV) precision of 10%. In another embodiment, the elevated troponin level is above the upper limit of normal (ULN), with a ULN of 0.014 ng / mL for cTnT or 47 pg / mL for cTnI. In another embodiment, the lower limit of quantification (LLOQ) for cTnT is 0.003 ng / ml and the LLOQ for cTnI is 2.5 pg / ml. In one embodiment, "high sensitivity" of a cTnT or cTnI assay refers to a lower limit of quantification (LLOQ) of 0.003 ng / ml for cTnT and a LLOQ of 2.5 pg / ml for cTnI, respectively.

[0202] Brain natriuretic peptide (BNP) is the first natriuretic hormone identified in the brain, but is primarily released from the heart, particularly the ventricles. Cleavage of the 108-amino acid prohormone proBNP produces the biologically active 32-amino acid BNP and the biologically inactive 76-amino acid N-terminal pro-BNP (NT-proBNP). Biologically active BNP, proBNP, and NT-proBNP can each be measured in the blood. BNP is released in response to muscle cell stretching caused by ventricular volume expansion or pressure overload.

[0203] "Elevated proBNP level," "elevated NT-proBNP level," "high pro-BNP," and "high NT-ProBNP" are interchangeable and refer to the concentration of NT-proB-type natriuretic peptide (NT-proBNP) in a blood sample, i.e., >125 pg / ml. In some embodiments, the elevated proBNP level is >300 pg / ml. In some embodiments, the elevated proBNP level is >200 pg / ml. In some embodiments, the elevated NT-proBNP in subjects with atrial fibrillation or flutter is >750 pg / ml.

[0204] "Elevated adjusted NT-proBNP level," "elevated adjusted NT-proBNP," or "elevated adjusted level of pro-BNP" refers to a higher-than-normal concentration of NT-proBNP in a blood sample. In some embodiments, the upper limit of normal (ULN) for any particular assay is provided in its product specification. In some embodiments, such an ULN is 125 pg / ml. The ULN may vary based on patient characteristics such as race, body mass index (BMI), age, and sex. For example, the ULN for African Americans may be lower than 125 pg / ml. Studies have shown that there may be an inverse correlation between BMI and NT-proBNP levels. The ULN for NT-proBNP in older adults tends to increase with age. Other studies have shown that NT-proBNP levels in healthy women under 80 years of age may be higher than in healthy men of the same age. Some studies have shown that NT-proBNP levels in patients with atrial fibrillation are relatively high (e.g., above 750). In some embodiments, the elevated NT-proBNP level is the elevated adjusted NT-proBNP level.

[0205] "Elevated BNP level" or "elevated BNP" refers to a higher-than-normal concentration of brain natriuretic peptide (BNP) in a blood sample. In some embodiments, elevated BNP is higher than the upper limit of normal provided by a given assay. The upper limit of normal (ULN) is usually best determined by the individual assay or detection approach. In some embodiments, elevated BNP level is >100 pg / ml.

[0206] E / e' refers to the ratio (E / e') of the early mitral valve inflow velocity to the early mitral annular diastolic velocity. E / e' is an echocardiographic (ECHO) surrogate measure of left ventricular filling pressure elevation. E / e' can be measured and calculated as the medial or septal E / e' ratio, the lateral wall E / e' ratio, or the mean E / e' ratio. In some embodiments, E / e' is E / e' 平均The elevated E / e' refers to a ratio value higher than the normal upper limit. In one embodiment, the elevated E / e' is >14. In one embodiment, the elevated E / e' is E / e' 平均 is >14. In another embodiment, the increased E / e' is E / e' 中隔 is >15. In another embodiment, the increased E / e' is E / e' 側壁 In another embodiment, it is >13, or >12.

[0207] "Desirable clinical conditions" include normal LVEF (52-74%), normal LVOT (resting gradient, Valsalva gradient, or post-exercise gradient <30 mmHg), normal interventricular septal thickness (IVS) (6-10 mm), normal LV posterior wall thickness (6-10 mm), normal left ventricular myocardial mass or weight index, and normal LAVI (16-34 mL / m²). 2 This refers to a better clinical state measured by one or a combination of scales selected from the group consisting of normal lateral wall E / e' (<8), normal NT-proBNP (<125 pg / ml); normal KCCQ overall symptom score; and normal cTnI levels (below elevated troponin levels).

[0208] "Stable" refers to a physician's determination that the degree or severity of the disease has neither decreased nor increased over a certain period of time.

[0209] "Individuals at risk of developing HCM or LVH" are those who are asymptomatic or may have NYHA class I. Such individuals at risk may also have one or a combination of elevated troponin levels, a predisposition to HCM or LVH, symptoms of HCM or LVH, or early LV hypertrophy or clinical suspicion of HCM. In one embodiment, a patient is at risk of developing nHCM.

[0210] "Predisposition to HCM or LVH" refers to a predisposition in an individual to develop HCM or LVH due to either (a) a genetic predisposition in the individual having a mutation associated with HCM or LVH, or (b) a familial predisposition in the individual where there is a history of HCM or LVH in the individual's family, but the genetic linkage to HCM or LVH is unclear. There are eight cardiomyocyte genes that most commonly cause HCM (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, ACTC, MLC2, and MLC3), as well as two glycogen metabolism genes (referred to as PRKAG2 and LAMP2) that cause a condition similar to HCM and also cause LVH. Analysis of five genes (MYH7, MYBPC3, TNNT2, TNNI3, and TPM1) can reveal mutations in 50-60% of individuals suspected of having HCM. By examining three additional genes—ACTC, MLC2, and MLC3—mutations may be detected in another 5–10% of individuals with HCM. Overall, current HCM genetic testing can detect mutations in approximately 55–70% of individuals suspected of having HCM.

[0211] "Reducing the likelihood of a subject receiving septal reduction therapy (SRT)" or similar means that, if the subject receives treatment, the likelihood of the subject receiving SRT is clinically significantly reduced compared to no treatment (e.g., placebo). In some embodiments, the reduction in the likelihood of a subject receiving septal reduction therapy is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, or at least 75%. In one embodiment, reducing the likelihood of a subject receiving SRT means (1) a reduced desire of the patient to continue SRT, and / or (2) the resulting change in SRT guideline eligibility that makes the patient ineligible for SRT.

[0212] "Reducing the short-term likelihood that a subject will receive septal reduction therapy (SRT)" or the like refers to the clinical significant reduction in the likelihood that a subject will receive SRT within one year of the start of treatment, compared to the case where the subject does not receive treatment (e.g., placebo). In some embodiments, the reduction in the likelihood that a subject will receive septal reduction therapy within one year of the start of treatment is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, or at least 75% reduction. In some embodiments, the short-term likelihood is evaluated after 16 weeks of treatment. In some embodiments, the short-term likelihood is evaluated after 32 weeks of treatment. In some embodiments, the reduction in the likelihood that a subject will receive SRT is maintained over the period from week 16 to week 32.

[0213] Myosin inhibitor In some embodiments, the myosin inhibitor is a compound of formula (I): [Chemical formula] Or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1~8 alkyl, C 3~8 cycloalkyl, or phenyl, and R 1 is optionally substituted with one or two halos; R 2 is phenyl optionally substituted with one or two halos; R 3 is C 1~8 alkyl or C 3~8 cycloalkyl, and each R 3 is optionally substituted with halo, hydroxyl, or C 1~2 alkoxy; R 4 is H; X is H.

[0214] In some embodiments, a myosin inhibitor of formula (I) or a pharmaceutically acceptable salt thereof is [ka] It is selected from group (I) consisting of the following.

[0215] In some embodiments, the myosin inhibitor of formula (I) has the following structure: [ka] It is mabacamten or a pharmaceutically acceptable salt thereof.

[0216] Mabacamten is also known as MYK-461. Its chemical name is (S)-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione or 6-[[(1S)-1-phenylethyl]amino]-3-propan-2-yl-1H-pyrimidine-2,4-dione.

[0217] In some embodiments, the myosin inhibitor of formula (I) has the following structure: [ka] It is MYK-581 or a pharmaceutically acceptable salt thereof.

[0218] The chemical name of MYK-581 is (S)-6-((1-(3-fluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.

[0219] Myosin inhibitors of formula (I), comprising compounds of group (I), mabacamten, or MYK-581, or pharmaceutically acceptable salts thereof, can be obtained by means of a manufacturing method described in U.S. Patent No. 9,181,200 (which is incorporated herein by reference in its entirety for all purposes).

[0220] In some embodiments, mabacamten is crystalline mabacamten. In some embodiments, mabacamten is amorphous mabacamten. In some embodiments, mabacamten is a mixture of crystalline mabacamten and amorphous mabacamten.

[0221] In some embodiments, mabacamten is crystalline mabacamten of form A. In some embodiments, mabacamten is a purified crystalline form that is substantially of form A.

[0222] As used herein, the term “purified” means a compound substantially free of enantiomers, diastereomers, or other isomers of the described compound, as well as impurities such as artifacts from the preparation process. Generally, a “purified” compound or composition has a purity of at least 95%, 96%, 97%, 98%, 98.5%, 99%, 99.2%, 99.4%, 99.6%, 99.8%, or 99.9% compared to other components (impurities).

[0223] The term “substantially” applied to a composition or substance indicates at least 80% (w / w) identity with the specified substance, preferably a higher level, for example, at least 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0224] This specification provides a purified crystalline form of mabacamtene that is substantially of type A.

[0225] In some embodiments, the purity of the type A crystal is at least 97%, or at least 98%, or at least 99%, or at least 99.6%.

[0226] In some embodiments, the crystalline solid has a differential scanning calorimetry thermogram containing three endothermic peaks at up to 238°C, 242°C, and 252°C. In some embodiments, the crystalline solid has a DSC thermogram substantially as shown in Figure 3.

[0227] In some embodiments, one or more peak values ​​of the thermogram are ±0.5, ±0.796, ±0.8, or ±1.0°C.

[0228] In some embodiments, the purified crystalline form (Type A) has an X-ray powder diffraction pattern that includes a peak at 18.8°²θ±0.1°²θ and at least four peaks selected from the group consisting of 10.0, 11.7, 14.6, 15.7, 16.2, 17.5, 20.0, 22.5, 25.7, 26.2 and 29.2°²θ (±0.1°²θ).

[0229] In some embodiments, the purified crystalline form (Type A) has an X-ray powder diffraction pattern that includes a peak at 18.8°²θ±0.1°²θ and at least eight peaks selected from the group consisting of 10.0, 11.7, 14.6, 15.7, 16.2, 17.5, 20.0, 22.5, 25.7, 26.2 and 29.2°²θ (±0.1°²θ).

[0230] In some embodiments, the purified crystalline form (Type A) has an X-ray powder diffraction pattern containing peaks at 10.0, 11.7, 14.6, 15.7, 16.2, 17.5, 18.8, 20.0, 22.5, 25.7, 26.2 and 29.2°²θ (±0.1°²θ).

[0231] In some embodiments, the XRPD pattern includes at least four, five, six, seven, eight, nine, ten, or eleven peaks selected from the above group. In some embodiments, the crystalline solid has an X-ray powder diffraction pattern substantially as shown in Figure 1A.

[0232] In some embodiments, the refined crystalline form (Type A) has an orthorhombic system. In some embodiments, the crystalline solid has a simple Bravais lattice. In some embodiments, the crystalline solid has a P212121 space group.

[0233] In some embodiments, the purified crystalline form (Type A) has an orthorhombic system. In some embodiments, the crystalline solid has unit cell parameters of approximately a=9.47 Å, b=12.09 Å, c=12.70 Å, α=90.00°, β=90.00°, and γ=90.00° at approximately 25°C.

[0234] In some embodiments, the purified crystalline form (Form A) is at least 90% by weight of Form A. In some embodiments, the purified crystalline form (Form A) is at least 91% by weight, 92% by weight, 93% by weight, 94% by weight, 95% by weight, 96% by weight, 97% by weight, 98% by weight, 99% by weight, or 99.6% by weight of Form A.

[0235] In one embodiment, this specification provides a method for producing a crystalline solid of type A, the method comprising recrystallizing (S)-3-isopropyl-6-((1-phenylethyl)amino)-pyrimidine-2,4(1H,3H)-dione in ethanol or an ethanol / water mixture to form a crystalline solid of type A. In another embodiment, the method further comprises adding a seed crystal of type A. In yet another embodiment, the method further comprises stirring the slurry of the crystalline solid at an internal temperature of about 5°C to about 10°C for about 24 hours. In yet another embodiment, the method further comprises washing the solid recrystallization product with methyl tert-butyl ether. In yet another embodiment, the solid comprises less than 2% by weight of other crystalline forms.

[0236] In one embodiment, this specification provides a method for producing mabacamten, the compound of structure II: [ka] This was reacted with POCl3 in the presence of acetonitrile to form a compound of structure III: [ka] To form; and The compound of structure III is heated with (S)-1-phenylethaneamine to obtain mabacamten: [ka] This includes forming.

[0237] In one embodiment, this specification provides a method for preparing mabacamten as described above, the method further including a method for producing a crystalline solid in the single-crystal form (e.g., type A) as described herein.

[0238] In some embodiments, the myosin inhibitor is a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, in the formula, R 1 Fluoro, chloro, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, or C 2~4 It is an alkynyl, where at least one R 1 is fluoro, and R 2a and R 2b One of them is fluoro, and R 2a and R 2b The other side is H.

[0239] In some embodiments, the myosin inhibitor of formula (II) or a pharmaceutically acceptable salt thereof is [ka] It is selected from group (II) consisting of the following.

[0240] Myosin inhibitors of formula (II), comprising compounds of group (II) or pharmaceutically acceptable salts thereof, can be obtained by means of a method described in International Application PCT / US2019 / 058297, filed October 29, 2019 (which is incorporated herein by reference in its entirety for all purposes).

[0241] In some embodiments, the myosin inhibitor is a compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof, in the formula, G1 is -C 4 R 5 -or -O-; G2 is a combination or -C 6 R 7 -and; G3 is -C 8 -or -N-; R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 Each of these is independently H, C1-C6 alkyl, halo, or hydroxyl; R 2 is H, C2-C6 alkyl, halo, or hydroxyl; Z is a bond, C1-C6 alkyl, -O-, -N(R) 9 )-,-R X O-, -OR Y , or -R Z It is S-; R 9 is H, C1-C6 alkyl, or cycloalkyl; A is selected from the group consisting of substituted C2 alkynyls, unsubstituted C2 alkynyls, substituted phenyls, unsubstituted phenyls, and 5-membered or 6-membered heteroaryls containing at least one cyclic N atom, where the 5-membered or 6-membered heteroaryl is unsubstituted or has one or more R 10 Substituting with a substituent; Each R 10 These are independently substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C2-C6 alkenyl groups, substituted or unsubstituted C2-C6 alkynyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocycloalkyl groups, or C(O)OR groups. a and; B is selected from the group consisting of H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, where the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl of B is either unsubstituted or has one or more R 11 Substituting with a substituent; Each R 11 This includes substituted or unsubstituted heterocycloalkyls, substituted or unsubstituted heteroaryls, substituted or unsubstituted cycloalkyls, substituted or unsubstituted aryls, unsubstituted C1-C6 alkyls, and one or more R 12 Substituent-substituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, halo, -OR b , -C(O)R c , -C(O)OR d , oxo, and -NR e R f Independently selected from the group consisting of; Each R 12 is, halo, -OR b , -C(O)R g , -C(O)OR h , and -C(O)NR i R j Independently selected from the group consisting of; Each R a , R b , R c , R d , R e , R f , R g , R h , R i , and R j These are independently H or C1-C6 alkyl groups; R X , R Y , and R Z These are C1-C6 alkyl groups, respectively.

[0242] In some embodiments, the myosin inhibitor of formula (III) or a pharmaceutically acceptable salt thereof is [ka] It is selected from group (III) consisting of the following.

[0243] Myosin inhibitors of formula (III), comprising compounds of group (III) or pharmaceutically acceptable salts thereof, can be obtained by means of a method described in international application WO2019 / 144041, filed July 25, 2019 (which is incorporated herein by reference in its entirety for all purposes).

[0244] In some embodiments, the myosin inhibitors include compounds disclosed in PCT patent applications published as WO2020 / 005887, WO2020 / 005888, and WO2020 / 047447 (the entirety of which is incorporated herein by reference for all purposes).

[0245] In some embodiments, compounds of formulas (I), (II), (III), and / or compounds of group (I), (II), (III), and / or mabacamten and / or MYK-581 are administered orally.

[0246] In some embodiments, the compounds of formulas (I), (II), and (III), and / or the compounds of group (I), (II), and (III), and / or mabacamten, and / or MYK-581 are administered in unit doses.

[0247] In some embodiments, mabacamten and / or MYK-581 are administered in daily doses of 1 mg, 2 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, or 15 mg.

[0248] In some embodiments, mabacamten and / or MYK-581 are administered daily in doses of 1 mg, 2 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, or 15 mg for 4, 8, 12, 18, 24, 30, 36, 48, or 56 weeks.

[0249] In some embodiments, mabacamten and / or MYK-581 are administered daily at an initial therapeutic dose of 2.5 mg per day, which may be optionally increased to 5 mg per day if certain conditions are met.

[0250] In some embodiments, mabacamten and / or MYK-581 are administered daily as maintenance therapy in doses of 1 mg, 2 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, or 15 mg for at least one, two, three, five years or longer, or as determined by a physician.

[0251] In some embodiments, the daily dose in maintenance therapy including mabacamten is less than 7.5 mg.

[0252] In some embodiments, the daily dose in maintenance therapy including mabacamten is less than 5 mg.

[0253] In some embodiments, the daily dose in maintenance therapy including mabacamten is 2 mg to 2.5 mg.

[0254] The term "maintenance therapy" refers to a treatment regimen designed to support the success of primary treatment. For example, maintenance therapy may be administered to individuals who have fully or partially recovered cardiac function after primary treatment to prevent, delay, or reduce the likelihood of disease recurrence or progression. Maintenance therapy may be administered over any period, including long-term periods up to the patient's lifespan. Maintenance therapy may be administered after primary treatment or in conjunction with additional therapy. The dosage used in maintenance therapy may vary and may include lower-intensity dosages compared to those used in primary treatment.

[0255] The term "primary therapy" refers to the initial treatment administered to a patient based on a diagnosis of their cardiac dysfunction.

[0256] In some embodiments, the therapeutically effective dose of mabacamten and / or MYK-581 for initiation treatment is approximately 5 mg, 7.5 mg, 10 mg, or 15 mg.

[0257] In some embodiments, a daily dose of 5 mg, 7.5 mg, 10 mg, or 15 mg of mabacamten and / or MYK-581 is sufficient to reduce the post-exercise or resting LVOT gradient to less than 30 mmHg (e.g., approximately 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). The post-exercise (load) LVOT gradient can be measured by any method known in the art.

[0258] In some embodiments, therapeutically effective doses of mavacamten and / or MYK-581 at daily doses of 5 mg, 7.5 mg, 10 mg, or 15 mg are sufficient to improve, stabilize, or delay exacerbations according to the New York Heart Association (NYHA) functional classification of the subject.

[0259] The NYHA functional classification categorizes the severity of heart failure symptoms into one of four functional classifications. The NYHA functional classification is widely used in clinical practice and research because it provides a standardized description of severity that can be used to guide the assessment and management of response to treatment. Based on the severity of symptoms and physical activity, the NYHA functional classification is as follows: • Grade I: No limitations on physical activity. No excessive shortness of breath, fatigue, or palpitations occur during normal physical activity. • Grade II: There is a mild limitation in physical activity. There are no symptoms at rest, but excessive shortness of breath, fatigue, or palpitations occur with normal physical activity. • Grade III: There is a severe limitation of physical activity. There are no symptoms at rest, but excessive shortness of breath, fatigue, or palpitations occur with physical activity below normal levels. • Grade IV: Symptoms are present with any physical activity. Symptoms may be present even at rest. Symptoms worsen with any physical activity.

[0260] In some embodiments, after administration of compounds of formula (I), (II), (III), and / or compounds of group (I), (II), (III), and / or mabacamten, and / or MYK-581, the NYHA functional classification is reduced from grade IV to grade III, from grade IV to grade II, or from grade IV to grade I. In some embodiments, the NYHA functional classification is reduced from grade III to grade II. In some embodiments, the NYHA functional classification is reduced from grade III to grade I. In some embodiments, the NYHA functional classification is reduced from grade II to grade I.

[0261] In some embodiments, therapeutically effective doses of compounds of formula (I), (II), (III), and / or compounds of group (I), (II), (III), and / or mabacamten and / or MYK-581 improve, stabilize, or delay deterioration in the New York Heart Association (NYHA) functional classification of the subject.

[0262] In some embodiments, therapeutically effective amounts of compounds of formula (I), (II), (III), and / or compounds of group (I), (II), (III), and / or mabacamten and / or MYK-581 improve maximum VO2.

[0263] In some embodiments, therapeutically effective amounts of compounds of formulas (I), (II), (III), and / or compounds of group (I), (II), (III), and / or mabacamten and / or MYK-581 improve VE / VCO2 or VE / VCO2 slope. In some embodiments, the subject has a VE / VCO2 of 34 or more. In some embodiments, the improvement includes reducing VE / VCO2 to 34 or less.

[0264] In some embodiments, therapeutically effective amounts of compounds of formula (I), (II), (III), and / or compounds of group (I), (II), (III), and / or mabacamten, and / or MYK-581 reduce the level of the target NT-proBNP or BNP (e.g., by a statistically significant amount or percentage).

[0265] In some embodiments, therapeutically effective amounts of compounds of formula (I), (II), (III), and / or compounds of group (I), (II), (III), and / or mabacamten, and / or MYK-581 reduce the level of the target cardiac troponin (e.g., cTnI, cTnT, hs-cTnI, or hs-cTnT) (e.g., by a statistically significant amount or percentage).

[0266] In some embodiments, the method of treating a subject with a myosin modulator (e.g., mabacamten) as described herein results in improvement of one or more clinical endpoints, e.g., one or more functional endpoints or one or more outcome endpoints. In some embodiments, the improved clinical endpoints are symptoms selected from the group consisting of shortness of breath (e.g., measured by a change in the dyspnea index), fatigue (e.g., measured by a change in maximal VO2 or NYHA classification), palpitations (e.g., measured by a change in atrial fibrillation), chest discomfort, edema, and early mortality, or any combination thereof. In some embodiments, the improved clinical endpoints are functional endpoints selected from the group consisting of maximal VO2, VE / VCO2, VE / VCO2 slope, 6-minute walk test, KCCQ subscore, Canadian Cardiovascular Society chest pain score, and Seattle angina score, or any combination thereof. In some embodiments, the improved clinical outcome measure is selected from a group consisting of a reduction in mortality, a reduction in hospitalization or readmission, a reduction in major cardiovascular events (MACE), a reduction in atrial fibrillation, and a reduction in atrial fibrillation embolic events, or any combination thereof. In some embodiments, the improvement is a change from baseline (e.g., increase or decrease) in either a percentage or a volume. In other embodiments, the improvement is the achievement of an absolute threshold.

[0267] In some embodiments, therapeutically effective amounts of compounds of formula (I), (II), (III), and / or compounds of group (I), (II), (III), and / or mabacamten, and / or MYK-581 improve, stabilize, or delay exacerbation according to the Kansas City Cardiomyopathy Questionnaire (KCCQ) score.

[0268] In some embodiments, therapeutically effective amounts of compounds of formulas (I), (II), (III), and / or compounds of group (I), (II), (III), and / or mabacamten and / or MYK-581 improve LV wall hypertrophy, for example, by volume increase, i.e., LVEDV increase.

[0269] The KCCQ is a 23-item self-report questionnaire developed to independently measure an individual's perception of their own health status, with heart failure affecting the subject's quality of life (QOL) over a two-week recall period. The KCCQ allows for the deriving of an overall summary score from the domains of physical function, symptoms (frequency and severity), social functioning, and quality of life. The score is converted to a range of 0-100, with higher scores reflecting better health status.

[0270] In some embodiments, the therapeutically effective dose of a compound of formula (II) or group (II) is a daily dose sufficient to reduce the LVOT gradient to less than 30 mm / Hg. A dose reduction regimen or low dose may be half to one-fifth of the daily dose.

[0271] In some embodiments, the therapeutically effective dose of a compound of formula (III) or group (III) is a daily dose sufficient to reduce the LVOT gradient to less than 30 mm / Hg. The dose reduction regimen may be half to one-fifth of the daily dose.

[0272] Some of the symptoms and signs that individuals with HCM may have include, but are not limited to, shortness of breath (especially during exercise), chest pain (especially during exercise), fainting (especially during or immediately after exercise), a sense of a rapid, pounding, or violent heartbeat, and heart murmurs.

[0273] Individuals with HCM can be subdivided based on the presence or absence of left ventricular outflow tract (LVOT) obstruction. The presence of LVOT obstruction, i.e., obstructive HCM (oHCM), is associated with more severe symptoms and an increased risk of heart failure and cardiovascular death. Limited data support medical treatments (beta-blockers, calcium channel blockers, disopyramide) in this subset of subjects, and those with persistent symptoms may be referred for invasive septal reduction therapy.

[0274] Individuals without outflow tract obstruction at rest or on elicited response, i.e., non-obstructive HCM (nHCM), account for approximately one-third of HCM patients receiving medical treatment. Patients without LVOT obstruction generally complain of dyspnea and / or angina and may progress to progressive heart failure. The underlying pathophysiology of nHCM patients is a hyperconstrictive, rigid ventricle that leads to impaired diastolic function and elevated filling pressure.

[0275] Non-obstructive high blood pressure (nHCM) is often clinically characterized by a pressure gradient of less than 30 mmHg across the entire LVOT in individuals at rest, during or immediately after the Valsalva maneuver, or after exercise.

[0276] In some embodiments, individuals having nHCM have an LVOT pressure gradient of less than 25 mmHg or less than 20 mmHg.

[0277] In some embodiments, the pressure gradient across the entire LVOT is measured at rest. In some embodiments, the pressure gradient across the entire LVOT of an individual is measured during or immediately after the Valsalva maneuver is performed. In some embodiments, the pressure gradient across the entire LVOT of an individual is measured after exercise.

[0278] Currently, there are no FDA-approved medical therapies for patients with symptomatic nHCM, and apart from heart transplantation, there are no available interventional options. Therefore, novel therapies are needed for patients with nHCM.

[0279] In some embodiments, the disclosure provides a method for administering mabacamten or a pharmaceutically acceptable salt thereof to a subject suffering from nHCM.

[0280] In some embodiments, the method involves administering an initial dose of mabacamten or a pharmaceutically acceptable salt thereof. The initial dose may be about 1 mg to about 10 mg, for example, about 5 mg.

[0281] In some embodiments, the initial dose is escalated to higher doses. For example, the initial dose may be administered over an initial treatment period of at least 4 weeks, at least 6 weeks, at least 8 weeks, 6–14 weeks, 8–12 weeks, or about 10 weeks, and then escalated to higher doses.

[0282] In some embodiments, the initial dose administered to subjects with nHCM is gradually increased to a higher dose based on the measurement of the subject's NT-proBNP or BNP levels, or on changes in NT-proBNP or BNP levels.

[0283] In some embodiments, if NT-proBNP does not decrease by at least 20–60% (e.g., at least 30–50%, or at least 40%) during treatment with the first dose during the initial treatment period, the initial dose is gradually increased to a higher dose.

[0284] In some embodiments, if NT-proBNP does not decrease by at least 20–60% (e.g., at least 30–50%, or at least 40%) during treatment with the first dose during the initial treatment period, and NT-proBNP exceeds 125–400 pg / mL, e.g., 300 pg / mL, the initial dose is escalated to a higher dose. In some embodiments, NT-proBNP or BNP levels are measured 6–10 weeks (e.g., about 8 weeks) after the initial dose administration.

[0285] In some embodiments, if NT-proBNP decreases by 40% or more, treatment is continued at the initial dose without escalation. In some embodiments, higher doses are approximately 2.5 mg to approximately 20 mg (e.g., approximately 5 mg to approximately 15 mg, or approximately 10 mg).

[0286] In some embodiments, a higher dose or a continued initial dose is administered to subjects who have nHCM during the second treatment period. In some embodiments, the dose during the second treatment period is escalated to a higher dose based on the measurement of the subject's NT-proBNP or BNP levels, or changes in NT-proBNP or BNP levels. In some embodiments, if NT-proBNP does not decrease by at least 20–60% (e.g., at least 30–50%, or at least 40%) during treatment during the initial and second treatment periods, and NT-proBNP exceeds 125–400 pg / mL, e.g., 300 pg / mL, the dose during the second treatment period is escalated to a higher dose.

[0287] In some embodiments, if, after treatment during the first and second treatment periods, NT-proBNP exceeds 400-600 pg / mL (e.g., exceed 500 pg / mL) and the NYHA class is 3, the dose for the second treatment period is gradually increased to a higher dose.

[0288] In some embodiments, a method of administering mabacamten or a pharmaceutically acceptable salt thereof to a subject suffering from nHCM may include tapering of the initial dose if the LVEF decreases during treatment, for example, if the LVEF is less than 80-90% of baseline (e.g., less than 85%) or if the LVEF is less than 55%. In some embodiments, the method may include tapering of the initial dose if NT-proBNP or BNP increases during treatment, for example, if the increase is greater than 20-40% (e.g., greater than 30%).

[0289] Diastolic dysfunction is the presence or a key feature of a range of diseases, including but not limited to hypertrophic cardiomyopathy (HCM), heart failure with preserved ejection fraction (HFpEF), and left ventricular hypertrophy (LVH) (including both impaired active relaxation and impaired ventricular stiffness (diabetic HFpEF)). Diastolic dysfunction may be diagnosed using one or more techniques and measurements, including invasive procedures such as catheterization, E / e', left atrial size, and BNP or NT-proBNP.

[0290] Ejection fraction is an indicator of normal or hypercontractile systolic function. Specifically, the ejection fraction is approximately 52% or greater than 50% in subjects with normal or hypercontractile systolic function.

[0291] LVH, characterized by wall thickness, can be diagnosed using one or more techniques and measurements, including echocardiography, cardiac MRI, non-invasive imaging techniques (e.g., tissue Doppler imaging), and E / e'.

[0292] Subjects requiring treatment for diastolic dysfunction include those from patient populations characterized by nHCM, LVH, or HFpEF. Subjects requiring treatment for diastolic dysfunction also include those exhibiting left ventricular stiffness measured by echocardiography or left ventricular stiffness measured by magnetic resonance imaging.

[0293] In some embodiments, subjects requiring treatment for diastolic dysfunction are from the HFpEF patient population. In some embodiments, subjects from the HFpEF patient population have been diagnosed with HCM. In some embodiments, subjects from the HFpEF patient population have not been diagnosed with HCM.

[0294] In some embodiments, subjects with HFpEF have an ejection fraction of 50% or more and evidence of diastolic dysfunction. Diastolic dysfunction includes impaired left ventricular relaxation, filling, diastolic extensibility, or stiffness. These features can be measured using echocardiography. In some embodiments, the following echocardiographic values ​​are observed: septal e' < 7 cm / sec; lateral e' < 10 cm / sec, mean E / e' ratio > 14; LA volume coefficient > 34 mL / m². 2 A subject is considered to have a dysfunction if at least one of the following conditions is met: maximum TR speed > 2.8 m / sec. In some embodiments, a subject is considered to have a dysfunction if at least three of the above values ​​are met.

[0295] In some embodiments, subjects requiring treatment for diastolic dysfunction are from the HCM patient population. In some embodiments, subjects from the HCM patient population have been diagnosed with HFpEF. In some embodiments, subjects from the HCM patient population have not been diagnosed with HFpEF.

[0296] In some embodiments, subjects requiring treatment for diastolic dysfunction present with left ventricular stiffness as measured by echocardiography. A subject is considered to have left ventricular stiffness as measured by echocardiography if at least one of the following characteristics is met: mitral valve E / A ratio > 0.8; septal e' < 7 cm / sec; lateral wall e' < 10 cm / sec, mean E / e' ≥ 14; LA volume coefficient > 34 mL / m2; maximum TR velocity > 2.8 m / sec. In some embodiments, a subject is considered to have left ventricular stiffness if at least three of the above values ​​are met.

[0297] Further determinants for the diagnosis of diastolic dysfunction using echocardiography are described in J Am Soc Echocardiogr. 29(4):277-314 (2016), and their contents are incorporated herein for all purposes.

[0298] In some embodiments, subjects requiring treatment for diastolic dysfunction exhibit left ventricular stiffness as measured by cardiac magnetic resonance (CRR). CRR is used to determine the maximum filling velocity, time to reach maximum filling velocity, and maximum diastolic strain rate. Therefore, in some embodiments, subjects have left ventricular stiffness as measured by CMR if at least one of the following is met: abnormal maximum filling velocity, time to reach maximum filling velocity, or maximum diastolic strain rate.

[0299] In some embodiments, patients requiring treatment for diastolic dysfunction are those suffering from diastolic dysfunction, left ventricular hypertrophy, left ventricular outflow tract obstruction, increased left ventricular wall thickness (or weight coefficient), increased interventricular septal (IVS) wall thickness, poor or reduced myocardial elasticity, poor or reduced diastolic left ventricular relaxation, abnormally high left atrial pressure, reduced E / e' ratio, decreased exercise capacity or tolerance, decreased maximal oxygen consumption (VO2), increased left ventricular diastolic pressure, or any combination thereof.

[0300] In some embodiments, subjects requiring treatment for diastolic dysfunction suffer from hypertrophic cardiomyopathy (HCM) characterized by at least one biomarker selected from elevated NT-proB natriuretic peptide (NT-proBNP) and elevated cardiac troponin I. In other embodiments, subjects with HCM requiring treatment for diastolic dysfunction have a predisposition to developing HCM.

[0301] In some embodiments, subjects requiring treatment for diastolic dysfunction are suffering from chest pain, shortness of breath, angina, syncope, or dizziness.

[0302] In some embodiments, the total daily dose is adjusted according to the requirements of the individual subject. For example, the total daily dose may be adjusted according to the subject's response profile 4 to 16 weeks after initiation of therapy with the compounds of formulas (I), (II), (III), and / or groups (I), (II), (III), and / or mabacamten and / or MYK-581 (e.g., 4, 5, 6, 7, 8, 8, 10, 11, 12, 13, 14, 15, 16 weeks, or any number of days in between). In some embodiments, the total daily dose is reduced if the subject's New York Heart Association (NYHA) functional classification declines.

[0303] In some embodiments, if the New York Heart Association (NYHA) functional classification of the subject does not decrease or worsens, the total daily dose of mavacamten is increased.

[0304] In some embodiments, the individual subject requirements used to adjust the total daily dose are the subject's resting left ventricular ejection fraction and maximum resting left ventricular outflow tract (LVOT) gradient. As a non-limiting example, in some embodiments, the total daily dose of mavacamten is 5 mg, and this dose is increased if the subject's resting left ventricular ejection fraction (LVEF) is 55% or greater and the maximum resting left ventricular outflow tract (LVOT) gradient is 30 mmHg or greater.

[0305] In some embodiments, the total daily dose of mavacamten is increased to 7.5 mg when the subject's resting left ventricular ejection fraction (LVEF) is 55% or greater and the maximum resting left ventricular outflow tract (LVOT) gradient is greater than 30 mmHg but less than 50 mmHg.

[0306] In some embodiments, the total daily dose of mavacamten is increased to 10 mg when the subject's resting left ventricular ejection fraction (LVEF) is 55% or greater and the maximum gradient of the resting left ventricular outflow tract (LVOT) is 50 mmHg or greater.

[0307] In some embodiments, the therapeutically effective dose of compounds of formula (I), (II), (III), and / or compounds of group (I), (II), (III), and / or mabacamten and / or MYK-581 can be adjusted according to the target left ventricular ejection fraction (LVEF) level.

[0308] In some embodiments, the methods provided herein also include measuring the left ventricular ejection fraction (LVEF) of the subject before administering the compounds of formula (I), (II), (III), and / or the compounds of group (I), (II), (III), and / or mabacamten, and / or MYK-581, thereby providing a first LVEF value (baseline).

[0309] In some embodiments, the methods provided herein also include measuring the LVEF of the subject after a certain 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 compounds of formulas (I), (II), (III), and / or groups (I), (II), (III), and / or mabacamten and / or MYK-581, thereby providing a second LVEF value, and calculating the percentage change of the second LVEF value compared to the first LVEF value. Thus, in some embodiments, the total daily dose is adjusted according to the percentage change in LVEF. Optimally, the LVEF is maintained within the normal range.

[0310] In some embodiments, the second LVEF is measured 4 weeks after administration of compounds of formula (I), (II), (III), and / or compounds of group (I), (II), (III), and / or mabacamten and / or MYK-581.

[0311] In some embodiments, a therapeutically effective dose of a compound of formula (I), (II), or (III), and / or a compound of group (I), (II), or (III), and / or mabacamten, and / or MYK-581, can be adjusted according to the cardiac troponin I level of the subject. Cardiac troponin I levels can be measured by any method known to those skilled in the art, or by clinically validated assays, such as Abbott's ARCHITECT Stat Troponin-I 2K41 assay or Siemens' Advia Centur® High Sensitivity Troponin I (TNIH) assay. Cardiac troponin T levels can be measured by any method known to those skilled in the art, or by Roche's Elecsys Troponin T hs assay. BNP levels can be measured by any one of the methods known to those skilled in the art, or by ADVIA Centaur XPT / XP / CP Immunoassay System.

[0312] In some embodiments, the therapeutically effective amount of a compound of formula (I), (II), or (III), and / or a compound of group (I), (II), or (III), and / or mabacamten, and / or MYK-581, can be adjusted according to the target NT-proBNP or BNP level. The target NT-proBNP level can be measured by any method known to those skilled in the art, or according to the procedure described in Roche's Elecsys proBNPII Immunoassay.

[0313] In some embodiments, the compound of formula (I), (II), or (III), and / or the compound of group (I), (II), or (III), and / or mabacamten, and / or MYK-581 is administered to a subject suffering from hypertrophic cardiomyopathy (HCM) characterized by at least one biomarker selected from elevated B-type natriuretic peptide (BNP), elevated NT-proB-type natriuretic peptide (NT-proBNP), and elevated cardiac troponin I, or a combination thereof. In yet another embodiment, the subject further has a predisposition to developing HCM.

[0314] In some embodiments, the therapeutically effective dose can be adjusted according to the plasma concentration of the compounds of formula (I), (II), (III), and / or the compounds of group (I), (II), (III), and / or mabacamten and / or MYK-581.

[0315] In some embodiments, the method also includes measuring the plasma concentrations of compounds of formula (I), (II), (III), and / or compounds of group (I), (II), (III), and / or mabacamten and / or MYK-581 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 the compound.

[0316] In some embodiments, the therapeutically effective dose can be adjusted based on “trough” measurements. A “trough” measurement (either concentration or any pharmacodynamic measurement) refers to the measurement obtained immediately before the next dose. For example, for once-daily (QD) dosing, trough measurements are obtained every 24 hours immediately before the subject takes the next dose (typically a tablet or capsule). For pharmacokinetic reasons, these measurements are used as a way to standardize the assessment and minimize variability. When an individual “achieves and maintains” a particular plasma concentration of a compound, that individual’s trough measurements will not fall below the minimum reference level or exceed the maximum reference level.

[0317] In some embodiments, the drug dosage decision may also be based on the individual's ability to metabolize the compounds of formulas (I), (II), (III), and / or the compounds of group (I), (II), (III), and / or mabacamten and / or MYK-581. In some embodiments, a lower starting dose is administered to the low metabolite.

[0318] In some embodiments, low metabolites of mabacamtene may include individuals possessing the CYP2C19 polymorphic enzyme. Low metabolites of mabacamtene may be administered a lower starting dose, and / or the dose may be adjusted to a lower amount, such as 1 mg per day.

[0319] In some embodiments, a low metabolite of mabacamten is administered at an initial daily dose of 2.5 mg, and if the trough level of mabacamten in the individual's serum exceeds the desired maximum level, the daily dose may be adjusted down to 1 mg.

[0320] In some embodiments, a low metabolite of mabacamten is administered at an initial daily dose of 5 mg, and if the trough measurement of mabacamten in the individual's serum exceeds the desired maximum level, the daily dose may be adjusted down to 2.5 or 2 mg.

[0321] In some embodiments, a low metabolite of mabacamten is administered at an initial daily dose of 7.5 mg, and if the trough level of mabacamten in the individual's serum exceeds the desired maximum level, the daily dose may be adjusted down to 5 mg.

[0322] In some embodiments, the low metabolite of mabacamten is associated with Asian descent due to the CYP2C19 polymorphism enzyme. In some embodiments, the low metabolite of mabacamten is associated with South Asian descent. In some embodiments, Asian descent includes, but is not limited to, the Japanese, Chinese, Thai, Korean, Filipino, Indonesian, and Vietnamese populations.

[0323] In some embodiments, Asian individuals possessing the CYP2C19 polymorphic enzyme may be administered at a lower initial starting dose, and / or the dose may be adjusted to a lower amount, such as 1 mg per day. In some embodiments, the initial daily dose is approximately 2.5 mg, and the dose may be adjusted down to 1 mg per day. In some embodiments, the initial daily dose is approximately 5 mg, and the dose may be adjusted down to 2.5 mg or 2 mg per day.

[0324] In some embodiments, the treatment may include the steps of: obtaining a biological sample from the patient or determining whether the patient has a CYP2C19 hypometabolite; performing or completing a genotyping assay on the biological sample to determine whether the patient has a CYP2C19 hypometabolite genotype; and, if the patient has a CYP2C19 hypometabolite genotype, administering the patient a low dose of mavacamten, such as less than 5 mg per day (e.g., 5 mg, 2.5 mg, 2 mg, or 1 mg / day); and if the patient does not have a CYP2C19 hypometabolite genotype, administering the patient a dose of mavacamten ranging from about 5 mg to about 15 mg, up to a maximum of 50 mg / day.

[0325] In some embodiments, this specification provides a method for treating a patient with hypertrophic cardiomyopathy (HCM) in a low metabolite of mabacamten, comprising administering an initial dose of mabacamten at a dose of 2.5 mg per day to the patient, and dose-setting subsequent doses based on the patient's pharmacokinetic measurements and / or LVOT gradient.

[0326] In some embodiments, the subsequent dose is based on the plasma concentration of the subject mabacamtene. In some embodiments, the subsequent dose is based on the subject's body weight. In some embodiments, the subsequent dose is based on both the plasma concentration of the subject mabacamtene and the subject's body weight.

[0327] In some embodiments, the subsequent dose is 1 mg. In some embodiments, the subsequent dose is 5 mg, 10 mg, or 15 mg.

[0328] In some embodiments, the low metabolite of mabacamtene has a CYP2C19 low metabolite genotype. * 2 / * 2. * 2 / * 3, or * 3 / * It has three genotypes.

[0329] In some embodiments, the low metabolic type of mabacamten is of Asian descent. In some embodiments, the low metabolic type of mabacamten is of Japanese descent.

[0330] In some embodiments, subsequent doses are administered to maintain the plasma concentration of the subject mavacamten at 350–700 ng / mL. In some embodiments, if the plasma concentration of the subject mavacamten exceeds 700 ng / mL after administration of the initial dose, the subsequent dose is approximately 1 mg. In some embodiments, if the plasma concentration of the subject mavacamten falls below 350 ng / mL after administration of the initial dose, and the Valsalva gradient of the subject after administration is 30 mmHg or higher, the subsequent dose is approximately 5 mg.

[0331] In some embodiments, the HCM is an occlusive HCM (oHCM).

[0332] In some embodiments, this method reduces the risk of adverse events in subjects with a low metabolism of mabacamten. In some embodiments, this method reduces the risk of systolic dysfunction in subjects with a low metabolism of mabacamten.

[0333] In some embodiments, this specification provides a method for treating a subject HCM that is of Asian descent, comprising administering a starting dose of mavacamten at an amount of 2.5 mg per day to the subject; and dose-setting for subsequent doses based on the subject's pharmacokinetic measurements and / or LVOT gradient.

[0334] In some embodiments, the subsequent dose is based on the plasma concentration of the subject mabacamtene. In some embodiments, the subsequent dose is based on the subject's body weight. In some embodiments, the subsequent dose is based on both the plasma concentration of the subject mabacamtene and the subject's body weight.

[0335] In some embodiments, the subsequent dose is 1 mg. In some embodiments, the subsequent dose is 5 mg, 10 mg, or 15 mg.

[0336] In some embodiments, the subsequent dose is administered to maintain the subject's plasma concentration of mabacamten at 350–700 ng / mL. In some embodiments, if the subject's body weight is less than 45 kg or less than 50 kg, the subsequent dose is approximately 1 mg. In some embodiments, if the subject's body weight is greater than 70 kg, the subsequent dose is approximately 5 mg.

[0337] In some embodiments, the HCM is an occlusive HCM (oHCM).

[0338] In some embodiments, the Asian person is of Japanese descent.

[0339] In some embodiments, people of Asian descent include Japanese, Chinese, Thai, Korean, Filipino, Indonesian, and Vietnamese.

[0340] Pharmaceutical composition Pharmaceutical compositions for the administration of compounds of formulas (I), (II), (III), and / or compounds of group (I), (II), (III), and / or mabacamten, and / or MYK-581 or pharmaceutically acceptable salts thereof can be conveniently presented in unit dosage forms and can be prepared by any method known in the fields of pharmacy and drug delivery. All methods involve the step of combining the active ingredient with a carrier containing one or more auxiliary components. Generally, pharmaceutical compositions are prepared by uniformly and homogeneously combining the active ingredient with a liquid carrier or a fine powder solid carrier, or both, and then, if necessary, shaping the product into the desired formulation. In pharmaceutical compositions, the activator is generally included in an amount sufficient to produce the desired effect on myocardial contractility (i.e., reduce the hypernormal systolic contractility that often occurs in HCM) and improve left ventricular relaxation in diastolic state. Such improvement in relaxation can alleviate the symptoms of hypertrophic cardiomyopathy and other pathogenesis of diastolic dysfunction. The pharmaceutical composition can also mitigate the effects of diastolic dysfunction causing impaired coronary blood flow and improve impaired coronary blood flow as an adjunct agent in angina pectoris and ischemic heart disease. The pharmaceutical composition can also provide benefits against harmful left ventricular remodeling in HCM and other causes of left ventricular hypertrophy resulting from chronic volume overload or pressure overload (e.g., from valvular heart disease or systemic hypertension).

[0341] Pharmaceutical compositions containing compounds of formulas (I), (II), (III), and / or compounds of group (I), (II), (III), and / or mabacamten and / or MYK-581 or pharmaceutically acceptable salts thereof may take the form of tablets, 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 may be prepared according to any method known in the art relating to the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, colorants, antioxidants, and preservatives to provide pharmaceutically refined and palatable preparations. Tablets contain the active ingredient in a mixture with pharmaceutically acceptable non-toxic excipients suitable for the manufacture of tablets. Such excipients may include, for example, inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, or sodium phosphate; granulators and disintegrants 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 coated by known methods, enterically coated, or otherwise, to provide a sustained effect over a long period by delaying breakdown and absorption in the gastrointestinal tract. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used. They may also be coated to form osmotic therapeutic tablets for controlled release.

[0342] Formulations for oral use may be presented as rigid gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as flexible gelatin capsules in which the active ingredient is mixed with a water or oil medium, such as peanut oil, liquid paraffin, or olive oil. Furthermore, emulsions can be prepared using water-immiscible components such as oils and stabilized with surfactants such as monodiglycerides and PEG esters.

[0343] In some embodiments, compounds of formulas (I), (II), (III), and / or compounds of group (I), (II), (III), and / or mabacamten, and / or MYK-581 can be used in the form of pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids.

[0344] Pharmaceutical dosage forms This disclosure includes novel pharmaceutical dosage forms of mabacamtene or pharmaceutically acceptable salts thereof. The dosage forms described herein are suitable for oral administration to subjects. The dosage forms may be any form suitable for oral administration, including but not limited to capsules or tablets. In some embodiments, this disclosure provides capsule or tablet forms in single unit doses containing 1 to 25 mg (e.g., 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 mg) of mabacamtene or a pharmaceutically acceptable salt thereof. In some embodiments, the amount of mabacamtene in a unit dose is about 2 to 5 mg, about 5 to 10 mg, about 2.5 mg, or about 5 mg. In some embodiments, the single unit dosage form is a capsule. In some embodiments, the single unit dosage form is a tablet.

[0345] Combination therapy This disclosure provides both monotherapy and combination therapy with myosin inhibitors. In combination therapy, the myosin inhibitor regimens of this disclosure are used in combination with additional therapy regimens, such as standard of care (SOC) therapy for the patient's cardiac condition or other therapies useful for treating related diseases or disorders. The additional therapeutic agents may be administered in the routes and amounts commonly used with the above-mentioned agents, or at reduced doses, and may be administered simultaneously, sequentially, or in parallel with the myosin inhibitors.

[0346] In certain embodiments, the myosin inhibitor may be another therapeutic agent, such as beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor antagonists (e.g., angiotensin II receptor blockers), angiotensin receptor neprilysin inhibitors (ARNIs) (e.g., sacubitril / valsartan), mineralocorticoid receptor antagonists (e.g., aldosterone inhibitors, potassium-sparing diuretics such as eplerenone, spironolactone, or canrenone), cholesterol-lowering agents (e.g., statins), neutral endopeptidase inhibitors (NEPi), and positive inotropic agents (e.g., digoxin, pimobendan). It is administered with beta-adrenergic receptor agonists such as dobutamine, phosphodiesterase (PDE)-3 inhibitors such as milrinone, or calcium sensitizers such as levocimendan), potassium or magnesium, proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors, vasodilators (e.g., calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin modulators), diuretics (e.g., furosemide), warfarin, RAAS inhibitors, antiarrhythmics, anticoagulants, antithrombotic agents, antiplatelet agents, or any combination thereof.

[0347] Suitable ARBs include, for example, A-81988, A-81282, BIBR-363, BIBS39, BIBS-222, BMS-180560, BMS-184698, candesartan, candesartan cilexetil, CGP-38560A, CGP-48369, CGP-49870, CGP-63170, CI-996, CV-11194, DA-2079, DE-3489, DMP-811, DuP-167, DuP-532, E-4177, erythritol, EMD-66397, EMD-73495, Eprosartan, EXP-063, EXP-929, EXP-3174, EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, GA-0056, HN-65021, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, Irbesartan, Isoteolin, KRI-1177, KT3-671, KW-3433, Losartan, LR-B / 057, L-158809, L-158978, L-15928 2, L-159874, L-161177, L-162154, L-163017, L-159689, L-162234, L-162441, L-163007, LR-B / 081, LRB087, LY-285434, LY-302289, LY-315995, LY-235656, LY-301875, ME-3221, Olmesartan, PD-150304, PD-123177, PD-123319, RG-13647, RWJ-38970, RWJ-46458, Salara Acetate This may include Syn, S-8307, S-8308, SC-52458, Supplisartan, Saracin, Salmesin, SL-91.0102, Tasosartan, Telmisartan, UP-269-6, U-96849, U-97018, UP-275-22, WAY-126227, WK-1492.2K, YM-31472, WK-1360, X-6803, Valsartan, XH-148, XR-510, YM-358, ZD-6888, ZD-7155, ZD-8731, and Zolasartan.

[0348] In certain embodiments, additional therapeutic agents may be ARNIs such as sacubitril / valsartan (Entresto®), or sodium-glucose cotransporter 2 inhibitors (SGLT2i) such as empagliflozin (e.g., Jardiance®), dapagliflozin (e.g., Farxiga®), or sotagliflozin.

[0349] In yet another embodiment, a patient receiving treatment for heart failure with a myosin inhibitor is also being treated with ARNI, beta-blockers, and / or MRAs.

[0350] In one embodiment, the antiarrhythmic drug is disopyramide.

[0351] If any adverse effects occur, patients may be treated for those effects. For example, patients experiencing headaches due to myosin inhibitor treatment may be treated with analgesics such as ibuprofen and acetaminophen. [Examples]

[0352] Abbreviation: Adverse events (AEs) AESI (Adverse Events of Particular Note) ALP (Alkaline Phosphatase) ALT (Alanine Aminotransferase) ASA alcohol septal ablation AST (Aspartate Aminotransferase) BP (Blood Pressure) CPET Cardiopulmonary Exercise Testing CV cardiovascular DILI (Drug-Induced Liver Injury) EC Ethics Committee (referring to IRB, IEC, or equivalent) ECG (Electrocardiogram) eCRF Electronic Case Report Form EDC (Electronic Data Collection) System End of EOS test ET early cancellation FDA (U.S. Food and Drug Administration) FSH (Follicle-Stimulating Hormone) GCP (Good Clinical Practice) standards for clinical trials of pharmaceuticals HCM (Hypertrophic Cardiomyopathy) HR (Heart Rate) IUD (Intrauterine Contraceptive Device) IUS (Intrauterine System) IXRS Automated Response System KCCQ Kansas City Cardiomyopathy Questionnaire LV left ventricle LVEF left ventricular ejection fraction LVOT left ventricular outflow tract MAD Repeated Dose Escalation MedDRA Glossary of Pharmaceutical Regulatory Terms NT-proBNP (N-terminal pro-b type natriuretic peptide) NYHA (New York Heart Association) oHCM (Obstructive Hypertrophic Cardiomyopathy) PD Pharmacodynamics (target) PK (Pharmacokinetics) PM poor metabolizer QD once a day QoL (Quality of Life) QTc Corrected QT interval QTcF Fridericia Corrected QT Interval SAD single dose escalation SAE (Serious Adverse Event) SD standard deviation SOC major classification by organ SRT septal reduction therapy SUSAR Suspected of unexpected serious side effects Stress echocardiography TBL Total Bilirubin Adverse events that occurred with TEAE treatment TTE transthoracic echocardiography, transthoracic echocardiogram ULN normal upper limit

[0353] Example 1. Observation results at 48 weeks of the PIONEER-OLE trial of mabacamten In a Phase 2 (PIONEER-HCM) clinical trial involving subjects with obstructive HCM, mavacamten reduced or eliminated left ventricular outflow tract obstruction, improved subject mood (measured by the New York Heart Association classification and the Kansas City Cardiomyopathy Questionnaire), and improved subject cardiac function (based on maximal VO2 measured by cardiopulmonary exercise testing). Heitner, SB, et al., (April 2019, online) Ann. Intern. Med. 170(11):741-748.

[0354] Below, we describe (1) the study design of the PIONEER OLE trial, a phase 2 open-label, multicenter trial in adults with symptomatic oHCM who have already completed the PIONEER-HCM trial, and (2) the observation results at week 48 for subjects treated with mabacamten in the PIONEER-OLE trial (currently ongoing). Objectives of the PIONEER-OLE test: (a) Primary objective: To evaluate the long-term safety and tolerability of mabacamten in individuals with symptomatic obstructive hypertrophic cardiomyopathy (oHCM). (b) Secondary objective: To evaluate the long-term effects of mabacamten on left ventricular outflow tract (LVOT) obstruction, functional capacity, and oHCM symptoms in individuals with symptomatic oHCM. (c) Pharmacokinetic objective: To conduct population pharmacokinetic (PK) analysis in symptomatic oHCM patients receiving mabacamten.

[0355] Test design and planning: The study was designed as shown in Figures 21 and 22. All subjects started with a dose of 5 mg QD.

[0356] To maximize safety, the starting dose is 5 mg for all subjects. At week 4 (±4 days), subjects are brought in for plasma PK sampling, drug concentration is measured, and echocardiography is performed to determine the LVOT gradient (at rest, after Valsalva maneuver, and after exercise) and left ventricular ejection fraction (LVEF). At week 6 (±7 days), subjects are brought in to evaluate the results from week 4 and to adjust the dose (i.e., mavacamten in 5, 10, or 15 mg QDs) to obtain a steady-state trough plasma concentration of approximately 250 ng / mL to 500 ng / mL based on PK modeling.

[0357] These plasma concentration levels are generally associated with a significant reduction in the LVOT gradient and are well-tolerated without excessively reducing the left ventricular ejection fraction (LVEF).

[0358] For eligible subjects, dose increases beyond the target dose may be permitted at later time points, starting from week 6. Dose reductions after week 6 may also be permitted if indicated by LVEF, PK, or the investigator's clinical judgment in consultation with the medical monitor. Subjects may continue their basal therapy with either a beta-blocker or a calcium channel blocker.

[0359] Stress echocardiography is performed at weeks 48 and 72 to evaluate the post-exercise LVOT gradient and determine whether further dose adjustments are necessary. If the post-exercise LVOT gradient is measured at 50 mmHg or higher, further dose adjustment may be considered.

[0360] Do not increase the dose if one or more of the following criteria are met: (a) LVEF is <55%, and / or (b) Post-exercise LVOT gradient is <30 mmHg, and / or (c) trough plasma concentration of mabacamten >350 ng / mL, and / or (d) The principal investigator's clinical judgment is not justified in increasing the dose.

[0361] Dose Reduction Rules: If the pharmacological effect is excessive, the dose may be reduced or discontinued at any point during the study, based on the clinical judgment of the principal investigator.

[0362] Temporary discontinuation: If the results reported by the central laboratory from any visit indicate a mabacamten plasma concentration of ≥1000 ng / mL, or an LVEF of <45% (central interpretation), or a Fridericia-corrected QT interval (QTcF) meeting the following criteria, the study site / principal investigator will notify the subject of further instructions: (a) If the QRS complex is narrow (<120ms), the criterion for temporary discontinuation is the smaller of either a 15% increase from baseline QTcF or QTcF ≥ 520ms. (b) If the QRS complex is wide (≥120ms), the criterion for temporary discontinuation is the smaller of either a 15% increase from baseline QTcF or QTcF ≥550ms. (c) If a subject is taking 5 mg, 10 mg, or 15 mg of the study drug, the subject will temporarily discontinue the study drug and will make an unscheduled visit 2 to 4 weeks later, including an electrocardiogram [ECG] and TTE evaluation. If LVEF ≥ 55% and QTcF < 500 ms during an unscheduled visit, the study drug should be restarted at a lower dose as shown below (previous dose → restart dose). (a) Restart with 5mg → 5mg (b) 10 mg → 5 mg, (c) 15mg → 10mg.

[0363] For subjects who temporarily discontinued treatment at 5 mg based on clinical evaluation, reintroduction of the 5 mg dose may be considered.

[0364] If LVEF, plasma drug concentration, and / or QTcF remain outside the range at follow-up visits, the subject will discontinue the study.

[0365] Further trial visits will be scheduled from week 6 onwards, at week 8 (±7 days), week 12 (±7 days), and every 12 weeks (±7 days) thereafter. Participants will also be contacted by telephone between clinic visits (at week 18 and every 12 weeks thereafter). The end-of-study (EOS) visit will take place 12 weeks (±7 days) after the final dose of the study drug. Each visit (including baseline screening visits) will include recording vital signs, targeted physical examination, ECG, safety clinical tests, N-terminal pro-β natriuretic peptide (NT-proBNP), adverse events (AEs), New York Heart Association (NYHA) functional classification, Kansas City Cardiomyopathy Questionnaire (KCCQ) score, and concomitant medications. Pre-administration blood samples for drug concentration assessment will be obtained at weeks 4, 8, 24, 36, 48, 60, 72, 96, 120, 144, 156 / Early Discontinuation (ET), and 168 / EOS. Standard TTE (including, but not limited to, assessment of resting and post-Valsalva maneuver LVOT gradients) will be performed at baseline, weeks 4, 8, 12, 24, 36, 48, 72, 96, 120, 144, 156 / ET, and 168 / EOS. In addition, stress echocardiography (including assessment of post-exercise LVOT gradients) will be performed at baseline, weeks 4, 48, 72, 156 / ET, and 168 / EOS.

[0366] Subjects will be followed up until completion of the End-of-Sustaining System (EOS) procedure. All adverse events (AEs), including serious adverse events (SAEs), will be collected throughout the study period, from the time of informed consent to week 168 / EOS visit. If there are any significant clinical abnormalities or clinically significant laboratory abnormalities requiring monitoring, subjects will be followed up until the abnormality disappears or is considered stable in the opinion of the principal investigator.

[0367] After receiving treatment with a stable dose of 10 mg or 15 mg for at least 24 weeks, subjects may have their dose reduced. Subjects whose dose has been reduced will have a follow-up visit 4–8 weeks (±7 days) later (to reflect the evaluation at week 8, including TTE assessment). Based on the results of the follow-up visit and clinical symptoms, a decision will be made regarding the subsequent dose. This cycle of potential dose reduction and follow-up can be repeated multiple times (at least 24 weeks after treatment with a stable dose of 10 or 15 mg).

[0368] Exam period: The trial period is 172 weeks (up to 4 weeks for screening, 156 weeks for treatment, and 12 weeks for post-treatment follow-up). The trial protocol may be amended to allow extensions beyond 3 years.

[0369] Test evaluation items: The trial endpoints include selected measures of safety, tolerability, and efficacy using individualized medication. Primary measures include LVOT gradient, LVEF, and NT-proBNP. Safety evaluation items include the following: 1. Frequency and severity of AEs and SAEs that occurred as a result of treatment. 2. Frequency of cardiovascular (CV) death, 3. Frequency of sudden death, 4. Frequency of CV hospitalization, 5. Frequency of heart failure requiring initiation of oral loop diuretics or administration of intravenous loop diuretics. 6. Frequency of myocardial infarction, 7. Frequency of ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation, ventricular flutter, torsades de pointes), 8. Frequency of syncope, 9. Frequency of seizures, 10. Frequency of stroke, 11. Frequency of LVEF ≤ 45% as measured by echocardiography. 12. QT and QTcF intervals over time. Efficacy and pharmacodynamics include the following: 1. LVOT gradient over time after exercise, after Valsalva maneuver, and at rest. 2. NYHA functional classification over time, 3. KCCQ score over time, 4. NT-proBNP over time, 5. Frequency of septal reduction therapy. Pharmacokinetic evaluation parameters include the following: Time course of plasma concentrations of mabacamten and population pharmacokinetics. [Table 1]

[0370] PIONEER-OLE test results: Results 1. PIONEER-OLE 48-week results: Maintained safety and efficacy over one year in an open-label continuation study involving 12 subjects with symptomatic obstructive HCM. Data from 12 subjects at 48 weeks of treatment with mabacamten were consistent with previous safety and efficacy observations in readings at 12, 24, and 36 weeks. The most important parts of the data include sustained safety and tolerability, as well as lasting clinical benefits such as reduced left ventricular outflow tract gradient (LVOT), improved NYHA functional classification, and improvements in multiple biomarkers towards the normal range. A reduction in septal wall thickness, a defining characteristic of HCM, was observed for the first time, and improvements in the subjects' quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), were also reported.

[0371] Data from the 12 subjects in this study at week 48 demonstrate continued safety, reduced LVOT gradient profile, and normal LVEF. Mabacamten was well-tolerated throughout the one-year treatment period. No cardiac adverse events (AEs) attributable to the study drug were reported during the 48-week period. To date, all treatment-related adverse events have been mild or moderate and transient.

[0372] The longest duration of mabacamten therapy was 1.5 years. There were no dose changes due to adverse events (AEs). Four SAEs occurred in three subjects, but they were not cardiovascular and were not associated with the study drug. There was one non-surgical cardiovascular AE (NSVT) unrelated to the study drug. Of the 64 AEs, the majority were mild or moderate and transient. Eight AEs in three subjects were considered potentially related to the study drug (fatigue, dyspnea, dizziness, lethargy). Seven were mild and one was moderate. One subject experienced three severe AEs and one critical AE, but these were unrelated (a male with a history of ulcerative colitis presented with upper abdominal pain, elevated AST (>5×ULN), and biliary obstruction four days after his visit at week 24, and was subsequently diagnosed with Klatskin-type cholangiocarcinoma. This subject discontinued the study drug and terminated the study early).

[0373] The LVOT gradient, a measure of left ventricular obstruction, consistently decreased from baseline in all subjects who made evaluable visits under multiple test conditions, namely at rest, after exercise, and during Valsalva maneuver induction, with statistical significance of p<0.01. At week 48, the resting LVOT gradient in all subjects was below the 50 mmHg threshold based on invasive intervention guidelines, and in 11 of the 12 subjects, it was below the 30 mmHg threshold for diagnosing obstructive HCM. Evoke gradient measurements taken using the Valsalva maneuver and after exercise were also below 50 mmHg in all subjects except two at week 48. In Figures 1A-1C, the mean resting LVOT gradient was 67.3 mmHg (standard deviation [SD], 42.8) at baseline and 14.0 mmHg (SD, 9.7) at week 48 (mean change -52.7 mmHg, P=0.0005). Similar improvements were observed in the Valsalva LVOT gradient (mean change -66.0 mmHg, P=0.001) and post-exercise LVOT gradient (mean change -85.1 mmHg, P=0.001) at week 48. Five patients achieved a post-exercise LVOT gradient of less than 30 mmHg. The mean change from baseline in LVEF was -1.8% (P=0.3013) at week 48 (1D). LVEF remained above 50% in all patients at all time points throughout the study. One subject was unable to complete the stress echocardiogram at week 48 due to lingering effects from a serious adverse event. Left ventricular ejection fraction (LVEF) remained above normal (50%) in all 12 subjects at all time points of evaluation. See Figure 1D.

[0374] Result 2. Improvements in both symptom burden and quality of life were observed among PIONEER-OLE subjects at week 48. At baseline, subjects enrolled in PIONEER-OLE were symptomatic, with NYHA class II or III. NYHA classifications were measured at weeks 24 and 48, showing improvement, with 9 out of 12 subjects reaching an asymptomatic state (class I). See Figure 2A. Positive results were also reported for the Kansas City Cardiomyopathy Questionnaire (KCCQ), designed to measure subjects' perceptions of their health status and its impact on daily living activities due to heart failure. In the PIONEER-OLE study, the mean KCCQ score increased from 74.1 at baseline to 87.3 at 48 weeks (the score ranges from 0 to 100, with higher scores reflecting better health). A clinically significant change in the KCCQ is defined as a score of 6 or higher. See Figure 2B. In Figure 2B, the score ranges from 0 to 100. Higher scores reflect better health.

[0375] Result 3. The evidence suggests favorable effects on cardiac structure, including a reduction in internal septal wall thickness and left ventricular filling. As shown below, mabacamten improved markers related to ventricular filling at weeks 12, 24, 36, and 48. During this period, early diastole (e' lat During this time, the mitral valve annular velocity increases significantly, and consequently, E / e' lat The levels decreased. Left atrial (LA) volume decreased significantly, and NT-proBNP levels decreased significantly. NT-proBNP, an established circulating blood marker of cardiac wall stress, was significantly reduced to near-normal range (considered less than 125 pg / mL). NT-proBNP levels <310 pg / mL in HCM subjects were associated with a 75 percent reduction in the rates of heart failure-related death or hospitalization, progression to end-stage disease, and stroke compared to subjects with levels ≥310 pg / mL. • The echocardiographic measurement of left ventricular filling pressure, E / e', decreased from 12.8 (mean baseline measurement) to 9.1. • The left atrial volume index was 41 mL / m², which is the baseline mean. 2 From an average value of 32 mL / m² 2 It then decreased to a normal level. Left atrial volume is a measure of left ventricular filling pressure, and an increase in volume may be associated with an increased risk of atrial fibrillation in HCM subjects. • A reduction in ventricular septal (IVS) thickness, as measured by echocardiography, was observed in PIONEER-OLE subjects. Overall, PIONEER-OLE subjects started the trial with a mean IVS of 17 mm at baseline, which gradually decreased to 15 mm after 48 weeks of mabacamten treatment. The trial of HCM subjects after septal reduction intervention showed that IVS reduction in HCM subjects was associated with improvements in LVOT gradient, functional capacity, and symptoms. The risk of sudden cardiac death in HCM subjects was observed to gradually increase as wall thickness increased beyond 15 mm.

[0376] The following data are the first to demonstrate that ventricular septal thickness was reduced in humans at weeks 12, 24, 36, and 48 with myosin inhibitors, without altering posterior wall thickness. See Tables 1.1, 1.2, and Figures 3A and 3B for biomarker measurements, mean (SD), wall stress, diastolic, and structural changes.

[0377] A significant reduction in serum NT-proBNP levels was observed. The median serum NT-proBNP level at week 48 was 136.5 pg / mL, a change of -472 pg / mL from baseline (P=0.0005). A similar reduction in median NT-proBNP levels was observed at week 60 (change of -481 pg / mL from baseline, P=0.0005). In exploratory evaluation, mabacamten improved markers associated with ventricular filling. lat E / e' increased significantly (mean change from baseline 1.6 cm / sec, P=0.002), and consequently E / e' lat The LA volume coefficient decreased (mean change from baseline -3.4, P=0.001). At week 48, the LA volume coefficient decreased significantly (mean change from baseline -9.8 mL / m²). 2 (P=0.0269). Mitral valve systolic anterior motion was observed in 12 out of 13 patients at baseline and in 4 out of 12 patients who could be evaluated by week 48. [Table 2] Mavacamten was associated with a reduction in interventricular septum thickness without significant change in posterior wall thickness over 48 weeks (mean change from baseline -1.2 mm, P = 0.1294). A significant reduction in the LV mass index (mean change from baseline -16.3 g / m 2 , P = 0.021) and LV maximal wall thickness (mean change from baseline -1.4 mm, P = 0.0259) was also seen at week 48.

Table 3

[0378] Example 2. Long-Term Effects of MYK-581 in a Min-Pig Genetic Model of Non-Obstructive Hypertrophic Cardiomyopathy: In Vivo Evidence for Improved Relaxation and Reserves Abstract: Hypertrophic cardiomyopathy (HCM) is a genetic disease characterized by cardiac remodeling, diastolic dysfunction, and exercise intolerance. Direct attenuation of myosin with mavacamten can normalize contractility and improve exercise capacity in subjects with obstructive HCM, resulting in sustained symptom reduction. However, mavacamten and its surrogate MYK-581 may also provide cardiac benefits beyond transient relief of obstruction, as they can improve relaxation by limiting cross-bridges remaining in diastole. In this in vivo study, the long-term effects of MYK-581 in a genetic large animal model of non-obstructive HCM were evaluated.

[0379] Methods: Cloned young Yucatan miniature pigs carrying the heterozygous MYH7 R403Q mutation were randomly assigned to one of two arms: a time-control group (n=10) or a daily MYK-581 group (n=10, PO). The miniature pigs were treated for at least 12 weeks and evaluated as shown in Schematic Figure 1 below. As shown in Schematic Figure 1 below, the dose of MYK-581 was gradually increased (5, 7.5, and 10 mg / day PO) to treat the animals, taking into account a body weight gain of 6.4 ± 0.3 to 28.3 ± 1.1 kg (P < 0.05). Approximately 14 weeks after treatment, in vivo cMR imaging was performed on all pigs to assess the function and morphology of the lvium (LV) and to evaluate myocardial composition using delayed gadolinium enhancement (LGE) and T1 mapping techniques (including extracellular volume (ECV) assessment). Furthermore, a final invasive hemodynamic assessment was performed on a subset of animals (MYK: n=6, control: n=5), including cardiac output (CO, due to thermodilution), load-independent systolic / diastolic function (due to pressure-volume relationship of LV), and β-adrenergic (β-AR) cardiac reserve (due to dobutamine IV at 5 ug / kg / min). See Figure 4.

[0380] The minipig model can be obtained according to the method disclosed in the presentation entitled “A Minipig Genetic Model of Hypertrophic Cardiomyopathy Uncovers the Pathophysiological Mechanisms of Disease Evolution” by E. Green et al at the University of Iowa, Carver College of Medicine.

[0381] result: In R403Q mutant pigs, treatment with MYK-581 reduced both EF (59±2 vs. 65±2%) and LV weight (51±4 vs. 66±5g) while maintaining CO (P<0.05). Treated pigs had smaller left atrial volume (16±1 vs. 29±4mL, P<0.05), shorter T1 time, and smaller ECV (27±1 vs. 32±2%, P<0.05), suggesting improved LV structure / compliance. Indeed, the MYK group had lower LV end-diastolic pressure (9±1 vs. 23±4mmHg) and stiffness (1.3±0.2 vs. 3.5±0.3mmHg / mL) (P<0.05), and a faster relaxation time constant (45±3 vs. 71±5ms, P<0.05). The treatment also restored β-AR stroke volume mobilization (+15±4 vs. -14±6%, P<0.05).

[0382] Result 1: Long-term use of MYK-581 normalized diastolic rhythm. a. Long-term use of MYK-581 reduces end-diastolic pressure (EDP) / stiffness (E ed ) was maintained • Improved compliance and early relaxation (tau w , dP / dt). b. Long-term MYK-581 treatment restored β-AR cardiac reserve (dobacteria exposure): • ↑SV (Control: -14±6% vs. MYK: +15±4%, P<0.05) • ↑CO (Control: +26±2% vs. MYK: +60±8%, P<0.05)

[0383] Result 1 demonstrates the sustained ability of the myocardium to respond to load. This suggests a potential capacity to maintain exercise performance. See also Figures 5A-C.

[0384] Result 2: Long-term use of MYK-581 normalized the cardiac phenotype. a. Long-term use of MYK-581 reduced hypercontractility while maintaining cardiac output through both cMR and thermodilution. b. Long-term use of MYK-581 resulted in the maintenance of LA volume, a gradual increase in mean diastolic wall thickness (WTd) across the left ventricle, and an increase in LV weight. c. Long-term use of MYK-581 maintained the LV structure (T1 and ECV were reduced). d. Improvement (trend) in mortality: At the end of the trial (approximately 5 months), the mortality rate for MYK was 0% compared to 40% for the control group. Please refer to Figures 6A-I.

[0385] Long-term direct myosin attenuation with the mabacamten substitute MYK-581 prevented disease-specific cardiac remodeling and reduced mortality in a genetic HCM model. Long-term treatment reduced left atrial size, a known prognostic indicator of HCM, while simultaneously improving diastolic function and cardiac reserve. These observations suggest potential beneficial effects beyond obstruction reduction in subjects with HCM, and that early and long-term administration of mabacamten suppresses the development of ventricular hypertrophy and cardiomyocyte dysorganization, and weakens the expression of hypertrophic genes.

[0386] From this long-term porcine study, total plasma concentrations of 30–140 ng / mL were observed. After correcting for species differences in plasma protein binding and differences in potency between MYK-581 and mabacamten, the levels observed in pigs were converted to human plasma concentrations in the range of 50–250 ng / mL, which are expected to have an equivalent effect. Based on our understanding of mabacamten PK, this was then converted to a dose in the range of 1–5 mg QD. This dose is approximately 1 / 2 to 1 / 5 of the dose required to alleviate obstruction in humans.

[0387] Comparative studies of MYK-581 and mabacamtene have shown that these two compounds behave similarly in terms of ATPase inhibition and the formation of the super-relaxed state (SRX). In particular, studies of MYK-581 and mabacamtene in bovine cardiac synthetic myosin filaments showed similar DRX ATPase rates and SRX ATPase rates (as a percentage of control) for both compounds over a range of concentrations. See Figures 26A-C. Due to these similarities, mabacamtene is expected to offer similar benefits in the nHCM-related measurements of Example 2.

[0388] Example 3. MAVERICK-HCM Study: A randomized, double-blind, placebo-controlled, concentration-induction, exploratory study of mavacamten in subjects with symptomatic non-obstructive hypertrophic cardiomyopathy (nHCM) and preserved left ventricular ejection fraction. This study was a Phase 2 trial designed to evaluate the safety and tolerability of a 16-week course of exposure to non-obstructive HCM in subjects with symptomatic non-obstructive HCM. All subjects had to be diagnosed with non-obstructive HCM with either a left ventricular wall thickness of ≥15 mm or ≥13 mm, a family history of HCM, ≥55% LVEF, NYHA class II or III, and NT-proBNP levels greater than 300 pg / mL at rest. Baseline characteristics such as age, weight, sex, pathogenicity variant status, use of beta-blockers in basal therapy, NYHA class, and exercise capacity were distributed nearly evenly between the active treatment arm and the placebo arm. The purpose of the exam: (a) Primary objective: To evaluate the safety and tolerability of a 16-week course of mabacamten in individuals with symptomatic nHCM. (b) Exploratory: 1. To evaluate the effect of a 16-week course of mabacamten on exercise capacity as measured by maximum oxygen uptake (VO2). 2. Evaluate the relationship between mabacamten concentration and pharmacodynamic response (e.g., echocardiographic measurements of diastolic and systolic function). 3. To evaluate the effects of a 16-week course of mabacamten on symptoms and quality of life. 4. To evaluate the effect of a 16-week course of mabacamten on the circulating levels of N-terminal pro-b natriuretic peptide (NT-proBNP). 5. Evaluate the effect of a 16-week course of mabacamten on daily activity levels measured by an accelerometer. 6. Evaluate the reversibility of the effects of mabacamten after discontinuing a 6-week treatment course for approximately 8 weeks. (c) Pharmacokinetic objective: To characterize the pharmacokinetic (PK) profile of mabacamten.

[0389] method: This double-blind trial enrolled 59 individuals with nHCM (resting or induced left ventricular outflow tract gradient <30 mmHg), NYHA class II or III, and LVEF ≥ 55%. Participants were randomized in a 1:1:1 ratio for 16 weeks to one of two target plasma drug concentrations (Group 1: approximately 200 ng / mL and Group 2: approximately 500 ng / mL) or placebo, followed by an 8-week washout. The starting dose of mavacamten was 5 mg daily, with a one-step dose adjustment at week 6 based on plasma drug concentration. Discontinuation of the study drug was advised as needed based on pre-defined criteria, including LVEF (LVEF ≤ 45%). Cardiopulmonary exercise testing was performed at baseline and at week 16 to assess the impact on exercise capacity.

[0390] Test design and planning: This study evaluates the safety, tolerability, preliminary efficacy, disease progression (PD), and pharmacokinetic (PK) of two target drug concentrations of mavacamten compared to placebo in subjects with symptomatic nHCM. The study scheme is shown in Figure 7.

[0391] Approximately 60 subjects with symptomatic nHCM will be randomized to receive either a 16-week course dose of mavacamten or placebo, adjusted to reach one of two target drug concentrations (Group 1: approximately 200 ng / mL, Group 2: approximately 500 ng / mL). Dose adjustment will be based on PK parameters. Assessments will include safety, standard cardiopulmonary exercise testing (CPET) with measurement of maximal oxygen consumption, echocardiography to assess left ventricular ejection fraction (LVEF), and parameters such as diastolic function, symptoms, quality of life, daily step count, and resting and post-exercise NT-proBNP. In addition, subjects may consent to genotyping and genetic pharmacological sampling of hypertrophic cardiomyopathy.

[0392] For subjects who consented and had previous HCM genotyping results showing pathogenic mutations known to be associated with HCM, further genotyping was not performed if data could be provided from the original documentation of the clinical laboratory and the subject consented to sharing this information. Untested subjects and subjects who did not have HCM genotyping results showing pathogenic mutations known to be associated with HCM may separately consent to blood collection before day 1 administration for HCM genotyping evaluation. For subjects who consented to genetic pharmacological evaluation, blood samples were collected before administration to analyze genetic biomarkers for efficacy, safety, PD, or PK parameters to be determined by future trials, using clinically meaningful endpoints through additional DNA sequencing or other genetic testing.

[0393] Cardiac troponin I levels were assessed in subject plasma and serum samples at baseline and at various time points during the study (Abbott Architect Stat Troponin-I assay (reference: 2K41)). Cardiac troponin T levels were assessed in subject plasma and serum samples at baseline and at various time points during the study (Roche Elecsys Troponin T hs assay performed with cobas e 801 analyzer (reference: 08469873190)). NT-proBNP levels were assessed in plasma samples using the Roche Elecsys proBNPII assay (reference: 07027664190) with the cobas e 801 analyzer.

[0394] Main selection criteria: 1. The person was 18 years of age or older at the time of screening and weighed more than 45 kg at the time of screening. 2. In line with the current guidelines of the American Heart Association Foundation / American Heart Association and the European Society of Cardiology, • Left ventricular (LV) wall thickness ≥ 15 mm, or • LV wall thickness ≥ 13 mm and family history of HCM is positive. He has been diagnosed with nHCM (hypertrophic non-diastolic left ventricle, systemic or other unknown cause), 3. LV ejection rate ≥ 55%, 4. The maximum LVOT gradient at rest, during Valsalva maneuver, and after exercise is <30 mmHg. 5. The maximum intracavitary gradient determined by the central echocardiography laboratory is <30 mmHg at rest, during Valsalva maneuver, and after exercise. 6. Having symptoms of New York Heart Association (NYHA) Class II or III 7. The patient has elevated resting NT-proBNP (>300 pg / mL). Main exclusion criteria: 1. The patient had a known infiltrative or accumulative disorder that causes cardiac hypertrophy similar to nHCM (e.g., Fabry disease with LV hypertrophy, amyloidosis, or Noonan syndrome), 2. Having any medical condition that prevents exercise stress testing in a standing position, 3. You have a history of exercise-induced syncope or persistent ventricular tachyarrhythmia within the past six months. 4. The patient had a history of resuscitated sudden cardiac arrest at any point in time, or had a known adequate discharge from an implantable cardioverter-defibrillator (ICD) within the past six months. 5. The subject has paroxysmal intermittent atrial fibrillation, and atrial fibrillation is present based on the investigator's assessment of the subject's electrocardiogram (ECG) at the time of screening. 6. Having persistent or permanent atrial fibrillation, not having received anticoagulation treatment for at least 4 weeks prior to screening, and / or not having adequately controlled heart rate within the past 6 months. 7. Currently being treated with disopyramide or lanolazine, 8. Fridericia-corrected QT interval (QTcF) greater than 480 ms, or any other ECG abnormality that is considered to pose a risk to the safety of the subject. 9. In subjects taking beta-blockers, verapamil, or diltiazem, any dose adjustments made less than 14 days prior to screening, 10. Current or planned treatments in trials involving a combination of a beta-blocker and verapamil, or a combination of a beta-blocker and diltiazem. 11. Within the six months prior to screening, you have been treated with an invasive septal reduction procedure (surgical myofascial resection or percutaneous alcohol septal ablation). 12. A proven history of LVOT or intracavitary gradient exceeding 30 mmHg at rest or after exercise (excluding cases subsequently treated with septal reduction therapy), 13. A history of obstructive coronary artery disease (stenosis of more than 70% of one or more epicardial coronary arteries) or myocardial infarction within the past six months is documented. 14. At the time of screening, the patient has known moderate or severe aortic stenosis. 15. Having a lung disease that limits exercise capacity or systemic arterial oxygen saturation, 16. You are currently taking or have taken any of the following prohibited medications within the past 14 days prior to screening: a cytochrome P450 (CYP) 2C19 inhibitor (e.g., omeprazole), a potent CYP 3A4 inhibitor, or St. John's wort.

[0395] Experimental treatment: Using a concentration-inductive approach, we evaluated which dose of mavacamten produced improved diastolic function in nHCM subjects. Subjects were randomized in a 1:1:1 ratio to three groups: two active treatment groups and one matching placebo group via an automated response system.

[0396] A 5 mg QD was used as the starting dose for the study. All subjects in the active treatment group started with a 5 mg QD. Subjects were assessed for plasma concentrations of mavacamten in blood samples collected at week 4 visit. PK modeling was used to induce blinded dose adjustments at week 6 visit based on the plasma concentrations collected at week 4. The same assessments were performed on subjects in the placebo group to maintain blinding. The study drug was provided in mavacamten capsules in available strengths of 2.5 mg, 5 mg, 10 mg, and 15 mg. Subjects were instructed to take the drug with 8 ounces of water at approximately the same time each day under fasting conditions.

[0397] In the first group of subjects, the target mabacamten plasma concentration was 200 ng / mL. To achieve the target concentration, if a subject's concentration at week 4 was >450 ng / mL, the subject's dose was reduced to 2.5 mg QD; if the concentration at week 4 was between 110 and 450 ng / mL, the dose was maintained at 5 mg QD; and if the concentration at week 4 was <110 ng / mL, the dose was increased to 10 mg QD.

[0398] In the second group of subjects, the target mabacamten plasma concentration was 500 ng / mL. To achieve the target concentration, if a subject's concentration at week 4 was >450 ng / mL, the subject's dose was reduced to 2.5 mg QD; if the concentration at week 4 was between 300 and 450 ng / mL, the dose was maintained at 5 mg QD; if the concentration at week 4 was between 175 and 300 ng / mL, the dose was increased to 10 mg QD; and if the concentration at week 4 was <175 ng / mL, the dose was increased to 15 mg QD.

[0399] Participants were monitored for adverse events (AEs), including hyperplasmic concentration, systolic dysfunction, QT prolongation, and decreased LVEF. Participants discontinued the drug if any of the following thresholds were reached: PK ≥1000, QTcF ≥500, or LVEF ≥45%. Specifically, hyperplasmic concentration was defined as a plasma concentration of ≥1000 ng / mL, QT prolongation as a QTcF ≥500 ms, and decreased LVEF as an LVEF ≤45% (including serious adverse events (SAEs) for LVEF ≤30%).

[0400] Efficacy and pharmacodynamic evaluations were also performed. Resting transthoracic echocardiography was measured at weeks 4, 8, 12, and 16. Ejection fraction (2-D) and LV diameter shortening were analyzed along with other echocardiograms at baseline measurements, including diastolic measurements. Post-exercise stress echocardiography was also performed following a standard symptomatic limit exercise test performed by the subjects. Instantaneous maximal LVOT gradient was assessed immediately after exercise. Cardiopulmonary exercise testing (CPET) was also performed. CPET was performed on day 1 and week 16 using a standard treadmill or upright bicycle ergometer. Subjects were encouraged to perform to the maximum extent possible to achieve their predicted heart rate. Oxygen consumption (VO2), carbon dioxide production (VCO2), expiratory volume (VE), VE / VO2, ventilatory efficiency (VE / VCO2), respiratory exchange ratio, circulatory force, and metabolic equivalents were evaluated during the work task.

[0401] Pharmacokinetic evaluations were also performed during the study. Blood samples were collected at weeks 4, 8, 12, and 16 to evaluate mabacamten plasma concentrations. Pre- and post-administration PK blood samples were collected at week 16.

[0402] Test evaluation items: The primary endpoint is the frequency and severity of treatment-induced adverse events. Secondary endpoints include diastolic echocardiographic measurements, NT-proBNP levels, subject-reported outcomes, and physical activity measured by a wearable accelerometer. Exploratory purpose: 1. Change in maximum VO2 from baseline to week 16, 2. Change in echocardiographic measurements of systolic function (e.g., LVEF) from baseline to week 16. 3. Changes in diastolic echocardiographic measurements from baseline to 16 weeks (maximum velocity of early diastolic septal and lateral parietal mitral annular motion [e'], ratio of maximum velocity of early diastolic mitral inflow [E] to e' [E / e'], ratio of E to maximum velocity of late mitral inflow [A] [E / A], pulmonary artery systolic pressure, left atrial size), 4. Change in NYHA classification from baseline to week 16. 5. Change in KCCQ score from baseline to week 16. 6. Change in EQ-5D score from baseline to week 16. 7. Change in the severity of HCM symptoms reported by the subject, as assessed by the HCMSQ score, from baseline to week 16. 8. Change in perceived symptom severity from baseline to week 16, as assessed by the PGIC and PGIS questionnaire scores. 9. Change in NT-proBNP from baseline to week 16 at rest (before exercise) and after maximal exercise. 10. Change in daily step count measured by accelerometer from baseline to week 16. 11. Changes in echocardiographic measurements of diastolic function (e', E / e', E / A, pulmonary artery systolic pressure, left atrial size) from week 16 to week 24. 12. Changes in NYHA classification, KCCQ score, EQ-5D score, HCMSQ score, and PGIC and PGIS questionnaire scores from week 16 to week 24. 13. Change in resting NT-proBNP from week 16 to week 24. Functional composite assessment items were also tested. These are described below.

[0403] result: Fifty-nine participants were randomized on a 19 / 21 / 19 basis to receive 200 ng / mL / 500 ng / mL / placebo. Baseline characteristics are shown in Table 3.1. Forty participants had detectable cTnI levels, with 19 (32%) showing elevated cTnI levels (>0.03 ng / mL or >99th percentile; 13 in the mabacamten group and 6 in the placebo group). Among participants with detectable cTnI, the baseline geometric mean cTnI level was 0.03 ng / mL in the mabacamten combined group and 0.05 ng / mL in the placebo group. Baseline E / e' 平均 The number of people experiencing an increase was 25 out of 59 participants (42.4%) (>14). [Table 4-1] [Table 4-2]

[0404] The primary objective of the trial was to demonstrate the achieved safety and tolerability in subjects with nHCM. The incidence of adverse events (AEs) was higher in the mavacamten group than in the placebo group. The majority of reported AEs and treatment-induced AEs (TEAEs) were mild to moderate in severity and were reversible or resolved spontaneously. Serious adverse events (SAEs) occurred twice as frequently in the placebo arm (21%) compared to subjects treated with mavacamten (10%). Transient ejection fraction reduction below the 45% threshold defined in the protocol occurred in five subjects in the active treatment arm.

[0405] The overall changes in LVEF were as follows: [Mean percentage change (SD)]: Group 1 -2.3% (5.3), Group 2 -5.6% (9.7), Mabacamten combined -4.1% (8.0), Placebo -2.3% (4.9). Planned echocardiographic evaluations at weeks 11-12 revealed that LVEF had decreased to ≤45% (range 38%-45%) in 5 out of 40 participants receiving active drug treatment (12.5%; 2 in Group 1 and 3 in Group 2), and treatment was discontinued according to pre-defined discontinuation rules. Four of the five participants (3 in Group 2 and 1 in Group 1) underwent dose escalation from 5 mg to 10 mg at week 6, as defined in the clinical trial protocol. The fifth participant (Participant 5, Group 1) maintained a dose of 5 mg.

[0406] In the intended treatment population, the exploratory endpoint of the biomarker NT-proBNP showed a statistically significant difference between the active treatment group and the placebo group at week 16. The level was significantly reduced in subjects receiving mabacamten compared to the placebo group across both treatment cohorts (p=0.004). At week 16, the geometric mean NT-proBNP decreased by 53% in the mabacamten combined group (47% in group 1 and 58% in group 2), compared to a 1% decrease in the placebo group, with geometric mean differences of -435 pg / mL and -6 pg / mL, respectively (the difference between mabacamten combined and placebo was P=0.0005). See Figure 8. NT-proBNP in the mabacamten combined group was lower than that of the placebo group at all time points from week 4 to week 16. The first decrease in NT-proBNP was observed at week 4 with the daily 5 mg dosage provided to both groups. Participants in Group 2 showed a further decrease in NT-proBNP at week 8 (after dose setting at week 6), consistent with a dose-dependent effect. These lower NT-proBNP levels were maintained until week 16 and increased to baseline levels at week 24 after drug discontinuation. NT-proBNP is a well-established biomarker of cardiac wall stress, and elevated NT-proBNP levels are associated with a higher risk of death or hospitalization related to heart failure, progression to end-stage disease, and stroke. NT-proBNP was measured using the Elecsys ProBNP II immunoassay on the Cobas platform.

[0407] In subjects with elevated cardiac troponin, which is associated with a higher risk of morbidity and mortality, a meaningful trend suggesting clinical benefit was observed in treated subjects across multiple endpoints, including symptoms, function, cardiac load biomarkers, and diastolic compliance, compared to placebo.

[0408] Furthermore, a similar trend was observed in a subgroup of subjects with elevated cardiac filling pressure (measured in E / e'), suggesting that improvement was facilitated by a reduction in left ventricular pressure, consistent with the mabacamten targeting mechanism.

[0409] In addition to a consistent safety profile, this trial demonstrated the ability to identify a profile of subjects with diastolic dysfunction who could benefit from mavacamten treatment. In the United States, 3 million people have a diastolic disorder called HFpEF, and these individuals have historically been treated as a single group in a uniform manner. Using the data from the MAVERICK trial, it is now possible to subtype these subjects (both those with and without HCM) and develop mavacamten in a more "accurate" and efficient manner.

[0410] In subjects with elevated troponin levels, improvements were observed in several parameters (see the asterisked parameters in the table below), particularly in the combined treatment groups (Group 1 and Group 2) compared to placebo, with respect to the internal E / e' ratio (resting), mean E / e' ratio (resting), serum NT-proBNP, and maximal VO2. See Table 3.2 below. Elevated troponin levels are linked to the evidence for cardiac magnetic resonance imaging in myocardial fibrosis, a clear prognostic factor for HCM. [Table 5-1] [Table 5-2]

[0411] Furthermore, in the subgroup with elevated cardiac troponin I (cTnI) levels at baseline, cTnI levels decreased in 11 out of 13 subjects (84.6%) at week 16 compared to baseline, while 2 out of 13 subjects (15.4%) showed no change. The reduction rates in the 11 subjects with reduction ranged from 12.5% ​​to 75.0%. Treated individuals showed a 30-80% change in cardiac troponin I from baseline. After discontinuation of the study drug at week 16, cTnI levels in the mabacamten combined group increased back to baseline by week 24. See Figures 9 and 10. The treatment was associated with a significant dose-dependent reduction in NT-proBNP and cTnI, suggesting improvement in myocardial wall stress and cardiac injury in nHCM patients, and generally indicating physiological benefits. cTnI was measured using the Abbott Stat Architect platform.

[0412] In the intention-to-treat (ITT) group, cTnI levels also decreased significantly. At week 16, the geometric mean cTnI decreased by 34% in the mabacamten combined group compared to a 4% increase in the placebo group, with geometric mean differences of -0.008 ng / mL and +0.001 ng / mL, respectively (P=0.009). See Table 3.3. After discontinuation of the study drug at week 16, cTnI levels in the mabacamten combined group increased back to baseline by week 24. [Table 6-1] [Table 6-2]

[0413] Post-hoc analysis of high-sensitivity cTnI (hs-cTnI) was performed using the ADVIA Centaur XPT immunoassay system (Siemens) on baseline and 16-week serum bank samples. The hs-cTnI results confirmed a reduction in cTnI levels due to mabacamten treatment. See Figure 11A. The hs-cTnT results also confirmed a trend toward a decrease in cardiac troponin levels. See Figure 11B. The hs-cTnT assay was also performed using the ADVIA Centaur XPT immunoassay system (Siemens) on baseline and 16-week serum bank samples.

[0414] In the mabacamten combined group, there was a statistically significant correlation between the change in NT-proBNP at week 4 and the change in cTnI at week 16 (r=0.45, P=0.006). See Figure 12. No significant correlation was observed in the placebo group (r=-0.31, P=0.212).

[0415] Table 3.4 shows the changes from baseline in key efficacy and pharmacodynamic parameters in participants with elevated baseline cTnI levels. [Table 7]

[0416] Exploratory analyses were conducted to evaluate the effects of 16 weeks of mabacamten treatment on diastolic (E / e', e' velocity) echo parameters and the functional composite endpoint defined as follows: 1) Improvement of pVO2 by at least 1.5 mL / kg / min and reduction of NYHA classification of grade 1 or higher, 2) Improvement of pVO2 by at least 3.0 mL / kg / min without deterioration of NYHA classification. At baseline and at week 16, pVO2 was determined by a central laboratory (Cardio-metabolic Diagnostic Research Institute, Palo Alto, CA) based on standard CPET. In the ITT population, no significant changes in the rate of E / e' or e' were observed between treatment groups. For participants with elevated baseline E / e', the changes from baseline in key efficacy and pharmacodynamic parameters are shown in Table 3.5. [Table 8]

[0417] No significant difference was observed in the proportion of participants achieving the functional composite endpoint in the ITT groups (16% in Group 1, 29% in Group 2, and 22% in placebo (p>0.05)). However, when analyzing a subgroup of participants with elevated cTnI (>99th percentile) or elevated mean E / e' (>14) at baseline (21 participants in mavacamten, 12 in placebo) ("composite subgroup"), 33% of participants treated with mavacamten met the functional composite endpoint, while none of the participants treated with placebo achieved this (P=0.03). See Figure 13 and Table 3.6. Therefore, in this initial exploratory analysis of this subset of participants with more severe disease (reflected by elevated baseline E / e' and / or elevated baseline cTnI), mavacamten therapy was associated with improvements in pVO2 and / or NYHA classification. Based on the data in Tables 3.4 and 3.5, a favorable trend appears to be observed across multiple biomarkers and parameters of symptoms and function (including the subgroup with elevated troponin: maximal VO2, NYHA, E / e', and KCCQ; and the subgroup with elevated E / e': maximal VO2, E / e', LVEDV, and KCCQ). Therefore, this subgroup is likely to benefit most from mabacamten therapy. [Table 9] An inverse correlation was observed between NT-proBNP levels and pVO2, a marker of clinical benefit in Maverick's patient subgroup (i.e., elevated troponin and / or E / e'). See Figure 14.

[0418] Example 4. Overdose of mabacamten In vitro experiments using isolated ventricular myocytes from adult rats and in vivo experiments using anesthetized rats have demonstrated that the pharmacological effects of mavacamtene can be counteracted by β-adrenergic agonists (isoproterenol and dobutamine, respectively). Therefore, in clinical trials of mavacamtene, if a subject experiences an adverse event (AE) that may be related to a reduction in cardiac output caused by mavacamtene administration, administration of a therapeutic dose of a β-adrenergic agonist (e.g., 5-10 μg / kg / min of dobutamine infusion) should be considered. Additional adjunctive measures, such as intravenous volume replacement and / or the use of arterial vasoconstrictors (α-adrenergic agonists), may complement the use of β-adrenergic agonists.

[0419] Methods: The responsiveness of mavacamten-induced cardiac depression to the induction of positive inotropy was evaluated in a set of conscious Sprague-Dawley rats. In these animals, reserve was assessed by induction with either dobutamine (+DOB, 10 ug / kg / min IV for 10 minutes, n=7) or levocimendan (+LEVO, >30 0.3 μmol / kg IV, n=6) 3 hours after a single dose of MAVA (4 mg / kg, PO). Cardiac function / morphology was recorded and compared at three separate time points / days: before administration (i.e., baseline) and 3 hours after administration (both before and during inotropy induction). To account for levocimendan-induced changes under load conditions, additional echocardiography was performed after recovery from acute preload in rats treated with LEVO (+LEVO / F, 0.9% NaCl IV at 30 mL / kg / h).

[0420] In these experiments, left ventricular shortening (FS), an indicator of systolic performance, as well as LV dimensions / volume and heart rate, were measured using a high-frequency transducer and parasternal transthoracic imaging (Vevo2100, VisualSonic). FS was defined as the standardized change in left ventricular dimensions / internal diameter between end-systole (LVESd) and end-diastolic (LVEDd) (i.e., FS = 100·[LVEDd-LVESd] / LVEDd). LV volume was derived assuming the Teichholz model (LVV = 7·[2.4+LVid]-1·LVid3).

[0421] Furthermore, the effect of MAVA (1.5 mg / kg PO, via enteral nutrition) on cardiac reserve was evaluated by acute β-AR induction (dobutamine: 2, 5, and 10 ug / kg / min IV) in fully-instrumented (LVPV group) conscious dogs with normal cardiac function. These inductions were performed pre- and post-(+3 hours) in both control and MAVA-treated animals under normal cardiac physiological conditions (n=4) and under (mild) associated cardiac suppression induced by either a selective β-AR blocker (+BB, metoprolol 0.5±0.1 mg / kg PO tid, n=4) or an L-type Ca2+ channel blocker (+CCB, verapamil 5±1 mg / kg PO tid, n=4). Pharmacological blockade was established 7 days prior to MAVA treatment. Both maximal and dose-response responses were evaluated at steady state.

[0422] Through these experiments, analog signals were digitally acquired (1000 Hz) and continuously recorded using a data acquisition / analysis system (IOX; EMKA Technologies). Heart rate (HR), end-systolic pressure (ESP) and end-diastolic pressure (EDP), as well as the maximum rate of pressure increase / decrease (dP / dtmax and dP / dtmin), contractility index (CI: dP / dt / P at dP / dtmax), and the time constant of myocardial relaxation (tau¹ / ², the time it takes for 50% decay from dP / dtmin) were derived from the LV pressure signal. Meanwhile, end-systolic volume (ESV) and end-diastolic volume (EDV) were measured from the LV volume signal derived from the transplanted myocardial crystal. Assuming the Teichholz model, LV volume was derived, and stroke volume (SV=EDV-ESV), ejection fraction (EF=SV / EDV), and cardiac output (CO=SV·HR) were calculated. In a subset of animals, SV and CO values ​​were validated from data obtained from implanted aortic blood flow probes. During each experiment, the pressure-volume relationship of the LV was also evaluated during a short-term reduction of cardiac preload (transient occlusion of the inferior vena cava due to expansion of an implanted cuff) using telemetry-based LV pressure and crystal-derived volume signals. The slope of preload recruitment work per stroke (PRSW; work per stroke versus EDV) and the end-systolic pressure-volume relationship (ESPVR; end-systolic elasticity, Ees) were derived using linear model software (IOX; EMKA Technologies) and used as load-independent inflorescence indices. Ventricular load was estimated by the effective arterial elasticity modulus (Ea = ESP / SV). Furthermore, functional left ventricular stiffness at end-diastolic pressure (LV-b) was estimated as the slope of the linear end-diastolic pressure-volume relationship (EDPVR), while the EDV / EDP ratio was used as an indicator of LV distensibility.

[0423] Both dobutamine (a synthetic β-AR agonist) and levocimendan (a phosphodiesterase-3 inhibitor) successfully restored echocardiographic indicators of systolic function (resulting in an approximately 50% reduction in ejection fraction) in healthy rats exposed to mavacamten at doses exceeding therapeutic levels. Similar observations were made in conscious dogs with long-term mavacamten implantation. In dogs, despite inducing suppression, dobutamine induced similar levels of stroke volume / cardiac output recruitment both before (i.e., control) and under acute mavacamten treatment. In particular, MAVA blunted the β-AR-induced increases in dP / dtmax and CI. Furthermore, in these animals, mavacamten not only enabled systolic recruitment but also enhanced the β-AR-induced acceleration of tau (and / or dP / dtmin, data not shown) at any given dP / dtmax, consistent with the observed improvement in myocardial distensibility described above.

[0424] Example 5. MYK-461-019 Study: An exploratory, open-label proof-of-concept study of mabacamten (MYK-461) in patients with heart failure with preserved ejection fraction (HFpEF) and chronically elevated cardiac troponin-I and / or NT-proBNP. This study is a multicenter, exploratory, open-label trial of mavacamten in approximately 35-40 walkable participants diagnosed with symptomatic HFpEF and elevated hs-cTnI or NT-proBNP (as defined in the selection / exclusion criteria). The number of participants without elevated hs-cTnI (>99th percentile) will be limited to 23. Participants will receive a 26-week course of mavacamten followed by an 8-week washout period. All participants will initially receive 2.5 mg orally daily. At week 14, the dose for some participants may be increased to 5 mg orally daily, as defined in the Study Treatment section below.

[0425] Experimental treatment: The doses of mabacamten used in this study are 2.5 and 5 mg. The dose adjustment at week 14 will be based on biomarkers (hs-cTnI and NT-proBNP) and left ventricular ejection fraction (LVEF) measured at the week 12 visit.

[0426] For participants joining the study with an hs-cTnI level above the 99th percentile, the dose will be increased to 5 mg at week 14 if the following conditions are met: 1. hs-cTnI (at week 12) has not decreased by at least 30% compared to the mean of all available pre-treatment values ​​(pre-screening, screening, and pre-medication on day 1), and 2. Resting LVEF (at week 12) has not decreased by more than 15% (relative reduction from the mean of all available screenings and the resting LVEF before medication on day 1), and 3. NT-proBNP levels have not increased by more than 50% from the mean of all available screening and pre-medication resting measurements on day 1. If the central laboratory determines that accurate quantitative estimation of LVEF from the 12-week ultrasound is impossible due to technical factors, repeat ultrasounds from unscheduled visits (if performed by 14 weeks) may be used for this purpose. If this is not possible, a qualitative assessment of LVEF from the 12-week TTE may be used.

[0427] For participants in the study with elevated NT-proBNP and hs-cTnI below the 99th percentile, the dose will be increased to 5 mg at week 14 if the following conditions are met: 1. NT-proBNP (at week 12) has not decreased by at least 50% or increased by at least 50% compared to the mean of all available pre-treatment values ​​(pre-screening, screening, and pre-medication on day 1), and 2. Resting LVEF (at week 12) has not decreased by more than 15% (relative reduction from the mean of all available screenings and the resting LVEF before medication on day 1).

[0428] Furthermore, after every visit in which the LVEF is measured as follows, there are provisions for temporary or permanent discontinuation of treatment based on the LVEF: • If the local ultrasound technician determines that the LVEF is 45% or less: In these circumstances, the ultrasound technician must notify the principal investigator and, in addition, re-examine and remeasure the findings with at least one other expert qualified in echocardiography (which may be the principal investigator). If the result is confirmed locally (LVEF ≤ 45%), the investigational drug will be permanently discontinued. If the central echocardiography laboratory determines that the LVEF has decreased by 20% (relative reduction) from baseline (average of all pre-screening / pre-medication values), or that the LVEF is between 45% and 50%, the investigational drug will be temporarily discontinued for two weeks. If the central laboratory determines that the quality of the TTE is insufficient for accurate estimation of LVEF, it will be necessary to attempt to obtain repeated unscheduled TTEs for this purpose. However, if this is not possible, or if the LVEF still cannot be quantitatively estimated, the central TTE laboratory will need to qualitatively determine whether the LVEF is likely to be below 50%, and this information will be used for medication administration. • If the local principal investigator is notified that the LVEF is less than 50% in non-test TTE, the investigational drug must be temporarily discontinued and TTE images obtained for further examination by the central TTE laboratory. If the central TTE laboratory determines that the LVEF is 45% or less in the TTE, the investigational drug must be permanently discontinued. If the central TTE laboratory determines that the LVEF is between 45% and 50%: the procedure in (2) above must be followed.

[0429] If the study drug is temporarily discontinued based on (2), the study drug may be restarted after two weeks if repeated TTEs demonstrate that the participant no longer meets the criteria for temporary discontinuation in the next TTE. The dose at restart will be 2.5 mg, regardless of the dose at the time of temporary discontinuation. If the participant meets the criteria for temporary discontinuation a second time after restarting the study drug, the study drug will be permanently discontinued.

[0430] Test objectives: [Table 10]

[0431] Test standards [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5]

[0432] Test evaluation items: [Table 12]

[0433] Example 6. VALOR trial: A randomized, double-blind, placebo-controlled trial to evaluate mabacamten in adults with symptomatic obstructive hypertrophic cardiomyopathy who are eligible for septal reduction therapy. This is a Phase 3 trial to evaluate the effect of mavacamten on reducing the number of septal reduction therapy (SRT) procedures in subjects with symptomatic obstructive hypertrophic cardiomyopathy (oHCM [also known as HOCM]) who are eligible for SRT based on the guidelines of the American Cardiology Foundation (ACCF) / American Heart Association (AHA) and / or the European Society of Cardiology (ESC) (i.e., the guidelines). The data from this trial will complement the results of the completed MYK-461-004 (PIONEER-HCM) trial and the ongoing MYK-461-005 (EXPLORER-HCM) trial in subjects with symptomatic oHCM and may extend the benefits of mavacamten to a population of severely symptomatic oHCM patients who are resistant to maximal medical therapy.

[0434] Test objectives and evaluation criteria: The primary, secondary, exploratory, and pharmacokinetic (PK) objectives and their respective evaluation criteria for the study are as follows: [Table 13-1] [Table 13-2] [Table 13-3]

[0435] Overall design: This study is a phase 3 randomized, double-blind, placebo-controlled, multicenter trial in men and women aged 18 years or older with oHCM who meet the ACCF / AHA and / or ESC guideline criteria for SRT (e.g., LVOT gradient ≥ 50 mmHg and NYHA class III-IV) and have been referred for invasive treatment. After completion of screening evaluations, eligible subjects will be randomized in a 1:1 ratio to either the mabacamten treatment group or the placebo treatment group. Randomization will be stratified by the type of SRT procedure recommended (muscle resection or alcohol septal ablation [ASA]) and NYHA functional classification.

[0436] The trial period is up to 138 weeks, including a 2-week screening period (-2 weeks), 128 weeks of treatment, and an 8-week follow-up visit after treatment (136 weeks).

[0437] There are three medication periods, as follows: • Placebo-controlled treatment period (Day 1 to Week 16): Subjects will receive either mavacamten or placebo once daily for 16 weeks in a double-blind study. • Active-control period (weeks 16-32): All subjects will be administered mabacamten once daily for 16 weeks. The dosage will be blinded. • Long-term continuous (LTE) dosing period (weeks 32-128): Mabacamten will be administered once daily to all subjects for 96 weeks. Dose blinding will be maintained unless the sponsor chooses to deblind after the completion of the primary analysis.

[0438] Testing procedures and treatment: • Trial visits will be conducted at screening, on day 1, every four weeks until week 32, every twelve weeks thereafter until week 128 (EOT), and at week 136 (end of trial). Visits must be conducted at the clinical trial site on day 1 and at weeks 8, 16, 24, and 32, every twelve weeks thereafter until week 128, and at week 136. At selected sites, trial visits may be conducted at the subject's home at weeks 4, 12, 20, and 28 with a qualified home healthcare professional contracted by the sponsor. Subjects who discontinue the study drug early at any point (excluding SRT) will participate in a treatment discontinuation visit within 14 days of discontinuation and will be followed up every 24 weeks thereafter until week 128. On day 1, eligible subjects will be double-blind and randomized to either the mavacamten group or the placebo group via an automated response system (IXRS). Randomization will be stratified by the type of SRT procedure (myoresection or ASA) and NYHA functional classification. Subjects will begin with mavacamten 5 mg or a matching placebo orally once daily for 16 weeks, after which dose adjustments will be evaluated. • At weeks 16, 32, 80, and 128, subjects will be reassessed for eligibility for SRT. The principal investigator will confirm that subjects are still receiving maximum medical care, determine their NYHA classification, and enter the information into the electronic case report form (eCRF). All efforts should be made to ensure that the same principal investigator who assessed NYHA at screening also assesses NYHA at weeks 16, 32, 80, and 128. A TTE will be performed alone and blinded to the principal investigator to assess the LVOT gradient at rest, induced, and after exercise. At weeks 16 and 32, the TTE will be interpreted by a central echocardiography laboratory, and the categorical LVOT gradient results (<50 mmHg or ≥50 mmHg) will be reported to the study site by the central laboratory. At weeks 80 and 128, LVOT <50 mmHg or ≥50 mmHg will be determined by echocardiography interpreted at the site. Maintain investigator blinding to LVOT gradient results until NYHA results are entered into the eCRF. Medical therapy, NYHA functional classification, and LVOT results will be reviewed by the investigator to determine whether (yes or no) the subject meets the ACCF / AHA and / or ESC eligibility criteria for SRT. The investigator will discuss recommendations with the subject. If the recommendation is to proceed with SRT, the subject may schedule SRT at a recommended HCM center after the recommended washout period of 6 weeks or more for the study drug has elapsed, or the subject may decline the recommendation and continue with the study drug. After the 16-week evaluation, subjects in the mabacamten treatment group who choose to continue treatment (i.e., do not decide to undergo SRT) will continue to receive mabacamten once daily for another 16 weeks at the same dose they were receiving at week 16. Subjects in the placebo group who choose to continue treatment (i.e., do not decide to undergo SRT) will begin receiving 5 mg of mabacamten once daily for 16 weeks, after which dose adjustments will be evaluated (placebo → active treatment group). Dose blinding of mabacamten will be maintained throughout the active treatment period. After the 32-week evaluation, all subjects who choose to continue treatment (i.e., do not decide to undergo SRT) (mavacamten group and placebo → active drug group) will continue daily mavacamten at the dose administered at 32 weeks for an additional 96 weeks, up to week 128 (EOT). Dose blinding of mavacamten will be maintained throughout the LTE treatment period unless the sponsor chooses to deblind after the completion of the primary analysis. Subjects will be re-evaluated for eligibility for SRT at weeks 80 and 128. During the trial, dose settings may be determined based on LVEF and LVOT as interpreted by the central echocardiography laboratory and in accordance with dose setting guidelines. Throughout the trial, all dose adjustments will be blinded and performed via IXRS. During the placebo-controlled treatment period (days 1-16), all subjects will be evaluated for the possibility of dose reduction at week 4 and dose increases at weeks 8 and 12. Subjects in the placebo group will be evaluated for dose determination but will continue to receive placebo. During the active-control period (weeks 16-32), the possibility of dose reduction at week 20 and dose increases at weeks 24 and 28 will be evaluated for subjects in the placebo-to-active drug group who started mabacamten at week 16. During the LTE treatment period (weeks 32-128), if the LVOT gradient measured by the Valsalva maneuver at the facility is 30 mmHg or higher and the LVEF is 50% or higher, the dose of mavacamten can be gradually increased at any scheduled visit after week 32. All dose increases during the LTE treatment period must be approved by the medical monitor before being implemented. Subjects whose mavacamten dose is increased during the LTE period will participate in an unscheduled trial visit 4 weeks after the dose increase, and then resume the normal trial visit schedule. • For safety reasons, the dose can be gradually reduced at any time. Safety will be monitored throughout the entire study. • The guidelines for determining the dosage in the trial are shown in Table 6.0. [Table 14]

[0439] Test scheme: The test scheme is shown in Figure 15.

[0440] Notes on the examination scheme: a. During the placebo-controlled treatment period (days 1 to 16), subjects will be evaluated for the possibility of dose reduction at week 4 and dose increases at weeks 8 and 12, based on independent assessment of TTE by a central echocardiography laboratory and in accordance with dose setting guidelines. For safety reasons, dose reduction may be used at any time. b. Evaluate the possibility of dose reduction at week 20 and dose increases at weeks 24 and 28 for subjects in the placebo-to-active drug group who started mabacamten at week 16. For safety reasons, the dose can always be gradually reduced. c. During the long-term continuous therapy (LTE) period (weeks 32-128), if the LVOT gradient measured by the Valsalva maneuver at the facility is 30 mmHg or higher and the LVEF is 50% or higher, the dose of mavacamten may be gradually increased at any scheduled visit after week 32. All dose increases during LTE therapy must be approved by the MyoKardia medical monitor before being implemented. Subjects whose mavacamten dose is increased during the LTE period will participate in an unscheduled trial visit 4 weeks after the dose increase, and then resume the normal trial visit schedule. For safety reasons, the dose may always be gradually decreased. d. At any point during the trial, subjects may discontinue the study drug and undergo SRT at an accredited HCM center after the recommended washout period of at least 6 weeks for the study drug has elapsed. Subjects who discontinue the study drug to undergo SRT will undergo an EOT assessment within 14 days and a telephone follow-up by the study site for assessment of adverse events 8 weeks after discontinuation of treatment (or before SRT, whichever comes first). Subjects will be followed up every 24 weeks from the date of SRT until week 128.

[0441] Investigational drug schedule: On day 1, subjects will begin a blinded 16-week course of either mavacamten or a matching placebo once daily (placebo-controlled period). After the 16-week evaluation, subjects in the mavacamten group will continue on mavacamten, while subjects in the placebo group will begin once-daily mavacamten from week 16 to week 32 (active-controlled period). During the active-controlled period, the mavacamten dose will be blinded. Starting at week 16 and continuing for the remainder of the study, the placebo group will be referred to as the placebo → active group. After the 32-week evaluation, all subjects will continue once-daily mavacamten until week 128 (LTE period). During the LTE period, the mavacamten dose will remain blinded unless the sponsor chooses to deblind after the completion of the primary analysis.

[0442] Evaluation criteria: Efficacy: The primary endpoint is a composite of 1) the number of subjects who decided to proceed with SRT before or at week 16, and 2) the number of subjects in the mabacamten group who were eligible for SRT guidelines at week 16 but declined, compared to the placebo group.

[0443] Safety: Safety assessments include monitoring of adverse events and concomitant medications, safety clinical laboratory evaluation, physical examination, vital sign measurement, TTE, cardiac / activity monitoring, and ECG.

[0444] SRT's rating: During screening, the principal investigator will verify the subject's NYHA functional classification and eligibility for SRT based on ACCF / AHA and / or ESC guidelines. At any point during the study, subjects may discontinue the study drug and proceed with SRT at an accredited HCM center after a minimum of six weeks, which is the recommended washout period for the study drug. Subjects who discontinue the study drug to receive SRT will undergo an End of Treatment (EOT) evaluation within 14 days and a telephone follow-up by the study site for adverse event (AE) assessment eight weeks after discontinuation (or before SRT, whichever comes first). Subjects will be followed up every 24 weeks from the date of SRT until week 128.

[0445] At weeks 16, 32, 80, and 128, subjects will be reassessed for SRT eligibility based on maximum medical therapy, NYHA functional classification, and TTE. Every effort should be made for the same investigator who assessed NYHA at screening to also assess NYHA at weeks 16, 32, 80, and 128. At weeks 16 and 32, after the investigator has determined NYHA, the central echocardiography laboratory will inform the study site of LVOT <50 mmHg or ≥50 mmHg. The investigator will make a guideline-based SRT recommendation (recommend or not recommend). Subjects must decide within 48 hours whether to accept the SRT recommendation or continue with the study treatment. At weeks 80 and 128, LVOT <50 mmHg or ≥50 mmHg will be determined by site-interpreted echocardiography.

[0446] To evaluate the efficacy results, an interim analysis will be conducted after all 50 participants have completed their 16-week trial visit.

[0447] Selection criteria: (A) The applicant must understand and comply with the test procedures, understand the risks associated with the test, and be able to provide written informed consent in accordance with federal, local, and facility guidelines before initiating any test-specific procedures. (B) Must be 18 years of age or older at the time of screening. (C) The patient weighs more than 45 kg at the time of screening. (D) Have an appropriate ultrasound window to enable accurate TTE (refer to the operating manual of the central echocardiography laboratory). (E) Diagnosed with oHCM (maximum septal thickness ≥15 mm or ≥13 mm, with a family history of HCM) in line with the current ACCF / AHA 2011 and / or ESC 2014 guidelines, and meeting the following invasive therapy recommendations of those guidelines: a. Clinical criteria: Despite maximally tolerable drug therapy, patients present with severe dyspnea or chest pain (NYHA Class III or IV) or exertional symptoms such as exertional syncope or presyncope, Class II. b. Hemodynamic criteria: A dynamic LVOT gradient of 50 mmHg or greater at rest or induced (i.e., Valsalva maneuver or exercise) with septal hypertrophy (interpreted by a central echocardiography laboratory), and c. Anatomical criteria: A target anterior septal thickness sufficient for the individual operator to perform the procedure safely and effectively. (F) You have been referred for SRT treatment within the past 12 months, or are actively considering it, and are willing to undergo SRT treatment. (G) Subjects referred to or considered for ASA must have coronary artery anatomical structures suitable for the operator to perform the procedure. (H) Resting oxygen saturation of 90% or higher is confirmed at the time of screening. (I) LVEF ≥ 60% is confirmed at the time of screening by interpretation of the central echocardiography laboratory. (J) Female subjects who are not pregnant or breastfeeding.

[0448] Exclusion criteria: 1. Participated in a clinical trial using mabacamten in the past (individuals who failed the screening in previous mabacamten trials are eligible to participate). 2. Hypersensitivity to any of the components of the mabacamten preparation. 3. You participated in a clinical trial in which any investigational drug was administered to subjects within 30 days prior to screening, or within at least five times the respective elimination half-life (whichever is longer) (or you are currently using an investigational device). 4. Known infiltrative or accumulative disorders that cause cardiac hypertrophy similar to that of oHCM (e.g., Fabry disease with LV hypertrophy, amyloidosis, or Noonan syndrome). 5. Invasive procedures planned during the first 32 weeks of the trial. 6. Papillary muscle or mitral valve requiring repair or any other planned intracardiac procedure (however, if the need for mitral valve repair is discovered during SRT treatment, the subject will continue to be followed up in the study). 7. For individuals taking beta-blockers, calcium channel blockers, or disopyramide, adjust the dosage of these medications at least 14 days prior to screening, or anticipate regimen changes during the first 16 weeks of the study. 8. Any medical condition that prevents exercise stress testing in a standing position. 9. Paroxysmal intermittent atrial fibrillation (atrial fibrillation is present at the time of screening based on the investigator's assessment of the subject's electrocardiogram (ECG)). 10. Persistent or permanent atrial fibrillation (subjects have not received anticoagulation treatment for at least 4 weeks prior to screening and / or have not had adequate heart rate control within 6 months prior to screening). 11. Previously treated with invasive septal reduction (surgical myofascial resection or percutaneous ASA). 12. Implantation of an implantable ICD or replacement of a pulse generator planned during the first 32 weeks of the trial. 13. If the QRS interval is less than 120 ms, use a QT interval greater than 500 ms with Fridericia correction (QTcF), or if the subject has left bundle branch block, use a QTcF greater than 520 ms if the QRS is 120 ms or longer. 14. Acute or serious comorbidities (e.g., serious infection or blood, renal, metabolic, gastrointestinal, or endocrine dysfunction) that, at the discretion of the principal investigator, could lead to early termination of participation in the study or interfere with the measurement or interpretation of efficacy and safety assessments of the study. 1. Lung diseases that limit exercise capacity or systemic arterial oxygen saturation. 2. History of malignant disease within 10 years prior to screening: 1. Subjects who have successfully received treatment for non-metastatic cutaneous squamous cell carcinoma or basal cell carcinoma, or who have been appropriately treated for cervical intraepithelial neoplasia or ductal carcinoma in situ, may be included in the study. 2. Subjects with other malignant tumors who have not had cancer for more than 10 years prior to screening may be included in the study. 15. Any other clinically significant impairment, condition, or disease history or evidence that, in the opinion of the principal investigator, could pose a risk to the safety of the subject or could interfere with the evaluation, procedure, or completion of the study. 16. Safety clinical laboratory parameters (chemistry, hematology, coagulation, and urinalysis) outside the normal range at the time of screening, as evaluated by the central laboratory. However, subjects with safety clinical laboratory parameters outside the normal range may be included if all of the following criteria are met: a. The principal investigator deems safety clinical laboratory parameters outside the normal range to be clinically non-critical. b. If alanine aminotransferase or aspartate aminotransferase results are available, the value must be less than three times the upper limit of the laboratory's reference range. c. Estimated glomerular filtration rate adjusted for body size: 30 mL / min / 1.73 m 2 That's all. 17. Positive serological test for infection with human immunodeficiency virus, hepatitis C virus, or hepatitis B virus at the time of screening (excluding positive results for hepatitis B s antibody, an immune marker). 18. Prior treatment with cardiotoxic agents such as doxorubicin or similar drugs. 19. Unable to comply with the trial requirements, including the required number of visits to the trial facility.

[0449] Test evaluation schedule [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4] [Table 16-1] [Table 16-2] [Table 16-3] [Table 17] [Table 18]

[0450] Example 7. EXPLORER-HCM trial: A phase 3, double-blind, randomized, placebo-controlled, multicenter, international, parallel-group trial to evaluate the safety, tolerability, and efficacy of mavacamten compared to placebo (1:1) in participants with symptomatic oHCM. A phase 3, double-blind, randomized, placebo-controlled, multicenter, international, parallel-group trial was conducted to evaluate the safety, tolerability, and efficacy of mavacamten compared to placebo (1:1) in participants with symptomatic oHCM. 251 participants were enrolled (123 receiving mavacamten and 128 receiving placebo). A subset of participants agreed to participate in a CMR substudy at a selected site. Randomization was stratified according to NYHA functional class (Grade II or III), current beta-blocker treatment (yes or no), type of ergometer planned for use during the trial (treadmill or exercise bike), and consent to the CMR substudy (yes or no).

[0451] The purpose of the exam: The purpose of the test was as follows: [Table 19]

[0452] Experimental design: This study included three periods conducted according to the following design.

[0453] 1) Screening Period (Day 35 to Day 1): Over a period of 1-2 days, participants will be evaluated for a variety of general, cardiopulmonary, clinical laboratory, symptomatic, and PRO assessments to determine eligibility. Key screening tests include electrocardiogram (ECG); transthoracic echocardiography (TTE) performed at rest, under the Valsalva maneuver, and after exercise; and cardiopulmonary exercise testing (CPET). Screening assessments of blood tests, ECG, and / or TTE may be repeated as long as they remain within the 35-day screening window. Repeated evaluations are permitted if the central laboratory requests them due to quality issues or to better assess the selection / exclusion values. For participants who fail screening, re-screening may be considered at the discretion of the principal investigator, taking into account the reason(s) for screening failure. Re-screening will be permitted as a single trial, and all procedures must be repeated.

[0454] 2) Double-blind treatment period (Day 1 [randomization] to Week 30 / end of treatment [EOT]): The double-blind treatment period includes a two-stage dose-setting scheme designed to achieve safe and effective medication for each participant based on each participant's response parameters. Participants who meet all eligibility criteria at screening are first randomized in a 1:1 ratio via an automated response system to receive treatment with a starting dose of mavacamten 5 mg once daily (QD) or a matching placebo. Subsequently, evaluations including ECG, PK (trough plasma concentration), and TTE are performed at each of the seven study visits starting from week 4 and determined by the central laboratory. At weeks 8 and 14, the dose may be increased, decreased, or left unchanged based on the results of the evaluations at weeks 6 and 12, respectively, and primarily based on the measured left ventricular outflow tract (LVOT) gradient at evoked, and the dose is limited by the target plasma concentration (PK) range and clinical tolerability (LVEF). At week 8, the dose can be increased to a maximum of 10 mg per day (i.e., from 5 mg QD to 10 mg QD), and at week 14, it can be increased to a maximum of 15 mg per day (i.e., from 10 mg QD to 15 mg QD). The dose increase is designed to be gradual, and skipping doses (e.g., from 5 mg to 15 mg) is prohibited.

[0455] At week 30 / EOT, participants will complete CPET and post-exercise TTE. Participants who permanently discontinue treatment before week 30 should undergo an early discontinuation (ET) visit, including CPET and post-exercise TTE, as soon as possible. ET participants are also encouraged to complete all remaining trial visits and evaluations, including the week 30 visit.

[0456] 3) Post-treatment follow-up period (week 30 / EOT to week 38 / end of study [EOS]): After the completion of double-blind treatment at week 30, participants will be contacted by phone at week 34 and will revisit the facility at week 38 for the end of study (EOS). Specific assessments will be repeated at the EOS visit. This post-treatment follow-up period applies only to participants who received the study drug from week 22 onwards. The study design is shown in Figure 16.

[0457] Safety monitoring: Safety monitoring was conducted as follows:

[0458] To maintain safety throughout the entire double-blind treatment period, clinic visits will be scheduled every 2–4 weeks starting from week 4 for initial assessments of clinical tolerability and safety. Clinic visits will include, but are not limited to, clinical assessments (symptoms, PRO assessment, adverse event [AE] / serious adverse event [SAE] assessment), ECG, PK sample, TTE, and clinical laboratory assessments. The results of TTE performed by the ultrasound technician at the study site at each scheduled visit after randomization must be blinded to the principal investigator and other site personnel. An exception may be made if a left ventricular ejection fraction (LVEF) of 30% or less is measured at the site, in which case the principal investigator will be immediately notified and the study drug will be permanently discontinued as described in the protocol.

[0459] The evaluations at weeks 4, 6, 8, 12, 18, 22, and 26 will be used to guide dose reduction or temporary discontinuation as necessary, based on pre-defined criteria detailed in the implementation protocol. If the dose of mavacamten is reduced from the previous dose during the double-blind treatment period, participants will continue the reduced dose until end-of-treatment (EOT) (week 30), unless further safety concerns or intolerances arise.

[0460] At selected sites, participants will have the option to participate in a CMR substudy. Approximately 80 participants will be enrolled (approximately 40 per treatment group). Participants will receive CMR on day 1 and week 30 (or up to 5 days before each visit), in addition to the main trial schedule of the procedure.

[0461] Experimental treatment: During the first eight weeks of the treatment period, participants were administered either 5 mg of mabacamten immediate-release capsules or a matching placebo via QD, and trough PK samples were collected at weeks 4, 6, and 8. If the trough PK level was between 700 ng / mL and 1000 ng / mL at week 4, the dose was reduced to 2.5 mg at week 6.

[0462] Otherwise, the dose was adjusted (increased, decreased, or left unchanged) at week 8 based on the evaluation at week 6, and at week 14 based on the evaluation at week 12. The acceptable doses after dose adjustment at week 8 were 2.5 mg, 5 mg, 10 mg, or placebo. The acceptable doses after dose adjustment at week 14 were 2.5 mg, 5 mg, 10 mg, 15 mg, or placebo.

[0463] To enhance safety, if PK < 1000 ng / mL at 700 ng / mL < 8 weeks, an unscheduled hospital visit was planned two weeks later (week 10) to reduce the dose. From week 14 onward, evaluations were continued every four weeks until week 30 / EOT for safety monitoring.

[0464] If the PK plasma concentration was 1000 ng / mL or higher, the test drug was always temporarily discontinued.

[0465] Each participant took part in the trial for a maximum of 43 weeks. Screening took up to 5 weeks, and the trial itself took 38 weeks (±7 days).

[0466] Selection criteria and exclusion criteria: The following selection and exclusion criteria were used. [Table 20-1] [Table 20-2] [Table 20-3] [Table 20-4] [Table 20-5]

[0467] Test evaluation items:

[0468] The following evaluation criteria were used in the test: [Table 21-1] [Table 21-2]

[0469] result Effectiveness: Of the 123 patients in the treatment-intended group, 45 (36.6%) met the primary efficacy endpoint of clinical response, defined as achieving either 1) an improvement of at least 1.5 mL / kg / min in maximal oxygen consumption (pVO2) as determined by CPET and a reduction of 1 degree or more in NYHA functional classification, or 2) an improvement of 3.0 mL / kg / min or more in pVO2 without deterioration of NYHA functional classification (referred to as a "combined functional response"). Of the 128 patients in the placebo group, only 22 (17.2%) met the primary efficacy endpoint. Mabacamten demonstrated a statistically significant benefit for the primary efficacy endpoint. Data for the primary efficacy endpoint are shown in Table 7.1. [Table 22]

[0470] Table 7.2 shows the data for secondary efficacy endpoints. Mabacamten provided a statistically significant benefit for all secondary efficacy endpoints. [Table 23]

[0471] 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 two-week recall period (Green et al, 2000). In addition to the individual domains, two summary scores can be calculated from the KCCQ-23: the overall summary score (OSS) (including scores for total symptoms, physical limitations, social limitations, and quality of life) and the clinical summary score (CSS) (a sum of the scales for total symptoms and physical limitations). The scores range from 0 to 100, with higher scores reflecting a better state of health.

[0472] The HCMSQ score is a patient-reported outcome measure (questionnaire) used to assess the symptoms of HCM in a clinical setting. It provides a diagnostic tool for specifically capturing HCM symptoms and longitudinally evaluating treatment response. The HCMSQ-SoB score is a subscore of questions 1-6 of the HCMSQ. Participants in the study received a handheld electronic device and training at screening. During screening, participants completed the HCMSQ daily for a minimum of 7 days, and daily for the first 6 weeks after the start of treatment. Participants completed the HCMSQ daily on the handheld electronic device for consecutive 7-day (1-week) periods prior to weeks 10, 14, 18, 22, 26, 30 (EOT), and 38 (EOS).

[0473] HCMSQ Questionnaire: [Table 24-1] [Table 24-2]

[0474] 65% of patients taking mabacamtene achieved NYHA Class I status, compared to 21% in the placebo group. 57% of patients taking mabacamtene achieved a post-exercise LVOT maximum gradient of less than 30 mmHg, compared to 7% in the placebo group. 27% of patients taking mabacamtene achieved complete response (NYHA Class I and all LVOT gradients less than 30 mmHg), compared to 1% in the placebo group.

[0475] Table 7.3 shows the data for the primary exploratory efficacy endpoints. Mabacamten demonstrated statistically significant improvement compared to placebo in each of the primary exploratory efficacy endpoints. [Table 25]

[0476] The results for the main biomarkers are shown in Table 7.4. Mabacamten showed a statistically significant reduction in NT-proBNP levels and hs-cTnI levels compared to placebo. [Table 26]

[0477] Table 7.5 shows the baseline characteristics of the test population. Baseline characteristics are measured before treatment. Improvement is defined as the change from baseline. [Table 27]

[0478] Safety: Several discontinuations were reported. Eight temporary discontinuations were reported in patients taking mabacamten (all patients were on a 5 mg dose), and seven temporary discontinuations were reported in patients taking placebo. One disease-related sudden death occurred in the placebo group. No other disease-related SAEs were reported. Five permanent treatment discontinuations were reported, three of which were due to adverse events: two in mabacamten (atrial fibrillation, syncope) and one in placebo (sudden death). Two discontinuations were due to the subjects discontinuing treatment themselves (one in mabacamten and one in placebo); one was due to the patient leaving the facility, and the other was due to the patient deciding to discontinue the study drug.

[0479] Mabacamten was well-tolerated and showed a placebo-matched safety profile at doses ranging from 2.5 to 15 mg. Ten subjects (8.1%) experienced a primary emergency encephalopathy (SAE) by 30 weeks in the mabacamten group. Eleven subjects (8.6%) in the placebo group experienced an adverse event (AE). There were 12 SAEs in the mabacamten group compared to 20 in the placebo group. Severe tetanic endothelial effect (TEAE) occurred in 7 subjects (5.7%) in the mabacamten group compared to 13 subjects (10.2%) in the placebo group. Cardiac SAEs occurred in 4 patients in the mabacamten group and 4 patients in the placebo group.

[0480] A medication approach based on standard echocardiography consistently performed well. Of the 251 participants, five experienced temporary discontinuation related to reduced ejection fraction (3 in mavacamten and 2 in placebo). After dose adjustment, all mavacamten patients returned to the study and completed it.

[0481] Conclusion: Mabacamten demonstrated robust therapeutic efficacy against the primary and all secondary endpoints of the Phase 3 EXPLORER pivotal trial, with statistical significance (p ≤ 0.0006 for all endpoints). In the majority of patients treated with mabacamten, symptoms decreased, motor function increased, and left ventricular obstruction (a definitive characteristic of the patient's condition) decreased or resolved.

[0482] Data from the EXPLORER pivotal trial demonstrate the ability of mavacamten to be safely administered to achieve statistically significant and clinically meaningful outcomes. Treatment with mavacamten resulted in a statistically significant benefit compared to placebo (p=0.0005) for the primary endpoint of the EXPLORER-HCM, a composite functional analysis designed to capture the effects of mavacamten on both symptoms and cardiac function. Secondary endpoints also showed statistically significant improvements compared to placebo.

[0483] Mavacumten was well-tolerated and consistent with previous clinical trials of mavacumten, exhibiting a safety profile similar to placebo. More serious adverse events (SAEs) occurred in the placebo arm than in the treatment arm (20 vs. 12). The overall incidence of cardiac AEs was similar between the active and placebo cohorts and was not directly attributable to mavacumten use.

[0484] Example 8. Open-label pharmacokinetic study of single-dose mavacamten in healthy adults with normal or low-metabolism CYP 2C19 based on genotype. overview: CYP2C19 is the major enzyme involved in the metabolism of mabacamtene. Specifically, in vitro experiments have shown that CYP2C19 contributes 74% to the metabolism of mabacamtene. Other CYP enzymes metabolize mabacamtene to a lower degree, with these enzymes and their contributions being CYP3A4 / 5 (18%), CYP2C9 (7.5%), and CYP2J2 (very small). Therefore, CYP2C19 plays a major role in the metabolism and pharmacokinetics of mabacamtene.

[0485] This study investigates the effects of CYP2C19 enzyme polymorphisms on the metabolism and pharmacokinetics of mabacamten. The main polymorphisms affecting CYP2C19 function include those that cause loss of function. * 2(rs4244285) and * 3 (rs4986893), and causing the acquisition of functionality* It includes 17(rs12248560). Polymorphisms of CYP3A4 / 5 and CYP2C9 are currently being further tested, but it has been found that they have only a slight effect on the pharmacokinetics of mavacamten.

[0486] Individuals can be classified as poor metabolizers (PM), intermediate metabolizers (IM), extensive / normal metabolizers (EM / NM), rapid metabolizers (RM), and ultra-rapid metabolizers (UM) according to genotype / phenotype. Individuals with a poor metabolism (PM) phenotype have a * 2 / * 2, * 2 / * 3, or * 3 / * 3 genotype. Intermediate metabolizers (IM) have a * 1 / * 2 or * 2 / * 17 genotype. Normal metabolizers (NM) have a * 1 / * 1 genotype. Ultra-rapid metabolizers (UM) have * 17 / * 17, and rapid metabolizers (RM) have * 1 / * 17 genotype.

[0487] For CYP2C19, two genotype identification platforms have been approved by the FDA. The first is the Amplichip® CYP450 Test (Roche Molecular Systems, Inc., Pleasanton, CA), which examines CYP2C19 * 2 and <00​​​​​​​​​​The influence of CYP2C19 phenotype and genotype on the metabolic function of the CYP2C19 enzyme is currently being investigated. Currently, CYP2C19 phenotype / genotype has been shown to be associated with the half-life and clearance rate of mabacamten. Specifically, normal metabolites typically have a half-life of about 6–9 days, e.g., about 7 days (1 week), while low metabolites have a longer half-life, e.g., about 12–30 days, or often, based on current human data, about 16–28 days. Furthermore, the clearance rate of normal metabolites is typically about 10–100 mL / min, while low metabolites have a lower clearance, e.g., less than about 15 mL / min (e.g., less than 10 mL / min).

[0489] Since the influence of CYP2C19 phenotype / genotype on the pharmacokinetics of mabacamten has been observed, treatment methods that are safe for patients with a low metabolic rate and effective for patients with a normal metabolic rate are currently being developed.

[0490] Dosage adjustments for treating HCM can be made based on an individual's ability to metabolize mabacamtene. Low metabolites of mabacamtene may include individuals with a variant of CYP 2C19. Low metabolites of mabacamtene may be administered a lower starting dose and / or the dose may be adjusted to lower amounts such as 1 mg, 1.5 mg, 2 mg, or 2.5 mg, and the dose may be adjusted upward or downward based on echocardiography. For example, in some embodiments, an initial dose of 2 mg or 2.5 mg is administered to low metabolites of mabacamtene, and the dose may be adjusted downward to 1 mg based on LVOT and LVEF, and the dose may be adjusted downward if it is above 1000 ng / ml. In some embodiments, an initial dose of 1 mg is administered to low metabolites of mabacamtene. Mabacamtene is partially metabolized by CYP 2C19, an enzyme affected by genetic polymorphism. The incidence of the CYP 2C19 hypometabolism (PM) phenotype varies from approximately 2% in Caucasians to over 10% in some Asian countries (see, e.g., Yusuf et al., Advances in Experimental Medicine and Biology, 531, pp. 37-46 (2003)). Our previous analyses have shown that individuals with the PM genotype may have approximately four times higher exposure to mabacamtene compared to individuals with the CYP 2C19 normal metabolism (NM) genotype. The following study is designed to more accurately determine the mabacamtene exposure of participants with the PM genotype and those with the NM genotype.

[0491] The purpose of the exam: (1) Evaluate the pharmacokinetics (PK) of a single dose of mabacamten in healthy participants who are either normally metabolized or hypometabolized based on their genotype of CYP2 C19.

[0492] (2) Evaluate the safety of a single dose of mabacamten in the above participants.

[0493] Test design and planning: This study is for normal metabolism (NM; * 1 / * 1) CYP 2C19 genotype or low metabolism (PM; * 2 / * 2 or * 3 / * 3 or * 2 / * 3) This is a phase 1, single-center, open-label, parallel-group study on the administration of a single oral dose of mabacamten 15 mg to healthy participants exhibiting any of the CYP 2C19 genotypes.

[0494] Upon signing the informed consent form and verifying eligibility, approximately eight healthy NM participants and eight healthy PM participants will be admitted to the Clinical Research Unit (CRU) the day before administration of the study drug (-1 day). On day 1, participants will receive a single oral dose of 15 mg of mabacamten. Participants will remain in the CRU until day 3 (48 hours after administration of the study drug). Blood samples will be collected in the CRU to determine mabacamten concentrations before administration and at 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, and 48 hours after administration of the study drug. Outpatient visits will be scheduled on days 7, 10, 14, 21, 28, 35, and 45 to obtain additional blood samples. The final blood sample will be collected at the final visit on day 60. In addition, urine and stool samples will be collected during the in-hospital period. For each identified PM participant, an NM participant was identified. The NM participant was of the same race as the corresponding PM, and their weight was within ±5 kg of the corresponding PM.

[0495] Genotype assessment: Blood will be drawn twice for genotyping. The first blood draw will be performed during the pre-screening evaluation for CYP 2C19 genotyping. Participants will sign an informed consent form (ICF) during the pre-screening evaluation to consent to blood collection. The second blood draw will be performed on day -1 of CYP 2C9 genotyping.

[0496] Experimental treatment: After fasting for 8 hours overnight, each participant is orally administered one 15 mg mabacamten immediate-release capsule with approximately 240 mL (8 fluid ounces) of water.

[0497] Exam period: A pre-screening period of up to 120 days, a 30-day screening period, and then up to 61 days thereafter (4 days in the hospital and 57 days on an outpatient basis).

[0498] Main selection criteria: The main selection criteria are as follows: 1. Male or female between the ages of 18 and 60, 2. Genotype determined by the central laboratory during the pre-screening period. * 1 / *CYP 2C19 NM or genotype having 1 * 2 / * 2. * 3 / * 3, or * 2 / * It is a PM that has 3, 3. Participants must have a Body Mass Index (BMI) of 18 kg / m². 2 ~30kg / m 2 That is, 4. Participants must be healthy based on their medical history, physical examination, vital signs, and routine laboratory parameters (chemistry, hematology, and urinalysis); as well as their electrocardiogram (ECG) at the screening visit and on day 1. Laboratory values ​​outside the normal range are acceptable if they are deemed clinically insignificant. 5. ECG and clinical laboratory evaluations can be repeated at the time of screening and on day 1.

[0499] Main exclusion criteria: The main exclusion criteria are as follows: 20. Participants have been previously exposed to mabacamten; 21. Participants have a history of clinically significant arrhythmia, LV systolic dysfunction, or coronary artery disease; 22. Participants must have a history of any type of malignant tumor other than cervical intraepithelial neoplasia or surgically excised non-melanoma skin cancer within 10 years prior to day 1; 23. Participants must be positive for infection by human immunodeficiency virus, hepatitis C virus, or hepatitis B virus at the time of screening; 24. Participants must test positive for alcohol or drug abuse at the time of screening or on day 1; 25. Participants have used prescription medications within 28 days of day 1, or over-the-counter medications (including herbal preparations and supplements) within 14 days of day 1 (maximum 1.5 g of acetaminophen per day is permitted); 26. Participants have a history or evidence of any other clinically significant impairment, condition, or disease (other than those outlined above) that, in the opinion of the Principal Investigator or a physician at MyoKardia, could pose a risk to participant safety or could interfere with the evaluation, procedure, or completion of the study; 27. Participants have or are being treated for any condition that could interfere with the conduct of the study or, in the opinion of the principal investigator, could put the participant's participation in the study at risk. This includes, but is not limited to, alcoholism, drug dependence or abuse, and psychiatric conditions; 28. Participants currently use more than 10 tobacco-containing or nicotine-containing products per day, or an equivalent amount; 29. Participants have received the investigational drug within 30 days prior to screening, or within at least five times the respective elimination half-life (whichever is longer) (or are currently using the investigational device); 30. Participants are unable to comply with the trial's constraints / requirements, including the required number of visits to the clinical site. 31. Participants had donated 500 mL or more of blood in the 60 days prior to their screening visit, or plasma in the 2 weeks prior to their screening visit.

[0500] Test evaluation items: Pharmacokinetic evaluation parameters include the following: Area under the concentration-time curve (AUC(0-∞)) from 3.0 to infinity. 4. Maximum blood concentration (Cmax) 5. Half-life (t 1 / 2)

[0501] Safety evaluation items include the following: 3.AE 4. Physical examination findings 5. ECG parameters 6. Vital signs 7. Clinical laboratory data, including routine chemical and hematological parameters.

[0502] Example 9. Analysis of half-life and clearance in initial clinical trials using mabacamten. In the initial clinical trial, 34 patients were administered mavacamten at various doses ranging from 1 mg QD to 48 mg QD. Half-life and clearance rate were analyzed after a single oral administration. Clearance rate was defined as CL = dose × F / AUC. inf The calculation was performed as follows. In the second clinical trial, 21 patients were administered mavacamten at various doses ranging from 1 mg BiD to 18.5 mg QD. The half-life and clearance rate were analyzed after the final dose, when a steady state was reached. The clearance rate was calculated as CL, SS = Dose x F / AUC (0-T) The results were calculated as follows. The data from both trials were combined and analyzed using one-way ANOVA followed by Tukey's multiple comparison test.

[0503] Figure 17 shows the half-lives of mavacamten in patients grouped by metabolic phenotype. UM (rapid / ultrarapid metabolism) * 1 / * 17 or * 17 / * 17, and EM (high metabolic type) * 1 / * 1, and IM (medium metabolic) is * 1 / * 2 or * 17 / * 2, and PM (low metabolic type) is * 2 / * 2 or * 2 / * The answer is 3.

[0504] Figure 18 shows the mavacamten clearance rate (CL / F) for patients grouped by metabolic phenotype. Patients with a low CYP2C19 metabolism had lower clearance and a longer terminal half-life than other patients (UM, EM, and IM).

[0505] Similar tests were conducted for CYP3A5 and CYP2C9 polymorphisms. The CYP3A5 and CYP2C9 genotypes did not significantly affect the half-life or clearance rate of mabacamten.

[0506] Example 10. 10A. Preliminary Population PK Modeling A model was constructed using data from clinical trials of mabacamten in healthy subjects and HCM patients. The model captures exposure and variability across the entire population.

[0507] The model used data from studies testing mavacamten in solution and tablet forms at various doses ranging from 1 to 48 mg per day in healthy controls and patients with oHCM.

[0508] A two-compartment linear PK model, including linear elimination and primary absorption, well characterized individual and mean concentrations for each dose and trial. Two major covariates were identified: CYP2C19 genotype and body weight. * One copy of the allele was predicted to reduce the clearance rate to 59% of that of wild-type CYP2C19. * Two copies of the allele were predicted to reduce the clearance rate to 24% of that of wild-type CYP2C19. Table 10.1 shows the predicted clearance rates and resulting exposure (AUC) for various genotypes. Figures 19A-C show the mean measured plasma concentrations as scatter plots (90% CI) and the modeled plasma concentrations as solid lines. Figure 19A shows the case of a single dose. Figure 19B shows the case of multiple doses. Figure 19C shows the case of multiple doses over a long period. [Table 28]

[0509] This model suggests that safety can be ensured in patients, including those with low metabolic rates, at a low starting dose. For example, according to the model, all patients, including those with low metabolic rates, will have concentrations below 800 ng / mL with a low starting dose (5 mg / day) administered daily for 8 weeks. Figure 20 shows a simulated experiment involving 1500 patients with different CYP2C19 genotypes and the predicted range of mavacamten plasma concentrations for these 1500 patients.

[0510] Simulation experiments in the Japanese population suggest that a starting dose of 2.5 mg / day is appropriate due to the high proportion of patients with a hypometabolic phenotype.

[0511] 10B. Population PK Modeling Body weight had a significant impact on total exposure, with heavier subjects experiencing higher clearance (CL) and larger volume of distribution. This resulted in a 1.25-fold higher predicted concentration in a typical oHCM subject weighing 70 kg compared to a subject weighing 90 kg, and a 1.67-fold higher predicted concentration in a typical oHCM subject weighing 50 kg compared to a subject weighing 90 kg. Patient type (oHCM vs. healthy subjects) also had a significant impact on total exposure. This resulted in a 1.73-fold higher predicted concentration in a typical oHCM subject compared to a typical healthy subject of the same weight. As shown in Table 10.2, CYP2C19 genotype was also found to have a significant impact on CL and therefore on exposure. Exposure levels were approximately four times higher in the low-metabolic type than in the wild type. [Table 29]

[0512] Simulation experiment A pharmacokinetic (PK) simulation was conducted to evaluate the concentration-related aspects of the safety monitoring and dose adjustment algorithms proposed in the protocol for the EXPLORER trial in patients with oHCM. While the additional dose adjustment criteria in the protocol based on left ventricular ejection fraction (LVEF) and left ventricular outflow tract (LVOT) gradients were not implemented in this simulation, they are expected to enhance the overall safety of the trial. These simulated experiments generated 1500 simulated subjects. The mean (SD) body weight of the subjects was 93.2 kg (14.1), as seen in the oHCM patient study (Study 004 Parts A and B), with a range of 44.6 to 142.6 kg. These simulated subjects also had a distribution of CYP2C19 genotype / phenotype, as suggested by the aggregated study data. [Table 30]

[0513] The distribution of PK parameters in the simulated subjects was as determined by the PK model. There are no known or expected correlations between CYP2C19 genotype / phenotype and body weight.

[0514] In the initial simulated experiment, all simulated subjects were administered 5 mg once daily (qd) for 30 weeks. In the aggregated trial, actual CYP2C19 low metabolism ( * 2 / * 2) Comparison with the predicted PK of the 5 mg qd dose for subjects (PM) showed that they were well-characterized in the simulated experiment. Only 2.9% of subjects were predicted to exceed the safety threshold of 700 ng / mL by week 30, and the vast majority of these were PMs. However, 85% of the simulated subjects failed to exceed the defined minimum efficacy threshold of 350 ng / mL by week 30, indicating the need for dose-setting.

[0515] In the second simulated trial, all simulated subjects started with a 5 mg qd dose. Following the dosing algorithm in the EXPLORER clinical trial protocol, safety assessments were conducted at weeks 4, 6, 12, 18, 22, and 26. Subjects recording concentrations above 700 ng / mL had their dose reduced after two weeks, or subjects recording concentrations above 1000 ng / mL had their medication discontinued. For subjects recording concentrations below 350 ng / mL, dose increases to 10 mg or 15 mg qd were considered based on the assessments at weeks 6 and 12.

[0516] Figure 20 shows the time course of concentrations for all 1500 simulated subjects (in the second simulated experiment), color-coded by final dose. The vertical dotted lines indicate the weeks in which safety or dose adjustments were evaluated (including the adjusted doses for affected subjects two weeks later). The horizontal dashed lines indicate the specified safety thresholds (700 and 1000 ng / mL) and the low concentration threshold (350 ng / mL).

[0517] At week 30, 85% of subjects were in the 350-700 ng / mL range, 15% were below this range, and no subjects were predicted to be above it. After the final dose adjustment at week 28, 13%, 38%, and 46% of subjects were taking doses of 5, 10, and 15 mg, respectively, 2.7% were taking 2.5 mg, and 0.73% were predicted to require discontinuation to placebo. Low metabolic rate (PM, * 2 / * 2) comprised all subjects who required discontinuation to placebo, and 60% of those with a low metabolic rate were taking a 2.5 mg dose by 28 weeks.

[0518] Of the PM subjects, 17% required discontinuation of placebo, and after final dose adjustment at week 28, 38%, 42%, and 3% were projected to be taking 2.5, 5, and 10 mg, respectively. No PM subjects were administered 15 mg.

[0519] The simulation shows that, under safety monitoring and dose adjustment algorithms, the majority of subjects are expected to remain within the estimated therapeutic range of 350–700 ng / mL.

[0520] analysis: A two-compartment linear PK model, including primary absorption and absorption lag, well characterized individual and mean concentrations for each dose and study. Body weight significantly influenced total exposure and was therefore input into the model as an influence on both CL and Q, and on both V2 and V3 (central and peripheral volume of distribution). This resulted in a 1.25-fold higher predicted concentration in a typical oHCM subject weighing 70 kg compared to a subject weighing 90 kg, and a 1.67-fold higher predicted concentration in a typical oHCM subject weighing 50 kg compared to a subject weighing 90 kg.

[0521] * The CYP2C19 genotype covariance for one or two copies of the two alleles was found to significantly reduce CL. * Two copies of the 17 alleles were found to slightly significantly increase CL, while, *No single copy of the 17 alleles was found to have a significant impact on CL. This study identified a phenotypic group (low metabotropic (PM); * 2 / * 2); intermediate metabolizer (IM; * 1 / * 2. * 2 / * 17);Extensive metabolizer (EM; * 1 / * 1. * 1 / * 17); and ultrafast metabolic (UM; * 17 / * 17)) was identified as a covariate. The EM group was considered the base case. Other phenotypic covariates were used in the final model.

[0522] In summary, the combination of low body weight and high prevalence of the CYP2C19 PM genotype in Asian countries suggests that a single, safe, medication regimen for oHCM should be a starting dose of 1–2.5 mg per day (e.g., QD) followed by a dose regularly adjusted based on the patient's response (LVOT gradient and LVEF) and / or plasma mavacamten concentration.

[0523] Example 11: Randomized, double-blind, placebo-controlled clinical trial and long-term safety extension study to evaluate mabacamten in Japanese adults with symptomatic oHCM. This study is a phase 3, double-blind, randomized, placebo-controlled, multicenter, parallel-group trial to evaluate the safety, tolerability, and efficacy of mavacamten in Japanese subjects with symptomatic oHCM. Approximately 45 subjects will be enrolled. Subjects will be randomized in a 2:1 ratio (30 to mavacamten, 15 to placebo). The study consists of four periods: a screening period (5 weeks), a treatment period (30 weeks), a long-term continuation period (102 weeks), and a post-treatment follow-up period (8 weeks).

[0524] During the treatment period, a dose-setting scheme will be used to achieve safe and effective medication for each subject based on their response parameters. The starting dose is 2.5 mg once daily (or a matching placebo). The dose can be adjusted to 1, 2.5, 5, 10, and 15 mg. Assessments including ECG, PK (pre-administration plasma concentration), CPET, and TTE will be performed at the trial visit. Depending on these assessments, the dose will be adjusted or temporarily discontinued. All subjects who complete the placebo-controlled treatment period are eligible for long-term continuation (LTE). Dose adjustments are permitted during LTE. Subjects receiving placebo will start at 2.5 mg during LTE.

[0525] Experimental treatment and administration During the placebo-controlled treatment period, randomized subjects were administered mabacamten immediate-release capsules 2.5 mg or a matching placebo in QD units for the first 8 weeks of the treatment period, with pre-administration PK samples taken at weeks 4, 6, and 8. If the pre-administration PK was 700–1000 ng / mL at week 4, the dose was reduced to 1 mg QD at week 6. At all other time points, the dose was adjusted based on the pre-administration PK and the central laboratory's TTE assessment (week 8 based on the assessment at week 6, week 14 based on the assessment at week 12, and week 20 based on the assessment at week 18). The acceptable doses at week 8 were 1, 2.5, 5 mg, or placebo. 10 mg was available from week 14, and 15 mg was available from week 20. The dose setting criteria for dose adjustments are shown in Tables 11.1 and 11.2. [Table 31] [Table 32]

[0526] After the third dose setting at week 20, no further dose increases will be made. This is intended to ensure that the dose is not changed unless there are safety concerns or other reasons for early discontinuation.

[0527] Example 12: Exploratory open-label Phase 2a proof-of-concept trial of mabacamten (MYK-461) in participants with heart failure with preserved ejection fraction (HFpEF) and chronically elevated cardiac troponin I and / or NT-proBNP. This study is a Phase 2a proof-of-concept trial to evaluate the safety, tolerability, and preliminary efficacy of mavacamten treatment for cardiac troponin I (cTnI) levels and N-terminal pro b-type natriuretic peptide (NT-proBNP) levels in participants with heart failure with preserved ejection fraction (HFpEF) and chronically elevated cTnI and / or NT-proBNP levels.

[0528] Objectives and Evaluation Criteria: The primary objectives, exploratory objectives, and pharmacokinetic (PK) objectives of the study, along with their respective evaluation criteria, are as follows: [Table 33-1] [Table 33-2]

[0529] Overall design This study is a multicenter, exploratory, open-label trial to explore the efficacy and / or pharmacodynamic effects, PK, safety, and tolerability of mavacamten in approximately 35 walkable participants with symptomatic HFpEF and elevated cTnI and / or NT-proBNP as defined by the inclusion / exclusion criteria. The study includes a screening period of up to 7 weeks (including pre-screening of initial biomarkers, which can be performed remotely via home healthcare nurses), a 26-week treatment period, and an 8-week post-treatment follow-up period. The number of participants without elevated high-sensitivity cTnI (hs-cTnI) (>99th percentile) will be limited to 20. Participants will receive a 26-week course of mavacamten followed by an 8-week washout period. All participants will initially receive 2.5 mg orally daily. At week 14, the dose for some participants may be increased to 5 mg orally daily. An interim analysis will be conducted after the first 10 participants complete treatment (week 26). The data will be used to evaluate the preliminary effects of mabacamten on NT-proBNP and hs-cTnI in the target HFpEF category and to determine whether changes to the treatment strategy and / or participant size are appropriate.

[0530] Selection Criteria Selection criteria: 1. You will understand and abide by the examination procedures, understand the risks associated with the examination, and be able to provide written informed consent in accordance with federal, local, and facility guidelines prior to the first examination-specific procedure. 2. The person is 50 years of age or older at the time of screening. 3. The animal's weight at the time of screening exceeds 45 kg. 4. There is prior objective evidence of heart failure as demonstrated by one or more of the following criteria: Previous hospitalization for heart failure accompanied by evidence of pulmonary congestion as confirmed by X-ray. Elevated left ventricular (LV) end-diastolic pressure or pulmonary capillary wedge pressure at rest (≥15 mmHg) or during exercise (≥25 mmHg). Elevated NT-proBNP (>400 pg / mL) or elevated brain natriuretic peptide (BNP) (>200 pg / mL). If there are no eligible historical NT-proBNP or BNP levels that meet this threshold, selection criterion 4 is met by screening for NT-proBNP that meets the threshold of selection criterion 5. Long-term treatment with spironolactone, eplerenone, or loop diuretics is required for a median E / e' ratio of ≥15 or left atrial enlargement (left atrial volume index >34 mL / m²). 2 Evidence from echocardiography. 5. Meet one or more of the following criteria: • The hs-cTnI level at screening exceeds the 99th percentile (at the initial screening measurement; the second measurement during screening should be within ±25% of the initial measurement), or • NT-proBNP during initial screening measurement * If the blood glucose level exceeds 300 pg / mL (if not in atrial fibrillation or atrial flutter), or exceeds 750 pg / mL (if in atrial fibrillation or atrial flutter), • Screened participants were of African descent or had a body mass index of 230.0 kg / m². 2 In that case, NT-proBNP at screening * If the blood glucose level exceeds 240 pg / mL (when atrial fibrillation or atrial flutter is not present), or exceeds 600 pg / mL (when atrial fibrillation or atrial flutter is present). * Fewer than 20 participants can take part in the trial even if their hs-cTnI level at screening does not exceed the 99th percentile. 6. The LVEF at the time of screening, as determined by the central echocardiography laboratory, is 60% or higher, and it has been confirmed that there is no history of LVEF below 45%. 7.2D imaging reveals an increase in left ventricular myocardial mass index (LVMI) (>95 g / m² in women). 2 For men, >115g / m² 2) has been verified, or the maximum left ventricular wall thickness has been verified to be 212 mm. The LVMI threshold for enrollment may be raised if deemed appropriate, after agreement between the study co-chair and MyoKardia following an interim review of the data (and such review and decision will be documented in the Note to File). 8. The central echocardiography laboratory has an appropriate ultrasound window for screening resting TTE, and there is a high probability of obtaining high-quality TTE throughout the entire examination. 9. Presence of NYHA Class II or III symptoms at the time of screening. 10. At the time of screening, safety clinical laboratory parameters (chemistry, hematology, coagulation, and urinalysis) are within the normal range (based on the reference range of the central laboratory). However, participants with safety clinical laboratory parameters outside the normal range may be included if all of the following criteria are met: • The principal investigator determines that safety clinical laboratory parameters outside the normal range are not clinically important. In this case, the principal investigator must consult with the study medical monitor about the results before enrollment. If alanine aminotransferase or aspartate aminotransferase results are available, the value must be less than three times the upper limit of the laboratory's reference range. • Estimated glomerular filtration rate adjusted for body size: 45 mL / min / 1.73 m 2 That's all. 11. Female participants must not be pregnant or breastfeeding, and if they are sexually active (and not postmenopausal or sterilized according to the definition below), they must use one of the following highly effective methods of contraception from their screening visit until three months after the final dose of the study drug. The male partner of a female participant must also use contraception (e.g., barrier, condom, or vasectomy). • A combination (containing estrogen and progestogen) hormonal contraceptive with ovulation suppression, or a progestogen-only hormonal contraceptive with ovulation suppression via oral, implantable, or injectable administration route. • Intrauterine contraceptive device. • Intrauterine hormone-releasing system. • The woman has been sterilized for six months or has been postmenopausal for one year. Permanent sterilization methods include hysterectomy, bilateral oophorectomy, bilateral salpingectomy, and / or certified bilateral fallopian tube occlusion at least six months prior to screening. A woman is considered postmenopausal if she has been amenorrhea for at least one year since discontinuing all exogenous hormone therapy and her follicle-stimulating hormone levels are within the postmenopausal range.

[0531] Exclusion criteria Exclusion criteria: 1. I previously participated in a clinical trial in which mabacamten was administered. 2. Hypersensitivity to any of the components of the mabacamten preparation. 3. You participated in a clinical trial in which participants were administered any investigational drug within 30 days prior to screening, or within five times the respective elimination half-life (whichever is longer) (or you are currently using an investigational device). 4. The patient has a history of hypertrophic cardiomyopathy, or has a known infiltrative or accumulative disorder that can cause HFpEF and / or cardiac hypertrophy, such as amyloidosis with LV hypertrophy, Fabry disease, or Noonan syndrome, or has a positive result on serological immunofixation. 5. Having any medical condition that interferes with the exercise stress test (for stress echocardiography). 6. The patient has a history of syncope within the past six months or a history of sustained ventricular tachycardia due to exercise within the past six months. 7. The patient has a history of resuscitated sudden cardiac arrest at any point in time, or has had a known adequate discharge from an implantable cardioverter-defibrillator within the six months prior to screening. 8. Having persistent or permanent atrial fibrillation, not having received anticoagulation treatment for at least 4 weeks prior to screening, and / or not having adequately controlled heart rate within 6 months prior to screening (Note: Participants with persistent or permanent atrial fibrillation who are receiving anticoagulation treatment and have adequately controlled heart rate are permitted). 9. Any dose adjustments made within 14 days prior to screening for participants taking beta-blockers, verapamil, or diltiazem. 10. Treatments currently in use or planned in trials, which include (a) a combination of a beta-blocker and verapamil, or a combination of a beta-blocker and diltiazem, (b) disopyramide, or (c) biotin or a biotin-containing supplement / multivitamin. 11. The participant has any electrocardiogram (ECG) abnormality (e.g., type II second-degree atrioventricular block) that the principal investigator considers to pose a risk to the participant's safety. 12. Having either (a) known non-regenerative coronary artery disease, or (b) acute coronary syndrome in the past three months. 13. Presence of known moderate or severe aortic stenosis, hemodynamically significant mitral stenosis, or severe mitral regurgitation or tricuspid regurgitation at the time of screening (all at the discretion of the principal investigator). 14. Any acute or serious comorbidity (e.g., a serious infection or a blood, renal, metabolic, gastrointestinal, or endocrine disorder) that, at the discretion of the principal investigator, could lead to early termination of participation in the study or interfere with the measurement or interpretation of the efficacy and safety assessments of the study. 15. You have severe chronic obstructive pulmonary disease, or another severe lung disease requiring home oxygen therapy, long-term nebulizer therapy, or long-term oral steroid therapy, or you have been hospitalized within the last 12 months due to pulmonary decompensation. 16. Hemoglobin level <10.0 g / dL. 17. Body Mass Index is ≥ 45.0 kg / m² 2 . 18. Positive serological test for infection with human immunodeficiency virus, hepatitis C virus, or hepatitis B virus at the time of screening. Participants who are positive for hepatitis BsAb are permitted because this positive serological test indicates the presence of neutralizing protective antibodies and does not indicate chronic infection. 19. Active 2019 coronavirus disease (COVID-19) infection and / or other acute respiratory infection at the time of screening or randomization. 20. History of clinically significant malignant disease within 5 years of screening: Participants who have successfully received treatment for non-metastatic cutaneous squamous cell carcinoma or basal cell carcinoma, or who have received appropriate treatment for cervical intraepithelial neoplasia, may be included in the study. 21. Any history or evidence of any other clinically significant impairment, condition, or disease (other than those outlined above) that, in the opinion of the principal investigator or medical monitor, could pose a risk to the participant's safety or could interfere with the evaluation, procedure, or completion of the study. 22. You are currently taking or have taken any of the following prohibited medications (including over-the-counter medications) within the 14 days prior to screening: cytochrome P450 (CYP) 2C19 inhibitors (e.g., omeprazole, esomeprazole), potent CYP3A4 inhibitors, or St. John's wort. 23. Prior or concomitant treatment with cardiotoxic agents such as doxorubicin or similar drugs. 24. Unable to comply with trial requirements, including the required number of visits to the clinical facility. 25. Employees of MyoKardia or their relatives, the principal investigator, or the staff or family members of the principal investigator. Global strain in the long axis direction of the left ventricle due to TTE in the range of 26.0 to -12.0 (assessed by the central TTE radiologist). Unable to participate in the 27.6MWT (e.g., unable to walk). 28. NT-proBNP level >2000 pg / mL at screening.

[0532] Testing procedures and treatment: The doses of mabacamten used in this study are 2.5 and 5 mg. The dose adjustment at week 14 will be based on biomarkers (hs-cTnI and NT-proBNP) and LVEF measured at the week 12 visit.

[0533] Trial visits will be conducted at screening, and at the end of the trial (EOS) at weeks 1, 6, 12, 14, 20, 26, and 34. Evaluations during the treatment period will include vital signs, adverse events, concomitant medications, a basic physical examination, body weight, 12-lead ECG, resting TTE, PK sampling, safety laboratory evaluation (chemistry, hematology, coagulation panel, and urinalysis), hs-cTnI, high-sensitivity cTnT, NT-proBNP, urine pregnancy test (for women of childbearing age only), exploratory biomarker blood samples, NYHA classification, KCCQ score, and SF-12 score. Two 6MWTs will be performed during screening, at week 26, and at week 34 / EOS. Post-exercise stress TTEs will be performed at week 26 and at week 34 / EOS, up to 5 days before the first dose. Acceleration measurements will be taken from the second screening visit until week 34. Genotyping and pharmacogenetic samples will be collected before the first day of medication. Furthermore, participants will be contacted by telephone at weeks 2, 4, 8, 10, 16, 18, 22, and 24 to collect information on adverse events (AEs) and concomitant medications. Participants who discontinue the study drug early at any time will attend an early drug discontinuation visit within 14 days of discontinuation and an end-of-syndrome (EOS) visit at week 34.

[0534] All participants will initially receive mabacamten 2.5 mg orally once daily (QD). At week 14, based on biomarkers (hs-cTnI and NT-proBNP) and LVEF measured at the week 12 visit, the dose for some participants may be increased to 5 mg QD.

[0535] For participants joining the trial with an hs-cTnI level above the 99th percentile, the dose will be increased to 5 mg at week 14 if all of the following conditions are met: - hs-cTnI (at week 12) is above the 99th percentile and has not decreased by at least 30% compared to the mean of all available pre-treatment values ​​(pre-screening, screening, and pre-medication on day 1), - Resting LVEF (at week 12) has not decreased by more than 15% (relative reduction from the mean of all available screenings and resting LVEF before medication on day 1), and - NT-proBNP levels have not increased by more than 50% from the mean of all available screening and pre-medication resting measurements on day 1.

[0536] For participants in the study with elevated NT-proBNP and hs-cTnI below the 99th percentile, the dose will be increased to 5 mg at week 14 if all of the following conditions are met: - NT-proBNP (at week 12) is above the upper limit of normal, and has not decreased by at least 50% compared to the mean of all available pre-treatment values ​​(pre-screening, screening, and pre-medication on day 1), nor has it increased by at least 50%, and - Resting LVEF (at week 12) has not decreased by more than 15% (relative reduction from the mean of all available screenings and the resting LVEF before medication on day 1).

[0537] Furthermore, after every visit in which the LVEF is measured as follows, there are provisions for temporary or permanent discontinuation of treatment based on the LVEF: -(1) If the local ultrasound technician determines that the LVEF is 45% or less: In these circumstances, the ultrasound technician must notify the principal investigator and, in addition, re-examine and remeasure the findings with at least one other expert qualified in echocardiography (which may be the principal investigator). If the result is confirmed locally (LVEF ≤ 45%), the investigational drug will be temporarily discontinued, and if confirmed by the central echocardiography laboratory, treatment will be permanently discontinued thereafter. If the central radiologist does not confirm a result of 45% or less, the principal investigator and medical monitor (including opinions from co-investigating physicians as necessary) will discuss the participant's results and decide whether treatment can be resumed and at what dose (including written documentation before resuming treatment). -(2) If the central echocardiography laboratory determines that the LVEF has decreased by 20% or more from baseline (average of all pre-screening / pre-medication values) or that the LVEF is less than 50% (but greater than 45%), the investigational drug will be temporarily discontinued for two weeks. If the central laboratory determines that the quality of the TTE is insufficient for accurate estimation of LVEF, it will be necessary to attempt to repeatedly obtain unscheduled TTEs for this purpose. However, if this is not possible, or if the LVEF still cannot be quantitatively estimated, the central TTE laboratory will need to qualitatively determine whether the LVEF is likely to be less than 50%, and this information will be used for the purpose of making decisions regarding the temporary discontinuation of medication. -(3) If the local principal investigator is notified that the LVEF is less than 50% in a non-test TTE, the investigational drug must be temporarily discontinued and non-test TTE images obtained for review by the central TTE laboratory. If the central TTE laboratory determines that the LVEF is 45% or less in the TTE, the investigational drug must be permanently discontinued. If the central TTE laboratory determines that the LVEF is less than 50% (but greater than 45%): The procedure for the conditions in (2) above must be followed. If non-test TTE images that would trigger a temporary discontinuation are not readily available at the central laboratory, unscheduled test TTEs must be performed in a timely manner to obtain images for review by the central laboratory for these purposes.

[0538] If the study drug is temporarily discontinued based on condition (2), repeated TTEs demonstrate that the participant no longer meets the criteria for temporary discontinuation in the next TTE, the study drug may be restarted after two weeks. The restart dose will be 2.5 mg, regardless of the dose at the time of temporary discontinuation. If the participant meets the criteria for temporary discontinuation a second time after restarting the study drug, the study drug will be permanently discontinued.

[0539] If the investigational drug is discontinued for any reason directly or indirectly related to the COVID-19 pandemic (including, but not limited to, inability to obtain TTE and / or biomarkers, drug supply issues, etc.), the principal investigator and medical monitor (including opinions from co-principals as appropriate) will discuss and mutually approve (including in writing) any plans for the resumption of the investigational drug for each individual participant.

[0540] For safety reasons, the dose can be gradually reduced at any time. Safety will be monitored throughout the entire study.

[0541] Example 13. Type A crystals of mabacamten Abbreviation API = Active pharmaceutical ingredient = Mabacamten DCM = Dichloromethane DSC = Differential Scanning Calorimetry h = time (multiple values ​​are possible) HFIPA = Hexafluoroisopropanol HPLC = High-Performance Liquid Chromatography HSM = Hot Stage Microscopy IPC = Integrated Process Control MIBK = Methyl isobutyl ketone MTBE = Methyl tert-butyl ether ND = Not detected RT or rt = room temperature TGA=thermogravimetric analysis TMS-NCO = Isocyanatotrimethylsilane (i.e., (trimethylsilyl)isocyanate) XRPD = X-ray Powder Diffraction

[0542] Example 13.1: Preparation of API [ka] Synthesis of Compound 1.1, Propan-2-ylurea. A solution of propan-2-amine (35.91 g, 607.51 mmol, 1.00 equivalent) in dichloromethane (1000 mL) was placed in a 1 L round-bottom flask purged and maintained under an inert argon atmosphere. Isocyanatotrimethylsilane (68.56 g, 595.11 mmol, 1.00 equivalent) was added to the solution. The resulting solution was stirred overnight at room temperature. Subsequently, methanol (300 mL) was added dropwise while stirring at 0°C. The resulting solution was reacted for a further 2 hours at room temperature while stirring. The resulting mixture was concentrated under vacuum. The crude product was recrystallized from ethanol / ether (1:40). The solid was collected by filtration. This yielded 53 g (85%) of propan-2-ylurea (Compound 1.1) as a white solid. [ka]

[0543] Synthesis of compound 1.2.1-isopropylpyrimidine-2,4,6(1H,3H,5H)-trione (methanol). 1000 mL of methanol was added to a 2 L round-bottom flask purged and maintained under an inert argon atmosphere. Subsequently, metallic sodium (39.1 g, 1.70 mol, 2.50 equivalents) was added in several portions at 0°C. The resulting mixture was stirred at 0°C for 1 hour. To this solution, propan-2-ylurea (69 g, 675.58 mmol, 1.00 equivalent; compound 1.1) and 1,3-dimethylpropanediote (98.2 g, 743.29 mmol, 1.10 equivalents) were added. The resulting solution was stirred overnight in an oil bath at 70°C. The pH of the solution was adjusted to 3 with concentrated hydrogen chloride. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using dichloromethane / methanol (20 / 1). This yielded 91 g (79%) of 1-(propan-2-yl)-1,3-diadinane-2,4,6-trione (compound 1.2) as a yellow solid. 1 H NMR (300 MHz, CDCl3, ppm): δ 8.75 (s, 1H), 4.96-5.05 (m, 1H), 3.63 (s, 2H), 1.43-1.45 (m, 6H). [ka]

[0544] Synthesis of compound 1.2.1-isopropylpyrimidine-2,4,6(1H,3H,5H)-trione (ethanol). 1-isopropylurea (4.983 kg, 48.79 mol; compound 1.1), anhydrous ethanol (15.8 kg), diethyl malonate (8.701 kg, 54.32 mol, 1.1 equivalents), and sodium ethoxide (21% by weight in ethanol) (20.7 kg, 63.9 mol, 1.3 equivalents) were added to a 100 L reactor and heated under reflux (75-80°C) for 20.7 hours with stirring (145 rpm). IPC LC / MS limiting tests showed less than 10% 1-isopropylurea. The mixture was cooled to 24°C. A solution of 2N HCl was prepared by mixing drinking water (30.0 kg) and concentrated HCl (6.3 kg). A 2N HCl solution was added to the reaction mixture over 25 minutes (in the temperature range of 23-25°C) to adjust the pH to 3. Next, the slurry was concentrated to approximately 27 L (5.5 L / kg) by vacuum distillation while maintaining the pot temperature below 50°C. IPC GC headspace limit testing showed less than 10% ethanol. The slurry was cooled to 9°C and mixed at 5-10°C for 15.5 hours. The solid was separated by filtration, washed with drinking water (30.0 kg), and vacuum dried at 40-45°C for 39 hours. From the dried product, 6.579 kg (79%) of 1-isopropylpyrimidine-2,4,6(1H,3H,5H)-trione (compound 1.2) was obtained as a pale yellow solid with a purity of 99.22% (a / a). [ka]

[0545] Synthesis of compound 1,3,6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (BTEAC). In a 2 L round-bottom flask purged and maintained under an inert argon atmosphere, 400 mL of phosphoryl trichloride (5.0-5.5 equivalents) containing 1-(propan-2-yl)-1,3-diadinane-2,4,6-trione (129 g, 758.08 mmol, 1.00 equivalent; compound 1.2) and N-benzyl-N,N-triethylethanaminonium chloride (241 g, 1.06 mol, 1.40 equivalents) was added. The resulting solution was stirred in an oil bath at 50°C for 3 hours. The resulting mixture was concentrated under vacuum. The residue was cooled to 0°C in a water / ice bath. The reaction was then quenched by adding 100 mL of water / ice. The obtained solution was extracted with 5 × 500 mL of dichloromethane, and the organic layers were dried together over anhydrous magnesium sulfate. Solid matter was removed by filtration. The filtrate was concentrated under vacuum. The residue was washed with 100 mL of dichloromethane. Solid matter was collected by filtration and washed with 200 mL of ether. This yielded 93 g (crude) of 6-chloro-3-(propan-2-yl)-1,2,3,4-tetrahydropyrimidine-2,4-dione (compound 1.3) as a pale yellow solid. LC-MS (ES, m / z) [M+H] + 189.3, [M+CH3CN] + 230.3. 1 H NMR (300 MHz, DMSO-d6, ppm): δ 12.19 (s, 1H), 5.82 (s, 1H), 4.90-4.99 (m, 1H), 1.33-1.35 (m, 6H). [ka]

[0546] Synthesis of compound 1,3,6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (acetonitrile). 1-isopropylpyrimidine-2,4,6(1H,3H,5H)-trione (6.200 kg, 36.43 mol; compound 1.2), anhydrous acetonitrile (24.4 kg), and phosphorus oxychloride (6.184 kg, 40.33 mol, 1.1 equivalents) were added to a 100 L reactor. The mixture was heated to 55°C and held at 55-60°C for 21.7 hours. In-process HPLC analysis showed that 0.6% of the trione starting material remained. Next, the mixture was cooled to 24°C, and drinking water (62.0 kg) was added over 31 minutes while maintaining the internal temperature below 35°C. The resulting suspension was stirred at 23-26°C for 3.1 hours and then filtered. After washing the solid with drinking water (37.2 kg), it was vacuum-dried at approximately 60°C for 18.5 hours to obtain 4.726 kg (69%) of 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (compound 1.3) as a light brown solid with a purity of 99.48% (a / a). [ka]

[0547] Compound 1.4. Synthesis of API (solvent-free 1-phenylethane-1-amine). In a 1000 mL round-bottom flask purged and maintained under an inert argon atmosphere, 6-chloro-3-(propan-2-yl)-1,2,3,4-tetrahydropyrimidine-2,4-dione (40 g, 212.08 mmol, 1.00 equivalent) was added to (1S)-1-phenylethane-1-amine (64.4 g, 531.44 mmol, 2.50 equivalents). The resulting solution was stirred in an oil bath at 100°C for 5 hours. The residue was applied to a silica gel column using dichloromethane / methanol (10 / 1). The crude product was recrystallized from ether. This yielded 30.7127 g (53%) of 6-[[(1S)-1-phenylethyl]amino]-3-(propan-2-yl)-1,2,3,4-tetrahydropyrimidine-2,4-dione (compound 1.4) as a pale yellow solid. LC-MS (ES, m / z) [M+H] + 274.10, [2M+H]+ 547.25. 1 H NMR (300 MHz, DMSO-d6, ppm): δ 9.78 (s, 1H), 7.31-7.39 (m, 4H), 7.23-7.29 (m, 1H), 6.50-6.52 (d, J = 6.9 Hz, 1H), 4.85-4.95 (m, 1H), 4.44-4.54 (m, 1H), 4.33 (s, 1H), 1.38-1.40 (d, J = 6.0 Hz, 3H), 1.25-1.28 (m, 6H). [ka]

[0548] Compound 1.4. Synthesis of Crude API (Large Scale). 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (3.715 kg, 19.70 mol; Compound 1.3), 1-propanol (9.0 kg), and (S)-(-)-1-phenylethylamine (5.980 kg, 49.35 mol, 2.5 equivalents) were added to a 100 L reactor. The reaction mixture was heated at 104°C for 20 hours with stirring (250 RPM). HPLC analysis showed that 0.9% of Compound 1.3 remained. Next, the solution was cooled to 87°C and drinking water (22.3 kg) was added. The mixture was cooled to 25°C, and the resulting slurry was stirred at 15-25°C for 21.5 hours. The resulting suspension was filtered. The solid material was washed with drinking water (19.7 kg) and MTBE (14.5 kg), and then vacuum-dried at 60°C for 18 hours to obtain 4.949 kg (92%) of crude API (compound 1.4). HPLC analysis of the material showed 100% purity (a / a). [ka]

[0549] Compound 1.5. Preparation of purified API (large scale). Crude API (4.942 kg, 18.08 mol; Compound 1.4) and 95% ethanol (39.0 kg) were added to a 100 L reactor. The suspension was heated to 75°C with stirring (250 RPM). The resulting solution was clarified and transferred to a second 100 L reactor by filtration through a 1.2 μm filter cartridge. The filter cartridge was rinsed with 95% EtOH (1.954 kg), and the rinsed liquid was transferred to a 100 L receiving reactor. The contents of the receiving vessel were heated under reflux for 10 minutes (76-78°C), and then the solution was cooled to 10°C over 3.5 hours. The resulting slurry was stirred at approximately 5-10°C for 25 hours, and then the suspension was filtered. The solid was washed with MTBE (14.5 kg), then vacuum-dried at 60°C for 15.5 hours to obtain 4.311 kg (87%) of purified API. The analytical data for the purified API will be described later in Table 13.1. [Table 34]

[0550] Example 13.2: Identification and Characterization of Type A Three samples of API (lots 2-4, 2-5, and 2-6) were analyzed and identified as a crystalline solid form called type A.

[0551] procedure X-ray Powder Diffraction (XRPD): PANalytical EXPERT Pro MPD Diffractometer - Transmission. XRPD patterns were collected using a PANalytical X'Pert PRO MPD diffractometer with an incident beam of Cu radiation generated using an Optix high-focusing long source. Cu Kα X-rays were focused onto the detector through the specimen using an elliptical gradient multilayer mirror. Prior to analysis, a silicon specimen (NIST SRM 640d) was analyzed to demonstrate that the observed position of the Si 111 peak coincided with the NIST-certified position. The specimen was sandwiched between 3 μm thick films and analyzed by transmission geometry. Background generated by air was minimized using a beam stop, a short scatter removal extension, and a scatter removal knife edge. Solar slits were used on the incident and diffracted beams to minimize broadening due to axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) positioned 240 mm away from the specimen and Data Collector software v.2.2b.

[0552] PANalytical EXPERT Pro MPD diffractometer - Reflection. XRPD patterns were collected using a PANalytical X'Pert PRO MPD diffractometer with an incident beam of Cu Kα radiation generated using a long, highly focused source and a nickel filter. The diffractometer was configured using a symmetric Bragg-Brentano configuration. Prior to analysis, a silicon sample (NIST SRM 640d) was analyzed to demonstrate that the observed location of the Si 111 peak coincided with the NIST-certified location. Samples were prepared as thin circular layers on the center of a silicon zero-background substrate. In some cases, samples were prepared under a nitrogen atmosphere. A scatter removal slit (SS) was used to minimize background generated by air. Solar slits were used on the incident and diffracted beams to minimize broadening due to axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) positioned 240 mm away from the sample and Data Collector software v.2.2b.

[0553] Differential Scanning Calorimetry (DSC): DSC was performed using a TA Instruments 2920 differential scanning calorimeter. Temperature calibration was performed using NIST-traceable indium metal. The sample was placed in an aluminum DSC pan, covered with a lid, and its weight was accurately recorded. The weighed aluminum pan, configured as the sample pan, was placed on the reference side of the cell. The method code in the thermogram is an abbreviation for the start temperature, end temperature, and heating rate. For example, -30-250-10 means "from -30°C to 250°C at 10°C / min". The table below summarizes the abbreviations used for pan placement. [Table 35]

[0554] Thermogravimetric Analysis (TGA): TG analysis was performed using a TA Instruments 2950 thermogravimetric analyzer. Temperature calibration was performed using nickel and nickel-aluminum alloy (Alumel®). Each sample was placed in a platinum pan and inserted into the TG furnace. The furnace was heated under nitrogen purge. The method code in the thermogram is an abbreviation of the start temperature, end temperature, and heating rate. For example, 25-350-10 means "from 25°C to 350°C at 10°C / min".

[0555] Hot Stage Microscopy (HSM): Hot stage microscopy was performed using a Linkam hot stage (model FTIR 600) mounted on a Leica DM LP microscope equipped with a SPOT Insight® color digital camera. Temperature ...

Claims

1. A pharmaceutical composition comprising mabacamten or a pharmaceutically acceptable salt thereof for use in the treatment of a subject suffering from obstructive hypertrophic cardiomyopathy (oHCM), wherein the subject is eligible for septal reduction therapy (SRT).

2. The composition according to claim 1, wherein the treatment reduces the likelihood of the subject receiving SRT, reduces the short-term likelihood of the subject receiving SRT, eliminates the need for the subject to receive SRT, and / or reduces the need for septal reduction therapy for the subject.

3. The composition according to claim 1, wherein the treatment reduces the thickness of the interventricular septum (IVS) wall.

4. The composition according to any one of claims 1 to 3, wherein, prior to treatment, the subject has a ventricular septal (IVS) wall thickness of 13 mm or more and a family history of HCM, and / or the subject has a ventricular septal (IVS) wall thickness of 15 mm or more.

5. The composition according to any one of claims 1 to 4, wherein, prior to the treatment, the subject has been diagnosed with NYHA class III or IV, or NYHA class II with or without exertional symptoms, has a dynamic LVOT gradient of 50 mmHg or more at rest or induced with septal hypertrophy, and has an LVEF of 60% or more.

6. The composition according to any one of claims 1 to 5, wherein the treatment improves the NYHA classification and / or improves the KCCQ.

7. The composition according to claim 1, wherein the amount of mabacamten or a pharmaceutically acceptable salt thereof is therapeutically effective, and such amount is 2.5 mg to 15 mg.

8. The composition according to claim 7, wherein the therapeutically effective dose is administered once daily for 16 weeks or more, 32 weeks or more, or 96 weeks or more.

9. The composition according to claim 7, wherein the therapeutically effective amount of mabacamten or a pharmaceutically acceptable salt thereof is 5 mg per day for 16 weeks or more.

10. The composition according to claim 9, wherein the subject is evaluated for dose adjustment at week 4, week 8, week 12, or week 16.

11. The composition according to claim 10, wherein the evaluation for the dose adjustment includes evaluation of one or more of the following: vital signs, body weight, NYHA functional classification, adverse events, concomitant medications, physical examination, KCCQ, resting Valsalva test, transthoracic echocardiography, transthoracic echocardiography, post-exercise, accelerometer, application of Holter monitor, single 12-lead ECG, PK sample, blood chemistry and coagulation, cardiac biomarkers, or exploratory biomarkers.

12. The composition according to claim 11, wherein the evaluation includes evaluation of one or more cardiac biomarkers, and the one or more cardiac biomarkers include NT-proBNP, BNP, or cardiac troponin.

13. The composition according to claim 11, wherein the evaluation includes analysis of the LVOT gradient, left ventricular ejection fraction (LVEF), left ventricular (LV) filling pressure, or left atrial size of the subject.

14. The aforementioned evaluation, (a) Evaluation of the change from baseline to week 16 in the subjects treated with mabacamten compared to the subjects treated with placebo; (b) Evaluation of the change from baseline to week 16 compared to the change from baseline to week 32 in the subjects treated with mabacamten; and (c) Evaluation of the change from baseline to week 32 in the subjects treated with mabacamten, compared to the subjects treated with placebo from week 1 to week 16 and then with mabacamten from week 17 to week 32; The composition according to claim 11, comprising one or more of the above.

15. The composition according to claim 13 or 14, wherein the evaluation is an evaluation of the change in the NYHA functional classification, KCCQ-23 score, NT-proBNP or BNP level, cardiac troponin cTnI or cTnT, or LVOT gradient of the subject.

16. The composition according to any one of claims 1 to 15, wherein the subject is re-evaluated for SRT eligibility at week 16, week 32, week 80, and / or week 128.

17. The composition according to any one of claims 11 to 16, wherein the evaluation indicates that the need for the SRT of the subject is reduced or eliminated.

18. The composition according to any one of claims 1 to 17, wherein the subject is eligible for an SRT consistent with the ACC / AHA 2011 and / or ESC 2014 guidelines.

19. The aforementioned subjects are (a) to (c): (a) NYHA Class III or IV, or NYHA Class II with or without exertional symptoms; (b) A dynamic LVOT gradient of 50 mmHg or greater at rest or induced (i.e., Valsalva maneuver or exercise) accompanied by septal hypertrophy; and (c) A target anterior septal thickness sufficient to allow the individual operator to safely and effectively perform the procedure, A composition according to any one of claims 1 to 18, characterized by one or more of the following.

20. The composition according to any one of claims 1 to 19, wherein the subject has an elevated troponin level, an elevated NT-proBNP or BNP level, and / or an E / e' greater than 14.

21. The composition according to any one of claims 1 to 20, wherein the subject is resistant to treatment with standard treatment for oHCM, and the treatment with standard treatment for oHCM includes treatment with a beta-blocker, a calcium channel blocker, disopyramide, or any combination thereof.

22. The composition according to any one of claims 1 to 21, wherein the subject has reached maximum tolerable medical treatment with standard oHCM therapy prior to treatment with mabacamten or a pharmaceutically acceptable salt thereof, remains symptomatic NYHA class III or IV, and has an LVOT gradient of 50 mmHg or more.

23. The composition according to any one of claims 1 to 20, wherein the subject receives adjunctive therapy, including treatment with standard treatment for oHCM, in the course of treatment with mabacamten or a pharmaceutically acceptable salt thereof, and the standard treatment includes treatment with a beta-blocker, a calcium channel blocker, disopyramide, or any combination thereof.

24. The composition according to any one of claims 1 to 23, wherein the subject is classified as NYHA degree IV.

25. The composition according to claim 2, wherein reducing the likelihood of a subject receiving SRT includes (1) reducing the patient's desire to continue SRT, and / or (2) resulting changes in SRT guideline eligibility that render the patient ineligible for SRT.

26. The composition according to any one of claims 2 or 25, wherein the change in likelihood is based on the likelihood assessment at baseline compared to the likelihood assessment at week 16 and / or week 32, and the reduction from baseline in the likelihood of the subject receiving SRT is achieved by week 16 and maintained at week 32.

27. The composition according to any one of claims 1 to 26, wherein the mabacamten or a pharmaceutically acceptable salt thereof is mabacamten.

Images