Methods for treating hypertrophic cardiomyopathy

Abstract

The method for treating obstructive hypertrophic cardiomyopathy is described herein.The treatment method includes administering a cardiac myosin inhibitor (CK-3773274, also called CK-274 or aficamten), and can include titrating the daily dose administered based on one or more components of echocardiogram.The daily dose can be increased, maintained, decreased, or discontinued based on echocardiogram.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 203,333, filed July 16, 2021, U.S. Provisional Application No. 63 / 299,753, filed January 14, 2022, U.S. Provisional Application No. 63 / 305,609, filed February 1, 2022, U.S. Provisional Application No. 63 / 331,197, filed April 14, 2022, and U.S. Provisional Application No. 63 / 343,975, filed May 19, 2022, the contents of which are incorporated by reference in their entireties herein for all purposes.

[0002] The disclosure herein relates to the treatment of obstructive hypertrophic cardiomyopathy, as well as compounds and compositions that can be used in the treatment of hypertrophic cardiomyopathy. [Background technology]

[0003] Hypertrophic cardiomyopathy (HCM) is a disease in which the heart muscle (myocardium) thickens (enlarges) abnormally. The thickening of the myocardium causes the left ventricle to become smaller and stiffer, which makes it harder for the ventricle to relax and fill with blood. Thus, patients with obstructive hypertrophic cardiomyopathy may suffer from abnormalities in diastology and mitral regurgitation (MR). This ultimately limits the pumping function of the heart, resulting in symptoms including chest pain, dizziness, shortness of breath, or fainting during physical activity. A subset of patients with HCM are at high risk for progressive disease that may lead to atrial fibrillation, stroke, and death from arrhythmias. Adverse cardiac remodeling in oHCM is a known risk factor for progression to arrhythmias and heart failure. Thus, there is a need for therapies to address this condition. Summary of the Invention [Means for solving the problem]

[0004] Methods and compositions for treating hypertrophic cardiomyopathy are described herein. Cardiac myosin inhibitor (CK-3773274, also called CK-274 or aficamten, herein called compound 1, or its pharma- ceutically acceptable salt) can be used to treat hypertrophic cardiomyopathy, to reduce the resting left ventricular outflow tract pressure gradient (LVOT-G) of patients with obstructive hypertrophic cardiomyopathy (oHCM) to less than 30 mmHg, and / or to reduce the post-Valsalva left ventricular outflow tract pressure gradient (LVOT-G) of patients with obstructive hypertrophic cardiomyopathy (oHCM) to less than 50 mmHg. As further described herein, the daily dose of compound 1 can be titrated based on the results of echocardiogram.

[0005] In one example, a method for reducing resting left ventricular outflow tract pressure gradient (LVOT-G) to less than 30 mmHg in a patient with obstructive hypertrophic cardiomyopathy (oHCM) comprises administering a therapeutically effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof to the patient. The reduction in resting LVOT-G to less than 30 mmHg can occur within 10 weeks of initiating treatment with Compound 1 or a pharma- ceutically acceptable salt thereof. The reduction in resting LVOT-G to less than 30 mmHg can occur within 2 weeks of initiating treatment with Compound 1 or a pharma- ceutically acceptable salt thereof. In some embodiments, the reduction in resting LVOT-G is sustained for at least 10 weeks of treatment. In some embodiments, the reduction in resting LVOT-G occurs within 2-6 weeks of the end of titration. In some embodiments, the reduction in resting LVOT-G peaks within 2-6 weeks of the end of titration.

[0006] In some embodiments, a method of reducing post-Valsalva left ventricular outflow tract gradient (LVOT-G) to less than 50 mmHg in a patient with obstructive hypertrophic cardiomyopathy (oHCM) comprises administering a therapeutically effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof to the patient. The reduction in post-Valsalva LVOT-G to less than 50 mmHg can occur within 2 weeks of initiating treatment with Compound 1 or a pharma- ceutically acceptable salt thereof. The reduction in post-Valsalva LVOT-G can be sustained for at least 10 weeks of treatment. In some embodiments, the reduction in post-Valsalva LVOT-G occurs within 2-6 weeks of the end of titration. In some embodiments, the reduction in post-Valsalva LVOT-G peaks within 2-6 weeks of the end of titration.

[0007] A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need of treatment for oHCM can include administering a therapeutically effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof to the patient, where the therapeutically effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof is selected by titrating a daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof administered to the patient. In some embodiments, the dose is titrated once during the course of treatment. In some embodiments, the dose is titrated two or more times during the course of treatment. The daily dose can be administered to the patient at a constant amount for about two weeks before the amount of the daily dose is titrated.

[0008] In some embodiments of the above method, Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 5 mg to about 30 mg. In some embodiments, the daily dose is about 5 mg. In some embodiments, the daily dose is about 10 mg. In some embodiments, the daily dose is about 15 mg. In some embodiments, the daily dose is about 20 mg. In some embodiments, the daily dose is about 30 mg.

[0009] In some embodiments, the daily dose is administered as a single dose each day. In some embodiments, the daily dose is administered in two divided doses.

[0010] In some embodiments, a method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need of treatment for oHCM includes administering a first daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof to the patient for a first period of time; and administering a second daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof to the patient for a second period of time or discontinuing administration of Compound 1 or a pharma- ceutically acceptable salt thereof to the patient based on one or more components of a first echocardiogram of the patient obtained after the first period of time. The method may include selecting the second daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof based on one or more components of the first echocardiogram. In some embodiments, the one or more components of the first echocardiogram include biplane LVEF, post-Valsalva LVOT-G, or resting LVOT-G. In some embodiments, the one or more components of the first echocardiogram include biplane LVEF, post-Valsalva LVOT-G, and resting LVOT-G. In some embodiments, the one or more components of the first echocardiogram include biplane LVEF and post-Valsalva LVOT-G.

[0011] In some embodiments of the above method, one or more components of the first echocardiogram include biplane LVEF, and if the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold, the second daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is lower than the first daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof. For example, the predetermined biplane LVEF threshold may be 50%.

[0012] In some embodiments of the above method, one or more components of the first echocardiogram include biplane LVEF, and when the biplane LVEF of the first echocardiogram falls below a predetermined biplane LVEF threshold, administration of Compound 1 or a pharma- ceutically acceptable salt thereof to the patient is discontinued. For example, the predetermined biplane LVEF threshold may be 50%.

[0013] In some embodiments of the above method, the one or more components of the first echocardiogram include biplane LVEF, resting LVOT-G, and post-Valsalva LVOT-G, wherein the second daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is the same as the first daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof if the biplane LVEF of the first echocardiogram is equal to or greater than a predefined biplane LVEF threshold, the resting LVOT-G of the first echocardiogram is below a predefined resting LVOT-G threshold, and the post-Valsalva LVOT-G of the first echocardiogram is below a predefined post-Valsalva LVOT-G threshold. In some embodiments, the predefined biplane LVEF threshold is 50%, the predefined resting LVOT-G threshold is 30mmHg, and the post-Valsalva LVOT-G threshold is 50mmHg.

[0014] In some embodiments of the above method, one or more components of the first echocardiogram include biplane LVEF, resting LVOT-G, and post-Valsalva LVOT-G, and when the first echocardiogram meets any of the following conditions: (1) biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold, and resting LVOT-G is equal to or greater than a predetermined resting LVOT-G threshold, or (2) biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold, resting LVOT-G is below a predetermined resting LVOT-G threshold, and post-Valsalva LVOT-G is equal to or greater than a predetermined post-Valsalva LVOT-G threshold, the second daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is greater than the first daily dose of Compound 1 or a pharma-ceutically acceptable salt thereof. In some embodiments, the predetermined biplane LVEF threshold is 50%, the predetermined resting LVOT-G threshold is 30mmHg, and the post-Valsalva LVOT-G threshold is 50mmHg.

[0015] In some embodiments of the above method, one or more components of the first echocardiogram include biplane LVEF and post-Valsalva LVOT-G, where the second daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is the same as the first daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof if the first echocardiogram meets any of the following conditions: (1) the biplane LVEF is equal to or greater than a predefined biplane LVEF threshold and is less than a second predefined biplane LVEF threshold, or (2) the biplane LVEF is equal to or greater than a second predefined biplane LVEF threshold and the post-Valsalva LVOT-G of the first echocardiogram is less than a second predefined post-Valsalva LVOT-G threshold. In some embodiments, the predefined biplane LVEF threshold is 50%, the second predefined biplane LVEF threshold is 55%, and the second predefined post-Valsalva LVOT-G threshold is 30 mmHg.

[0016] In some embodiments of the above method, the one or more components of the first echocardiogram include biplane LVEF and post-Valsalva LVOT-G, and wherein if the biplane LVEF of the first echocardiogram is above a second predetermined biplane LVEF threshold and the post-Valsalva LVOT-G of the first echocardiogram is equal to or greater than the second predetermined post-Valsalva LVOT-G threshold, the second daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is greater than the first daily dose of Compound 1. In some embodiments, the predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the second predetermined post-Valsalva LVOT-G threshold is 30 mmHg.

[0017] In some embodiments of the above method, the first daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, is about 5 mg of Compound 1. In some embodiments, the second daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, is about 5 mg or about 10 mg of Compound 1.

[0018] In some embodiments of the above methods, the method further comprises measuring one or more components of the first echocardiogram.

[0019] In some embodiments of the above method, the first period of time is about 2 weeks. In some embodiments, the second period of time is about 2 weeks.

[0020] In some embodiments of the above method, a second daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is administered to the patient for a second period of time, and the method further comprises administering a third daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof to the patient for a third period of time or ceasing administration of Compound 1 or a pharma- ceutically acceptable salt thereof to the patient based on one or more components of a second echocardiogram of the patient obtained after the second period of time and the second daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof. In some embodiments, the method comprises selecting a third daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof based on one or more components of the second echocardiogram and the second daily dose. In some embodiments, the one or more components of the second echocardiogram include biplane LVEF, post-Valsalva LVOT-G, or resting LVOT-G. In some embodiments, the one or more components of the second echocardiogram include biplane LVEF, post-Valsalva LVOT-G, and resting LVOT-G. In some embodiments, the one or more components of the second echocardiogram include biplane LVEF and post-Valsalva LVOT-G.

[0021] In some embodiments of the above method, one or more components of the second echocardiogram include a biplane LVEF, and if the biplane LVEF of the second echocardiogram is below a predetermined biplane LVEF threshold, the third daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is lower than the second daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof, or administration of Compound 1 or a pharma- ceutically acceptable salt thereof to the patient is discontinued. In some embodiments, the predetermined biplane LVEF threshold is 50%.

[0022] In some embodiments of the above method, administration of Compound 1 or a pharma- ceutically acceptable salt thereof to the patient is discontinued if the biplane LVEF of the second echocardiogram falls below a predefined biplane LVEF threshold and the second daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is equal to or lower than the first daily dose of Compound 1. In some embodiments, the predefined biplane LVEF threshold is 50%.

[0023] In some embodiments of the above method, if the second daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is higher than the first daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof and the biplane LVEF of the second echocardiogram is below a pre-determined biplane LVEF threshold, the third daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is the same as the first daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof. In some embodiments, the pre-determined biplane LVEF threshold is 50%.

[0024] In some embodiments of the above method, one or more components of the second echocardiogram include biplane LVEF, resting LVOT-G, and post-Valsalva LVOT-G, where the biplane LVEF of the second echocardiogram is equal to or greater than a predetermined biplane LVEF threshold, the resting LVOT-G of the second echocardiogram is below a predetermined resting LVOT-G threshold, and the post-Valsalva LVOT-G of the second echocardiogram is below a predetermined post-Valsalva LVOT-G threshold, and the third daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is the same as the second daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof. In some embodiments, the predetermined biplane LVEF threshold is 50%, the predetermined resting LVOT-G threshold is 30mmHg, and the post-Valsalva LVOT-G threshold is 50mmHg.

[0025] In some embodiments of the above method, one or more components of the second echocardiogram include biplane LVEF, resting LVOT-G, and post-Valsalva LVOT-G, and when the second echocardiogram meets any of the following conditions: (1) biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold, and resting LVOT-G is equal to or greater than a predetermined resting LVOT-G threshold, or (2) biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold, resting LVOT-G is below a predetermined resting LVOT-G threshold, and post-Valsalva LVOT-G is equal to or greater than a predetermined post-Valsalva LVOT-G threshold, the third daily dose of Compound 1 or a pharma- ceutical acceptable salt thereof is greater than the second daily dose of Compound 1 or a pharma-ceutical acceptable salt thereof. In some embodiments, the predetermined biplane LVEF threshold is 50%, the predetermined resting LVOT-G threshold is 30mmHg, and the post-Valsalva LVOT-G threshold is 50mmHg.

[0026] In some embodiments of the above method, the one or more components of the second echocardiogram include biplane LVEF and post-Valsalva LVOT-G, where if the second echocardiogram meets any of the following conditions: (1) the biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold and is below a second predetermined biplane LVEF threshold, or (2) the biplane LVEF is equal to or greater than a second predetermined biplane LVEF threshold and post-Valsalva LVOT-G is below a second predetermined post-Valsalva LVOT-G threshold, the third daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is the same as the second daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof. In some embodiments, the predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the second predetermined post-Valsalva LVOT-G threshold is 30 mmHg.

[0027] In some embodiments of the above method, the one or more components of the second echocardiogram include biplane LVEF and post-Valsalva LVOT-G, and when the biplane LVEF of the second echocardiogram is above a second predetermined biplane LVEF threshold and the post-Valsalva LVOT-G of the second echocardiogram is equal to or greater than the second daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof. In some embodiments, the predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the second predetermined post-Valsalva LVOT-G threshold is 30 mmHg.

[0028] In some embodiments of the above method, the first daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg of compound 1, the second daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg or about 10 mg of compound 1, and the third daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg, about 10 mg, or about 15 mg of compound 1.

[0029] In some embodiments of the above methods, the method further comprises measuring one or more components of the second echocardiogram.

[0030] In some embodiments of the above methods, the third period of time is about two weeks.

[0031] In some embodiments of the above method, a third daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is administered to the patient for a third period of time, and the method further comprises administering a fourth daily dose of compound 1 or a pharma- ceutically acceptable salt thereof to the patient for a fourth period of time or ceasing administration of compound 1 or a pharma- ceutically acceptable salt thereof to the patient based on one or more components of a third echocardiogram of the patient obtained after the third period of time and the third daily dose of compound or a pharma- ceutically acceptable salt thereof. In some embodiments, the method further comprises selecting a fourth daily dose of compound 1 or a pharma- ceutically acceptable salt thereof based on one or more components of the third echocardiogram and the third daily dose. In some embodiments, the one or more components of the third echocardiogram include biplane LVEF, post-Valsalva LVOT-G, or resting LVOT-G. In some embodiments, the one or more components of the third echocardiogram include biplane LVEF, post-Valsalva LVOT-G, and resting LVOT-G. In some embodiments, the one or more components of the third echocardiogram include biplane LVEF and post-Valsalva LVOT-G.

[0032] In some embodiments of the above method, one or more components of the third echocardiogram include a biplane LVEF, and if the biplane LVEF of the third echocardiogram is below a predetermined biplane LVEF threshold, the fourth daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is lower than the third daily dose of compound 1 or a pharma- ceutically acceptable salt thereof, or the administration of compound 1 or a pharma- ceutically acceptable salt thereof to the patient is discontinued. In some embodiments, if the biplane LVEF of the third echocardiogram is below a predetermined biplane LVEF threshold and the third daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is equal to or lower than the first daily dose of compound 1 or a pharma- ceutically acceptable salt thereof, the administration of compound 1 or a pharma- ceutically acceptable salt thereof to the patient is discontinued. In some embodiments, the predetermined biplane LVEF threshold is 50%.

[0033] In some embodiments of the above method, when the third daily dose of compound 1 or its pharma- ceutically acceptable salt is higher than the second daily dose of compound 1 or its pharma- ceutically acceptable salt, and the biplane LVEF of the third echocardiogram is below a predefined biplane LVEF threshold, the fourth daily dose of compound 1 or its pharma- ceutically acceptable salt is the same as the second daily dose of compound 1 or its pharma- ceutically acceptable salt; or when the third daily dose of compound 1 or its pharma- ceutically acceptable salt is the same as the second daily dose of compound 1 or its pharma- ceutically acceptable salt, and the biplane LVEF of the third echocardiogram is below a predefined biplane LVEF threshold, the fourth daily dose of compound 1 or its pharma- ceutically acceptable salt is the same as the first daily dose of compound 1 or its pharma- ceutically acceptable salt.In some embodiments, the predefined biplane LVEF threshold is 50%.

[0034] In some embodiments of the above method, one or more components of the third echocardiogram include biplane LVEF, resting LVOT-G, and post-Valsalva LVOT-G, wherein the fourth daily dose of Compound 1 or its pharma- ceutically acceptable salt is the same as the third daily dose of Compound 1 or its pharma- ceutically acceptable salt if the biplane LVEF of the third echocardiogram is equal to or greater than a predefined biplane LVEF threshold, the resting LVOT-G of the third echocardiogram is below a predefined resting LVOT-G threshold, and the post-Valsalva LVOT-G of the third echocardiogram is below a predefined post-Valsalva LVOT-G threshold. In some embodiments, the predefined biplane LVEF threshold is 50%, the predefined resting LVOT-G threshold is 30mmHg, and the post-Valsalva LVOT-G threshold is 50mmHg.

[0035] In some embodiments of the above method, the one or more components of the third echocardiogram include biplane LVEF, resting LVOT-G, and post-Valsalva LVOT-G, and the fourth daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is greater than the third daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof if the third echocardiogram meets any of the following conditions: (1) the biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold, and the resting LVOT-G is equal to or greater than a predetermined resting LVOT-G threshold, or (2) the biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold, the resting LVOT-G is below a predetermined resting LVOT-G threshold, and the post-Valsalva LVOT-G is equal to or greater than a predetermined post-Valsalva LVOT-G threshold. In some embodiments, the predetermined biplane LVEF threshold is 50%, the predetermined resting LVOT-G threshold is 30mmHg, and the post-Valsalva LVOT-G threshold is 50mmHg.

[0036] In some embodiments of the above method, the one or more components of the third echocardiogram include biplane LVEF and post-Valsalva LVOT-G, wherein if any of the following conditions are met on the third echocardiogram: (1) biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold and is less than a second predetermined biplane LVEF threshold, or (2) biplane LVEF is equal to or greater than a second predetermined biplane LVEF threshold and post-Valsalva LVOT-G is less than a second predetermined post-Valsalva LVOT-G threshold, the fourth daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is the same as the third daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof. In some embodiments, the predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the second predetermined post-Valsalva LVOT-G threshold is 30 mmHg.

[0037] In some embodiments of the above method, the one or more components of the third echocardiogram include biplane LVEF and post-Valsalva LVOT-G, and wherein the fourth daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is greater than the third daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof when the biplane LVEF of the third echocardiogram is greater than a second pre-determined biplane LVEF threshold and the post-Valsalva LVOT-G of the third echocardiogram is greater than or equal to the second pre-determined post-Valsalva LVOT-G threshold. In some embodiments, the pre-determined biplane LVEF threshold is 50%, the second pre-determined biplane LVEF threshold is 55%, and the second pre-determined post-Valsalva LVOT-G threshold is 30 mmHg.

[0038] In some embodiments of the above method, the first daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg of compound 1, the second daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg or about 10 mg of compound 1, the third daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg, about 10 mg, or about 15 mg of compound 1, and the fourth daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg, about 10 mg, about 15 mg, or about 20 mg of compound 1.

[0039] In some embodiments of the above methods, the method further comprises measuring one or more components of a third echocardiogram.

[0040] In some embodiments of the above methods, the fourth period of time is about two weeks.

[0041] In some embodiments, a method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need of such treatment comprises administering a first daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, to the patient for a first period of time; and administering a second daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, to the patient for a second period of time or discontinuing administration of Compound 1 to the patient based on a first echocardiogram comprising a biplane LVEF and a post-Valsalva LVOT-G of the patient obtained after the first period of time, wherein administration of Compound 1, or a pharma- ceutically acceptable salt thereof, to the patient is discontinued if the biplane LVEF of the first echocardiogram is below a first pre-determined biplane LVEF threshold; and administering a second daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, to the patient based on the first echocardiogram comprising a biplane LVEF and a post-Valsalva LVOT-G of the patient obtained after the first period of time, wherein administration of Compound 1, or a pharma- ceutically acceptable salt thereof to the patient is discontinued if the biplane LVEF of the first echocardiogram is below a first pre-determined biplane LVEF threshold; or (2) the biplane LVEF of the first echocardiogram is greater than or equal to the second predetermined biplane LVEF threshold and less than a second predetermined biplane LVEF threshold; or (2) the biplane LVEF is greater than or equal to the second predetermined biplane LVEF threshold and the post-Valsalva LVOT-G of the first echocardiogram is less than a predetermined post-Valsalva LVOT-G threshold, the second daily dose of Compound 1 or a pharma- ceutical acceptable salt thereof is the same as the first daily dose of Compound 1 or a pharma-ceutical acceptable salt thereof; if the biplane LVEF of the first echocardiogram is greater than the second predetermined biplane LVEF threshold and the post-Valsalva LVOT-G of the first echocardiogram is greater than or equal to the pre-determined post-Valsalva LVOT-G threshold, the second daily dose of Compound 1 or a pharma-ceutical acceptable salt thereof is greater than the first daily dose of Compound 1 or a pharma-ceutical acceptable salt thereof.

[0042] In some embodiments of the above method, the first daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg of Compound 1, and the second daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg or about 10 mg of Compound 1.

[0043] In some embodiments of the above methods, the method further comprises measuring a biplane LVEF and a post-Valsalva LVOT-G on the first echocardiogram.

[0044] In some embodiments of the above methods, the first period of time is about two weeks.

[0045] In some embodiments of the above methods, the second period of time is about two weeks.

[0046] In some embodiments of the above method, a second daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is administered to the patient for a second period of time, and the method includes administering a third daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof to the patient for a third period of time or discontinuing administration of Compound 1 or a pharma- ceutically acceptable salt thereof to the patient based on a second echocardiogram, including a biplane LVEF and a post-Valsalva LVOT-G of the patient obtained after the second period of time and the second daily dose of Compound 1 or a pharma- ceutical acceptable salt thereof. wherein if the biplane LVEF of the second echocardiogram falls below the first predetermined biplane LVEF threshold and the second daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, is the same as the first daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, then administration of Compound 1, or a pharma- ceutically acceptable salt thereof, to the patient is discontinued; and if the biplane LVEF of the second echocardiogram falls below the first predetermined biplane LVEF threshold and the second daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, is the same as the first daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, then administration of Compound 1, or a pharma- ceutically acceptable salt thereof to the patient is discontinued; and if the first daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is higher than the first daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof, the third daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is lower than the second daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof; and if the second echocardiogram shows the following: (1) biplane LVEF equal to or greater than the first pre-determined biplane LVEF threshold and below the second pre-determined biplane LVEF threshold; or (2) biplane LVEF equal to or greater than the second pre-determined biplane LVEF threshold and post-Valsalva LVOT-G equal to or greater than the pre-determined post-Valsalva LVOT-G threshold. the third daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is equal to the second daily dose of compound 1 or a pharma- ceutically acceptable salt thereof if either the biplane LVEF of the second echocardiogram is above a second pre-determined biplane LVEF threshold and the post-Valsalva LVOT-G of the second echocardiogram is equal to or greater than a pre-determined post-Valsalva LVOT-G threshold, the third daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is equal to the second daily dose of compound 1 or a pharma- ceutically acceptable salt thereof if either the biplane LVEF of the second echocardiogram is above a second pre-determined biplane LVEF threshold and the post-Valsalva LVOT-G of the second echocardiogram is equal to or greater than a pre-determined post-Valsalva LVOT-G threshold.

[0047] In some embodiments of the above method, the first daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg of compound 1, the second daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg or about 10 mg of compound 1, and the third daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg, about 10 mg, or about 15 mg of compound 1.

[0048] In some embodiments of the above methods, the method further comprises measuring biplane LVEF and post-Valsalva LVOT-G on a second echocardiogram.

[0049] In some embodiments of the above methods, the third period of time is about two weeks.

[0050] In some embodiments of the above method, a third daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is administered to the patient for a third period of time, the method further comprising administering a fourth daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof to the patient for a fourth period of time or discontinuing administration of Compound 1 to the patient based on a third echocardiogram, including a biplane LVEF and a post-Valsalva LVOT-G of the patient obtained after the third period of time and the second third dose of Compound 1 or a pharma- ceutically acceptable salt thereof, if the biplane LVEF of the third echocardiogram falls below the first predetermined biplane LVEF threshold and the third daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, is the same as the first daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, administration of Compound 1, or a pharma- ceutically acceptable salt thereof, to the patient is discontinued; ... and if the fourth daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is higher than the first daily dose of the salt, the fourth daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is lower than the third daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof; and if a third echocardiogram shows: (1) a biplane LVEF equal to or greater than a first pre-determined biplane LVEF threshold and below a second pre-determined biplane LVEF threshold; or (2) a biplane LVEF equal to or greater than a second pre-determined biplane LVEF threshold and a post-Valsalva LVOT-G below a pre-determined post-Valsalva LVOT-G threshold. the fourth daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is equal to the third daily dose of compound 1 or a pharma- ceutically acceptable salt thereof if any of the following conditions are met: the biplane LVEF of the third echocardiogram is above a second pre-determined biplane LVEF threshold and the post-Valsalva LVOT-G of the third echocardiogram is equal to or greater than the third daily dose of compound 1 or a pharma- ceutically acceptable salt thereof.In some embodiments, the first daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg of compound 1, the second daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg or about 10 mg of compound 1, the third daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg, about 10 mg, or about 15 mg of compound 1, and the fourth daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg, about 10 mg, about 15 mg, or about 20 mg of compound 1. In some embodiments, the method further comprises measuring biplane LVEF and post-Valsalva LVOT-G on the second echocardiogram. In some embodiments, the third period is about 2 weeks.

[0051] In some embodiments of the above method, the first predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the predetermined post-Valsalva LVOT-G threshold is 30 mmHg.

[0052] In some embodiments of any of the above methods, prior to administration of Compound 1 or a pharma- ceutically acceptable salt thereof, the patient has (i) a resting LVOT-G of ≧50 mmHg; or (ii) a resting LVOT-G of ≧30 mmHg and <50 mmHg with a post-Valsalva LVOT-G of ≧50 mmHg.

[0053] In some embodiments of any of the above methods, prior to administration of Compound 1, or a pharma- ceutically acceptable salt thereof, the patient has a left ventricular ejection fraction (LVEF) of ≧60%.

[0054] In some embodiments of any of the above methods, the patient is not administered disopyramide during treatment with Compound 1, or a pharma- ceutically acceptable salt thereof.

[0055] In some embodiments of any of the above methods, the patient is administered disopyramide during treatment with Compound 1, or a pharma- ceutically acceptable salt thereof.

[0056] In some embodiments of any of the above methods, the patient has not been treated with disopyramide or an antiarrhythmic drug with negative inotropic effects within 4 weeks prior to treatment with Compound 1, or a pharma- ceutical acceptable salt thereof.

[0057] In some embodiments of any of the above methods, the patient is administered an antiarrhythmic agent during treatment with Compound 1, or a pharma- ceutically acceptable salt thereof.

[0058] In some embodiments of any of the above methods, the patient is a CYP2D6 poor metabolizer.

[0059] In some embodiments of any of the above methods, the patient is in a fasted state when Compound 1, or a pharma- ceutically acceptable salt thereof, is administered.

[0060] In some embodiments of any of the above methods, the patient is in a postprandial state when Compound 1, or a pharma- ceutically acceptable salt thereof, is administered.

[0061] In some embodiments of any of the above methods, the method does not include taking a blood sample from the patient.

[0062] In some embodiments of any of the above methods, the method does not include analyzing a blood sample of the patient.

[0063] In some embodiments of any of the above methods, the patient is administered a beta-blocker during treatment with Compound 1, or a pharma- ceutically acceptable salt thereof.

[0064] Also provided herein is a method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need of treatment thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharma- ceutical acceptable salt thereof.

[0065] In some embodiments of any of the above methods, the method results in one or more of the following: improved mitral regurgitation, improved cardiac relaxation, beneficial cardiac remodeling, cardiac reverse remodeling, beneficial cardiac structural remodeling, beneficial cardiac functional remodeling, reversal of adverse cardiac remodeling, reduction in mean left ventricular mass index (LVMI), improvement in left ventricular (LV) filling pressures, reduction in left atrial volume index (LAVI), reduction in categorical assessment of systolic anterior motion of the mitral valve leaflets, reduction in systolic anterior motion of the mitral valve leaflets, reduction in frequency of eccentric mitral regurgitation, reduction in mitral regurgitation, reduction in lateral wall E / e', reduction in lateral wall E / E, reduction in brain natriuretic peptide (BNP), and reduction in N-terminal prohormone of brain natriuretic peptide (NT-proBNP).

[0066] In some embodiments, one or more results of the treatment occur within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of initiating treatment with Compound 1, or a pharma- ceutically acceptable salt thereof.

[0067] In some embodiments of any of the above methods, the patient's left ventricular mass index (LVMI) is reduced.

[0068] In some embodiments of any of the above methods, the patient's left atrial volume index (LAVI) is reduced.

[0069] In some embodiments of any of the above methods, the patient's e' is reduced.

[0070] In some embodiments of any of the above methods, the patient's sidewall E / e' is reduced.

[0071] In some embodiments of any of the above methods, the likelihood of systolic anterior motion of the mitral valve leaflets is reduced.

[0072] In some embodiments of any of the above methods, the likelihood of mitral regurgitation is reduced.

[0073] In some embodiments of any of the above methods, the level of brain natriuretic peptide or N-terminal prohormone of brain natriuretic peptide (NT-proBNP) is reduced in the patient.

[0074] In some embodiments of any of the above methods, the level of cardiac troponin I in the patient is reduced.

[0075] In some embodiments of any of the above methods, the patient's left ventricular wall stress is reduced.

[0076] In some embodiments of any of the above methods, myocardial damage in the patient is reduced.

[0077] In some embodiments of any of the above methods, the patient's heart failure symptoms are reduced, e.g., the method reduces the patient's NYHA classification.

[0078] In some embodiments of any of the above methods, the method provides sustained effect(s) for at least 10 weeks, 12 weeks, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years.

[0079] In some embodiments of any of the above methods, administration for the second, third, or fourth period of time can be, for example, administration for about 2 weeks, about 10 weeks, about 12 weeks, about 6 months, about 1 year, about 2 years, about 3 years, about 4 years, or about 5 years, or indefinitely. As used herein, administration for an indefinite period of time can refer to administration until the patient no longer requires treatment, administration until there is no further therapeutic benefit, or administration until there is no further reason to treat. [Brief description of the drawings]

[0080] [Figure 1] An exemplary method for treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient is provided, comprising titrating the daily dose of CK-274, or a pharma- ceutical acceptable salt thereof.

[0081] [Diagram 2] A schematic overview of the Phase 1 clinical trial of CK-274 (also called aficamten) is shown. The study included the SAD cohort, the MAD cohort, the CYP2D6-PM cohort, and the food effect cohort. The MAD and CYP2D6-PM cohorts were initiated when a tolerable pharmacologically active dose (approximately 5% reduction in LVEF) was identified in the SAD cohort. The food effect cohort was initiated after the completion of the last SAD cohort. The criteria for stopping dose escalation were met in the SAD 75 mg dose cohort, and the remaining patients in this cohort were administered 50 mg. The final SAD cohort was then completed using 40 mg aficamten. CYP2D6-PM = cytochrome P450 2D6 poor metabolizer phenotype; d = days; LVEF = left ventricular ejection fraction; MAD = repeated escalating doses; qd = once daily; SAD = single escalating dose.

[0082] [Diagram 3] A shows the mean (SE) maximum plasma concentration (Cmax) of aficamten in a dose-proportional manner after single oral doses of 1 mg to 50 mg. B shows the mean (SE) maximum plasma concentration (Cmax) of aficamten in a dose-proportional manner after single oral doses of 1 mg to 50 mg. B shows the mean (SE) maximum plasma concentration (Cmax) of aficamten in a dose-proportional manner after single oral doses of 1 mg to 50 mg. AUC24 = area under the plasma drug concentration-time curve from 0 to 24 hours; Cmax = maximum plasma concentration; SE = standard error.

[0083] [Figure 4]Figure 1 shows plasma concentrations over time with repeated doses of aficamten from an exemplary clinical trial. Mean (SE) plasma concentrations of aficamten are shown. Data points have been offset for clarity. Aficamten plasma concentrations increased between the 5 mg dose and the two higher doses, but there was no difference in mean concentrations between the 7.5 mg and 10 mg doses on day 2. Clearance was similar for the 5 mg and 10 mg doses, and accumulation rates were similar for all three doses. Only trough measurements are shown for days 7, 8, 10, 11, 12, and 13. For the 5 mg and 10 mg cohorts, dosing duration was 14 days with follow-up of 3 days. For the 7.5 mg cohort, dosing was extended to 17 days with follow-up of 3 days, with steady state confirmed to be reached after 10-12 days. SE = standard error.

[0084] [Diagram 5] A shows the SAD cohort and B shows the MAD cohort from an exemplary Aficamten clinical trial. Mean (SE) change from baseline in LVEF is displayed. Data points are offset for clarity. Both the SAD and MAD cohorts observed reductions in LVEF within the target range (5% to 15% reduction). In the SAD cohort, the decline in LVEF was generally small, with a mean maximum reduction of 5.8% in the 50 mg group (1.5 hours post-dose). In the MAD cohort, the greatest mean reduction in LVEF from baseline occurred in the 10 mg group (mean change of 5.0% at 1.5 hours post-dose on day 14). LVEF = left ventricular ejection fraction; MAD = repeated escalating doses; qd = once daily; SAD = single escalating dose; SE = standard error.

[0085] [Figure 6]A shows an analysis of the SAD cohort from an exemplary clinical trial, showing that LVEF tended to decrease with increasing plasma concentrations of aficamten. B shows an analysis of the MAD cohort from an exemplary clinical trial, showing that LVEF depression was minimal in most participants at plasma concentrations of aficamten of ≦180 ng / ml. CI=confidence interval; LVEF=left ventricular ejection fraction; MAD=multiple ascending doses; SAD=single ascending dose.

[0086] [Figure 7] 1 shows resting LVOT-G of treatment and placebo cohorts from an exemplary clinical trial of CK-274 (Aficamten).

[0087] [Figure 8] 1 shows post-Valsalva LVOT-G of treatment and placebo cohorts from an exemplary clinical trial of CK-274 (Aficamten).

[0088] [Figure 9] 1 shows the change in left atrial volume index (LAVI) for treatment and placebo cohorts from an exemplary clinical trial of CK-274.

[0089] [Figure 10] 1 shows the change in sidewall E / e' ratio for treatment and placebo cohorts from an exemplary clinical trial of CK-274 (Aficamten).

[0090] [Figure 11] 1 shows changes in mitral valve characteristics including mitral regurgitation (MR), eccentric MR, and systolic anterior motion (SAM) in treatment and placebo cohorts from an exemplary clinical trial of CK-274 (Aficamten).

[0091] [Figure 12] 1 shows changes in resting LVOT-G for treatment and placebo cohorts from an exemplary clinical trial of CK-274 (Aficamten).

[0092] [Figure 13] 1 shows changes in resting Valsalva LVOT-G for treatment and placebo cohorts from an exemplary clinical trial of CK-274 (Aficamten).

[0093] [Figure 14] 1 shows changes in LVEF for treatment and placebo cohorts from an exemplary clinical trial of CK-274 (Aficamten).

[0094] [Figure 15] FIG. 1 shows NYHA functional class response for treatment and placebo cohorts from an exemplary clinical trial of CK-274 (Aficamten).

[0095] [Figure 16] 1 shows mean NT-proBNP change in treatment and placebo cohorts from an exemplary clinical trial of CK-274 (Aficamten).

[0096] [Figure 17] 1 shows changes in resting LVOT-G for treatment and placebo cohorts from an exemplary clinical trial of CK-274 (Aficamten).

[0097] [Figure 18] 1 shows changes in resting Valsalva LVOT-G for treatment and placebo cohorts from an exemplary clinical trial of CK-274 (Aficamten).

[0098] [Figure 19] 1 shows changes in LVEF for treatment and placebo cohorts from an exemplary clinical trial of CK-274 (Aficamten).

[0099] [Figure 20]1 shows hemodynamic responses of treatment and placebo cohorts from an exemplary clinical trial of CK-274 (Aficamten).

[0100] [Figure 21] FIG. 1 shows NYHA functional class response for treatment and placebo cohorts from an exemplary clinical trial of CK-274 (Aficamten).

[0101] [Figure 22] 1 shows mean NT-proBNP change in treatment and placebo cohorts from an exemplary clinical trial of CK-274 (Aficamten).

[0102] [Diagram 23] 1 shows hs-troponin for treatment and placebo cohorts from an exemplary clinical trial of CK-274 (Aficamten).

[0103] [Figure 24] FIG. 1 shows NYHA functional class response for treatment and placebo cohorts from an exemplary clinical trial of CK-274 (Aficamten).

[0104] [Diagram 25] FIG. 1 shows NYHA functional class response for treatment and placebo cohorts from an exemplary clinical trial of CK-274 (Aficamten).

[0105] [Figure 26] 1 shows the open-label extension design of an exemplary clinical trial for CK-274 (Aficamten).

[0106] [Figure 27] 1 shows patient distribution over time among doses in an open-label extension of an exemplary clinical trial for CK-274 (Aficamten).

[0107] [Figure 28]1 shows resting LVOT-G of patients in an open-label continuation of an exemplary clinical trial of CK-274 (Aficamten).

[0108] [Figure 29] 1 shows post-Valsalva LVOT-G in patients in an open-label continuation of an exemplary clinical trial of CK-274 (Aficamten).

[0109] [Diagram 30] 1 shows the change in LVEF for patients in an open-label extension of an exemplary clinical trial of CK-274 (Aficamten).

[0110] [Diagram 31] 1 shows the distribution of NYHA functional class at various time points for patients in an open-label continuation of an exemplary clinical trial of CK-274 (Aficamten).

[0111] [Diagram 32] 1 shows NYHA functional class response at various time points for patients in an open-label continuation of an exemplary clinical trial of CK-274 (Aficamten).

[0112] [Diagram 33] 1 shows the mean NT-proBNP change for patients in an open-label extension of an exemplary clinical trial of CK-274 (Aficamten).

[0113] [Diagram 34] 1 shows the mean cardiac troponin I change for patients in an open-label extension of an exemplary clinical trial of CK-274 (Aficamten).

[0114] [Diagram 35] 1 shows the change from baseline in KCCQ scores for patients in an open-label extension of an exemplary clinical trial of CK-274 (Aficamten).

[0115] [Diagram 36]1 shows the percentage of patients with various levels of change from baseline in KCCQ scores for patients in an open-label extension of an exemplary clinical trial of CK-274 (Aficamten).

[0116] [Figure 37] 1 shows the percent change from baseline in hs-troponin I for treatment and placebo cohorts from an exemplary clinical trial of CK-274 (Aficamten). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0117] Described herein are cardiac myosin inhibitors (CK-3773274, also referred to as CK-274 or aficamten) and methods for treating hypertrophic cardiomyopathy using cardiac myosin inhibitors. Treatment methods can include adjusting the dose, for example to increase, decrease, or maintain the dose, based on the results of one or more measured left ventricular outflow tract pressure gradients (LVOT-G), biplane left ventricular ejection fraction (LVEF) measurements, and / or post-Valsalva LVOT-G measurements. These measurements can be obtained, for example, using echocardiograms.

[0118] CK-3773274 (Compound 1) is a small molecule cardiac myosin inhibitor having the structure shown below. [ka] The chemical name of CK-274 is (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. This small molecule inhibitor can be orally administered to patients for the treatment of, for example, hypertrophic cardiomyopathy.

[0119] CK-274 is described in WO2019 / 144041, which is incorporated herein by reference. CK-274 or a pharma- ceutically acceptable salt thereof can be obtained according to the methods described therein. The CK-274 used in the disclosed methods can exist as a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, or combinations thereof, and can be formulated into any suitable pharmaceutical formulation. Polymorphs of CK-274 are described in WO2021 / 011807, which is incorporated herein by reference. Formulations of CK-274 are described in WO2021 / 011808, which is incorporated herein by reference. CK-274 was designed to reduce hypercontractility associated with hypertrophic cardiomyopathy (HCM). Without being bound by theory, in preclinical models, CK-274 reduces myocardial contractility by directly binding to cardiac myosin at a unique and selective allosteric binding site, thereby preventing myosin from entering a force-generating state. CK-274 reduces the number of active actin-myosin cross-bridges during each cardiac cycle, thereby reducing myocardial contractility. This mechanism of action may be therapeutically effective in conditions characterized by excessive hypercontractility, such as HCM (e.g., obstructive HCM, also referred to as oHCM).

[0120] definition As used herein, the following words and phrases are generally intended to have the following meanings, unless the context in which they are used indicates otherwise.

[0121] Reference herein to "about" a value or parameter includes (and describes) the value or parameter itself, as well as any value or parameter 5% above or below that parameter. For example, a description of "about X" includes the descriptions "X" and "X+ / -5%."

[0122] "NYHA classification" or "NYHA class" refers to the New York Heart Association functional classification of heart failure symptoms. Descriptions of each of the NYHA classes I, II, III, and IV can be found in: 1) Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart Association. Criteria Committee. "Nomenclature and criteria for diagnosis of diseases of the heart and great vessels". 9th ed. Boston, MA: Lippincott Williams and Wilkins; March 1, 1994; and 2) "Classes of Heart Failure", American Heart Association, https: / / www.heart.org / en / health-topics / heart-failure / what-is-heart-failure / classes-of-heart-failure, adapted from the Criteria Committee, New York Heart Association, Inc. Diseases of the Heart and Blood Vessels. Nomenclature and Criteria for diagnosis, 6th edition Boston, Little, Brown and Co. 1964, p 114. Briefly, NYHA class I indicates that the patient has no limitations in physical activity and that ordinary physical activity does not cause undue fatigue, agitation, or dyspnea (shortness of breath). NYHA class II indicates that the patient has mild limitations in physical activity and no complaints at rest, but ordinary physical activity causes fatigue, palpitations, or dyspnea (shortness of breath). NYHA class III indicates that the patient has significant limitations in physical activity and no complaints at rest, but less than ordinary physical activity causes fatigue, palpitations, or dyspnea. NYHA class IV indicates that the patient has complaints with any physical activity, symptoms of heart failure are present at rest, and complaints increase with any physical activity.

[0123] The term "pharmaceutically acceptable salt" refers to any salt of the compounds herein that is known to be non-toxic and is commonly used in the pharmaceutical literature. In some embodiments, a pharmaceutically acceptable salt of a compound retains the biological effectiveness of the compounds described herein and is not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines such as naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharma- ceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0124] When the compound described herein is obtained as an acid addition salt, the solution of the acid salt can be basified to obtain the free base.On the other hand, when the compound is a free base, the addition salt, particularly the pharma-ceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to the conventional procedure for preparing an acid addition salt from a base compound (see, for example, Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19).Those skilled in the art will recognize various synthetic methods that can be used to prepare pharma-ceutically acceptable addition salts.

[0125] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharma- ceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

[0126] The terms "patient," "individual," and "subject" refer to animals, e.g., mammals. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows, and humans. In some embodiments, a patient or subject is a human, e.g., a human who has been or will be the object of treatment, observation, or experiment. The compounds, compositions, and methods described herein can be useful in both human therapy and veterinary applications.

[0127] The term "therapeutically effective amount" or "effective amount" refers to an amount of a compound disclosed and / or described herein that is sufficient to affect such treatment when administered to a patient in need of such treatment as defined herein. A therapeutically effective amount of a compound may be an amount sufficient to treat a disease that responds to modulation of the myocardial node. The therapeutically effective amount will vary depending, for example, on the subject and condition being treated, the subject's weight and age, the severity of the condition, the particular compound, the dosing regimen to be followed, the timing of administration, and the mode of administration, all of which can be readily determined by one of ordinary skill in the art. A therapeutically effective amount can be ascertained experimentally, for example, by assaying blood levels of the chemical, or theoretically, by calculating bioavailability.

[0128] "Treatment" (and related terms such as "treat", "treated", "treating") includes one or more of inhibiting a disease or disorder, delaying or preventing the onset of clinical symptoms of a disease or disorder, and / or alleviating a disease or disorder (i.e., causing the alleviation or regression of clinical symptoms). The term encompasses situations in which a disease or disorder is already experienced by a patient, as well as situations in which a disease or disorder is not currently experienced but is expected to occur. The term encompasses both complete and partial reduction or prevention of a condition or disorder, and complete or partial reduction of clinical symptoms of a disease or disorder. Thus, the compounds described and / or disclosed herein may prevent the worsening of an existing disease or disorder, may assist in the management of a disease or disorder, or may reduce or eliminate a disease or disorder. When used prophylactically, the compounds disclosed and / or described herein may prevent the onset of a disease or disorder, or may reduce the extent of a disease or disorder that may occur.

[0129] References to the amount of any dosage of a compound described herein or a pharma- ceutically acceptable salt thereof (e.g., 5 mg, 10 mg, 20 mg of Compound 1, etc.) refer to the amount of that compound without any salt (i.e., equivalent mass).

[0130] Treatment of hypertrophic cardiomyopathy As further described herein, a therapeutically effective amount of CK-274 may be administered to a patient for the treatment of hypertrophic cardiomyopathy. CK-274 may be administered at a constant dose level. CK-274 may be administered at a dose-adjusted dose level. For example, the dose of CK-274 may be adjusted according to the patient's response to the drug. That is, the dose of CK-274 may be periodically increased, decreased, or maintained according to a measurement of drug response, such as one or more of a left ventricular outflow tract pressure gradient (LVOT-G) measurement, a biplane left ventricular ejection fraction (LVEF) measurement, and / or a post-Valsalva LVOT-G measurement.

[0131] Results from a recent clinical trial (see Example 1) demonstrated that 10 weeks of CK-274 treatment resulted in large and statistically significant reductions from baseline in mean resting left ventricular outflow tract gradient (LVOT-G) (p=0.0003, p=0.0004 for cohort 1 and cohort 2, respectively) and mean post-Valsalva LVOT-G (p=0.001, p<0.0001 for cohort 1 and cohort 2, respectively) compared to placebo. The majority of patients treated with CK-274 (78.6% in cohort 1 and 92.9% in cohort 2) achieved the intended goal of treatment, defined as a resting gradient of <30 mmHg and a post-Valsalva gradient of <50 mmHg at week 10, compared to placebo (7.7%). Reductions in LVOT-G occurred within 2 weeks of initiating treatment with CK-274, peaked within 2–6 weeks of the end of dose titration, and persisted through the end of treatment at week 10. The observed reductions in LVOT-G were dose-dependent, with patients achieving greater reductions in LVOT-G with increasing doses of CK-274.

[0132] Treatment with CK-274 in the clinical trial was well tolerated. Overall, the incidence of adverse events was similar between treatment arms. There were no serious adverse events attributable to CK-274, and no treatment interruptions of CK-274 occurred. No new cases of atrial fibrillation were reported by the investigators. In this dose-ranging study, one patient experienced a transient decrease in left ventricular ejection fraction (LVEF) that required dose adjustment but not dose interruption. LVEF returned toward baseline within 2 weeks of the end of treatment in both cohorts, confirming the reversibility of the CK-274-induced effects, as was similarly observed in healthy participants in the Phase 1 study of CK-274.

[0133] CK-274 is administered at a therapeutically effective dose, e.g., a dose sufficient to provide treatment of a disease state. For humans, the daily dose can be about 1 mg to about 50 mg. For example, the daily dose can be about 5 mg, about 10 mg, about 15 mg, about 20 mg, or about 30 mg, or any amount therebetween. The daily dose is the total amount administered in one day. The daily dose can be administered, without limitation, daily, every other day, weekly, biweekly, monthly, or at various intervals. In some embodiments, the daily dose is administered for a period ranging from one day to the subject's lifetime. In some embodiments, the daily dose is administered once a day. In some embodiments, the daily dose is administered in multiple divided doses, such as two, three, or four divided doses. In some embodiments, the daily dose is administered in two divided doses.

[0134] In one example, the patient is treated for hypertrophic cardiomyopathy by administering to the patient a daily dose of about 5 mg to about 30 mg of CK-274. In one example, the patient is treated for hypertrophic cardiomyopathy by administering to the patient a daily dose of about 5 mg of CK-274. In one example, the patient is treated for hypertrophic cardiomyopathy by administering to the patient a daily dose of about 10 mg of CK-274. In one example, the patient is treated for hypertrophic cardiomyopathy by administering to the patient a daily dose of about 15 mg of CK-274. In one example, the patient is treated for hypertrophic cardiomyopathy by administering to the patient a daily dose of about 20 mg of CK-274. In one example, the patient is treated for hypertrophic cardiomyopathy by administering to the patient a daily dose of about 25 mg of CK-274. In one example, the patient is treated for hypertrophic cardiomyopathy by administering to the patient a daily dose of about 30 mg of CK-274. In some embodiments of any of the foregoing, the treating of hypertrophic cardiomyopathy further comprises administering to the patient disopyramide.

[0135] In some embodiments, a method for treating hypertrophic cardiomyopathy is provided, comprising administering CK-274, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing CK-274 or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent, where the second therapeutic agent is disopyramide. In some embodiments, the hypertrophic cardiomyopathy is obstructive hypertrophic cardiomyopathy and / or treatment-resistant hypertrophic cardiomyopathy. In some embodiments, a method for treating obstructive hypertrophic cardiomyopathy, treatment-resistant hypertrophic cardiomyopathy, or treatment-resistant obstructive hypertrophic cardiomyopathy is provided, comprising administering CK-274, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing CK-274 or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent, where the second therapeutic agent is disopyramide. In some embodiments, the combination of CK-274 or a pharmaceutically acceptable salt thereof and disopyramide comprises simultaneous administration of CK-274 or a pharmaceutically acceptable salt thereof and disopyramide. In some embodiments, the combination of CK-274 and disopyramide comprises sequential administration of CK-274, or a pharma- ceutically acceptable salt thereof, and disopyramide.In some embodiments, the combination of CK-274, or a pharma- ceutically acceptable salt thereof, and disopyramide comprises administration of CK-274, or a pharma- ceutically acceptable salt thereof, to a patient already undergoing treatment with disopyramide.

[0136] During the course of treatment of hypertrophic cardiomyopathy, the dose of CK-274 administered to the patient may be titrated, for example, by increasing, decreasing, or maintaining the dose. The titration may be performed once during treatment, or may be performed repeatedly at intervals. For example, in some embodiments, the dose of CK-274 is titrated two or more times (e.g., 3, 4, 5 or more times) during the course of treatment. In some embodiments, the new daily dose amount is administered to the patient at a constant amount for about 1 week to about 8 weeks (or about 2 weeks to about 6 weeks, or about 4 weeks) before the daily dose amount is titrated. In some embodiments, the new daily dose amount is administered to the patient at a constant amount for about 2 weeks before the titration. For example, a first daily dose may be administered to the patient for about 2 weeks before the first titration, during which the daily dose amount is increased, decreased, or maintained. A second titration may then be performed approximately 2 weeks after the first titration. Dosage titration allows for individualization of dosage to a patient's response to a drug, thereby maximizing the potential therapeutic benefit to the patient.

[0137] The titration of the dose may be based on one or more of the left ventricular outflow tract gradient (LVOT-G), biplane left ventricular ejection fraction (LVEF), and / or post-Valsalva LVOT-G measured in the patient. These measurement(s) may be determined, for example, using an echocardiogram. The echocardiogram is taken after administration of the daily dose, for example, about 1 hour to about 3 hours after administration of the dose. In some embodiments, the echocardiogram is taken about 2 hours after administration of the daily dose.

[0138] In some embodiments, an initial daily dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, or about 30 mg of CK-274, or any amount therebetween, is administered to the patient. After a period of time (e.g., about 2 weeks), resting LVOT-G, biplane LVEF, and / or post-Valsalva LVOT-G are measured, e.g., by echocardiography, after dose administration (e.g., about 1-3 hours, or about 2 hours after dose administration). If resting LVOT-G is equal to or greater than a predetermined resting LVOT-G threshold (e.g., equal to or greater than about 25 mmHg, equal to or greater than about 30 mmHg, or equal to or greater than about 35 mmHg) and biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold (e.g., equal to or greater than about 40%, equal to or greater than about 45%, equal to or greater than about 50%, equal to or greater than about 55%, or equal to or greater than about 60%), the daily dose is increased. Alternatively, if the resting LVOT-G is not equal to or greater than the predetermined resting LVOT-G threshold, the dose may still be increased if the post-Valsalva LVOT-G is equal to or greater than the predetermined post-Valsalva LVOT-G threshold (e.g., about 40 mmHg or greater, about 45 mmHg or greater, about 50 mmHg or greater, about 55 mmHg or greater, or about 60 mmHg or greater) and the biplane LVEF is equal to or greater than the predetermined biplane LVEF threshold. If the biplane LVEF is equal to or greater than the predetermined threshold but the resting LVOT-G is below the resting LVOT-G threshold and the post-Valsalva LVOT-G is below the post-Valsalva LVOT-G threshold, the dose may be maintained. If the biplane LVEF is below the biplane LVEF threshold, the dose may be decreased or discontinued. For example, if the biplane LVEF is below the biplane LVEF threshold and the current dose is not the lowest (e.g., first) dose, the dose may be decreased. If the biplane LVEF falls below the biplane LVEF threshold and the current dose is the lowest (e.g., first) dose, the dose may be discontinued. In some embodiments, the resting LVOT-G threshold is about 30 mmHg, the biplane LVEF threshold is about 50%, and the post-Valsalva LVOT-G threshold is about 50 mmHg.In some embodiments, titration of the dose of CK-274 includes maintaining the dose at the current dose; increasing the dose by about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 10 mg, or any amount therebetween; decreasing the dose by about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 10 mg, or any amount therebetween; or ceasing administration. In some embodiments, titration of the dose includes maintaining the dose at the current dose; increasing the dose by about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 10 mg, or any amount therebetween; or decreasing the dose by about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 10 mg, or any amount therebetween.

[0139] After a period of time (e.g., about two weeks) during which the patient is administered the first titrated dose, the dose may again be titrated (i.e., increased, decreased, or maintained) based on the patient's resting LVOT-G, biplane LVEF, and / or post-Valsalva LVOT-G, e.g., using the same threshold parameters as described above. Exemplary titration schedules include administering the first titrated dose for about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about eight weeks, about ten weeks, or about twelve weeks, or any period therebetween, followed by titration based on the patient's resting LVOT-G, biplane LVEF, and / or post-Valsalva LVOT-G, e.g., using the same threshold parameters as described above. Further iterations of administration and titration may be performed as appropriate.

[0140] In some embodiments, the method reduces the patient's resting left ventricular outflow tract pressure gradient (LVOT-G) below a particular value. The reduction in resting LVOT-G below a particular value can occur within 10 weeks of initiating treatment with Compound 1 or a pharma- ceutically acceptable salt thereof. The reduction in resting LVOT-G below a particular value can occur within 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 9 weeks, or 10 weeks of initiating treatment with Compound 1 or a pharma- ceutically acceptable salt thereof. In some embodiments, the reduction in resting LVOT-G is sustained for at least 10 weeks of treatment. In some embodiments, the reduction in resting LVOT-G occurs within 2-6 weeks of the end of titration. In some embodiments, the reduction in resting LVOT-G peaks within 2-6 weeks of the end of titration. In some embodiments, the specific resting LVOT-G value is 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, or 25 mmHg.

[0141] In some embodiments, the method reduces the patient's post-Valsalva left ventricular outflow tract gradient (LVOT-G) below a particular value. The reduction in post-Valsalva LVOT-G below a particular value may occur within 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 9 weeks, or 10 weeks of the start of treatment with Compound 1 or a pharma- ceutically acceptable salt thereof. The reduction in post-Valsalva LVOT-G may be sustained for at least 10 weeks of treatment. In some embodiments, the reduction in post-Valsalva LVOT-G occurs within 2-6 weeks of the end of titration. In some embodiments, the reduction in post-Valsalva LVOT-G peaks within 2-6 weeks of the end of titration. In some embodiments, the specific post-Valsalva LVOT-G value is 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, or 30 mmHg.

[0142] Provided herein is a method of reducing resting left ventricular outflow tract pressure gradient (LVOT-G) below a particular value in a patient with obstructive hypertrophic cardiomyopathy (oHCM), comprising administering a therapeutically effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof to the patient. The reduction in resting LVOT-G below a particular value may occur within 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 9 weeks, or 10 weeks of the initiation of treatment with Compound 1 or a pharma- ceutically acceptable salt thereof. The reduction in resting LVOT-G below a particular value may occur within 2 weeks of the initiation of treatment with Compound 1 or a pharma- ceutically acceptable salt thereof. In some embodiments, the reduction in resting LVOT-G is sustained for at least 10 weeks of treatment. In some embodiments, the reduction in resting LVOT-G occurs within 2-6 weeks of the end of titration. In some embodiments, the reduction in resting LVOT-G peaks within 2-6 weeks of the end of titration. In some embodiments, the specific resting LVOT-G value is 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, or 25 mmHg.

[0143] Provided herein is a method of reducing post-Valsalva left ventricular outflow tract gradient (LVOT-G) below a particular value in a patient with obstructive hypertrophic cardiomyopathy (oHCM), comprising administering a therapeutically effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof to the patient. The reduction of post-Valsalva LVOT-G below a particular value may occur within 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 9 weeks, or 10 weeks of initiation of treatment with Compound 1 or a pharma- ceutically acceptable salt thereof. The reduction of post-Valsalva LVOT-G may be sustained for at least 10 weeks of treatment. In some embodiments, the reduction of post-Valsalva LVOT-G occurs within 2-6 weeks of completion of titration. In some embodiments, the reduction of post-Valsalva LVOT-G peaks within 2-6 weeks of completion of titration. In some embodiments, the specific post-Valsalva LVOT-G value is 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, or 30 mmHg.

[0144] Provided herein is a method for reducing the resting left ventricular outflow tract pressure gradient (LVOT-G) below a specific value and reducing the post-Valsalva left ventricular outflow tract pressure gradient (LVOT-G) below a specific value in a patient with obstructive hypertrophic cardiomyopathy (oHCM), comprising administering a therapeutically effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof to the patient. The reduction of the resting LVOT-G below a specific value and the reduction of the post-Valsalva LVOT-G below a specific value may occur within 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 9 weeks, or 10 weeks of the start of treatment with Compound 1 or a pharma- ceutically acceptable salt thereof. The reduction of the resting LVOT-G below a specific value and the reduction of the post-Valsalva LVOT-G below a specific value may occur within 2 weeks of the start of treatment with Compound 1 or a pharma- ceutically acceptable salt thereof. In some embodiments, the reduction in resting LVOT-G and the reduction in post-Valsalva LVOT-G are sustained for at least 10 weeks of treatment. In some embodiments, both the reduction in resting LVOT-G and the reduction in post-Valsalva LVOT-G may occur within 2-6 weeks of the end of titration. In some embodiments, both the reduction in resting LVOT-G and the reduction in post-Valsalva LVOT-G peak within 2-6 weeks of the end of titration. In some embodiments, the particular resting LVOT-G value is 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, or 25 mmHg. In some embodiments, the particular post-Valsalva LVOT-G value is 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, or 30 mmHg. In some embodiments, the particular resting LVOT-G value is 30 mmHg and the particular post-Valsalva LVOT-G value is 50 mmHg.

[0145] Provided herein is a method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient eligible for septal reduction therapy (SRT), comprising administering to the patient a therapeutically effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof. Also provided herein is a method of treating oHCM in a patient in need of SRT, comprising administering to the patient a therapeutically effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, wherein the method eliminates the need for SRT in the patient. In some embodiments, the SRT is a myectomy. In some embodiments, the SRT is an alcohol septal ablation.

[0146] Further provided herein is a method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient with heart failure symptoms, comprising administering a therapeutically effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof to the patient, the method resulting in a reduction in heart failure symptoms as assessed by NYHA classification. In some of the above-mentioned embodiments, the method improves the heart failure symptoms of the patient by at least one NYHA class, e.g., by one or two NYHA class(es). In some of the above-mentioned embodiments, the method changes the patient from NYHA class III to class II or class I. In some of the above-mentioned embodiments, the method changes the patient from NYHA class III to class II. In some of the above-mentioned embodiments, the method changes the patient from NYHA class III to class I. In some of the above-mentioned embodiments, the method changes the patient from NYHA class II to class I. In some of the above-mentioned embodiments, the reduction in heart failure symptoms occurs within 10 weeks of initiating treatment with Compound 1 or a pharma- ceutically acceptable salt thereof.

[0147] In some embodiments, the titration of the daily dose of CK-274 or a pharma- ceutically acceptable salt thereof is based on the results of echocardiograms, including biplane LVEF and post-Valsalva LVOT-G. For example, based on the results of biplane LVEF and / or post-Valsalva LVOT-G, the daily dose of CK-274 or a pharma- ceutically acceptable salt thereof may be increased, maintained, or decreased (or discontinued, for example, if the subject has already received the lowest (e.g., first) daily dose). For example, based on the results of biplane LVEF and / or post-Valsalva LVOT-G, the daily dose of CK-274 or a pharma- ceutically acceptable salt thereof may be increased, maintained, or decreased (or discontinued, for example, if the subject has already received the first daily dose). The first daily dose of CK-274 or a pharma- ceutically acceptable salt thereof is administered to the patient for a first period (e.g., about 2 weeks). The second daily dose or discontinuation of administration of CK-274 or its pharma- ceutically acceptable salt to the subject is then selected based on the patient's biplane LVEF and post-Valsalva LVOT-G obtained after the first period. If the biplane LVEF of the echocardiogram falls below a first predefined biplane LVEF threshold (e.g., 50%), administration of CK-274 or its pharma- ceutically acceptable salt may be discontinued. If the biplane LVEF of the echocardiogram falls below a first predefined biplane LVEF threshold (e.g., 50%) and the patient has already received a minimum (e.g., first) daily dose, administration of CK-274 or its pharma- ceutically acceptable salt may be discontinued. If the biplane LVEF of the echocardiogram falls below a first predefined biplane LVEF threshold (e.g., 50%) and the patient has not yet received a minimum daily dose, the daily dose may be reduced (i.e., the second daily dose is less than the first daily dose).If the biplane LVEF is equal to or greater than the first predetermined biplane threshold and is less than the second predetermined biplane LVEF threshold (e.g., 55%), or if the biplane LVEF is equal to or greater than the second predetermined biplane LVEF threshold and the post-Valsalva LVOT-G is less than the predetermined post-Valsalva LVOT-G threshold (e.g., 30 mmHg), the daily dose is maintained (i.e., the second daily dose is the same as the first daily dose). If the biplane LVEF is equal to or greater than the second predetermined biplane threshold and the post-Valsalva LVOT-G is greater than the predetermined post-Valsalva LVOT-G threshold, the daily dose can be increased (i.e., the second daily dose is greater than the first daily dose).

[0148] The second daily dose may be administered to the patient for a second period (e.g., about 2 weeks), and then titrated again based on the results of a second echocardiogram, including the patient's biplane LVEF and post-Valsalva LVOT-G, obtained after the second period. For example, a third daily dose or discontinuation of administration may be selected, or administration may be discontinued based on the second echocardiogram and the second daily dose. If the second daily dose is the same as (or lower than) the first daily dose, and the biplane LVEF of the second echocardiogram is below a first predetermined biplane LVEF threshold, administration may be discontinued. If the second daily dose is higher than the first daily dose, and the biplane LVEF of the second echocardiogram is below a first predetermined biplane LVEF threshold, the third daily dose may be reduced relative to the second daily dose (e.g., to the amount of the first daily dose). If the second daily dose is the same as (or lower than) the first daily dose (e.g., if the second daily dose is the lowest dose) and the biplane LVEF of the second echocardiogram falls below the first predetermined biplane LVEF threshold, administration may be discontinued. If the second daily dose is higher than the lowest (e.g., first) daily dose and the biplane LVEF of the second echocardiogram falls below the first predetermined biplane LVEF threshold, the third daily dose may be reduced relative to the second daily dose (e.g., to the amount of the first daily dose). If the biplane LVEF is equal to or greater than the first predetermined biplane LVEF threshold and falls below the second predetermined biplane LVEF threshold, or if the biplane LVEF is equal to or greater than the second predetermined biplane LVEF threshold and the post-Valsalva LVOT-G falls below the predetermined post-Valsalva LVOT-G threshold, the daily dose may be maintained (i.e., the third daily dose is the same as the second daily dose). If the biplane LVEF of the second echocardiogram is above a second predetermined biplane LVEF threshold and the post-Valsalva LVOT-G of the second echocardiogram is equal to or greater than a predetermined post-Valsalva LVOT-G threshold, the third daily dose may be increased relative to the second daily dose. The third daily dose is then administered to the patient for a third period of time (e.g., two weeks).

[0149] The titration of the daily dose can be repeated an additional number of times to select a fourth daily dose of CK-274 or a pharma- ceutically acceptable salt thereof or to discontinue administration, if necessary. For example, a third echocardiogram including biplane LVEF and post-Valsalva LVOT-G for the patient can be obtained after a third period of time, and a fourth daily dose of CK-274 or a pharma- ceutically acceptable salt thereof can be selected based on the third echocardiogram and the third daily dose. If the biplane LVEF of the third echocardiogram is below the first pre-determined biplane LVEF threshold and the third daily dose is the same as (or lower than) the first daily dose, administration of CK-274 or a pharma- ceutically acceptable salt thereof can be discontinued. If the third daily dose is higher than the first daily dose and the biplane LVEF of the third echocardiogram is below the first pre-determined biplane LVEF threshold, the fourth daily dose is reduced relative to the third daily dose. If the biplane LVEF of the third echocardiogram falls below the first predetermined biplane LVEF threshold and the third daily dose is the same as (or lower than) the first daily dose (e.g., the third daily dose is the lowest dose), administration of CK-274 or a pharma- ceutically acceptable salt thereof may be discontinued.If the third daily dose is higher than the lowest (e.g., first) daily dose and the biplane LVEF of the third echocardiogram falls below the first predetermined biplane LVEF threshold, the fourth daily dose is reduced relative to the third daily dose. The fourth daily dose may be the same as the third daily dose if the biplane LVEF of the third echocardiogram is equal to or greater than the predetermined biplane LVEF threshold and is below the second predetermined biplane LVEF threshold, or if the biplane LVEF of the third echocardiogram is equal to or greater than the second predetermined biplane LVEF threshold and the post-Valsalva LVOT-G of the third echocardiogram is below the predetermined post-Valsalva LVOT-G threshold.The fourth daily dose may be increased relative to the third daily dose if the biplane LVEF of the third echocardiogram is greater than the second predetermined biplane LVEF threshold and the post-Valsalva LVOT-G of the third echocardiogram is equal to or greater than the predetermined post-Valsalva LVOT-G threshold.

[0150] FIG. 1 illustrates an exemplary method for treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient, including titration of a daily dose of CK-274 or a pharma- ceutically acceptable salt thereof. The exemplary method illustrated in FIG. 1 provides four daily dose levels, with the first daily dose level being the lowest daily dose level, but can be easily modified to include additional or lesser dose levels. The exemplary method illustrated in FIG. 1 can be further modified such that the first daily dose level is not the lowest daily dose level. At 102, a first daily dose level (e.g., about 5 mg) of CK-274 or a pharma- ceutically acceptable salt thereof is administered to the patient. After a first period of time, at 104, the daily dose level is increased or maintained, or administration is discontinued. This selection can be based on a first echocardiogram obtained for the patient after the first period of time. Discontinuation 106 may be selected if the biplane LVEF of the first echocardiogram falls below a predetermined biplane LVEF threshold (e.g., 50%) and no further doses of CK-274 or a pharma- ceutically acceptable salt thereof are administered to the patient. Maintenance of the first daily dose level (e.g., about 5 mg) may be selected if either of the following conditions is met on the first echocardiogram: (1) the biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold (e.g., 50%) and falls below a second predetermined biplane LVEF threshold (e.g., 55%), or (2) the biplane LVEF is equal to or greater than a second predetermined biplane LVEF threshold (e.g., 55%) and the post-Valsalva LVOT-G of the first echocardiogram falls below a predetermined post-Valsalva LVOT-G threshold (e.g., 30 mmHg). Alternatively, maintenance of the first daily dose level (e.g., about 5 mg) may be selected if the biplane LVEF of the first echocardiogram is equal to or greater than a predetermined biplane LVEF threshold (e.g., 50%), the resting LVOT-G of the first echocardiogram is below a predetermined resting LVOT-G threshold (e.g., 30 mmHg), and the post-Valsalva LVOT-G of the first echocardiogram is below a predetermined post-Valsalva LVOT-G threshold (e.g., 50 mmHg).If maintenance is selected, a first daily dose level of CK-274 or a pharma- ceutically acceptable salt thereof is administered to the patient for a second period of time at 102, and optionally the daily dose may be titrated again after the second period of time at 104. If either of the following conditions is met on the first echocardiogram: (1) the biplane LVEF is equal to or greater than a predefined biplane LVEF threshold (e.g., 50%) and is below a second predefined biplane LVEF threshold (e.g., 55%), or (2) the biplane LVEF is equal to or greater than a predefined biplane LVEF threshold (e.g., 55%) and the post-Valsalva LVOT-G of the first echocardiogram is below a second predefined post-Valsalva LVOT-G threshold (e.g., 30 mmHg), the daily dose level may be increased to a second daily dose level (e.g., 10 mg). Alternatively, if the first echocardiogram meets any of the following conditions: (1) the biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold (e.g., 50%) and the resting LVOT-G is equal to or greater than a predetermined resting LVOT-G threshold (e.g., 30 mmHg), or (2) the biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold (e.g., 50%), the resting LVOT-G is below a predetermined resting LVOT-G threshold (e.g., 30 mmHg), and the post-Valsalva LVOT-G is equal to or greater than a predetermined post-Valsalva LVOT-G threshold (e.g., 50 mmHg). If an increase in the daily dose level is selected, the second daily dose level of CK-274 or a pharma- ceutically acceptable salt thereof is administered to the patient for a second period of time at 108.

[0151] If a second daily dose level (e.g., 10 mg) of CK-274 or a pharma- ceutically acceptable salt thereof is administered to the patient at 108, the daily dose may be titrated again (i.e., select to increase, decrease, or maintain the daily dose) based on the echocardiogram at 110. If the biplane LVEF of the echocardiogram falls below a pre-determined biplane LVEF threshold (e.g., 50%), the daily dose may be reduced to the first daily dose level (e.g., from 10 mg to 5 mg). If the daily dose is reduced to the first daily dose level, the first daily dose level is administered to the patient at 102. Maintenance of the second daily dose level (e.g., about 10 mg) may be selected if either of the following conditions is met on echocardiogram: (1) the biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold (e.g., 50%) and is below a second predetermined biplane LVEF threshold (e.g., 55%), or (2) the biplane LVEF is equal to or greater than a second predetermined biplane LVEF threshold (e.g., 55%) and the echocardiogram post-Valsalva LVOT-G is below a predetermined post-Valsalva LVOT-G threshold (e.g., 30 mmHg). Alternatively, if the biplane LVEF of the echocardiogram is equal to or greater than a predetermined biplane LVEF threshold (e.g., 50%), the resting LVOT-G of the echocardiogram is below a predetermined resting LVOT-G threshold (e.g., 30 mmHg), and the post-Valsalva LVOT-G of the second echocardiogram is below a predetermined post-Valsalva LVOT-G threshold (e.g., 50 mmHg), then maintenance of the second daily dose level (e.g., about 10 mg) may be selected. If maintenance is selected, the second daily dose level of CK-274 or a pharma- ceutically acceptable salt thereof is administered to the patient for a further period of time at 108, and optionally the daily dose may be titrated again at 110 after the period of time.If either of the following conditions are met on the echocardiogram: (1) the biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold (e.g., 50%) and is below a second predetermined biplane LVEF threshold (e.g., 55%), or (2) the biplane LVEF is equal to or greater than a second predetermined biplane LVEF threshold (e.g., 55%) and the echocardiogram post-Valsalva LVOT-G is below a second predetermined post-Valsalva LVOT-G threshold (e.g., 30 mmHg), the daily dose level may be increased to a third daily dose level (e.g., 15 mg). Alternatively, if the echocardiogram meets any of the following conditions: (1) the biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold (e.g., 50%) and the resting LVOT-G is equal to or greater than a predetermined resting LVOT-G threshold (e.g., 30 mmHg), or (2) the biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold (e.g., 50%), the resting LVOT-G is below a predetermined resting LVOT-G threshold (e.g., 30 mmHg), and the post-Valsalva LVOT-G is equal to or greater than a predetermined post-Valsalva LVOT-G threshold (e.g., 50 mmHg). If an increase in the daily dose level is selected, a second daily dose level of CK-274 or a pharma- ceutically acceptable salt thereof is administered to the patient for a period of time at 112.

[0152] If a third daily dose level (e.g., 10 mg) of CK-274 or a pharma- ceutically acceptable salt thereof is administered to the patient at 112, the daily dose may be titrated again (i.e., select to increase, decrease, or maintain the daily dose) based on the echocardiogram at 114. If the biplane LVEF of the echocardiogram falls below a pre-determined biplane LVEF threshold (e.g., 50%), the daily dose may be reduced to a second daily dose level (e.g., from 15 mg to 10 mg). If the daily dose is reduced to the second daily dose level, the second daily dose level is administered to the patient at 108. Maintenance of the third daily dose level (e.g., about 15 mg) may be selected if either of the following conditions are met on echocardiogram: (1) the biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold (e.g., 50%) and is below a second predetermined biplane LVEF threshold (e.g., 55%), or (2) the biplane LVEF is equal to or greater than a second predetermined biplane LVEF threshold (e.g., 55%) and the echocardiogram post-Valsalva LVOT-G is below a predetermined post-Valsalva LVOT-G threshold (e.g., 30 mmHg). Alternatively, if the biplane LVEF of the echocardiogram is equal to or greater than a predetermined biplane LVEF threshold (e.g., 50%), the resting LVOT-G of the echocardiogram is below a predetermined resting LVOT-G threshold (e.g., 30 mmHg), and the post-Valsalva LVOT-G of the echocardiogram is below a predetermined post-Valsalva LVOT-G threshold (e.g., 50 mmHg), then maintenance of the third daily dose level (e.g., about 15 mg) may be selected. If maintenance is selected, the third daily dose level of CK-274 or a pharma- ceutically acceptable salt thereof is administered to the patient at 112 for a further period of time, and optionally the daily dose may be titrated again at 114 after that period of time.If either of the following conditions are met on the echocardiogram: (1) the biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold (e.g., 50%) and is below a second predetermined biplane LVEF threshold (e.g., 55%), or (2) the biplane LVEF is equal to or greater than a second predetermined biplane LVEF threshold (e.g., 55%) and the echocardiogram post-Valsalva LVOT-G is below a second predetermined post-Valsalva LVOT-G threshold (e.g., 30 mmHg), the daily dose level may be increased to a fourth daily dose level (e.g., 20 mg). Alternatively, if the echocardiogram meets any of the following conditions: (1) the biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold (e.g., 50%) and the resting LVOT-G is equal to or greater than a predetermined resting LVOT-G threshold (e.g., 30 mmHg), or (2) the biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold (e.g., 50%), the resting LVOT-G is below a predetermined resting LVOT-G threshold (e.g., 30 mmHg), and the post-Valsalva LVOT-G is equal to or greater than a predetermined post-Valsalva LVOT-G threshold (e.g., 50 mmHg). If an increase in the daily dose level is selected, the fourth daily dose level of CK-274 or a pharma- ceutically acceptable salt thereof is administered to the patient for a second period of time at 116.

[0153] 1, the first daily dose level is a minimum dose and therefore will not be further reduced. Nevertheless, in other embodiments, the first daily dose level may be other than a minimum dose and may be reduced to a lower dose level (e.g., from 10 mg to 5 mg) if the echocardiographic biplane LVEF falls below a predetermined biplane LVEF threshold (e.g., 50%).

[0154] In the exemplary method shown in FIG. 1, the fourth daily dose level is the maximum dose and is not further increased. Nevertheless, in other embodiments, additional dose levels may be available and the daily dose may be further increased at 118. In the method shown in FIG. 1, a selection is made at 118 to maintain the fourth daily dose level or to decrease the daily dose level based on the echocardiogram. If the biplane LVEF of the echocardiogram is below a predetermined biplane LVEF threshold (e.g., 50%), the daily dose may be decreased to a third daily dose level (e.g., from 20 mg to 15 mg). If the daily dose is decreased to the third daily dose level, the second daily dose level is administered to the patient at 112. Maintenance of the third daily dose level (e.g., about 20 mg) may be selected if either of the following conditions are met on echocardiogram: (1) the biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold (e.g., 50%) and is below a second predetermined biplane LVEF threshold (e.g., 55%), or (2) the biplane LVEF is equal to or greater than a second predetermined biplane LVEF threshold (e.g., 55%) and the echocardiogram post-Valsalva LVOT-G is below a predetermined post-Valsalva LVOT-G threshold (e.g., 30 mmHg). Alternatively, if the biplane LVEF of the echocardiogram is equal to or greater than a predetermined biplane LVEF threshold (e.g., 50%), the resting LVOT-G of the echocardiogram is below a predetermined resting LVOT-G threshold (e.g., 30 mmHg), and the post-Valsalva LVOT-G of the echocardiogram is below a predetermined post-Valsalva LVOT-G threshold (e.g., 50 mmHg), then maintenance of the third daily dose level (e.g., about 15 mg) may be selected. If maintenance is selected, the third daily dose level of CK-274 or a pharma- ceutically acceptable salt thereof is administered to the patient at 116 for a further period of time, and optionally the daily dose may be titrated again at 118 after that period of time.

[0155] Exemplary daily dose increases include increases of about 5 mg to about 10 mg of CK-274, about 10 mg to about 15 mg of CK-274, about 10 mg to about 20 mg of CK-274, or about 20 mg to about 30 mg. Other dose increases can be easily envisioned, such as increasing a given initial daily dose by about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 10 mg, or any amount therebetween. Exemplary daily dose decreases include decreases of about 30 mg to about 20 mg, about 20 mg to about 10 mg, about 15 mg to about 10 mg, or about 10 mg to about 5 mg. Other dose decreases can be easily envisioned, such as decreasing a given initial daily dose by about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 10 mg, or any amount therebetween.

[0156] Exemplary embodiments of the methods described herein include administering a first daily dose of CK-274 or a pharma- ceutically acceptable salt thereof (e.g., a first daily dose of about 1 mg to about 20 mg, e.g., 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, or 20 mg, or any amount therebetween) for a first period of time (e.g., about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 12 weeks, or any length of time therebetween), followed by measuring the patient's resting LVOT-G, biplane LVEF, and / or post-Valsalva LVO. Based on the T-G, this includes maintaining the daily dose, decreasing the daily dose (e.g., decreasing the daily dose by about 1 mg to about 10 mg, e.g., decreasing the daily dose by 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg, or any amount therebetween), increasing the daily dose (e.g., increasing the daily dose by about 1 mg to about 10 mg, e.g., increasing the daily dose by 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg, or any amount therebetween), or discontinuing administration to reach the second daily dose. Another exemplary embodiment of the method described herein includes administering a first daily dose of CK-274 or a pharma- ceutically acceptable salt thereof for about two weeks, followed by maintaining the daily dose, decreasing the daily dose by about 5 mg, increasing the daily dose by about 5 mg, or ceasing administration to reach the second daily dose, based on the patient's resting LVOT-G, biplane LVEF, and / or post-Valsalva LVOT-G. Another exemplary embodiment of the method described herein includes administering a first daily dose of CK-274 or a pharma- ceutically acceptable salt thereof for about three weeks, followed by maintaining the daily dose, decreasing the daily dose by about 5 mg, increasing the daily dose by about 5 mg, or ceasing administration to reach the second daily dose, based on the patient's resting LVOT-G, biplane LVEF, and / or post-Valsalva LVOT-G.Another exemplary embodiment of the method described herein includes administering a first daily dose of CK-274 or a pharma- ceutically acceptable salt thereof for about two weeks, followed by maintaining the daily dose, decreasing the daily dose by about 10 mg, increasing the daily dose by about 10 mg, or ceasing administration to reach the second daily dose, based on the patient's resting LVOT-G, biplane LVEF, and / or post-Valsalva LVOT-G. Another exemplary embodiment of the method described herein includes administering a first daily dose of CK-274 or a pharma- ceutically acceptable salt thereof for about three weeks, followed by maintaining the daily dose, decreasing the daily dose by about 10 mg, increasing the daily dose by about 10 mg, or ceasing administration to reach the second daily dose, based on the patient's resting LVOT-G, biplane LVEF, and / or post-Valsalva LVOT-G. Another exemplary embodiment of the methods described herein includes administering a first daily dose of CK-274, or a pharma- ceutically acceptable salt thereof, for about 2 weeks to about 12 weeks, followed by maintaining the daily dose, decreasing the daily dose by about 10 mg, increasing the daily dose by about 10 mg, or ceasing administration to arrive at the second daily dose, based on the patient's resting LVOT-G, biplane LVEF, and / or post-Valsalva LVOT-G.

[0157] Treatment of hypertrophic cardiomyopathy may result in improved exercise capacity and / or alleviation of symptoms in patients with hypertrophic ventricular contractions due to hypertrophic cardiomyopathy. In some embodiments, the method comprises administering a therapeutically effective daily dose of CK-274 or a pharmaceutically acceptable salt thereof to an individual with hypertrophic cardiomyopathy, thereby improving the exercise capacity of the individual. In some embodiments, the method comprises administering a therapeutically effective daily dose of CK-274 or a pharmaceutically acceptable salt thereof to an individual with hypertrophic cardiomyopathy, thereby alleviating one or more symptoms of hypertrophic ventricular contractions. In some embodiments, the method comprises administering a therapeutically effective daily dose of CK-274 or a pharmaceutically acceptable salt thereof in combination with disopyramide to an individual with hypertrophic cardiomyopathy, thereby improving the exercise capacity of the individual. In some embodiments, the method comprises administering a therapeutically effective daily dose of CK-274 or a pharmaceutically acceptable salt thereof in combination with disopyramide to an individual with hypertrophic cardiomyopathy, thereby alleviating one or more symptoms of hypertrophic ventricular contractions.

[0158] In some embodiments, a therapeutically effective amount of CK-274 or a pharma- ceutically acceptable salt thereof is administered to a patient with hypertrophic cardiomyopathy, thereby decreasing the patient's resting LVOT-G. In some embodiments, the patient has a baseline resting LVOT-G of about 30 mmHg or more, about 40 mmHg or more, or about 50 mmHg or more. In response to administration of a therapeutically effective amount of CK-274 or a pharma- ceutically acceptable salt thereof, the resting LVOT-G can be decreased to less than 30 mmHg, for example, about 25 mmHg or less, about 20 mmHg or less, or about 15 mmHg or less. In some embodiments, in response to administration of a therapeutically effective amount of CK-274 or a pharma- ceutically acceptable salt thereof, the resting LVOT-G is decreased by about 10 mmHg or more, about 15 mmHg or more, about 20 mmHg or more, about 25 mmHg or more, about 30 mmHg or more, or about 35 mmHg or more. In some embodiments, in response to administration of a therapeutically effective amount of CK-274 or a pharma- ceutically acceptable salt thereof, resting LVOT-G is reduced by about 10 mmHg to about 40 mmHg. The reduction in resting LVOT-G can occur about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after administration of the daily dose.

[0159] In some embodiments, a therapeutically effective amount of CK-274 or a pharma- ceutically acceptable salt thereof is administered to a patient with hypertrophic cardiomyopathy, thereby decreasing the patient's post-Valsalva LVOT-G. In some embodiments, a therapeutically effective amount of CK-274 or a pharma- ceutically acceptable salt thereof is administered to a patient with hypertrophic cardiomyopathy in combination with disopyramide, thereby decreasing the patient's post-Valsalva LVOT-G. In some embodiments, the patient has a baseline post-Valsalva LVOT-G of about 30 mmHg or more, about 40 mmHg or more, 50 mmHg or more, about 60 mmHg or more, or about 70 mmHg or more. In response to administration of a therapeutically effective amount of CK-274 or a pharma- ceutically acceptable salt thereof, the post-Valsalva LVOT-G may decrease to less than 50 mmHg, for example, about 45 mmHg or less, about 40 mmHg or less, about 35 mmHg or less, or about 30 mmHg or less. In some embodiments, in response to administration of a therapeutically effective amount of CK-274 or a pharma- ceutically acceptable salt thereof, post-Valsalva LVOT-G is reduced by about 10 mmHg or more, about 15 mmHg or more, about 20 mmHg or more, about 25 mmHg or more, about 30 mmHg or more, or about 35 mmHg or more. In some embodiments, in response to administration of a therapeutically effective amount of CK-274 or a pharma- ceutically acceptable salt thereof, post-Valsalva LVOT-G is reduced by about 10 mmHg to about 40 mmHg. The reduction in post-Valsalva LVOT-G may occur about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after administration of the daily dose.

[0160] In some embodiments, a therapeutically effective amount of CK-274 or a pharma- ceutically acceptable salt thereof is administered to a patient with hypertrophic cardiomyopathy to treat the hypertrophic cardiomyopathy, and the biplane LVEF is maintained at 50% or more. In some embodiments, a therapeutically effective amount of CK-274 or a pharma- ceutically acceptable salt thereof is administered to a patient with hypertrophic cardiomyopathy in combination with disopyramide to treat the hypertrophic cardiomyopathy, and the biplane LVEF is maintained at 50% or more. In some embodiments, in response to administration of a therapeutically effective amount of CK-274 or a pharma- ceutically acceptable salt thereof, the biplane LVEF is decreased by less than about 20%, less than about 15%, less than about 10%, or less than about 5%. The interval during which the biplane LVEF is maintained can be about 1 week or more, about 2 weeks or more, about 3 weeks or more, about 4 weeks or more, about 5 weeks or more, about 6 weeks or more, about 8 weeks or more, or about 10 weeks or more from daily dose administration.

[0161] In some embodiments, a therapeutically effective amount of CK-274, or a pharma- ceutical acceptable salt thereof, is administered to a patient with hypertrophic cardiomyopathy, thereby lowering the patient's left ventricular mass index (LVMI). In response to administration of a therapeutically effective amount of CK-274, or a pharma- ceutical acceptable salt thereof, the LVMI is reduced to about 1 g / m 2 More than about 1.5g / m 2 More than about 2g / m 2 More than about 2.5g / m 2 More than about 3g / m 2 Above, about 3.5g / m 2 or more, or about 4 g / m 2 In some embodiments, in response to administration of a therapeutically effective amount of CK-274, or a pharma- ceutical acceptable salt thereof, the LVMI can be reduced by about 1 g / m 2 ~about 10g / m 2 mmHg, e.g., about 1 g / m 2 ~about 6g / m 2 or about 2 g / m 2 ~about 5g / m 2 The decrease in LVMI can occur about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after administration of the daily dose.

[0162] In some embodiments, a therapeutically effective amount of CK-274 or a pharma- ceutical acceptable salt thereof is administered to a patient with hypertrophic cardiomyopathy, thereby decreasing the patient's left atrial volume index (LAVI). In response to administration of a therapeutically effective amount of CK-274 or a pharma- ceutical acceptable salt thereof, the LAVI is reduced to about 0.5 mL / m 2 Approximately 1mL / m 2 Approximately 1.5mL / m 2 Approximately 2mL / m 2 or more, or about 2.5 mL / m 2 In some embodiments, in response to administration of a therapeutically effective amount of CK-274, or a pharma- ceutical acceptable salt thereof, the LAVI can be reduced by about 0.5 mL / m 2 ~about 5mL / m 2 mmHg, e.g., about 0.5 mL / m 2 ~ approx. 4g / m 2 or about 1 mL / m 2 ~about 3mL / m 2 The decrease in LAVI can occur about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after administration of the daily dose.

[0163] In some embodiments, a therapeutically effective amount of CK-274 or a pharma- ceutically acceptable salt thereof is administered to a patient having hypertrophic cardiomyopathy, thereby decreasing the patient's e' value. In response to administration of a therapeutically effective amount of CK-274 or a pharma- ceutically acceptable salt thereof, the e' value may decrease by about 0.1 cm / s or more, about 0.15 cm / s or more, about 0.2 cm / s or more, or about 0.25 cm / s or more. In some embodiments, in response to administration of a therapeutically effective amount of CK-274 or a pharma- ceutically acceptable salt thereof, the e' value decreases by about 0.05 cm / s to about 0.3 cm / s, e.g., about 0.1 cm / s to about 0.25 cm / s or about 0.15 cm / s to about 0.25 cm / s. The decrease in e' value may occur about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after administration of a daily dose.

[0164] In some embodiments, a therapeutically effective amount of CK-274 or a pharma- ceutically acceptable salt thereof is administered to a patient having hypertrophic cardiomyopathy, thereby decreasing the patient's lateral wall E / e' ratio. In response to administration of a therapeutically effective amount of CK-274 or a pharma- ceutically acceptable salt thereof, the lateral wall E / e' ratio may decrease by about 0.5 or more, 1 or more, about 1.2 or more, about 1.5 or more, or about 1.8 or more. In some embodiments, in response to administration of a therapeutically effective amount of CK-274 or a pharma- ceutically acceptable salt thereof, the lateral wall E / e' ratio decreases by about 0.5 to about 2, e.g., about 1 to about 1.8 or about 1.5 to about 1.8. The decrease in the lateral wall E / e' ratio may occur about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after administration of the daily dose.

[0165] In some embodiments, a therapeutically effective amount of CK-274, or a pharma- ceutically acceptable salt thereof, is administered to a patient having hypertrophic cardiomyopathy, thereby reducing the likelihood of systolic anterior motion (SAM) of the mitral valve leaflets in the patient.

[0166] In some embodiments, a therapeutically effective amount of CK-274, or a pharma- ceutically acceptable salt thereof, is administered to a patient having hypertrophic cardiomyopathy, thereby reducing the likelihood of mitral regurgitation or eccentric mitral regurgitation in the patient.

[0167] In some embodiments, a therapeutically effective amount of CK-274 or its pharmacologic acceptable salt is administered to a patient with hypertrophic cardiomyopathy, thereby reducing the patient's brain natriuretic peptide or N-terminal prohormone of brain natriuretic peptide (NT-proBNP) level. The reduction in the patient's brain natriuretic peptide or N-terminal prohormone of brain natriuretic peptide (NT-proBNP) level can occur about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after daily dose administration. In some of the above embodiments, the hypertrophic cardiomyopathy is obstructive hypertrophic cardiomyopathy (oHCM).

[0168] In some embodiments, a therapeutically effective amount of CK-274 or a pharma- ceutically acceptable salt thereof is administered to a patient with hypertrophic cardiomyopathy, thereby reducing the level of cardiac troponin I. The reduction in the patient's cardiac troponin I level may occur about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after administration of the daily dose. In some of the above embodiments, the hypertrophic cardiomyopathy is obstructive hypertrophic cardiomyopathy (oHCM).

[0169] In some embodiments of any of the foregoing, the patient with hypertrophic cardiomyopathy is classified as NYHA class III when administration with CK-274 or a pharmaceutically acceptable salt thereof is initiated. In some embodiments, the patient with hypertrophic cardiomyopathy is classified as NYHA class II when administration with CK-274 or a pharmaceutically acceptable salt thereof is initiated.

[0170] In some embodiments of any of the foregoing, administration of CK-274 or a pharma- ceutically acceptable salt thereof to a patient with hypertrophic cardiomyopathy further results in a reduction in left ventricular wall stress and / or a reduction in myocardial damage in the patient. The reduction in left ventricular wall stress may be measured by a reduction in serum NT-proBNP levels. The reduction in myocardial damage may be measured by a change in hs-troponin. The reduction in left ventricular wall stress and / or the reduction in myocardial damage in the patient may occur about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after daily dose administration. In some embodiments of the foregoing, the hypertrophic cardiomyopathy is obstructive hypertrophic cardiomyopathy (oHCM).

[0171] In some embodiments of any of the foregoing, administration of CK-274 or a pharma- ceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in an improvement in the patient's exercise capacity. In some embodiments of any of the foregoing, administration of CK-274 or a pharma- ceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in an improvement in the patient's exercise capacity, e.g., as measured by change in maximal oxygen uptake (pVO2) or change in maximal oxygen uptake (pVO2) by cardiopulmonary exercise testing (CPET).

[0172] In some embodiments of any of the foregoing, administration of CK-274, or a pharma- ceutically acceptable salt thereof, to patients with obstructive hypertrophic cardiomyopathy results in an improvement in total burden during CPET.

[0173] In some embodiments of any of the foregoing, administration of CK-274, or a pharma- ceutically acceptable salt thereof, to patients with obstructive hypertrophic cardiomyopathy results in improvements in other CPET parameters, including, but not limited to, one or more of: (1) ventilatory efficiency (VE / VCO2 slope); (2) circulatory power (VO2 x systolic BP); and (3) ventilatory anaerobic threshold (VAT).

[0174] In some embodiments of any of the foregoing, administration of CK-274 or a pharma- ceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in an improvement in the patient's health status. In some embodiments of any of the foregoing, administration of CK-274 or a pharma- ceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in an improvement in the patient's health status as determined by a change in the Kansas City Cardiomyopathy Questionnaire-Overall Summary Score (KCCQ-OSS). In some embodiments of any of the foregoing, administration of CK-274 or a pharma- ceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in an improvement in the patient's health status as determined by a change in the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS). In some embodiments of any of the foregoing, administration of CK-274 or a pharma- ceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in an improvement in the patient's health status as determined by a change in the Kansas City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS). In some embodiments of any of the foregoing, administration of CK-274 or a pharma- ceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in an improvement in the patient's health as determined by a change in the Kansas City Cardiomyopathy Questionnaire-Physical Limitations Score (KCCQ-PLS). In some embodiments of any of the foregoing, administration of CK-274 or a pharma- ceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in an improvement in the patient's health as determined by a change in the Kansas City Cardiomyopathy Questionnaire-Social Limitations Score (KCCQ-SLS). In some embodiments of any of the foregoing, administration of CK-274 or a pharma- ceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in an improvement in the patient's health as determined by a change in the Kansas City Cardiomyopathy Questionnaire-Quality of Life (KCCQ-QoL). In some embodiments, administration of CK-274, or a pharma- ceutically acceptable salt thereof, to a patient with obstructive hypertrophic cardiomyopathy results in an improvement in one or more KCCQ domain scores (e.g., KCCQ-OSS, KCCQ-CSS, KCCQ-TSS, KCCQ-PLS, KCCQ-SLS, or KCCQ-QoL) of at least about 5 points, at least about 10 points, or at least about 20 points.In some embodiments, administration of CK-274 or a pharma- ceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in an improvement of about 5 to less than 10 points, about 10 to less than 20 points, or at least 20 points in one or more KCCQ scores (e.g., KCCQ-OSS, KCCQ-CSS, KCCQ-TSS, KCCQ-PLS, KCCQ-SLS, or KCCQ-QoL). In some such embodiments, the improvement in one or more KCCQ domain scores is an improvement in KCCQ-OSS. In some embodiments, the improvement in one or more KCCQ domain scores is sustained for about 6 months. In some embodiments, administration of CK-274 or a pharma- ceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in an improvement in KCCQ-CSS of 1 point, 2 points, 3 points, 4 points, 5 points, or more than 5 points. In some embodiments of any of the foregoing, administration of CK-274, or a pharma- ceutically acceptable salt thereof, to a patient with hypertrophic obstructive cardiomyopathy results in an improvement in the patient's health status and health-related quality of life as measured by a PRO questionnaire, as determined by the change in responses to the EuroQol 5 Dimension 5 Level instrument (EQ-5D-5L).

[0175] Combinations of the foregoing are also contemplated. In some embodiments of any of the foregoing, administration of CK-274 or a pharma- ceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in improved exercise capacity and functional class, as determined by, for example, (1) a change from baseline in pVO2 of ≥ 1.5 mL / kg / min and an improvement in NYHA functional class of ≥ 1 class, or (2) a change from baseline in pVO2 of ≥ 3.0 mL / kg / min and no worsening of NYHA functional class. In some embodiments of any of the foregoing, administration of CK-274 or a pharma-ceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in the patient having a resting LVOT-G of < 30 mmHg, a post-Valsalva LVOT-G of < 50 mmHg, and a NYHA functional class of I. In some embodiments of any of the foregoing, administration of CK-274, or a pharma- ceutical acceptable salt thereof, to a patient with obstructive hypertrophic cardiomyopathy results in the patient's resting LVOT-G of <30 mmHg, post-Valsalva LVOT-G of <50 mmHg, and improvement in NYHA functional class by at least one class.

[0176] In some embodiments, administration of CK-274 or a pharma- ceutically acceptable salt thereof to a patient with hypertrophic cardiomyopathy results in a sustained effect for at least 10 weeks, 12 weeks, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, administration of CK-274 or a pharma- ceutically acceptable salt thereof to a patient with hypertrophic cardiomyopathy results in a sustained effect for at least 6 months. In some embodiments, administration of CK-274 or a pharma- ceutically acceptable salt thereof to a patient with hypertrophic cardiomyopathy results in a sustained effect for at least 1 year. In some embodiments, administration of CK-274 or a pharma- ceutically acceptable salt thereof to a patient with hypertrophic cardiomyopathy results in a sustained effect for at least 5 years. Sustained effects include, for example, reduction of resting LVOT-G to less than 30 mmHg, reduction of post-Valsalva LVOT-G to less than 50 mmHg, improvement of mitral regurgitation, improvement of cardiac relaxation, beneficial cardiac remodeling, cardiac reverse remodeling, beneficial structural cardiac remodeling, beneficial functional cardiac remodeling, reversal of adverse cardiac remodeling, reduction in mean left ventricular mass index (LVMI), improvement of left ventricular (LV) filling pressures, reduction in left atrial volume index (LAVI), and categories related to systolic anterior motion of the mitral valve leaflets. The effects of the present invention include one or more effects selected from the group consisting of reduced Lee score, reduced systolic anterior motion of the mitral valve leaflets, reduced frequency of eccentric mitral regurgitation, reduced mitral regurgitation, reduced lateral wall E / e', reduced lateral wall E / E, reduced brain natriuretic peptide (BNP) levels, reduced N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels, reduced cardiac troponin I levels, reduced left ventricular wall stress, reduced myocardial damage, and reduced heart failure symptoms (e.g., reduced NYHA classification).

[0177] Administration of the compounds and compositions disclosed and / or described herein can be via any mode of administration accepted for therapeutic agents, including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. In some embodiments, the compounds or compositions are administered orally or intravenously. In some embodiments, the compounds or compositions disclosed and / or described herein are administered orally.

[0178] Pharmaceutically acceptable compositions include solid, semi-solid, liquid, and aerosol dosage forms, such as tablets, capsules, powders, solutions, suspensions, suppositories, and aerosol forms. The compounds disclosed and / or described herein can also be administered in sustained or controlled release dosage forms (e.g., controlled / sustained release pills, depot injections, osmotic pumps, or transdermal (including electrotransport) patch forms) for extended timed administration and / or pulsed administration at a predetermined rate. In some embodiments, the compositions are provided in unit dosage forms suitable for single administration of precise doses.

[0179] CK-274 may be administered alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical compositions may also contain small amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents, and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate). In general, pharmaceutical compositions contain about 0.005% to 95% by weight, or about 0.5% to 50% by weight, of the compounds disclosed and / or described herein, depending on the intended mode of administration. Actual methods for preparing such dosage forms are known, or will become apparent, to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0180] In some embodiments, CK-274 or a pharmaceutical composition containing CK-274 takes the form of a pill or tablet, and thus the composition may contain one or more of a diluent (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesium stearate), and / or a binder (e.g., starch, gum arabic, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives) along with a compound disclosed and / or described herein. Other solid dosage forms include powders, marume, solutions or suspensions (e.g., in propylene carbonate, vegetable oils, or triglycerides) enclosed in gelatin capsules.

[0181] Liquid pharma- ceutically administrable compositions can be prepared, for example, by dissolving, dispersing, or suspending the compounds disclosed and / or described herein and optional pharmaceutical excipients in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycol, ethanol, etc.) to form a solution or suspension. Injectables can be prepared in conventional forms, as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolving or suspending in liquid prior to injection. The percentage of compound in such parenteral compositions depends, for example, on the physical properties of the compound, the activity of the compound, and the needs of the subject. However, percentages of active ingredient from 0.01% to 10% in solution can be used, and may be higher if the composition is solid and will be subsequently diluted to another concentration. In some embodiments, the composition contains about 0.2-2% of the compounds disclosed and / or described herein in solution.

[0182] Pharmaceutical compositions of the compounds disclosed and / or described herein may be administered to the respiratory tract as an aerosol or solution for nebulizers or as a superfine powder for insufflation, either alone or in combination with an inert carrier such as lactose.In such cases, the particles of the pharmaceutical composition may have a diameter of less than 50 microns, or in some embodiments, less than 10 microns.

[0183] Additionally, pharmaceutical compositions may include a compound disclosed and / or described herein, as well as one or more additional drugs, pharmaceutical agents, adjuvants, etc. Suitable drugs and pharmaceutical agents include those described herein.

[0184] kit Also provided are articles of manufacture and kits that contain any of the compounds or pharmaceutical compositions provided herein. The articles of manufacture may include a container with a label. Suitable containers include, for example, bottles, vials, and test tubes. The container may be formed from a variety of materials, such as glass or plastic. The container may hold a pharmaceutical composition provided herein. The label on the container may indicate that the pharmaceutical composition is used to prevent, treat, or inhibit a condition described herein, and may indicate instructions for either in vivo or in vitro use.

[0185] In one aspect, the present specification provides a kit that contains the compound or composition described herein and instructions for use.The kit can include instructions for use in treating cardiac disease in an individual or subject that requires it.The kit can further include any material or device that can be used to administer the compound or composition, such as vial, syringe, or IV bag.The kit can also include a sterile package.

[0186] Enumeration of embodiments Embodiment 1. A method of reducing resting left ventricular outflow tract pressure gradient (LVOT-G) to less than 30 mmHg in a patient with obstructive hypertrophic cardiomyopathy (oHCM), comprising administering to said patient a therapeutically effective amount of Compound 1, or a pharma- ceutical acceptable salt thereof.

[0187] Embodiment 2. The method of embodiment 1, wherein said reduction in resting LVOT-G to less than 30 mmHg occurs within 10 weeks of initiating treatment with Compound 1, or a pharma- ceutically acceptable salt thereof.

[0188] Embodiment 3. The method of embodiment 1, wherein said reduction in resting LVOT-G to less than 30 mmHg occurs within 2 weeks of initiating treatment with Compound 1, or a pharma- ceutically acceptable salt thereof.

[0189] Embodiment 4. The method of any one of embodiments 1-3, wherein said reduction in resting LVOT-G is sustained for at least 10 weeks of treatment.

[0190] Embodiment 5. The method of any one of embodiments 1-4, wherein the reduction in resting LVOT-G peaks within 2-6 weeks of ending titration.

[0191] Embodiment 6. A method of reducing a post-Valsalva left ventricular outflow tract gradient (LVOT-G) to less than 50 mmHg in a patient with obstructive hypertrophic cardiomyopathy (oHCM), comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharma- ceutical acceptable salt thereof.

[0192] Embodiment 7. The method of embodiment 6, wherein said reduction in post-Valsalva LVOT-G to less than 50 mmHg occurs within 2 weeks of initiating treatment with Compound 1, or a pharma- ceutically acceptable salt thereof.

[0193] Embodiment 8. The method of embodiment 6 or 7, wherein said reduction in post-Valsalva LVOT-G is sustained for at least 10 weeks of treatment.

[0194] Embodiment 9. The method of any one of embodiments 6-8, wherein the reduction in post-Valsalva LVOT-G peaks within 2-6 weeks of ending titration.

[0195] Embodiment 10. A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of Compound 1, or a pharma- ceutical acceptable salt thereof, wherein said therapeutically effective amount of Compound 1, or a pharma-ceutical acceptable salt thereof, is selected by titrating the daily dose of Compound 1, or a pharma-ceutical acceptable salt thereof, administered to said patient.

[0196] Embodiment 11. The method of embodiment 10, wherein the dose is titrated once during the course of treatment.

[0197] Embodiment 12. The method of embodiment 10, wherein the dose is titrated two or more times during the course of treatment.

[0198] Embodiment 13. The method of any one of embodiments 10-12, wherein the daily dose is administered to the patient at a constant amount for about two weeks before the amount of said daily dose is titrated.

[0199] Embodiment 14. The method of any one of embodiments 1-13, wherein compound 1, or a pharma- ceutically acceptable salt thereof, is administered in a daily dose of about 5 mg to about 30 mg.

[0200] Embodiment 15. The method of embodiment 14, wherein the daily dose is about 5 mg.

[0201] Embodiment 16. The method of embodiment 14, wherein the daily dose is about 10 mg.

[0202] Embodiment 17. The method of embodiment 14, wherein the daily dose is about 15 mg.

[0203] Embodiment 18. The method of embodiment 14, wherein the daily dose is about 20 mg.

[0204] Embodiment 19. The method of embodiment 14, wherein the daily dose is about 30 mg.

[0205] Embodiment 20. The method of any one of embodiments 10-19, wherein the daily dose is administered as a single dose each day.

[0206] Embodiment 21. The method of any one of embodiments 10-19, wherein the daily dose is administered in two divided doses.

[0207] Embodiment 22. A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need of such treatment, comprising: administering to said patient a first daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, for a first period of time; and administering a second daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, to the patient for a second period of time or discontinuing administration of Compound 1, or a pharma- ceutically acceptable salt thereof, to the patient based on one or more components of a first echocardiogram of the patient obtained after the first period of time.

[0208] Embodiment 23. The method of embodiment 22, comprising selecting a second daily dose of compound 1, or a pharma- ceutically acceptable salt thereof, based on said one or more components of said first echocardiogram.

[0209] Embodiment 24. The method of embodiment 22 or 23, wherein the one or more components of the first echocardiogram include biplane LVEF, post-Valsalva LVOT-G, or resting LVOT-G.

[0210] Embodiment 25. The method of embodiment 22 or 23, wherein the one or more components of the first echocardiogram include biplane LVEF, post-Valsalva LVOT-G, and resting LVOT-G.

[0211] Embodiment 26. The method of embodiment 22 or 23, wherein the one or more components of the first echocardiogram include biplane LVEF and post-Valsalva LVOT-G.

[0212] Embodiment 27. The method of any one of embodiments 22-26, wherein the one or more components of the first echocardiogram include a biplane LVEF, and when the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold, the second daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, is lower than the first daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof.

[0213] Embodiment 28. The method of any one of embodiments 22-26, wherein the one or more components of the first echocardiogram include a biplane LVEF, and if the biplane LVEF of the first echocardiogram falls below a predetermined biplane LVEF threshold, administration of Compound 1, or a pharma- ceutically acceptable salt thereof, to the patient is discontinued.

[0214] Embodiment 29. The method of embodiment 27 or 28, wherein the predetermined biplane LVEF threshold is 50%.

[0215] Embodiment 30. The method of any one of embodiments 22-29, wherein the one or more components of the first echocardiogram include biplane LVEF, resting LVOT-G, and post-Valsalva LVOT-G, and wherein if the biplane LVEF of the first echocardiogram is equal to or greater than the predetermined biplane LVEF threshold, the resting LVOT-G of the first echocardiogram is below a predetermined resting LVOT-G threshold, and the post-Valsalva LVOT-G of the first echocardiogram is below a predetermined post-Valsalva LVOT-G threshold, then the second daily dose of Compound 1, or a pharma- ceutical acceptable salt thereof, is the same as the first daily dose of Compound 1, or a pharma-ceutical acceptable salt thereof.

[0216] Embodiment 31. The method of any one of embodiments 22-30, wherein the one or more components of the first echocardiogram include biplane LVEF, resting LVOT-G, and post-Valsalva LVOT-G, and wherein the second daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, is greater than the first daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, when any of the following conditions are met on the first echocardiogram: (1) the biplane LVEF is equal to or greater than the predetermined biplane LVEF threshold, and the resting LVOT-G is equal to or greater than the predetermined resting LVOT-G threshold, or (2) the biplane LVEF is equal to or greater than the predetermined biplane LVEF threshold, the resting LVOT-G is below the predetermined resting LVOT-G threshold, and the post-Valsalva LVOT-G is equal to or greater than the predetermined post-Valsalva LVOT-G threshold.

[0217] Embodiment 32. The method of embodiment 30 or 31, wherein the predetermined biplane LVEF threshold is 50%, the predetermined resting LVOT-G threshold is 30 mmHg, and the post-Valsalva LVOT-G threshold is 50 mmHg.

[0218] Embodiment 33. The method of any one of embodiments 22-29, wherein the one or more components of the first echocardiogram include biplane LVEF and post-Valsalva LVOT-G, and wherein the second daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, is the same as the first daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, if any of the following conditions are met in the first echocardiogram: (1) the biplane LVEF is equal to or greater than the predefined biplane LVEF threshold and is below a second predefined biplane LVEF threshold, or (2) the biplane LVEF is equal to or greater than the second predefined biplane LVEF threshold and the post-Valsalva LVOT-G of the first echocardiogram is below a second predefined post-Valsalva LVOT-G threshold.

[0219] Embodiment 34. The method of any one of embodiments 22-29 and 33, wherein the one or more components of the first echocardiogram include biplane LVEF and post-Valsalva LVOT-G, and wherein the second daily dose of compound 1, or a pharmacologic acceptable salt thereof, is greater than the first daily dose of compound 1 if the biplane LVEF of the first echocardiogram is above the second predetermined biplane LVEF threshold and the post-Valsalva LVOT-G of the first echocardiogram is equal to or greater than the second predetermined post-Valsalva LVOT-G threshold.

[0220] Embodiment 35. The method of embodiment 33 or 34, wherein the predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the second predetermined post-Valsalva LVOT-G threshold is 30 mmHg.

[0221] Embodiment 36 The method of any one of embodiments 22-35, wherein the first daily dose of compound 1, or a pharma- ceutically acceptable salt thereof, is about 5 mg of compound 1.

[0222] Embodiment 37. The method of embodiment 36, wherein the second daily dose of compound 1, or a pharma- ceutically acceptable salt thereof, is about 5 mg or about 10 mg of compound 1.

[0223] Embodiment 38. The method of any one of embodiments 22 to 37, further comprising measuring the one or more components of the first echocardiogram.

[0224] Embodiment 39. The method of any one of embodiments 22 to 38, wherein the first period of time is about two weeks.

[0225] Embodiment 40 The method of any one of embodiments 22 to 39, wherein the second period of time is about two weeks.

[0226] Embodiment 41. The method of any one of embodiments 22-40, wherein a second daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is administered to the patient for the second period of time, and the method further comprises administering a third daily dose of compound 1 or a pharma- ceutically acceptable salt thereof to the patient for a third period of time or discontinuing administration of compound 1 or a pharma- ceutically acceptable salt thereof to the patient based on one or more components of a second echocardiogram of the patient obtained after the second period of time and the second daily dose of compound 1 or a pharma- ceutically acceptable salt thereof.

[0227] Embodiment 42. The method of embodiment 41, comprising selecting a third daily dose of compound 1, or a pharma- ceutically acceptable salt thereof, based on the one or more components of the second echocardiogram and the second daily dose.

[0228] Embodiment 43. The method of embodiment 41 or 42, wherein the one or more components of the second echocardiogram include biplane LVEF, post-Valsalva LVOT-G, or resting LVOT-G.

[0229] Embodiment 44. The method of embodiment 41 or 42, wherein the one or more components of the second echocardiogram include biplane LVEF, post-Valsalva LVOT-G, and resting LVOT-G.

[0230] Embodiment 45. The method of embodiment 41 or 42, wherein the one or more components of the second echocardiogram include biplane LVEF and post-Valsalva LVOT-G.

[0231] Embodiment 46. The method of any one of embodiments 41 to 45, wherein the one or more components of the second echocardiogram include a biplane LVEF, and if the biplane LVEF of the second echocardiogram is below the predetermined biplane LVEF threshold, the third daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is lower than the second daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof, or administration of Compound 1 or a pharma- ceutically acceptable salt thereof to the patient is discontinued.

[0232] Embodiment 47. The method of embodiment 46, wherein administration of Compound 1, or a pharma- ceutically acceptable salt thereof, to the patient is discontinued if the biplane LVEF of the second echocardiogram falls below the predefined biplane LVEF threshold and the second daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, is the same as or lower than the first daily dose of Compound 1.

[0233] Embodiment 48. The method of embodiment 46, wherein if the second daily dose of compound 1, or a pharma- ceutically acceptable salt thereof, is higher than the first daily dose of compound 1, or a pharma- ceutically acceptable salt thereof, and the biplane LVEF of the second echocardiogram is below the predefined biplane LVEF threshold, then the third daily dose of compound 1, or a pharma- ceutically acceptable salt thereof, is the same as the first daily dose of compound 1, or a pharma- ceutically acceptable salt thereof.

[0234] Embodiment 49. The method of any one of embodiments 46 to 48, wherein the predetermined biplane LVEF threshold is 50%.

[0235] Embodiment 50. The method of any one of embodiments 41-49, wherein the one or more components of the second echocardiogram include biplane LVEF, resting LVOT-G, and post-Valsalva LVOT-G, and wherein the third daily dose of Compound 1, or a pharmacologic acceptable salt thereof, is the same as the second daily dose of Compound 1, or a pharmacologic acceptable salt thereof, if the biplane LVEF of the second echocardiogram is equal to or greater than the predetermined biplane LVEF threshold, the resting LVOT-G of the second echocardiogram is below the predetermined resting LVOT-G threshold, and the post-Valsalva LVOT-G of the second echocardiogram is below the predetermined post-Valsalva LVOT-G threshold.

[0236] Embodiment 51. The method of any one of embodiments 41-50, wherein the one or more components of the second echocardiogram include biplane LVEF, resting LVOT-G, and post-Valsalva LVOT-G, and wherein the third daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, is greater than the second daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, when any of the following conditions are met on the second echocardiogram: (1) the biplane LVEF is equal to or greater than the predetermined biplane LVEF threshold, and the resting LVOT-G is equal to or greater than the predetermined resting LVOT-G threshold, or (2) the biplane LVEF is equal to or greater than the predetermined biplane LVEF threshold, the resting LVOT-G is below the predetermined resting LVOT-G threshold, and the post-Valsalva LVOT-G is equal to or greater than the predetermined post-Valsalva LVOT-G threshold.

[0237] Embodiment 52. The method of embodiment 50 or 51, wherein the predetermined biplane LVEF threshold is 50%, the predetermined resting LVOT-G threshold is 30 mmHg, and the post-Valsalva LVOT-G threshold is 50 mmHg.

[0238] Embodiment 53. The method of any one of embodiments 41-49, wherein the one or more components of the second echocardiogram include biplane LVEF and post-Valsalva LVOT-G, and wherein the third daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, is the same as the second daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, if any of the following conditions are met on the second echocardiogram: (1) the biplane LVEF is equal to or greater than the predefined biplane LVEF threshold and is below the second predefined biplane LVEF threshold, or (2) the biplane LVEF is equal to or greater than the second predefined biplane LVEF threshold and the post-Valsalva LVOT-G is below the second predefined post-Valsalva LVOT-G threshold.

[0239] Embodiment 54. The method of any one of embodiments 41-49 and 53, wherein the one or more components of the second echocardiogram include biplane LVEF and post-Valsalva LVOT-G, and wherein the third daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, is greater than the second daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, if the biplane LVEF of the second echocardiogram is above the second predefined biplane LVEF threshold and the post-Valsalva LVOT-G of the second echocardiogram is equal to or greater than the second predefined post-Valsalva LVOT-G threshold.

[0240] Embodiment 55. The method of embodiment 53 or 54, wherein the predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the second predetermined post-Valsalva LVOT-G threshold is 30 mmHg.

[0241] Embodiment 56. The method of any one of embodiments 41-55, wherein the first daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg of compound 1, the second daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg or about 10 mg of compound 1, and the third daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg, about 10 mg, or about 15 mg of compound 1.

[0242] Embodiment 57. The method of any one of embodiments 41 to 56, further comprising measuring said one or more components of said second echocardiogram.

[0243] Embodiment 58. The method of any one of embodiments 41 to 57, wherein the third period of time is about 2 weeks.

[0244] Embodiment 59. The method of any one of embodiments 41-58, wherein a third daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is administered to the patient for the third period of time, and the method further comprises administering a fourth daily dose of compound 1 or a pharma- ceutically acceptable salt thereof to the patient for a fourth period of time or discontinuing administration of compound 1 or a pharma- ceutically acceptable salt thereof to the patient based on one or more components of a third echocardiogram of the patient obtained after the third period of time and the third daily dose of the compound or a pharma- ceutical acceptable salt thereof.

[0245] Embodiment 60. The method of embodiment 59, comprising selecting a fourth daily dose of compound 1, or a pharma- ceutically acceptable salt thereof, based on the one or more components of the third echocardiogram and the third daily dose.

[0246] Embodiment 61. The method of embodiment 59 or 60, wherein the one or more components of the third echocardiogram include biplane LVEF, post-Valsalva LVOT-G, or resting LVOT-G.

[0247] Embodiment 62. The method of embodiment 59 or 60, wherein the one or more components of the third echocardiogram include biplane LVEF, post-Valsalva LVOT-G, and resting LVOT-G.

[0248] Embodiment 63. The method of embodiment 59 or 60, wherein the one or more components of the third echocardiogram include biplane LVEF and post-Valsalva LVOT-G.

[0249] Embodiment 64. The method of any one of embodiments 59 to 63, wherein the one or more components of the third echocardiogram include a biplane LVEF, and if the biplane LVEF of the third echocardiogram is below the predetermined biplane LVEF threshold, the fourth daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is lower than the third daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof, or administration of Compound 1 or a pharma- ceutically acceptable salt thereof to the patient is discontinued.

[0250] Embodiment 65. The method of embodiment 64, wherein administration of Compound 1 or a pharma- ceutically acceptable salt thereof to the patient is discontinued if the biplane LVEF of the third echocardiogram falls below the predefined biplane LVEF threshold and the third daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is the same as or lower than the first daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof.

[0251] Embodiment 66. If the third daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is higher than the second daily dose of compound 1 or a pharma- ceutically acceptable salt thereof, and the biplane LVEF of the third echocardiogram is below the predefined biplane LVEF threshold, then the fourth daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is the same as the second daily dose of compound 1 or a pharma- ceutically acceptable salt thereof; or The method of embodiment 64 or 65, wherein the third daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is the same as the second daily dose of compound 1 or a pharma- ceutically acceptable salt thereof, and, if the biplane LVEF of the third echocardiogram is below the pre-determined biplane LVEF threshold, the fourth daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is the same as the first daily dose of compound 1 or a pharma- ceutically acceptable salt thereof.

[0252] Embodiment 67. The method of any one of embodiments 64 to 66, wherein the predetermined biplane LVEF threshold is 50%.

[0253] Embodiment 68. The method of any one of embodiments 59-67, wherein the one or more components of the third echocardiogram include biplane LVEF, resting LVOT-G, and post-Valsalva LVOT-G, and wherein the fourth daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, is the same as the third daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, if the biplane LVEF of the third echocardiogram is equal to or greater than the predefined biplane LVEF threshold, the resting LVOT-G of the third echocardiogram is below the predefined resting LVOT-G threshold, and the post-Valsalva LVOT-G of the third echocardiogram is below the predefined post-Valsalva LVOT-G threshold.

[0254] Embodiment 69. The method of any one of embodiments 59-68, wherein the one or more components of the third echocardiogram include biplane LVEF, resting LVOT-G, and post-Valsalva LVOT-G, and wherein the fourth daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, is greater than the third daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, if any of the following conditions are met in the third echocardiogram: (1) the biplane LVEF is equal to or greater than the predetermined biplane LVEF threshold, and the resting LVOT-G is equal to or greater than the predetermined resting LVOT-G threshold, or (2) the biplane LVEF is equal to or greater than the predetermined biplane LVEF threshold, the resting LVOT-G is below the predetermined resting LVOT-G threshold, and the post-Valsalva LVOT-G is equal to or greater than the predetermined post-Valsalva LVOT-G threshold.

[0255] Embodiment 70. The method of embodiment 68 or 69, wherein the predetermined biplane LVEF threshold is 50%, the predetermined resting LVOT-G threshold is 30 mmHg, and the post-Valsalva LVOT-G threshold is 50 mmHg.

[0256] Embodiment 71. The method of any one of embodiments 59-67, wherein the one or more components of the third echocardiogram include biplane LVEF and post-Valsalva LVOT-G, and wherein the fourth daily dose of Compound 1, or a pharmacologic acceptable salt thereof, is the same as the third daily dose of Compound 1, or a pharmacologic acceptable salt thereof, if any of the following conditions are met in the third echocardiogram: (1) the biplane LVEF is equal to or greater than the predetermined biplane LVEF threshold and is below the second predetermined biplane LVEF threshold, or (2) the biplane LVEF is equal to or greater than the second predetermined biplane LVEF threshold and the post-Valsalva LVOT-G is below the second predetermined post-Valsalva LVOT-G threshold.

[0257] Embodiment 72. The method of any one of embodiments 59 to 67 and 71, wherein the one or more components of the third echocardiogram include biplane LVEF and post-Valsalva LVOT-G, and wherein the fourth daily dose of compound 1, or a pharmacologic acceptable salt thereof, is greater than the third daily dose of compound 1, or a pharmacologic acceptable salt thereof, if the biplane LVEF of the third echocardiogram is above the second predetermined biplane LVEF threshold and the post-Valsalva LVOT-G of the third echocardiogram is equal to or greater than the second predetermined post-Valsalva LVOT-G threshold.

[0258] Embodiment 73. The method of embodiment 71 or 72, wherein the predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the second predetermined post-Valsalva LVOT-G threshold is 30 mmHg.

[0259] Embodiment 74. The method of any one of embodiments 59-73, wherein the first daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg of compound 1, the second daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg or about 10 mg of compound 1, the third daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg, about 10 mg, or about 15 mg of compound 1, and the fourth daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg, about 10 mg, about 15 mg, or about 20 mg of compound 1.

[0260] Embodiment 75. The method of any one of embodiments 59 to 74, further comprising measuring the one or more components of the third echocardiogram.

[0261] Embodiment 76 The method of any one of embodiments 59 to 75, wherein the fourth period of time is about 2 weeks.

[0262] Embodiment 77. A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need of such treatment, comprising: administering to said patient a first daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, for a first period of time; and administering a second daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, to said patient for a second period of time or discontinuing administration of Compound 1 to said patient based on a first echocardiogram, including a biplane LVEF and post-Valsalva LVOT-G of said patient obtained after said first period of time, wherein if the biplane LVEF of the first echocardiogram falls below a first predetermined biplane LVEF threshold, administering Compound 1, or a pharma- ceutically acceptable salt thereof, to the patient is discontinued; a second daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, is the same as the first daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, if the first echocardiogram meets either of the following conditions: (1) the biplane LVEF is equal to or greater than the first predefined biplane LVEF threshold and is below a second predefined biplane LVEF threshold, or (2) the biplane LVEF is equal to or greater than the second predefined biplane LVEF threshold and the post-Valsalva LVOT-G is below a predefined post-Valsalva LVOT-G threshold; The method, wherein a second daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, is greater than a first daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, if the biplane LVEF of the first echocardiogram is above the second predefined biplane LVEF threshold and the post-Valsalva LVOT-G of the first echocardiogram is equal to or greater than the predefined post-Valsalva LVOT-G threshold.

[0263] Embodiment 78. The method of embodiment 77, wherein the first daily dose of compound 1, or a pharma- ceutically acceptable salt thereof, is about 5 mg of compound 1, and the second daily dose of compound 1, or a pharma- ceutically acceptable salt thereof, is about 5 mg or about 10 mg of compound 1.

[0264] Embodiment 79. The method of embodiment 77 or 78, further comprising measuring the biplane LVEF and the post-Valsalva LVOT-G on the first echocardiogram.

[0265] Embodiment 80. The method of any one of embodiments 77-79, wherein the first period of time is about 2 weeks.

[0266] Embodiment 81. The method of any one of embodiments 79-80, wherein the second period of time is about 2 weeks.

[0267] Embodiment 82. A second daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is administered to the patient for the second period of time, and the method further comprises administering a third daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof to the patient for a third period of time or discontinuing administration of Compound 1 or a pharma- ceutically acceptable salt thereof to the patient based on a second echocardiogram, including a biplane LVEF and a post-Valsalva LVOT-G of the patient obtained after the second period of time and the second daily dose of Compound 1 or a pharma- ceutical acceptable salt thereof, wherein if the biplane LVEF of the second echocardiogram falls below the first predetermined biplane LVEF threshold and the second daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, is the same as the first daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, then administration of Compound 1, or a pharma- ceutically acceptable salt thereof, to the patient is discontinued; if the biplane LVEF of the second echocardiogram is below the first predetermined biplane LVEF threshold and the second daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, is higher than the first daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, then a third daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, is lower than the second daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof; if the second echocardiogram meets either of the following conditions: (1) the biplane LVEF is equal to or greater than the first predetermined biplane LVEF threshold and is less than the second predetermined biplane LVEF threshold; or (2) the biplane LVEF is equal to or greater than the second predetermined biplane LVEF threshold and the post-Valsalva LVOT-G is less than the predetermined post-Valsalva LVOT-G threshold, then a third daily dose of Compound 1, or a pharmacologic acceptable salt thereof, is the same as the second daily dose of Compound 1, or a pharmacologic acceptable salt thereof; The method of any one of embodiments 77 to 81, wherein the third daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, is greater than the second daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, if the biplane LVEF of the second echocardiogram is above the second predefined biplane LVEF threshold and the post-Valsalva LVOT-G of the second echocardiogram is equal to or greater than the predefined post-Valsalva LVOT-G threshold.

[0268] Embodiment 83. The method of embodiment 82, wherein the first daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg of compound 1, the second daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg or about 10 mg of compound 1, and the third daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg, about 10 mg, or about 15 mg of compound 1.

[0269] Embodiment 84. The method of embodiment 82 or 83, further comprising measuring the biplane LVEF and the post-Valsalva LVOT-G on the second echocardiogram.

[0270] Embodiment 85. The method of any one of embodiments 82-84, wherein the third period of time is about 2 weeks.

[0271] Embodiment 86. A third daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is administered to the patient for the third period of time, and the method further comprises administering a fourth daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof to the patient for a fourth period of time or discontinuing administration of Compound 1 to the patient based on a third echocardiogram, including a biplane LVEF and a post-Valsalva LVOT-G of the patient obtained after the third period of time and the second third dose of Compound 1 or a pharma- ceutical acceptable salt thereof, if the biplane LVEF of the third echocardiogram falls below the first predetermined biplane LVEF threshold and the third daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, is the same as the first daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, then administration of Compound 1, or a pharma- ceutically acceptable salt thereof, to the patient is discontinued; if the biplane LVEF of the third echocardiogram is below the first predetermined biplane LVEF threshold and the third daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, is higher than the first daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, then the fourth daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, is lower than the third daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof; if the third echocardiogram meets either of the following conditions: (1) the biplane LVEF is equal to or greater than the first predetermined biplane LVEF threshold and is less than the second predetermined biplane LVEF threshold; or (2) the biplane LVEF is equal to or greater than the second predetermined biplane LVEF threshold and the post-Valsalva LVOT-G is less than the predetermined post-Valsalva LVOT-G threshold, then a fourth daily dose of Compound 1, or a pharmacologic acceptable salt thereof, is the same as the third daily dose of Compound 1, or a pharmacologic acceptable salt thereof; The method of any one of embodiments 82-85, wherein the fourth daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, is greater than the third daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, if the biplane LVEF of the third echocardiogram is above the second predefined biplane LVEF threshold and the post-Valsalva LVOT-G of the third echocardiogram is equal to or greater than the predefined post-Valsalva LVOT-G threshold.

[0272] Embodiment 87. The method of embodiment 86, wherein the first daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg of compound 1, the second daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg or about 10 mg of compound 1, the third daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg, about 10 mg, or about 15 mg of compound 1, and the fourth daily dose of compound 1 or a pharma- ceutically acceptable salt thereof is about 5 mg, about 10 mg, about 15 mg, or about 20 mg of compound 1.

[0273] Embodiment 88. The method of embodiment 86 or 87, further comprising measuring the biplane LVEF and the post-Valsalva LVOT-G on the third echocardiogram.

[0274] Embodiment 89. The method of any one of embodiments 86 to 88, wherein the third period of time is about 2 weeks.

[0275] Embodiment 90. The method of any one of embodiments 77 to 89, wherein the first predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the predetermined post-Valsalva LVOT-G threshold is 30 mmHg.

[0276] Embodiment 91. The method of any one of embodiments 1 to 90, wherein prior to administration of compound 1 or a pharma- ceutically acceptable salt thereof, the patient has: (i) a resting LVOT-G of ≥ 50 mmHg; or (ii) a resting LVOT-G of ≥ 30 mmHg and < 50 mmHg with a post-Valsalva LVOT-G of ≥ 50 mmHg.

[0277] Embodiment 92. The method of any one of embodiments 1 to 91, wherein, prior to administration of Compound 1 or a pharma- ceutically acceptable salt thereof, the patient has a left ventricular ejection fraction (LVEF) of ≧60%.

[0278] Embodiment 93. The method of any one of embodiments 1 to 92, wherein the patient is not administered disopyramide during treatment with Compound 1, or a pharma- ceutically acceptable salt thereof.

[0279] Embodiment 94. The method of any one of embodiments 1 to 92, wherein the patient is administered disopyramide during treatment with Compound 1, or a pharma- ceutically acceptable salt thereof.

[0280] Embodiment 95. The method of any one of embodiments 1 to 92, wherein the patient has not been treated with disopyramide or an antiarrhythmic drug with negative inotropic effects within 4 weeks prior to treatment with Compound 1 or a pharma- ceutically acceptable salt thereof.

[0281] Embodiment 96. The method of any one of embodiments 1 to 94, wherein the patient is administered an antiarrhythmic agent during treatment with Compound 1, or a pharma- ceutically acceptable salt thereof.

[0282] Embodiment 97. The method of any one of embodiments 1 to 96, wherein the patient is a CYP2D6 poor metabolizer.

[0283] Embodiment 98. The method of any one of embodiments 1 to 97, wherein the patient is in a fasted state when Compound 1, or a pharma- ceutically acceptable salt thereof, is administered.

[0284] Embodiment 99. The method of any one of embodiments 1 to 97, wherein the patient is in a postprandial state when Compound 1, or a pharma- ceutically acceptable salt thereof, is administered.

[0285] Embodiment 100. The method of any one of embodiments 1 to 99, wherein the method does not include taking a blood sample from the patient.

[0286] Embodiment 101. The method of any one of embodiments 1 to 100, wherein the method does not include analyzing a blood sample of the patient.

[0287] Embodiment 102. The method of any one of embodiments 1 to 101, wherein the patient is administered a beta-blocker during treatment with Compound 1, or a pharma- ceutically acceptable salt thereof.

[0288] Embodiment 103. A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need of treatment thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharma- ceutical acceptable salt thereof.

[0289] Embodiment 104. The method of any one of embodiments 1 to 103, wherein said method results in one or more of the following: improvement of mitral regurgitation, improvement of cardiac relaxation, beneficial cardiac remodeling, cardiac reverse remodeling, beneficial cardiac structural remodeling, beneficial cardiac functional remodeling, reversal of adverse cardiac remodeling, reduction in mean left ventricular mass index (LVMI), improvement in left ventricular (LV) filling pressure, reduction in left atrial volume index (LAVI), reduction in categorical assessment of systolic anterior motion of the mitral valve leaflets, reduction in systolic anterior motion of the mitral valve leaflets, reduction in the frequency of eccentric mitral regurgitation, reduction in mitral regurgitation, reduction in lateral wall E / e', reduction in lateral wall E / E, reduction in brain natriuretic peptide (BNP), and reduction in N-terminal prohormone of brain natriuretic peptide (NT-proBNP).

[0290] Embodiment 105. The method according to any one of embodiments 1 to 103, wherein said method results in one or more of the following: improvement in maximal oxygen uptake (pVO2) by cardiopulmonary exercise testing (CPET), improvement in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), improvement in one or more classes of NYHA functional class(es), improvement in post-Valsalva left ventricular outflow tract gradient (LVOT-G), and improvement in total workload during CPET.

[0291] Embodiment 106. The method of embodiment 105, wherein said method results in a change from baseline in pVO2 of ≧1.5 mL / kg / min and an improvement in NYHA functional class by one or more classes(es).

[0292] Embodiment 107. The method of embodiment 105, wherein said method results in a change from baseline in pVO2 of ≧3.0 mL / kg / min and no worsening of NYHA functional class.

[0293] Embodiment 108. The method of embodiment 105, wherein the method improves the KCCQ-CSS score by 5 or more points.

[0294] Embodiment 109. The method of embodiment 105, wherein said method achieves a resting LVOT-G of <30 mmHg, a post-Valsalva LVOT-G of <50 mmHg, and a NYHA functional class of I.

[0295] Embodiment 110. The method according to embodiment 105, wherein said method achieves a resting LVOT-G of <30 mmHg, a post-Valsalva LVOT-G of <50 mmHg, and an improvement in NYHA functional class by one or more classes (multiple classes are possible).

[0296] Embodiment 111. The method of any one of embodiments 104 to 110, wherein one or more of the results of said treatment occur within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of initiation of treatment with Compound 1 or a pharma- ceutically acceptable salt thereof.

[0297] Embodiment 112. A method of reducing the resting left ventricular outflow tract pressure gradient (LVOT-G) to less than 30 mmHg and reducing the post-Valsalva left ventricular outflow tract pressure gradient (LVOT-G) to less than 50 mmHg in a patient with obstructive hypertrophic cardiomyopathy (oHCM), comprising administering to the patient a therapeutically effective amount of Compound 1 or a pharmacologic acceptable salt thereof.

[0298] Embodiment 113. The method of embodiment 112, wherein the reduction in the resting left ventricular outflow tract pressure gradient (LVOT-G) to less than 30 mmHg and the reduction in the post-Valsalva left ventricular outflow tract pressure gradient (LVOT-G) to less than 50 mmHg occurs within 10 weeks of initiating treatment with compound 1 or a pharma- ceutically acceptable salt thereof.

[0299] Embodiment 114. The method of embodiment 113, wherein the reduction in the resting left ventricular outflow tract pressure gradient (LVOT-G) to less than 30 mmHg and the reduction in the post-Valsalva left ventricular outflow tract pressure gradient (LVOT-G) to less than 50 mmHg occurs within 2 weeks of initiating treatment with compound 1 or a pharma- ceutically acceptable salt thereof.

[0300] Embodiment 115. The method of any one of embodiments 112-114, wherein the reduction in resting LVOT-G and the reduction in post-Valsalva LVOT-G are sustained for at least 10 weeks of treatment.

[0301] Embodiment 116. The method of any one of embodiments 112-114, wherein the therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof, is selected by titrating the daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, administered to the patient.

[0302] Embodiment 117. The method of embodiment 116, wherein the dose is titrated once during the course of treatment.

[0303] Embodiment 118. The method of embodiment 116, wherein the dose is titrated two or more times during the course of treatment.

[0304] Embodiment 119. The method of any one of embodiments 116-118, wherein the daily dose is administered to the patient at a constant amount for about two weeks before the amount of said daily dose is titrated.

[0305] Embodiment 120. The method of any one of embodiments 116-118, wherein compound 1, or a pharma- ceutically acceptable salt thereof, is administered in a daily dose of about 5 mg to about 30 mg.

[0306] Embodiment 121. The method of embodiment 120, wherein the daily dose is about 5 mg.

[0307] Embodiment 122. The method of embodiment 120, wherein the daily dose is about 10 mg.

[0308] Embodiment 123. The method of embodiment 120, wherein the daily dose is about 15 mg.

[0309] Embodiment 124. The method of embodiment 120, wherein the daily dose is about 20 mg.

[0310] Embodiment 125. The method of embodiment 120, wherein the daily dose is about 30 mg.

[0311] Embodiment 126. The method of any one of embodiments 116 to 125, wherein the daily dose is administered as a single dose each day.

[0312] Embodiment 127. The method of any one of embodiments 116 to 125, wherein the daily dose is administered in two divided doses.

[0313] Embodiment 128. The method of any one of embodiments 116 to 127, wherein the reduction in resting LVOT-G and the reduction in post-Valsalva LVOT-G peak within 2 to 6 weeks of the end of titration.

[0314] Embodiment 129. A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need of treatment thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharma-ceutical acceptable salt thereof, wherein the patient has a resting left ventricular outflow tract gradient (LVOT-G) of at least 50 mmHg prior to administration of Compound 1, or a pharma-ceutical acceptable salt thereof.

[0315] Embodiment 130. A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need of treatment thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharmacologic acceptable salt thereof, wherein the patient has a resting left ventricular outflow tract gradient (LVOT-G) of at least 30 mmHg and less than 50 mmHg and a post-Valsalva left ventricular outflow tract gradient (LVOT-G) of at least 50 mmHg prior to administration of Compound 1, or a pharmacologic acceptable salt thereof.

[0316] Embodiment 131. A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need of treatment thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharma- ceutical acceptable salt thereof, wherein the patient is eligible for septal reduction therapy (SRT).

[0317] Embodiment 132. The method of embodiment 131, wherein the method eliminates the need for septal reduction therapy in the patient.

[0318] Embodiment 133. The method of embodiment 131 or 132, wherein the septal reduction therapy is a myectomy.

[0319] Embodiment 134. The method of embodiment 131 or 132, wherein the septal reduction therapy is alcohol septal ablation.

[0320] Embodiment 135. A method for treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient having heart failure symptoms, comprising administering to the patient a therapeutically effective amount of Compound 1 or a pharma- ceutical acceptable salt thereof, resulting in a reduction in heart failure symptoms as assessed by NYHA classification.

[0321] Embodiment 136 The method of embodiment 135, wherein said method changes the patient from NYHA class III to class II or class I.

[0322] Embodiment 137. The method of embodiment 135, wherein said method changes the patient from NYHA class II to class I.

[0323] Embodiment 138. The method of embodiment 135, wherein said method changes the patient from NYHA class III to class I.

[0324] Embodiment 139. The method of embodiment 135, wherein said method changes the patient from NYHA class III to class II.

[0325] Embodiment 140. The method of any one of embodiments 135-139, wherein said reduction in heart failure symptoms occurs within 10 weeks of initiating treatment with Compound 1 or a pharma- ceutically acceptable salt thereof.

[0326] Embodiment 141. The method of embodiment 135, wherein the method results in an improvement of at least one class of the patient's NYHA class.

[0327] Embodiment 142. The method of embodiment 141, wherein the method results in an improvement of one class of NYHA class.

[0328] Embodiment 143. The method of embodiment 141, wherein the method results in an improvement of 2 classes of NYHA class.

[0329] Embodiment 144. The method of any one of embodiments 135-143, wherein said reduction in heart failure symptoms occurs within 10 weeks of initiating treatment with Compound 1 or a pharma- ceutically acceptable salt thereof.

[0330] Embodiment 145. A method for reducing NT-proBNP levels in a patient, comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof.

[0331] Embodiment 146. The method of embodiment 145, wherein the patient has obstructive hypertrophic cardiomyopathy (oHCM).

[0332] Embodiment 147. A method for reducing cardiac troponin I levels in a patient, comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof.

[0333] Embodiment 148. The method of embodiment 147, wherein the patient has obstructive hypertrophic cardiomyopathy (oHCM).

[0334] Embodiment 149. The method of any one of embodiments 129-148, wherein the therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof, is selected by titrating the daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, administered to the patient.

[0335] Embodiment 150. The method of embodiment 149, wherein the dose is titrated once during the course of treatment.

[0336] Embodiment 151. The method of embodiment 149, wherein the dose is titrated two or more times during the course of treatment.

[0337] Embodiment 152. The method of any one of embodiments 149-151, wherein the daily dose is administered to the patient at a constant amount for about two weeks before the amount of said daily dose is titrated.

[0338] Embodiment 153. The method of any one of embodiments 149-152, wherein compound 1, or a pharma- ceutically acceptable salt thereof, is administered in a daily dose of about 5 mg to about 30 mg.

[0339] Embodiment 154. The method of embodiment 153, wherein the daily dose is about 5 mg.

[0340] Embodiment 155. The method of embodiment 153, wherein the daily dose is about 10 mg.

[0341] Embodiment 156. The method of embodiment 153, wherein the daily dose is about 15 mg.

[0342] Embodiment 157. The method of embodiment 153, wherein the daily dose is about 20 mg.

[0343] Embodiment 158. The method of embodiment 153, wherein the daily dose is about 30 mg.

[0344] Embodiment 159. The method of any one of embodiments 154 to 158, wherein the daily dose is administered as a single dose each day.

[0345] Embodiment 160. The method of any one of embodiments 154 to 158, wherein the daily dose is administered in two divided doses.

[0346] Embodiment 161. The method of any one of embodiments 1 to 160, wherein the patient is classified as NYHA class III when administration of compound 1 or a pharmacologic salt thereof is initiated.

[0347] Embodiment 162. The method of any one of embodiments 1 to 160, wherein the patient is classified as NYHA class II when administration of compound 1 or a pharmacologic salt thereof is initiated.

[0348] Embodiment 163. The method of any one of embodiments 1 to 162, wherein the method reduces left ventricular wall stress in the patient.

[0349] Embodiment 164. The method of any one of embodiments 1 to 163, wherein the method reduces myocardial damage in the patient.

[0350] Embodiment 165. The method of any one of embodiments 1 to 164, wherein administration of compound 1 or a pharma- ceutically acceptable salt thereof has a sustained effect for at least 6 months.

[0351] Embodiment 166. The method of any one of embodiments 1 to 164, wherein administration of compound 1 or a pharma- ceutically acceptable salt thereof has a sustained effect for at least 5 years.

[0352] Embodiment 167. The method of any one of embodiments 1 to 164, wherein administration of compound 1 or a pharma- ceutically acceptable salt thereof has a sustained effect for at least 10 weeks, 12 weeks, 1 year, 2 years, 3 years, or 4 years.

[0353] Embodiment 168. A method of reducing left ventricular wall stress in a patient, comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof, wherein the patient has obstructive hypertrophic cardiomyopathy (oHCM).

[0354] Embodiment 169. The method of embodiment 168, wherein the therapeutically effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof is selected by titrating the daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof administered to the patient. EXAMPLES

[0355] The present application can be better understood by reference to the following non-limiting examples, which are provided as exemplary embodiments of the present application. The following examples are presented to more fully illustrate the embodiments, but should in no way be construed as limiting the broad scope of the present application. Although specific embodiments of the present application have been shown and described herein, it will be apparent that such embodiments are provided by way of example only. Those skilled in the art will be able to envision numerous variations, modifications, and substitutions without departing from the spirit and scope of the present invention. It will be understood that various alternatives to the embodiments described herein may be employed in the practice of the methods described herein.

[0356] Example 1 This first-in-human study of aficamten (also called CK-274) was conducted to evaluate its safety, pharmacokinetic, and pharmacodynamic profile, including the effects of diet or CYP2D6 poor metabolizer (CYP2D6-PM) phenotype. Aficamten, a selective cardiac myosin inhibitor, reduced measures of left ventricular contractility preclinically in vitro and in vivo and may therefore have therapeutic potential for the management of hypertrophic cardiomyopathy. This phase 1, double-blind, randomized, placebo-controlled study enrolled healthy adults aged 18-55 years who received single ascending or multiple ascending doses of aficamten or placebo (for 14 or 17 days). In addition to standard safety and pharmacokinetic assessments, pharmacodynamic effects were assessed by echocardiography. The study enrolled 102 participants (57 in the single-dose cohort, 24 in the multiple-dose cohort, 9 in the CYP2D6-PM cohort, and 12 in the food effect cohort). Adverse events were generally mild and not more frequent than with placebo at single doses of 50 mg or less and at multiple doses of 10 mg or less. In the single ascending dose cohorts, plasma concentrations of aficamten increased dose-proportionally, and the half-life of aficamten was 75-85 hours. Neither food nor CYP2D6-PM phenotype had a clinically meaningful effect on pharmacokinetics. At a single dose of 50 mg, mean left ventricular ejection fraction (LVEF) was reduced by 5.5% from baseline (p=0.0001). At multiple doses, a mean reduction in LVEF of 5.0% was observed after 14 days of aficamten at 10 mg once daily. Aficamten appears to be safe and well tolerated at the doses evaluated. A pharmacodynamic effect on LVEF was demonstrated, providing support for further clinical studies of aficamten.

[0357] method Study Overview and Ethics. The study used a randomized, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) design (Figure 2). The study was not designed to identify a maximum tolerated dose, but rather to identify a pharmacologically active dose range, defined as producing an absolute reduction in left ventricular ejection fraction (LVEF) from baseline within the range of 5% to 15% (e.g., a reduction of 55% to 65% of a baseline LVEF value of 70%). Dose escalation was to be stopped when this range was reached or earlier when an intolerable dose was identified.

[0358] Participants and treatment. To be eligible for the study, participants were healthy adults aged 18-55 years with a body mass index of 18.0-32.0 kg / m 2 Participants were required to have normal electrocardiograms (ECGs) and clinical laboratory values ​​or only minor abnormalities judged to be not clinically significant. Participants were also required to have normal cardiac structure and function, with LVEF ≥ 60% in the first four SAD cohorts, ≥ 65% in the subsequent SAD cohorts, all MAD cohorts, and the dietary influence cohort, and ≥ 55% in the CYP2D6-PM cohort. Prior to the study, participants were not permitted to use any prescription medications within 14 days, any over-the-counter medications (except acetaminophen) within 7 days, or any tobacco or nicotine within 3 months. In addition, participants were prohibited from consuming alcohol, caffeine, or grapefruit within 48 hours prior to study check-in.

[0359] Randomization schedules were generated centrally for each cohort and treatment period. All cohorts received aficamten or matching placebo in granular form in capsules administered with approximately 240 ml of water. Study medication was administered after an overnight fast, except during the postprandial period in the food effect cohort.

[0360] Single Ascending Dose (SAD) Cohorts. The SAD portion of the study used a randomized, double-blind, placebo-controlled, sequential, dose-escalation design in which participants received single ascending oral doses of the study drug. Seven cohorts were dosed sequentially (Figure 2). Of the eight participants within each cohort, the first two were randomly assigned (1:1) to aficamten or placebo and followed for a minimum of 2 days before dosing the remaining participants in the group. The remaining six participants were then randomly assigned (5:1) to receive a single oral dose of either aficamten (1, 3, 10, 25, 40, 50, or 75 mg) or placebo.

[0361] The initial dose of aficamten was selected using criteria from the US Food and Drug Administration guidance based on previous animal studies, with a safety margin of at least 10. Dose escalation was to be stopped when the results identified a pharmacologically active dose range that reduced LVEF by 5% to 15% or an intolerable dose, whichever occurred first.

[0362] Recommendations regarding dose escalation in the SAD cohort (and the MAD cohort described below) were made by the treating investigator (who was blinded to treatment arm) and were either approved or not approved by an open-label Dose Level Review Committee (DLRC). Decisions were made once ≥6 participants had been treated and followed for ≥3 days, including collection of clinical, laboratory, ECG, and telemetry data, as well as maximum plasma drug concentrations (C max) included suitable echocardiograms to assess LV function before and after the first dose. Escalation criteria included no more than two participants in a dose group having an LVEF less than 50% and no individual having an LVEF less than 45%. Dose escalation criteria were as follows: (1) no individual had a serious cardiac adverse event related to the study drug; (2) no two individuals had a similar serious non-cardiac adverse event in the same organ system that was deemed related to the study drug; (3) no two Aficamten-treated individuals had a decrease in left ventricular ejection fraction (LVEF) of more than 15% compared to the most recent pre-dose value (as determined by the Dose Level Review Committee [DLRC]); (4) no individual had an LVEF less than 45% (unless determined by the DLRC and treating investigator to be unrelated to study drug); and (5) both the treating investigator and DLRC approved the escalation and next level dose based on clinical judgment.

[0363] Multiple Ascending Dose (MAD) Cohorts. The MAD cohorts also used a randomized, double-blind, placebo-controlled, sequential design. Enrollment for the MAD cohorts began once a single oral dose that was well tolerated and associated with observed PD effects had been identified in the SAD cohort. Each of the three MAD cohorts included eight participants who were randomized (6:2) to aficamten or placebo. Participants received a once-daily oral dose of study medication for 14 days (for cohorts comparing 5 mg or 10 mg aficamten with placebo) or 17 days (for cohorts comparing 7.5 mg aficamten with placebo).

[0364] CYP2D6 poor metabolizer cohort. A separate cohort was enrolled to evaluate the potential impact of CYP2D6 genetic variants on the PK properties of aficamten. The CYP2D6 gene encodes the cytochrome P450 2D6 enzyme, described as the most extensively characterized polymorphic drug-metabolizing enzyme, and previous in vitro studies suggested that CYP2D6 is a potential metabolizer of aficamten.

[0365] CYP2D6 genotype was determined at screening for all study participants. Participants identified as CYP2D6-PM were excluded from the SAD and MAD cohorts, but were invited to participate in the CYP2D6-PM cohort. The first individual in the CYP2D6-PM cohort was dosed after the SAD 25 mg cohort (Figure 2). Each participant received a single dose of aficamten (10 mg) or placebo. Nine participants were randomized (7:2), including a sentinel dose group consisting of the first two participants treated.

[0366] Food effect cohort. To evaluate the effect of food on the PK of aficamten, a separate cohort was enrolled after completion of the last SAD cohort, planned to enroll 8–12 participants. In an open-label, 2-way crossover design, participants were to receive two single doses of 10 mg aficamten, at least 14 days apart. Participants were randomized in a 1:1 ratio to one of two sequences: fasting / prandial or prandial / fasting. In the fasting period, aficamten was administered after an overnight fast, and in the prandial period, aficamten was administered 30 min after the start of a high-fat breakfast.

[0367] evaluation Safety and Tolerability. Safety was assessed by the incidence of adverse events (AEs) and incidence of LVEF reduction. Treatment-emergent AEs (TEAEs) were defined as AEs that began or increased after administration of study drug. All AEs were coded using the Regulatory Terminology of Medicines and Medical Devices, version 21.1, and graded using the 5-point severity scale of the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Each AE was judged by the treating investigator as either related or unrelated to study drug. Laboratory investigations were performed at regular intervals in all cohorts.

[0368] For safety monitoring, participants in all cohorts underwent periodic echocardiograms, which were evaluated by a cardiologist. In the SAD and MAD cohorts, echocardiograms were also reviewed by a central echocardiographic laboratory for PD assessment, as described below. In addition, participants in all cohorts were monitored with continuous 12-lead ECG recordings using a Holter monitor. For safety monitoring, single 12-lead ECGs were drawn at screening, pre-dose, and periodically throughout follow-up and interpreted by the investigator. In the SAD, MAD, and CYP2D6-PM cohorts, cardiac dynamic ECGs (three 10-second 12-lead ECG recordings) were obtained before the corresponding PK blood, and ECG intervals were quantified by a qualified reader.

[0369] Pharmacokinetic Analysis. For all study groups, blood samples for PK assessment were obtained pre-dose and up to 12 times daily on Day 1, then at regular intervals throughout the study. Blood samples were collected according to the following schedule: SAD cohort: Day 1: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, and 216 hours post-dose. MAD cohort (14-day dosing): Day 1: pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post-dose; Days 2, 4, 5, 6, and 9: pre-dose (corresponding to post-dose trough samples on days 1, 3, 4, 5, and 8) and 1.5 hours post-dose; Days 3, 7, 8, 10, 11, 12, and 13: pre-dose (corresponding to post-dose trough samples on days 2, 6, 7, 9, 10, 11, and 12); Day 14: pre-dose and 0.25, 0.5, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 168 hours post-dose. MAD cohort (17-day dosing): Day 1: pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post-dose; Days 2, 4, 5, 6, and 9: pre-dose (corresponding to post-dose trough samples on days 1, 3, 4, 5, and 8) and 1.5 hours post-dose; Days 3, 7, 8, 10, 11, 12, 13, 14, 15, and 16: pre-dose (corresponding to post-dose trough samples on days 2, 6, 7, 9, 10, 11, and 12); Day 17: pre-dose and 0.25, 0.5, 1.5, 2, 2.5, 3, 5, 7, 9, 12, 24, 36, 48, 72, and 168 hours post-dose. CYPD6-PM cohort: Day 1: pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 216, 312, and 552 hours post-dose. Food effect cohort: Day 1: pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 216 hours post-dose. PK parameters were calculated using Phoenix® WinNonlin® version 7.0 using standard non-compartmental methods. Actual sample collection times were utilized.

[0370] Plasma concentrations of aficamten were measured using a high-performance liquid chromatography-tandem mass spectrometry method validated at Celerion (Lincoln, Nebraska) for accuracy, precision, linearity, sensitivity, and specificity. The analytical range (lower to upper limit of quantification) for aficamten was 1.00 to 500 ng / mL.

[0371] Echocardiograms. For PD assessment of LVEF, echocardiograms of the SAD and MAD cohorts were interpreted at a central echocardiographic laboratory and used for all data analyses and dose level review decisions. Meanwhile, immediate interpretation of echocardiograms was performed on-site for safety monitoring. In the SAD cohorts receiving 1, 3, or 10 mg aficamten, echocardiograms were obtained pre-dose on day -1, day 1, and 1.5, 4, and 24 hours post-dose. In the SAD cohorts receiving 25, 40, 50, or 75 mg aficamten, echocardiograms were obtained pre-dose on day -1, day 1, and 1.5, 6, and 24 hours post-dose. An echocardiogram on day 3 (48 hours post-dose) was obtained only if the 24-hour LVEF had not returned near or above baseline, as determined by the investigator. In the MAD cohort, echocardiograms were obtained pre-dose on day -1, day 1, and 1.5 hours post-dose on days 2, 4, and 9, and 1.5, 24, and 72 hours post-dose on day 14 (for the 5 mg and 10 mg cohorts) or day 17 (for the 7.5 mg cohort). Echocardiograms were obtained 3 days after the final dose (day 17 or day 20) only if the participant's prior LVEF was not near or above baseline, as determined by the investigator.

[0372] Statistical Analysis: The sample size selected for this study was based on precedent set in other first-in-human PK studies of similar nature and was not based on power calculations. All participants who received at least one dose of study drug (aficamten or placebo) were included in the safety analysis. All participants who received at least one dose of study drug and had at least one evaluable PK plasma profile were included in the PK analysis set.

[0373] The PK analysis aimed to evaluate single-dose kinetics, repeated-dose (steady-state) kinetics, the effect of CYP2D6 phenotype on aficamten absorption and excretion, and the effect of food on aficamten absorption and excretion. For the SAD cohort, dose proportionality of aficamten was assessed using a power model on day 1. For the MAD cohort, dose proportionality was assessed using a power model on days 1 and 14 or 17. Several considerations were taken into account when assessing the dose proportionality of a drug, including results derived from the statistical analysis of the power model (e.g., slope estimate and width of two-sided 95% confidence interval [CI]), qualitative assessments specific to the PK of the drug, and clinical relevance. For the SAD cohort, the parameter used to assess dose proportionality was the area under the plasma drug concentration-time curve (AUC) from time 0 to the time of the last measurable concentration (AUC last ), AUC extrapolated from time 0 to infinity (AUC inf ), AUC from time 0 to 24 hours (AUC 24 ), and maximum plasma concentration (C max In the MAD cohort, the parameters were AUC 24 and C max On the 14th or 17th day, the AUC (AUC tau ) and C max The statistically linear relationship between the ln-transformed PK parameters and the ln-transformed dose was calculated using the quadratic (ln dose) 2 and tertiary (ln dose). 3 The dose proportionality was verified by including the effect of the dose-dependent parameter. A statistically linear relationship was established if the secondary and tertiary effects were not statistically significant using a 5% significance level, or if the effect was statistically significant but small enough to be clinically inconsequential. Dose proportionality analysis was performed using SAS® PROC MIXED. Dose proportionality was established if a statistically linear relationship was demonstrated and the two-sided 95% CI around the estimated parameter of the slope included a value of 1 for the dose-dependent parameter.

[0374] In the MAD cohort, Helmert contrasts were used to estimate ln-transformed plasma trough concentrations (C trough Steady-state analysis of Aficamten was performed on α- and β-reductase (α = 0.01) values. Separate analysis of variance (ANOVA) models were performed for each dose level. Day was included as a fixed effect. Helmert contrasts were constructed to compare each time point to the mean of subsequent time points. Steady-state was established when subsequent time points were not statistically different (alpha = 5%, two-tailed).

[0375] All participants who received at least one dose of study drug and had at least one pre-dose and at least one post-dose echocardiographic measurement were included in the PD analysis set. Descriptive analyses included absolute reduction in LVEF relative to baseline and categorical LVEF response (proportion of participants with LVEF reduction from baseline of ≥ 5%, ≥ 10%, and > 15%, and proportion of participants with LVEF < 50% and < 45%). Descriptive statistics of echocardiographic parameters were generated using SAS® version 9.3 or higher.

[0376] Dose-response analysis was performed using analysis of covariance (ANCOVA) to determine least squares mean differences (aficamten minus placebo). To analyze the effect of drug dose on echocardiographic parameters in the SAD and MAD cohorts, inferential analysis was performed on the PD analysis set using a linear mixed model for repeated measures analysis of covariance (ANCOVA). The ANCOVA used baseline values ​​as covariates, included treatment, time point, and time point × treatment interactions as fixed effects, and included change from baseline as the dependent variable. An unstructured variance-covariance structure was used, and the model accounted for repeated measurements of time points. Separate ANCOVA analyses were performed for each study part and each PD parameter. For each comparison, least squares means, least squares mean differences (active minus placebo), and associated two-sided 95% CIs are presented.

[0377] Concentration "bin" and exposure-response analyses were also performed using ANCOVA. SAS® PROC MIXED was used for all comparison analyses. Additional inferential analyses were performed in the SAD and MAD cohorts to evaluate the relationship between aficamten concentration and LVEF for participants in the PK / PD analysis set. Concentration bin ANCOVA was performed using a linear mixed model for repeated measures analysis with concentration bin group as fixed effect, baseline PD parameters as covariates, change from baseline as dependent variable, and a random intercept for adjustment for repeated measures. An unstructured variance-covariance structure was used. Aficamten plasma concentrations were paired with contemporaneous PD parameters. The ANCOVA compared the change in PD parameters between each bin and the placebo pooled group. For each comparison, least squares means, least squares mean differences (bin group minus placebo), and associated two-sided 95% CIs are presented. ANCOVA analyses were performed separately for each study part. For all time points where both PK data and PD measurements were available, time points were pooled for analysis. For each part of the study, Aficamten concentrations with time-matched PD data were pooled and sorted in ascending order. The data were then divided into five observational groups ("bins") from lowest to highest. Each observational group consisted of 20% of the data points. Each bin was treated as a separate group. The concentration bins consisted of a placebo group and a group of five bins based on pooling concentrations from all time points of Aficamten treatment.

[0378] The above analyses were then repeated using concentration as a continuous variable to estimate exposure-response trends. Both random intercept and random concentration effects were added to the ANCOVA. Concentration slope estimates and ANCOVA analyses with corresponding two-sided 95% CIs are presented for each study part.

[0379] For all time points where both PK data and PD measurements were available, time points were combined for analysis. A nominal significance level of 5% was used for statistical comparisons without adjustment for multiplicity.

[0380] result Study population. A total of 102 participants were enrolled (57 in the SAD cohort, 24 in the MAD cohort, 9 in the CYP2D6-PM cohort, and 12 in the dietary influence cohort). All participants completed the study. The mean age ranged from 32 to 40 years across cohorts, and the majority of participants were male (Table 1). [Table 1]

[0381] In the SAD cohort, there were no safety concerns prohibiting dose escalation between 1 mg and 25 mg. At the next planned dose (50 mg), one participant had an LVEF below 50% after dosing (46.2%), which did not meet the dose escalation stopping rule, and the 75 mg cohort was initiated. A sentinel participant in the 75 mg cohort had an LVEF below 45% after dosing, and as a result, no further participants were dosed with 75 mg. As a result, the 50 mg group was expanded and dosed to an additional 5 participants within this cohort. After expansion, one participant in the 50 mg dose group experienced an LVEF below 45%, again a decline of more than 15%. Thus, no further participants were dosed with more than 50 mg. The DLRC determined that the appropriate dose for the final cohort of single doses was 40 mg.

[0382] Following results from the 1 mg to 25 mg SAD cohort, the first MAD cohort was initiated at 5 mg aficamten once daily for 14 days. Without any safety concerns, the next cohort was initiated at 10 mg once daily for 14 days. In this cohort, two participants met stopping criteria based on echocardiographic findings. The DLRC determined that the next treatment level should be 7.5 mg to better characterize PK at steady state. Therefore, the dosing period was extended from 14 to 17 days to ensure that PK had reached steady state by the last day of dosing.

[0383] Safety and Tolerability. There were no serious AEs and no participants discontinued the study due to an AE. TEAEs observed were generally mild (grade 1) and were not more frequent with aficamten than placebo for both single and multiple dose administration (Tables 2 and 3). Overall, the most common TEAE in both the SAD and MAD cohorts was headache (Tables 2 and 3). [Table 2] [Table 3]

[0384] Echocardiogram-related AEs of reduction in ejection fraction to <45% based on assessment by the study's echocardiogram expert were reported in three participants (one each in the SAD 40 mg, 50 mg, and 75 mg cohorts) (Table 4). All were grade 1 and all resolved at the next echocardiogram evaluation (within 2.5–4.6 hours). One participant receiving 75 mg aficamten had an LVEF of 34.6% 1.5 hours after dosing, a 31.5% reduction in LVEF, which led to the termination of dose escalation of the SAD portion of the study, as previously described. At the next evaluation 2.5 hours later, the LVEF had returned to 51.9%. No AEs of reduction in ejection fraction to <45% were reported in the MAD, CYP2D6-PM, or food effect cohorts.

[0385] In all cohorts, the mean safety ECG parameters at the time points evaluated were within the normal range. No clinically significant changes from baseline were observed for any parameter. The QT interval corrected for heart rate using the Fridericia formula (QTcF) did not exceed 450 ms at baseline or at any evaluation time during the dosing interval (except for two individuals with a baseline QTcF of ≥440 ms who experienced increases in QTcF values ​​of 3 ms and 13 ms, respectively). There were no increases in the QTcF interval of >30 ms in all cohorts (except for one participant in the SAD placebo group whose QTcF interval increased by 33 ms on day 5 (427 ms vs. a baseline value of 394 ms)). In the cardiac dynamics evaluation, categorical analysis of ECG parameters revealed no cardiac safety concerns, and there was no evidence of a positive QT effect following single or repeated doses of aficamten.

[0386] All vital signs were within normal limits at post-dose time points. No clinically significant serum chemistry, hematology, or urinalysis findings were observed during the study. [Table 4]

[0387] Pharmacokinetics Single-dose kinetics. The plasma profile of aficamten was generally well characterized at all dose levels, except for the lowest dose of 1 mg (due to concentrations close to the lower limit of quantification) and the highest dose of 75 mg, which was administered to only one participant as mentioned above. Over the dose range of 1 mg to 50 mg, the mean maximum plasma concentrations and exposures were C max and the area under the plasma concentration-time curve from time 0 to 24 hours (AUC 24) increased with increasing dose (Figures 3A-B and Table 5). Mean clearance and volume of distribution were similar across doses. Median times to peak plasma concentrations ranged from 0.5 to 2.8 hours, with the longest time across all participants being 4.0 hours. Mean half-lives ranged from 75 to 85 hours. [Table 5]

[0388] Repeat-dose kinetics. With once-daily dosing, mean plasma concentrations increased between the 5 mg dose and the two higher doses (7.5 mg and 10 mg), but there was little difference in mean concentrations between the 7.5 mg and 10 mg doses on day 2 (Figure 4). Plasma PK parameters are displayed in Table 6. By the end of the treatment period (day 14 or 17), mean plasma concentrations were 2-2.5-fold higher than on day 1. Estimates of terminal elimination half-life were consistent between doses, ranging from 77 to 86 hours. Clearance was similar for the 5 mg and 10 mg doses, and accumulation rates were similar for the three doses. Steady state was reached after 10-12 days, consistent with the observed terminal elimination half-life estimates (Figure 4). [Table 6]

[0389] CYP2D6 poor metabolizer cohort. In CYP2D6-PMs, the mean half-life was prolonged to 110 hours compared with 85 hours in extensive metabolizers (i.e., the 10 mg SAD cohort), but no increase in AUC was observed in this group, and the geometric mean AUC 24 was 495 ng·h / ml (19 geometric CV%) (Table 7) compared with 679 ng·h / ml (35 geometric coefficient of variation percent [CV%]) for normal metabolizers (Table 5). CYP2D6-PMs did not appear to have a reduction in clearance that resulted in a clinically meaningful difference in exposure. [Table 7]

[0390] Food Effects. PK parameters of aficamten in the food effect cohort are displayed in Table 8. When taken with food, the C max increased by approximately 30%, and the time to peak concentration was shortened (1.5 vs. 2.3 hours). However, food had little effect on AUC, and the fasted geometric mean AUC 24 (geometric CV%) was 601 (33) ng·h / ml in the normal state compared with 631 (25) in the postprandial state. [Table 8]

[0391] Pharmacodynamics Left ventricular ejection fraction. At baseline, mean LVEF ranged from 61.0% to 67.5% across cohorts (Table 1). In the SAD cohort, a decline in mean LVEF was observed in those receiving the highest dose of aficamten (Figure 5A). The greatest mean reduction from baseline was seen 1.5 hours after dosing in the 50 mg cohort (least squares mean difference 5.5%, p=0.0001). LVESV and LVEDV were statistically significantly increased by 8.1 mL and 6.6 mL, respectively (Table 9). Other echocardiographic parameters such as stroke volume, cardiac output, cardiac time intervals, and measures reflecting diastolic function were not significantly changed (Table 9). One participant receiving 75 mg aficamten showed a 31.5% reduction in LVEF 1.5 hours after dosing, which recovered 2.5 hours after occurrence, leading to the end of dose escalation of the SAD portion of the study, as previously described. In the MAD cohort, a clear decline in LVEF emerged as dosing continued in the 10 mg cohort (Figure 5B). The greatest mean maximum percent decrease from baseline, 5.0%, was seen 1.5 hours after dosing in the 10 mg cohort on day 14 (Figure 5B). The placebo-corrected decrease of 3.2% (least squares mean difference) did not reach statistical significance (p=0.21), likely due to a lack of power in this small group comparison. [Table 9-1] [Table 9-2]

[0392] LVEF response by category. In the SAD cohort, 1 of 15 participants (7%) in the placebo cohort, 1 of 6 (17%) in the 3 mg cohort, 2 of 6 (33%) in the 40 mg cohort, 7 of 11 (64%) in the 50 mg cohort, and 1 of 1 (100%) in the 75 mg cohort experienced an absolute reduction in LVEF of ≥5% from baseline, whereas no participants in the 1 mg, 10 mg, or 25 mg cohorts experienced a reduction of ≥5%. An absolute reduction in LVEF of ≥10% occurred in 1 of 6 participants (17%) in the 40 mg cohort, 2 of 11 (18%) in the 50 mg cohort, and 1 (100%) in the 75 mg cohort. Reductions in LVEF below 50% were observed in 2 of 11 participants (18%) in the 50 mg cohort (48.2% and 45.5% by central laboratory assessment) and 1 of 1 (100%) in the 75 mg cohort. Only participants in the 75 mg cohort experienced an LVEF below 45%.

[0393] In the MAD cohort, four participants (1 of 6 participants (17%) receiving placebo, 1 of 6 participants (17%) receiving 7.5 mg aficamten once daily, and 2 of 6 participants (33%) receiving 10 mg aficamten once daily) experienced an absolute reduction in LVEF of 5% or greater from baseline. Of these, 2 participants in the 10 mg cohort experienced a reduction of 10% or greater. No reductions in LVEF below 50% were observed in any of the MAD cohorts by central laboratory assessment.

[0394] Relationship of plasma concentration to change in LVEF. The PK / PD relationship of aficamten is illustrated by plotting aficamten plasma concentration against change in LVEF for the SAD and MAD cohorts (Figures 6A and 6B). In the SAD cohort, there was a trend for LVEF to decrease with increasing aficamten plasma concentration. The relationship of LVEF to aficamten plasma concentration was statistically significant in both bin concentration analysis (122-524 ng / ml, p<0.0001) and concentration-slope analysis (p=0.0027) for the highest plasma concentration bin. In the MAD cohort, the relationship of LVEF to plasma aficamten did not reach statistical significance in bin concentration analysis or linear regression analysis. This may be due to the more limited range of plasma concentrations investigated and the small group size.

[0395] Consideration This phase 1, first-in-human study established doses at which aficamten was physiologically effective in reducing LVEF and well tolerated in healthy participants (up to 50 mg as a single oral dose or up to 10 mg after repeated doses) and identified a pharmacologically active dose that would be the starting dose for trials in patients with HCM. In addition, a single 10 mg oral dose was well tolerated among individuals with the CYP2D6-PM phenotype, and there was no significant effect of food on the PK of aficamten. Taken together, these observations support the continued development of aficamten for patients with HCM and provide a roadmap for phase 2 trials.

[0396] Safety of Aficamten. No serious AEs were observed in the study, and all participants completed the intended dose as planned. Overall, AEs were mild and similar in frequency between Aficamten- and placebo-treated participants. Importantly, participants whose LVEF fell below 50% and whose LVEF in these cases returned to baseline within 24 hours did not have any associated symptoms or adverse changes in vital signs. This study was not intended to find a maximum tolerated dose, and therefore dose escalation was halted once clear PD effects were observed in the SAD and MAD portions of the study. Thus, no doses were identified that were not tolerated by AEs.

[0397] Effect on LVEF. In the SAD cohort, the 50 mg dose caused a mean 5.8% decrease in LVEF, whereas in the MAD cohort, the 10 mg dose once daily for 14 days caused a mean absolute decrease in LVEF of approximately 5%. The proportion of participants with an absolute decrease in LVEF of ≥5% from baseline increased with increasing dose. Up to 64% of participants in the 50 mg SAD cohort and 33% of participants in the 10 mg MAD cohort experienced an absolute decrease in LVEF of ≥10% from baseline. In the SAD cohort, which explored the widest range of aficamten exposure, there was a statistically significant decrease in LVEF as aficamten plasma concentrations increased. Thus, the study achieved its secondary objectives of identifying the pharmacologically active dose and describing its PK / PD relationship.

[0398] Three participants experienced a decline in LVEF below 50%, which was rapidly reversible after discontinuation of study drug. After a single dose of 50 mg, two participants (18%) experienced an LVEF below 50% (48.2% and 45.5%). After a single dose of 75 mg, one participant experienced a reduction in LVEF to 34.1%. In both cases, the event was noted approximately 1.5 hours after dosing, and LVEF recovered to >50% 4-6 hours after dosing. The SAD results informed dose selection for other parts of the study, with no echocardiographic AEs in the MAD, CYP2D6-PM, or food effect cohorts.

[0399] Significance of PK Results: Aficamten demonstrated linear kinetics over the dose range of 1 mg to 50 mg, with a concentration-independent half-life and dose-independent clearance. Steady state was reached by the end of day 10 for the 10 mg dose and by the end of day 12 for the 5 mg and 7.5 mg doses. There was no food effect suggesting the need for dosing modifications. These findings support once-daily dosing in either fasted or fed states.

[0400] The relationship between plasma concentrations and LVEF suggests a wide therapeutic index, facilitating optimization of individual doses in patients with HCM, which are expected to be titrated over an escalating dose range until the desired PD effect is achieved. In addition, the half-life of aficamten (75-85 hours after a single dose; 77-86 hours after repeated doses) and the reversibility of the observed effects offer potential advantages in that steady state is reached within 2 weeks and excess effects on LVEF are easily reversed.

[0401] Conclusions: Aficamten demonstrated a favorable safety profile in healthy participants with no serious AEs or meaningful changes in clinical laboratory tests, ECGs, or health assessments. Reductions in LVEF to values ​​below 50% were reversible within 6 hours after a single dose. We identified a pharmacologically active dose of aficamten that could serve as the starting dose for studies in patients with HCM.

[0402] Example 2 A multicenter, randomized, placebo-controlled, double-blind, dose-finding phase 2 clinical trial of CK-274 in patients with symptomatic obstructive HCM (oHCM) was conducted. The primary objective of the study was to determine the safety and tolerability of CK-274. Secondary objectives were to describe the concentration-response relationship of CK-274 on resting and post-Valsalva left ventricular outflow tract gradients measured by echocardiography during 10 weeks of treatment, to describe the dose-response relationship of CK-274, and to evaluate plasma concentrations of CK-274 in patients with oHCM. Seventeen clinical trial sites in North America and Europe screened patients for enrollment in cohorts 1 and 2. A third cohort (cohort 3) was also studied to evaluate the safety and efficacy of CK-274 in combination with disopyramide, a class IA antiarrhythmic drug.

[0403] The first two cohorts (Cohort 1 and Cohort 2) excluded patients receiving disopyramide. Cohort 3 included patients receiving disopyramide. In each of the first two cohorts, patients were randomized 2:1 to active or placebo treatment and received up to three ascending doses of CK-3773274 or placebo guided by echocardiography. In the third cohort, all patients received up to three ascending doses of CK-3773274 guided by echocardiography. Overall, treatment duration was 10 weeks, with a follow-up period of 4 weeks after the last dose.

[0404] Because patient characteristics vary widely in this disease, individualized dose adjustment to pharmacodynamic (PD) response (reducing LVOT-G to <30 mmHg while maintaining LVEF >50%) was employed to maximize efficacy and safety.

[0405] Patients were eligible for inclusion in the study only if they met all of the following criteria: 1. Able to understand and willing to sign the Informed Consent Form (ICF) and willing to comply with all study procedures and restrictions during the period specified in the evaluation schedule; 2. Male or female aged 18-85 years at screening; 3. Weight ≥ 45 kg at screening; 4. Diagnosed with oHCM according to the following criteria: (a) as LV hypertrophy and non-dilated LV cavity without other cardiac disease; and (b) had a minimum wall thickness of ≥ 15 mm (a minimum wall thickness of ≥ 13 mm was allowed if there was a positive family history of HCM or a known disease-causing genetic mutation); 5. Suitable acoustic window for echocardiography; 6. Had LVOT-G during screening as follows:For cohorts 1 and 2: (a) resting gradient ≥ 50mmHg; or (b) resting gradient ≥ 30mmHg and < 50mmHg with post-Valsalva LVOT-G ≥ 50mmHg; or for cohort 3: persistent resting LVOT obstruction (≥ 30mmHg) and induced LVOT obstruction (≥ 50mmHg); 7. Left ventricular ejection fraction (LVEF) ≥ 60% at screening; 8. New York Heart Association (NYHA) class II or III at screening; 9. Patients taking beta-blockers, verapamil, diltiazem, or ranolazine must have been on a stable dose for > 4 weeks prior to randomization and expected to maintain the same drug regimen during the study; 10. Male patients were eligible to participate if they agreed to the following during the study and for at least 10 weeks after the final dose: (a) abstain from sperm donation; and in addition, (b)(i) engage in heterosexual intercourse as their preferred and usual lifestyle. abstinent (sustained abstinence for a long period of time) and agree to continue abstinence; or (b)(i) must agree to use male condoms and, if the male patient's female partner is of childbearing potential, must have the female partner use a highly effective method of contraception; 11. Female patients were eligible to participate if they were not pregnant or breastfeeding and met at least one of the following conditions: (a)(i) not a woman of childbearing potential, or (a)(ii) a woman of childbearing potential and using a highly effective method of contraception during the study and for at least 4 weeks after the final dose; and (b) a woman of childbearing potential must have a negative pregnancy test (urine or serum, as required by local regulations) within 3 days prior to the first dose of the study intervention; 12. Able to complete all screening procedures; 13. Taking a stable dose of disopyramide for more than 4 weeks prior to screening (Cohort 3 only).

[0406] Patients were excluded from the study if they met any of the following criteria: 1. Aortic stenosis or fixed subaortic obstruction; 2. Known infiltrative or storage disorders causing cardiac hypertrophy similar to oHCM (e.g., Noonan syndrome, Fabry disease, amyloidosis); 3. History of left ventricular (LV) systolic dysfunction (LVEF < 45%) at any time during the clinical course; 4. Documented history of current obstructive coronary artery disease (>70% stenosis in one or more epicardial coronary arteries) or documented history of myocardial infarction; 5. Treated with septal reduction therapy (surgical myectomy or percutaneous alcohol septal ablation) or planned for either treatment during the study period; 6. Previous treatment with cardiotoxic agents such as doxorubicin or similar; 7. For cohorts 1 and 2: treated with disopyramide or antiarrhythmic drugs with negative inotropic effects within 4 weeks prior to screening.For Cohort 3: Treated with an antiarrhythmic drug other than disopyramide with negative inotropic effects within 4 weeks prior to screening; 8. Have any ECG abnormality (e.g., type II second-degree atrioventricular block) deemed by the investigator to pose a risk to patient safety; 9. Paroxysmal atrial fibrillation or flutter documented during the screening period; 10. Paroxysmal or permanent atrial fibrillation requiring rhythm restoration therapy (e.g., direct current cardioversion, ablation procedures, or antiarrhythmic therapy) within 6 months prior to screening (this exclusion does not apply if the atrial fibrillation has been treated with anticoagulation and has been adequately rate controlled for >6 months); 11. Within 6 months prior to screening 11. History of syncope or sustained ventricular tachyarrhythmia on exercise;12. Implantable cardioverter defibrillator (ICD) placement within 3 months prior to screening or planned ICD placement during the study;13. History of appropriate ICD shocks for life-threatening ventricular arrhythmias within 6 months prior to screening;14. Recipient of a major organ transplant (e.g., heart, lung, liver, bone marrow, kidney) or anticipated transplant within 12 months of randomization;15. Hepatic dysfunction defined as total bilirubin (TBL) ≥ 1.5 times the upper limit of normal (ULN) or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 times the ULN at screening. However, patients with documented Gilbert syndrome due to unconjugated hyperbilirubinemia without other liver disease and a TBL ≥ 1.5 times the ULN are permitted;16. History or evidence of any other clinically significant disorder, malignancy, active infection, other condition or disease that, in the opinion of the Investigator or Medical Monitor, poses a risk to the participant's safety or interferes with the study evaluations, procedures, or completion;17. Hemoglobin < 10.0 g / dL at screening;18. Estimated glomerular filtration rate (eGFR) < 30 mL / min / 1.73 m at screening. 2(according to the Modification of Diet in Renal Disease (MDRD) formula);19. Currently involved in another investigational device or drug trial or received an investigational device or drug less than 1 month (or 5 half-lives of the drug, whichever is longer) prior to screening;20. Previously treated with CK-3773274 or currently receiving mavacamten;21. Known hypersensitivity to any excipients in the CK-3773274 film-coated tablet.

[0407] In each cohort, patients received up to three escalating doses of CK-3773274 as shown in Table 11. Dose 1 was administered once daily to each patient for 2 weeks. At week 2, patients underwent echocardiography 2 hours after dose administration. Patients were titrated to Dose 2 if either of the following conditions were met on echocardiography: (1) resting LVOT-G ≥ 30mmHg and biplane LVEF ≥ 50%; or (2) resting LVOT-G < 30mmHg, post-Valsalva LVOT-G ≥ 50mmHg, and biplane LVEF ≥ 50%. Otherwise, patients continued on Dose 1. If LVEF was < 50% at week 2, patients were tapered to placebo. The dose adjustment algorithm is shown in Table 10 below.

[0408] After 2 additional weeks on the assigned dose (i.e., week 4), each patient underwent an echocardiogram 2 hours after dose administration. If the echocardiogram met either of the following criteria: (1) resting LVOT-G ≥ 30 mmHg and biplane LVEF ≥ 50%; or (2) resting LVOT-G < 30 mmHg, post-Valsalva LVOT-G ≥ 50 mmHg, and biplane LVEF ≥ 50%, patients were escalated to the next higher dose. Otherwise, patients continued on the same dose. If LVEF was < 50% at week 4, patients were returned to the previous dose level or to placebo if they were on dose 1.

[0409] After an additional 2 weeks of taking the assigned dose (i.e., week 6), each patient underwent an echocardiogram 2 hours after dose administration. If LVEF was <50% at week 6, patients were tapered to their previous dose level or, if the patient was on dose 1, to placebo. [Table 10]

[0410] Whenever a patient was tapered to placebo, the patient continued on placebo for the duration of the study. [Table 11]

[0411] The baseline characteristics of patients in Cohort 1, Cohort 2, and Cohort 3 are shown in Tables 12 and 13. [Table 12] [Table 13-1] [Table 13-2]

[0412] Echocardiograms obtained every 2 weeks and 2 weeks after the final dose were analyzed for several important structural and physiological indices, as well as N-terminal prohormone of brain natriuretic peptide (NT-proBNP).

[0413] Initial results from the clinical trial included data from two sequential cohorts, Cohort 1 (n=21) and Cohort 2 (n=20), in which patients were randomized 2:1 to receive CK-274 or placebo. Patients received up to three escalating doses of CK-274 once daily (5, 10, 15 mg in Cohort 1 and 10, 20, 30 mg in Cohort 2) or placebo. To determine the possibility of escalating to the next higher dose, patients underwent echocardiograms after 2 weeks of treatment at each dose. Overall, each patient in the study was treated for 10 weeks, with echocardiograms performed 2 weeks after the final dose.

[0414] In cohort 1 (n=14) patients receiving CK-274, mean resting LVOT-G changed from 53.8 mmHg at baseline to 13.4 mmHg at week 10; in cohort 2 (n=14) patients receiving CK-274, mean resting LVOT-G changed from 58.2 mmHg at baseline to 15.1 mmHg at week 10; and in the combined placebo group (n=13), mean resting LVOT-G changed from 52.1 at baseline to 44.0 mmHg at week 10 (Figure 7; p=0.0003 for cohort 1 and p=0.0004 for cohort 2 compared with placebo at week 10).

[0415] In cohort 1 (n=14) patients receiving CK-274, mean Valsalva LVOT-G changed from 77.4 mmHg at baseline to 38.1 mmHg at week 10; in cohort 2 (n=14) patients receiving CK-274, mean Valsalva LVOT-G changed from 82.3 mmHg at baseline to 29.8 mmHg at week 10; and in placebo combined (n=13) patients, mean Valsalva LVOT-G changed from 84.6 at baseline to 76.0 mmHg at week 10 (Figure 8; p=0.001 for cohort 1 and p<0.0001 for cohort 2 compared with placebo at week 10).

[0416] In cohort 1 (n=14) patients receiving CK-274, the mean ejection fraction changed from 72.8% at baseline to 67.3% at week 10; in cohort 2 (n=14) patients receiving CK-274, the mean ejection fraction changed from 75.4% at baseline to 64.1% at week 10; and in patients in the combined placebo group (n=13), the mean ejection fraction changed from 74.5% at baseline to 74.9% at week 10 (p=0.01 for cohort 1, p=<0.0001 for cohort 2 compared with placebo at week 10).

[0417] Overall, the incidence of adverse events was similar between treatment arms. Treatment with CK-274 in the study was well tolerated, with adverse events reported as mild or moderate in severity. No treatment-related serious adverse events were reported by the investigators.

[0418] No patients receiving CK-274 in cohort 1 had an LVEF <50%. In cohort 2, one patient with a baseline LVEF of 58% was titrated to 20 mg CK-274 and experienced a transient decline in LVEF <50% (maintained >40%) necessitating tapering. No interruptions or discontinuations of CK-274 treatment occurred in any patient across both cohorts.

[0419] The distribution of patients across doses of CK-274 in this study (Cohorts 1 and 2) is shown in Table 14. The distribution of patients across doses of CK-274 in Cohort 3 of this study is shown in Table 15. [Table 14] [Table 15]

[0420] Secondary outcomes of this clinical trial included data from cohort 3 (n=13). All patients received up to three escalating doses of CK-274 once daily (5, 10, 15 mg). To determine the possibility of escalation to the next higher dose, patients underwent echocardiograms after 2 weeks of treatment with each dose. Overall, the treatment period for each patient in this study was 10 weeks, with echocardiograms performed 2 weeks after the final dose. Efficacy endpoints included resting and induced LVOT gradients, NYHA class, and NT-proBNP.

[0421] Cohort 3 enrolled 13 patients (59 ± 14 years; 54% female) with NYHA class II (n = 5) and III (n = 8). Patients in cohort 3 had similar demographics, LVEF, and severity of obstruction compared to cohorts 1 and 2, but were more symptomatic and had higher baseline NT-proBNP. Patients in cohort 3 had symptomatic obstructive HCM, resting or post-Valsalva left ventricular outflow tract gradient (LVOT-G) ≥ 50 mmHg, and had been previously treated with disopyramide and mostly beta-adrenergic blockers. All patients received up to three escalating doses of aficamten once daily (5, 10, 15 mg), titrated based on echocardiographic guidance as previously described. Overall, treatment duration was 10 weeks, with a follow-up period of 4 weeks after the last dose. A total of 13 patients were enrolled, and all patients completed the treatment study.

[0422] Results from cohort 3 showed that significant reductions in mean resting LVOT-G and post-Valsalva LVOT-G (defined as a resting gradient of <30 mmHg and a post-Valsalva gradient of <50 mmHg) were achieved. These clinically important reductions in gradients were achieved with only modest reductions in mean left ventricular ejection fraction (LVEF), with no patients experiencing a LVEF below the predefined safety threshold of 50%. The majority of patients enrolled in cohort 3 of the study experienced improvements in New York Heart Association functional class. Pharmacokinetic data were similar to those observed in cohorts 1 and 2. In addition, the safety and tolerability of Aficamten were consistent with no treatment-related discontinuations and no serious adverse events reported by the investigators.

[0423] CK-274 in combination with disopyramide may represent a treatment option for the most severe and treatment-resistant oHCM patients.

[0424] Results after 10 weeks of treatment At baseline, there were no significant differences between aficamten and placebo in important echocardiographic indices and NT-proBNP values. Patients taking aficamten had a trend toward a reduction in mean left ventricular mass index (LVMI) compared with placebo (-4.8 g / m 2 (±2.4) vs. 3.3g / m 2 (±3.6); Average difference: 8.1g / m 2 , p = 0.063). Indices of left ventricular (LV) filling pressure were significantly increased from baseline to week 10, including left atrial volume index (LAVI) (-2.9 mL / m 2 (±1.5) vs. 2.2mL / m 2(±1.5), P=0.004) (FIG. 9); e' (0.5 cm / s (±0.4) vs. -0.5 cm / s (±0.3), p=0.03), and lateral wall E / e' (-2.0 (±1.1) vs. 1.8 (±0.8), p=0.006) (FIG. 10). Similarly, reductions versus baseline in categorical assessments of mitral leaflet systolic anterior motion (SAM; -50% vs. -17.3%) (FIG. 11) and frequency of eccentric mitral regurgitation (MR; -35.8% vs. +13.3%) (FIG. 11), respectively, were observed with Aficamten vs. placebo at week 10. At week 10, aficamten resulted in a significantly greater reduction in NT-proBNP compared with placebo (geometric least squares mean ratio 0.38 (0.25 to 0.56), p=0.0002).

[0425] Figure 12 shows the change in resting LVOT-G for the treatment and placebo cohorts. Figure 13 shows the change in resting Valsalva LVOT-G for the treatment and placebo cohorts. In patients treated with disopyramide (cohort 3), the effect on LVOT-G was largely attenuated by CK-274 treatment compared to patients in cohort 1 (same CK-274 dose). Figure 14 shows the change in LVEF for the treatment and placebo cohorts. Figure 15 shows the NYHA functional class response for the treatment and placebo cohorts. Figure 16 shows the change in mean NT-proBNP for the treatment and placebo cohorts.

[0426] The safety profile of all three treatment cohorts is shown in Table 16. Six moderate adverse events were recorded in cohort 3, including pneumonia, whooping cough, pulmonary mass, back pain, shortness of breath, and orthopnea. One adverse event of asymptomatic atrial fibrillation was recorded in a patient with a known history. The remaining adverse events included gastrointestinal symptoms (a known side effect of disopyramide) as well as other adverse events seen in cohorts 1 and 2 (headache, dizziness). The overall safety profile in cohort 3 supports the combination of CK-274 and disopyramide. [Table 16]

[0427] These findings indicate that aficamten treatment results in beneficial early cardiac remodeling associated with reduced LVMI, LAVI, lateral wall E / e', SAM, eccentric mitral regurgitation, and brain natriuretic peptide, accompanied by increased e' velocity, further indicating that aficamten favorably influences cardiac remodeling in oHCM.

[0428] Results of Cohort 1 and Cohort 2 For cohorts 1 and 2, a complete hemodynamic response (resting LVOT gradient <30mmHg and Valsalva gradient <50mmHg at week 10) occurred in 11 of 14 patients (79%) in Aficamten cohort 1 and 13 of 14 patients (93%) in Aficamten cohort 2, compared with only 1 of 12 patients (8%) in the placebo pool (Figures 17, 18, 20).

[0429] Over the treatment period, EF declined from 73±6% to 67±9% in Aficamten cohort 1 (LS mean difference vs. placebo p=0.007), from 75±6% to 64±8% in Aficamten cohort 2 (LS mean difference vs. placebo p<0.001), and was unchanged in the placebo group (75±6% to 75±4%; p=0.5) (Figure 19). Analysis of the relationship between Aficamten dose and EF over time revealed a dose-dependent decline, with a mean reduction in EF per mg of Aficamten of -0.6% (SE 0.084).

[0430] In the Aficamten treatment pool (cohorts 1 and 2), 15 of 28 patients (53%) experienced a change in NYHA class of 1 or more classes (Figure 21), including 6 patients who improved from class III to II, 8 from class II to I, and 1 from class III to I (Figure 24).

[0431] Aficamten treatment was associated with a 62% proportional reduction in NT-proBNP levels compared with placebo at week 10 (p<0.001). Importantly, 25 of 27 patients (93%) receiving Aficamten experienced at least some reduction in NT-proBNP levels compared with only 6 of 12 placebo-treated patients (50%).

[0432] Baseline levels of hs-troponin were 17 ng / L (290% CV) in the Aficamten pooled group and 17 ng / L (290% CV) in the placebo pooled group (Figure 23). At week 10, Aficamten-treated patients in cohort 1 experienced an 18% relative reduction compared to placebo pooled (p=0.29), and patients in cohort 2 experienced a 26% relative reduction compared to placebo pooled (p=0.097). The change in hs-troponin I levels for the placebo pooled group and Aficamten-treated patients in cohorts 1, 2, and 3 is shown in Figure 37.

[0433] The early and sustained hemodynamic effects of Aficamten were accompanied by a significant clinical benefit in the majority of patients' heart failure symptoms. An improvement in symptoms of one or more NYHA classes occurred in more than half of the Aficamten-treated patients, with the majority of improvements moving patients from class II to completely asymptomatic (class I) in 64% of cohort 2. Of note, Aficamten transformed seven patients from advanced heart failure symptoms (class III) to a less symptomatic state (class II or I).

[0434] This robust hemodynamic response is particularly noteworthy because Aficamten shifted the majority of patients with obstructive HCM to gradient levels below the current threshold for considering septal reduction therapies such as myectomy or alcohol septal ablation, which is particularly important because one of the advantages of septal reduction therapy is the opportunity to convert patients with limiting, advanced symptoms (Class III) to an asymptomatic or mildly symptomatic state.

[0435] Aficamten was also associated with significant reductions in NT-proBNP and hs-troponin, highlighting that this compound may have other potential downstream pathophysiological benefits, including reduced LV wall stress and reduced myocardial injury.

[0436] Example 3 An open-label extension clinical trial of CK-274 in patients with symptomatic oHCM was initiated. The primary objective of the study was to determine the safety and tolerability of CK-274 over a 5-year period.

[0437] Patients who completed the study as described in Example 2 and did not have atrial fibrillation were eligible for enrollment in the study. Echo-guided dose adjustments based on on-site reading were administered by the investigator and could be made at any time during the study, as described below.

[0438] Study design Each patient received dose 1 of CK-274 once daily for 2 weeks. In week 2, each patient underwent an abbreviated echocardiogram 2 hours after dose administration. Patients were titrated to dose 2 if echocardiograms met either of the following criteria: (1) resting LVOT-G ≥30 mmHg and biplane LVEF ≥50%; or (2) resting LVOT-G <30 mmHg, post-Valsalva LVOT-G ≥50 mmHg, and biplane LVEF ≥50%. Otherwise, patients continued on 5 mg of CK-274. Treatment was discontinued if LVEF was <50%. Treatment was interrupted if LVEF was <40%.

[0439] At weeks 4, 6, 12, and every 12 weeks thereafter, each patient will undergo an echocardiogram or an abbreviated echocardiogram (abbreviated echocardiogram at weeks 4 and 6, and echocardiogram at week 12 and every 12 weeks thereafter) 2 hours after dose administration to determine if additional dose adjustments are necessary (see Tables 17 and 18). Ambulatory cardiac monitoring will be performed at weeks 48, 96, 144, 192, and 240. Cardiac magnetic resonance will be monitored at weeks 48, 144, and 240 (see Figure 26). Baseline characteristics of patients enrolled in this open-label extension study are shown in Table 19. [Table 17] [Table 18] [Table 19]

[0440] Preliminary results Preliminary results are shown in Figures 27-34. Figure 27 shows the patient distribution over time among doses. At the time of data collection, 38 patients were enrolled in the study, with all 38 patients reaching at least 2 weeks of dosing, 37 of 38 patients reaching at least 6 weeks of dosing, 30 of 38 patients reaching at least 12 weeks of dosing, and 19 of 38 patients reaching at least 24 weeks of dosing. The percentage of patients receiving each dose level (5, 10, or 15 mg) at each time point is shown in Figure 27. Significant reductions in resting LVOT-G and Valsalva LVOT-G over time based on echocardiographic data from on-site reading for these patients are shown in Figures 28 and 29. Significant and sustained reductions in LVOT gradient were confirmed from weeks 2 to 24. In addition, minimal and stable reductions in LVEF were noted through week 24, as shown in Figure 30.

[0441] At baseline, 53% of patients were in NYHA class III and 47% were in NYHA class II.

[0442] Of patients who reached at least Week 12 of dosing, only 7% of patients were in NYHA class III, 52% of patients were in NYHA class II, and 41% of patients were in NYHA class I at Week 12 (Figure 31). Relative to baseline, 72% of patients experienced an improvement of 1 NYHA class, and 7% of patients experienced an improvement of 2 NYHA classes (Figure 32).

[0443] Of patients who reached at least Week 24 of dosing, only 6% of patients were in NYHA class III, 39% were in NYHA class II, and 56% were in NYHA class I at Week 24 (Figure 31). Relative to baseline, 61% of patients experienced a one-class improvement in NYHA class, and 17% experienced a two-class improvement in NYHA class (Figure 32).

[0444] No patients in this study showed a worsening of NYHA class from baseline. Preliminary Safety [Table 20]

[0445] One patient with LVEF <50% and TESAE had a history of alcohol-induced atrial fibrillation prior to the study, which reduced LVEF to <50%. At 15 mg CK-274, episodes of alcohol-induced atrial fibrillation recurred, as did a reduction in LVEF to 47%, and CK-274 was tapered. The patient subsequently experienced worsening atrial fibrillation and failed cardioversion, leading to CK-274 discontinuation. The patient returned to sinus rhythm on amiodarone, abstained from alcohol, and resumed CK-274 at dose 1 (5 mg) as LVEF was 60% with evidence of obstruction.

[0446] One patient underwent a temporary taper due to investigator concerns regarding QTc prolongation in a subject with an abnormal baseline EKG. A temporary aficamten taper was performed until the QTc was interpreted by a central laboratory. The QTc was confirmed to be normal, after which aficamten was increased.

[0447] One subject with severe TESAE presented with altered mental status prior to planned cardioversion for worsening atrial fibrillation while on a DOAC (direct acting oral anticoagulant), resulting in hospitalization. MRI demonstrated presumed embolic stroke. The patient was subsequently diagnosed with a congenital heart anomaly (ostium secundum atrial septal defect). No tapering or interruption of CK-274 was required.

[0448] Kansas City Cardiomyopathy Questionnaire (KCCQ) Participants' health status was assessed with the KCCQ before starting Aficamten in the OLE and at weeks 12 and 24 of treatment. Changes from baseline in KCCQ scores, including OSS=Global Summary Score, CSS=Clinical Summary Score, TSS=Total Symptom Score, PLS=Physical Limitation Score, SLS=Social Limitation Score, and QoL=Quality of Life, were determined. Patients were classified as worse (<-5 points), unchanged (<-5 to <5 points), slightly improved (<5 to <10 points), moderately to significantly improved (<10 to <20 points), and significantly to very significantly improved (>20 points) compared to baseline.

[0449] These results show a significant improvement in KCCQ scores among OLE participants at week 12 that was sustained over 24 weeks. The percentage of participants with clinically important improvement (global summary score ≥ 5) was 72.7% at week 12 and 72.0% at week 24. Highly significant clinical improvement (≥ 20 points) was seen in 36.4% at week 12 and 40.0% at week 24 (Figures 35, 36). Treatment with CK-274 resulted in significant and sustained improvements in all KCCQ domain scores for up to 6 months.

[0450] conclusion In this open-label extension study of patients with obstructive HCM treated with medical background therapy (including disopyramide), CK-274 was associated with significant and sustained reductions in LVOT gradient (Figures 28 and 29) and substantial improvements in heart failure symptoms (improvement of NYHA class by ≥1 in approximately 80% of patients) (Figures 31 and 32), as well as significant reductions in cardiac biomarkers (NT-proBNP and hs-cTnI) (Figures 33 and 34). CK-274 was well tolerated, with no events of LVEF <50% attributable to CK-274. These data demonstrate that the therapeutic effect of CK-274 is sustained for up to 6 months.

[0451] Example 4 The following examples describe a Phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of CK-3773274 (also referred to as CK-274 or aficamten) in adults with symptomatic hypertrophic cardiomyopathy and left ventricular outflow tract obstruction. The study evaluates the effect of 24 weeks of treatment with CK-3773274 on cardiopulmonary exercise capacity and health status in patients with symptomatic oHCM. The study aims to establish the efficacy and safety of CK-3773274 in improving exercise capacity and patient symptoms, as well as reducing left ventricular outflow tract gradient (LVOT-G) in patients with oHCM.

[0452] This is a Phase 3, randomized, placebo-controlled, double-blind, multicenter study in patients with symptomatic oHCM. Approximately 270 eligible patients will be randomized in a 1:1 ratio to receive CK-3773274 or placebo. Doses of 5, 10, 15, or 20 mg or matching placebo will be administered in escalating doses using echocardiography to guide dose adjustments. Randomization was stratified by beta-blocker use and CPET exercise modality.

[0453] The study will consist of three periods. The screening period will be of up to 6 weeks duration. The double-blind, placebo-controlled treatment period will last 24 weeks. There will be a 4-week safety follow-up period after the last dose of CK-3773274. CK-3773274 will be administered orally once daily. During the first 6 weeks of the treatment period, the dose of CK-3773274 will be titrated individually at weeks 2, 4, and 6 using echocardiography. Dose escalation will occur at visits at weeks 2, 4, and 6 only if patients have a post-Valsalva LVOT-G of ≥ 30mmHg and a biplane LVEF of ≥ 55%. Echocardiography will be performed at each subsequent visit during the study, and doses will be tapered as necessary. The primary endpoint of pVO2 will be measured by CPET at screening and at the end of treatment (week 24). Where applicable, patients will continue to take foundational therapy medications for HCM consistent with local clinical practice guidelines during the study.

[0454] A CMR imaging substudy will be initiated with approximately 40 patients who consent to participate.

[0455] A personalized dose adjustment scheme based on each patient's PD response to CK-3773274, applying pre-specified echocardiographic criteria including LVEF thresholds for dose escalation, tapering, and drug discontinuation, will facilitate the primary mitigation strategy.

[0456] Patients enrolled in this study must have an LVEF of ≥60% confirmed by a central echocardiography facility prior to randomization. A low starting dose of 5 mg and a maximum dose of 20 mg were chosen because they were well tolerated in a Phase 2 study (CY 6021) in patients with oHCM and were found to be effective in reducing LVOT-G without adversely affecting overall LVEF. Individualized dose escalation will be performed only if both of the following criteria are met: post-Valsalva LVOT-G of ≥30 mmHg and biplane LVEF of ≥55%. Importantly, in contrast to CY 6021, the lower LVEF limit for dose escalation is raised from 50% to 55% to provide a safety margin from the LVEF threshold (<50%) that would trigger dose reduction. The dose of CK-3773274 will be tapered if LVEF is <50% at any time, and CK-3773274 will be temporarily interrupted if LVEF is <40% at any time.

[0457] The primary objective of this study is to evaluate the effect of CK-3773274 on exercise capacity in patients with symptomatic oHCM. The outcome measure presented is change in maximal oxygen uptake (pVO2) from baseline to week 24 during cardiopulmonary exercise testing (CPET).

[0458] A secondary objective of the study is to evaluate the effect of CK-3773274 on patient health status, as determined by change from baseline to weeks 12 and 24 in the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS).

[0459] A further secondary objective of the study is to evaluate the effect of CK-3773274 on New York Heart Association (NYHA) functional class, as determined by the proportion of patients who achieve an improvement of at least one NYHA class from baseline to weeks 12 and 24.

[0460] Additional secondary objectives are to evaluate the effect of CK-3773274 on post-Valsalva left ventricular outflow tract gradient (LVOT-G), as determined by change from baseline to weeks 12 and 24, and the proportion of patients with post-Valsalva LVOT-G <30mmHg at weeks 12 and 24.

[0461] A further secondary objective is to evaluate the effect of CK-3773274 on exercise capacity as determined by change in total load during CPET from baseline to week 24.

[0462] To evaluate the safety and tolerability profile of CK-3773274 in patients with symptomatic oHCM, the following will be recorded: (1) incidence of reported serious adverse cardiac events (cardiovascular [CV] death, cardiac arrest, nonfatal stroke, nonfatal myocardial infarction, CV hospitalization); (2) incidence of new-onset persistent atrial fibrillation; (3) incidence of adequate implantable cardioverter defibrillator (ICD) discharge and averted sudden cardiac death; (4) incidence of left ventricular ejection fraction (LVEF) <50%; and (5) incidence of treatment-emergent adverse events.

[0463] The exploratory objectives of this study are to evaluate the effect of CK-3773274 on exercise capacity and functional class, as determined by the number of patients at week 24 compared to baseline who achieve either: (1) a change from baseline in pVO2 of ≥ 1.5 mL / kg / min and an improvement in ≥ 1 NYHA functional class; or (2) a change from baseline in pVO2 of ≥ 3.0 mL / kg / min and no worsening of NYHA functional class.

[0464] Further exploratory objectives of this study are to evaluate the effect of CK-3773274 on patient response over time, as determined by: (1) the proportion of patients with a >5-point improvement in KCCQ-CSS at weeks 12 and 24; (2) the proportion of patients with a resting LVOT-G <30mmHg, post-Valsalva LVOT-G <50mmHg, and NYHA functional class I at weeks 12 and 24; and (3) the proportion of patients with a resting LVOT-G <30mmHg, post-Valsalva LVOT-G <50mmHg, and an improvement in NYHA functional class of ≥1 at weeks 12 and 24.

[0465] Further exploratory objectives of this study are to evaluate the effects of CK-3773274 on other CPET parameters, as determined by change from baseline to week 24 in: (1) ventilatory efficiency (VE / VCO2 slope); (2) circulatory power (VO2 x systolic BP); and (3) ventilatory anaerobic threshold (VAT).

[0466] Further exploratory objectives of the study are to evaluate the effects of CK-3773274 on health status and health-related quality of life, as measured by PRO questionnaires, as determined by change from baseline to week 24 in individual responses to the EuroQol 5 Dimensions 5 Levels instrument (EQ-5D-5L).

[0467] Further exploratory objectives of the study are to evaluate the effects of CK-3773274 on cardiac function and structure as determined by changes from baseline to week 24 in echocardiographic measures of cardiac structure and contractile function, including LVEF, left ventricular end-systolic and end-diastolic volumes (LVESV and LVEDV, respectively), and left atrial volumes.

[0468] Further exploratory objectives of the study are to evaluate the effect of CK-3773274 on biomarker levels, as determined by change from baseline to week 24 in NT-pro-BNP, hs-cardiac TnI, and other biomarkers.

[0469] Further exploratory objectives of the study are to evaluate the effect of CK-3773274 on left ventricular (LV) mass, function, and structure by cardiac magnetic resonance (CMR) imaging, as determined by changes from baseline to week 24 in CMR measures of LV mass index, LVEF, septal and free wall thickness, left atrial volume index, LVESV, and LVEDV.

[0470] A further exploratory objective of this study is to evaluate the pharmacokinetics of CK-3773274 and its metabolites, as determined by pharmacokinetic parameters out to 24 weeks.

[0471] Overall design. This is a phase 3, randomized, placebo-controlled, double-blind, multicenter study in patients with symptomatic oHCM. Approximately 270 eligible patients will be randomized in a 1:1 ratio to receive CK-3773274 or placebo. Randomization will be stratified by beta-blocker use (yes or no) and CPET exercise modality (treadmill or bicycle) and will be performed with an interactive web response system (IWRS). There will be a cap on the number of patients taking beta-blockers, so that the number of patients will not exceed approximately 70% of the total enrollment. The number of patients with persistent atrial fibrillation at screening will also be capped at approximately 15%, and the number of patients using bicycles for their CPET exercise modality will be capped at approximately 50%.

[0472] CK-3773274 will be administered orally once daily with or without food. During the first 6 weeks of the treatment period, the dose of CK-3773274 will be individualized using echocardiography at weeks 2, 4, and 6. Dose escalation will occur at weeks 2, 4, and 6 only if patients have a post-Valsalva LVOT-G of ≥ 30 mmHg and a biplane LVEF of ≥ 55%. Echocardiography will be performed at each subsequent visit during the study, and doses will be tapered as needed. The primary endpoint of pVO2 will be measured by CPET at screening and at the end of treatment (week 24). Where applicable, patients will continue to receive foundational HCM medications consistent with local clinical practice guidelines during the study.

[0473] Regardless of whether the patient continues to receive CK-3773274, all patients will be followed from randomization to the last visit according to the Schedule of Assessments (SoA), unless they prematurely discontinue the study or withdraw consent. An early discontinuation visit will be conducted for patients who prematurely discontinue the study.

[0474] The study is designed to provide data supporting the clinical efficacy and safety of CK-3773274 in patients with symptomatic oHCM and LVOT-G >50mmHg after Valsalva. Reduction in LVOT-G is expected to correlate with improvements in patient symptoms, health status, and exercise capacity. Because patient characteristics vary widely in this disease, individualized dose adjustments to PD response (reducing LVOT-G <30mmHg after Valsalva while maintaining LVEF ≥55%) will be used to maximize efficacy and safety. Eligibility criteria are designed to allow enrollment of a patient population representative of the population of patients with oHCM while ensuring patient safety in the study. To avoid bias in data collection, including safety assessments and PD measurements that constitute the primary and secondary endpoints, the study will employ a placebo-controlled and double-blind approach.

[0475] Patients were eligible for inclusion in the study only if they met all of the following criteria: (1) were able to understand and willing to sign the ICF and willing to comply with all study procedures and restrictions during the time period specified in the assessment schedule, (2) were male or female and aged 18–85 years (inclusive) at screening, and (3) had a body mass index <35 kg / m 2(4) diagnosed with HCM according to the following criteria: (a) LV hypertrophy and non-dilating LV cavity without other cardiac disease, and (b) end-diastolic LV wall thickness ≥ 15 mm in one or more myocardial segments or ≥ 13 mm in one or more wall segments as measured by a central echocardiographic laboratory, and a known disease-causing genetic mutation or positive family history of HCM. (5) resting LVOT-G ≥ 30 mmHg and post-Valsalva LVOT-G ≥ 50 mmHg during screening as determined by a central echocardiographic laboratory. (6) LVEF ≥ 60% at screening as determined by a central echocardiographic laboratory. (7) New York Heart Association (NYHA) functional class II or III at screening. (8) hemoglobin ≥ 10 g / dL at screening. (9) centrally predicted gas exchange ratio (RER) ≥ 1.05 and pVO2 < 80% on screening CPET. (10) Patients taking beta-blockers, verapamil, or diltiazem must have been on a stable regimen for >6 weeks prior to randomization and expected to maintain the same drug regimen during the study.(11) Male patients are eligible to participate if they agree to: (a) abstain from sperm donation during the study and for at least 4 weeks after the last dose of CK-3773274, and in addition, (b) either (i) abstain from heterosexual intercourse as a preferred and usual lifestyle (long-term sustained abstinence) and agree to continue abstinence, or (ii) agree to use male condoms and, if the male patient's female partner is of childbearing potential, have her use a highly effective method of contraception. (12) Female patients are eligible to participate if they are not pregnant, lactating, or planning egg donation and meet at least one of the following conditions: (a) they are not women of childbearing potential (WOCBP) or they are WOCBP and agree to use highly effective contraception and that their male partner uses condoms during the study and for at least 4 weeks after the final dose of CK-3773274, and (b) WOCBP must have a negative pregnancy test (urine or serum, as required by local regulations) on day 1 prior to their first dose of study CK-3773274.(13) Able to complete all screening procedures.

[0476] Patients will be excluded from the study if they meet any of the following criteria: (1) significant valvular heart disease (as determined by the investigator), including moderate to severe valvular aortic stenosis and / or regurgitation, or moderate to severe mitral regurgitation not due to systolic anterior motion of the mitral valve; (2) documented history of current obstructive coronary artery disease (>70% stenosis in one or more epicardial coronary arteries) or documented history of myocardial infarction; (3) known or suspected infiltrative, hereditary, or storage disorder causing cardiac hypertrophy similar to oHCM (e.g., Noonan syndrome, Fabry disease, amyloidosis); (4) previous treatment with cardiotoxic agents such as doxorubicin or similar; (5) history of LV systolic dysfunction (LVEF <45%) or stress cardiomyopathy at any time during the clinical course. (6) Any ECG abnormality deemed by the investigator to pose a risk to patient safety (e.g., type II second-degree atrioventricular block). (7) Proven paroxysmal atrial fibrillation during the screening period. (8) Paroxysmal or permanent atrial fibrillation requiring rhythm restoration therapy (e.g., direct current cardioversion, atrial fibrillation ablation procedure, or antiarrhythmic therapy) within 6 months prior to screening. (This exclusion does not apply if the atrial fibrillation has been treated with anticoagulation therapy and has had adequate heart rate control for more than 6 months.) (9) History of syncope during exercise or sustained ventricular tachyarrhythmia within 6 months prior to screening. (10) ICD placement within 3 months prior to screening or planned ICD placement during the study. (11) History of appropriate ICD discharge for life-threatening ventricular arrhythmia within 6 months prior to screening. (12) Treated with septal reduction therapy (surgical myectomy or percutaneous alcohol septal ablation) or planning for either treatment during the study period. (13) Inability to exercise on a treadmill or bicycle (e.g., orthopedic limitations). (14) Documented room air oxygen saturation reading of <90% at screening. (15) Hepatic dysfunction defined by total bilirubin (TBL) ≥1.5 times the upper limit of normal (ULN) or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 times the ULN at screening.Patients with documented Gilbert syndrome due to unconjugated hyperbilirubinemia without other hepatic dysfunction and a TBL ≥ 1.5 times the ULN are permitted. (16) Recipient of a major organ transplant (e.g., heart, lung, liver, bone marrow, kidney) or anticipated transplant within 12 months of randomization. (17) History or evidence of any other clinically significant disorder, malignancy, active infection, other condition or disease that, in the opinion of the investigator or medical monitor, poses a risk to the participant's safety or interferes with the evaluations, procedures, or completion of the study. (18) Estimated glomerular filtration rate (eGFR) < 30 mL / min / 1.73 m2 (by the revised MDRD equation) at screening. (19) Currently involved in another investigational device or drug study or has received an investigational device or drug < 1 month (or 5 half-lives of the drug, whichever is longer) prior to screening. Other investigational procedures are prohibited while participating in this study. (20) Previous treatment with CK-3773274 or mavacamten. (21) Any known hypersensitivity to the excipients in the study drug tablets.

[0477] Exclusion criteria for the CMR substudy included (1) inability to tolerate CMR, (2) having an ICD, or (3) having a cardiac pacemaker.

[0478] Dose Modifications and Planned Dose Adjustments. Patients randomized to CK-3773274 may receive up to four escalating doses of CK-3773274 over the first 6 weeks of the study, as outlined in Table 21. CK-3773274-treated patients will be initiated at a dose of 5 mg once daily (Dose 1) and may be escalated to doses of 10, 15, and 20 mg once daily if they continue to meet the escalation criteria, or will be stopped at the current dose if they do not meet the escalation criteria. [Table 21]

[0479] After randomization, each patient will receive Dose 1 (5 mg) once daily for 2 weeks. At the week 2 visit, patients will undergo an echocardiogram 2 hours after CK-3773274 dose administration. If the following criteria are met on echocardiogram: post-Valsalva LVOT-G ≥ 30 mmHg and biplane LVEF ≥ 55%, patients will be titrated to Dose 2 (10 mg). Otherwise, patients will continue on Dose 1 (unless patients are assigned to placebo via IWRS if LVEF is < 50% at week 2).

[0480] After an additional 2 weeks at the assigned dose, at the week 4 visit, each patient will undergo an echocardiogram 2 hours after administration of the CK-3773274 dose. If the following criteria are met on echocardiogram: post-Valsalva LVOT-G ≥ 30mmHg and biplane LVEF ≥ 55%, patients will be titrated to the next higher dose. Otherwise, patients will continue on the same dose (unless the IWRS assigns patients to the previous dose level or placebo (if patients were on dose 1) if LVEF is < 50% at week 4).

[0481] After an additional 2 weeks on the assigned dose, at the week 6 visit, each patient will undergo an echocardiogram 2 hours after administration of the CK-3773274 dose. If the following criteria are met on echocardiogram: post-Valsalva LVOT-G ≥ 30mmHg and biplane LVEF ≥ 55%, patients will be titrated to the next higher dose. Otherwise, patients will continue on the same dose (unless the IWRS assigns patients to the previous dose level or placebo (if patient was on dose 1) if LVEF is < 50% at week 6).

[0482] After an additional 2 weeks on the assigned dose, at the week 8 visit, each patient will undergo an echocardiogram 2 hours after administration of the CK-3773274 dose to ensure that LVEF is ≥ 50%. If LVEF is < 50% at week 8, the patient will be assigned via IWRS to the next lower dose or placebo (if the patient was on dose 1).

[0483] After week 6, no further dose escalation may occur. During the study, dose reductions may occur at scheduled or unscheduled visits for safety reasons. Dose reductions will be determined by the IWRS system based on echocardiogram results. After week 8, dose reductions will be based on echocardiogram results at the originally scheduled or unscheduled visit. If LVEF is <50%, the IWRS will assign the patient to the next lower dose or placebo (if the patient was on dose 1). The IWRS will not allow further dose reductions for at least 7 days after the previous reduction.

[0484] Cardiopulmonary exercise testing (CPET). All patients undergo CPET including gas exchange analysis, and the technique is standardized across all participating centers as described in the CPET manual. The test includes continuous ECG monitoring by trained personnel, and the test is performed in an area equipped for cardiopulmonary resuscitation. The treadmill is the preferred modality for exercise testing. For CPET laboratories that do not perform treadmill testing, the bicycle ergometer is an acceptable alternative. Exercise protocols for both modalities are provided in the CPET manual. Patients must use the same testing modality for all exercise tests during the study. Whenever possible, CPET is performed by the same study personnel using the same equipment and after other study procedures on that day (including echocardiogram, KCCQ, EQ-5D-5L, CGI, PGI-C, NYHA class, SAQ-7, vital signs, ECG, blood draws, IP administration). Patients who are naive to the exercise protocol will be familiarized with the technique during screening.

[0485] All CPET tests are symptom-limited and patients are strongly encouraged to perform maximal effort and achieve an RER of 1.05 or greater. The reason(s) for discontinuing a less than maximal exercise test will be recorded. A test is confirmed as maximal if the RER is 1.05 or greater.

[0486] The Week 24 CPET should be performed at approximately the same time of day (e.g., morning, midday, afternoon) as the baseline CPET at screening, at a consistent time after the last dose of beta-blocker and IP. Whenever possible, patients should perform the exercise stress test between 3-10 hours after taking a beta-blocker.

[0487] If the investigator identifies life-threatening arrhythmias, early ischemia, severe hypotension, or other serious findings during CPET, the patient will be asked to stop the exercise stress test and the patient's physician will be notified of the results. If the patient is undergoing a screening test, the patient will not be randomized into the study. Enrolled patients with non-life-threatening events or findings that cause the study to be stopped may resume the study as per the investigator's instructions if it is safe to do so and after appropriate treatment.

[0488] Echocardiograms. Echocardiograms will be performed during screening and pre-dose on Day 1. Echocardiograms will also be performed 2 hours after dosing in the clinic at Weeks 2, 4, 6, 8, 12, 16, 20, 24, and 28.

[0489] A certified sonographer performs the echocardiogram using standard high quality, high fidelity equipment. Whenever possible, the same sonographer performs all studies on a single patient. Echocardiograms are performed according to the echocardiography manual after the patient is at rest in the supine position for at least 10 minutes. Instructions for performing the Valsalva maneuver and imaging the LVOT-G are also included in the echocardiography manual.

[0490] If an echocardiogram is scheduled at the same time as blood draws, vital signs, and / or an ECG, the order of assessment is vital signs, ECG, blood draw, and echocardiogram. Blood draws should be obtained at the scheduled times, followed by the echocardiogram.

[0491] The echocardiographic parameters measured include at least left ventricular parameters (left ventricular outflow tract gradient at rest (LVOT-G), LVOT-G after Valsalva, LVEF, LVFS, global longitudinal strain (GLS), left ventricular end-diastolic dimension (LVEDD), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic dimension (LVESD), left ventricular end-systolic volume (LVESV), left ventricular cardiac output (LVCO), LV stroke volume, LVOT velocity time integral (VTI), interventricular septum thickness (IVST), isovolumic contraction time (IVCT), IVRT, E / E ratio (septum and lateral wall), and left atrial volume (LAV)) in addition to the right ventricular function indices detailed in the echocardiographic examination protocol.

[0492] Unscheduled echocardiograms may be obtained if clinically indicated, e.g., at the discretion of the investigator, to evaluate AEs or to follow up clinically significant changes on previous echocardiograms. Results will be interpreted by an unblinded echocardiographer at the study site.

[0493] All echocardiograms (including unscheduled) will be sent to a central laboratory for interpretation. Local interpretation of LVEF and LVOT-G will be used to determine dose escalation and de-escalation via the IWRS. Central quantification of echocardiograms will be used for all statistical analyses.

[0494] Cardiac Magnetic Resonance. The CMR imaging substudy will evaluate the effect of CK-3773274 administration on cardiac morphology, function, and fibrosis in approximately 40 patients with oHCM who are eligible and consent to participate. CMR will be performed during screening and at week 24. Patients with eGFR <30 mL / min / 1.73 m 2 Patients who are aged 18-24 years or have an allergy to gadolinium may undergo non-contrast CMR.

Claims

Claim 1 A composition for use in a method for reducing in a patient having obstructive hypertrophic cardiomyopathy (oHCM): (a) the left ventricular outflow tract pressure gradient (LVOT-G) at rest to less than 30 mmHg, or (b) the left ventricular outflow tract pressure gradient (LVOT-G) after Valsalva maneuver to less than 50 mmHg, or (c) the left ventricular outflow tract pressure gradient (LVOT-G) at rest to less than 30 mmHg and the left ventricular outflow tract pressure gradient (LVOT-G) after Valsalva maneuver to less than 50 mmHg, the composition comprising a therapeutically effective amount of Compound 1 【Chemical 2】 or a pharmaceutically acceptable salt thereof. Claim 2 The reduction of the LVOT-G at rest to less than 30 mmHg, the reduction of the left ventricular outflow tract pressure gradient (LVOT-G) after Valsalva maneuver to less than 50 mmHg, or the reduction of the left ventricular outflow tract pressure gradient (LVOT-G) at rest to less than 30 mmHg and the reduction of the left ventricular outflow tract pressure gradient (LVOT-G) after Valsalva maneuver to less than 50 mmHg occurs within 10 weeks from the start of treatment with Compound 1 or a pharmaceutically acceptable salt thereof. The composition according to Claim 1 Claim 3 The reduction of the LVOT-G at rest to less than 30 mmHg, the reduction of the left ventricular outflow tract pressure gradient (LVOT-G) after Valsalva maneuver to less than 50 mmHg, or the reduction of the left ventricular outflow tract pressure gradient (LVOT-G) at rest to less than 30 mmHg and the reduction of the left ventricular outflow tract pressure gradient (LVOT-G) after Valsalva maneuver to less than 50 mmHg occurs within 2 weeks from the start of treatment with Compound 1 or a pharmaceutically acceptable salt thereof. The composition according to Claim 2 Claim 4 The reduction of the LVOT-G at rest to less than 30 mmHg, the reduction of the left ventricular outflow tract pressure gradient (LVOT-G) after Valsalva maneuver to less than 50 mmHg, or the reduction of the left ventricular outflow tract pressure gradient (LVOT-G) at rest to less than 30 mmHg and the reduction of the left ventricular outflow tract pressure gradient (LVOT-G) after Valsalva maneuver to less than 50 mmHg occurs and persists for at least 10 weeks of treatment. The composition according to Claim 1 Claim 5 The reduction of the LVOT-G at rest to less than 30 mmHg, the reduction of the left ventricular outflow tract pressure gradient (LVOT-G) after Valsalva maneuver to less than 50 mmHg, or the reduction of the left ventricular outflow tract pressure gradient (LVOT-G) at rest to less than 30 mmHg and the reduction of the left ventricular outflow tract pressure gradient (LVOT-G) after Valsalva maneuver to less than 50 mmHg occurs The composition according to claim 1, which reaches a peak within 2 to 6 weeks from the end of dose adjustment.

6. A composition for use in a method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, wherein the composition comprises a therapeutically effective amount of Compound 1 【Chemical Formula 3】 or a pharmaceutically acceptable salt thereof, and the patient has a resting left ventricular outflow tract pressure gradient (LVOT-G) of at least 50 mmHg prior to administration of Compound 1 or a pharmaceutically acceptable salt thereof.

7. A composition for use in a method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, wherein the composition comprises a therapeutically effective amount of Compound 1 【Chemical 4】 or a pharmaceutically acceptable salt thereof, and the patient has a resting left ventricular outflow tract pressure gradient (LVOT-G) of at least 30 mmHg and less than 50 mmHg and a post-Valsalva left ventricular outflow tract pressure gradient (LVOT-G) of at least 50 mmHg prior to administration of Compound 1 or a pharmaceutically acceptable salt thereof.

8. A composition for use in a method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, wherein the composition comprises a therapeutically effective amount of Compound 1 [Chemical Formula 5] or a pharmaceutically acceptable salt thereof, and the patient is eligible for septal reduction therapy (SRT).

9. The composition according to claim 8, wherein the method excludes the need for septal reduction therapy in the patient.

10. The composition according to claim 8, wherein the septal reduction therapy is myectomy or alcohol septal ablation.

11. A composition for use in a method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient with heart failure symptoms, wherein the composition comprises a therapeutically effective amount of Compound 1 【Chemical Formula 6】 or a pharmaceutically acceptable salt thereof, and the method results in a reduction in heart failure symptoms as evaluated by NYHA classification.

12. The composition according to claim 11, wherein the method results in an improvement in Class 1 or Class 2 of the NYHA class of the patient.

13. The composition according to claim 11, wherein the reduction in heart failure symptoms occurs within 10 weeks from the start of treatment with Compound 1 or a pharmaceutically acceptable salt thereof.

14. A composition for use in a method of reducing a patient's NT-proBNP level, wherein the composition comprises a therapeutically effective amount of Compound 1 【Chemical Formula 7】 A composition comprising or a pharmaceutically acceptable salt thereof.

15. A composition for use in a method of reducing a patient's myocardial troponin I level, wherein the composition comprises a therapeutically effective amount of Compound 1 【Chemical Formula 8】 or a pharmaceutically acceptable salt thereof.

16. The composition according to claim 14, wherein the patient has obstructive hypertrophic cardiomyopathy (oHCM).

17. The composition according to claim 1, wherein the method reduces the left ventricular wall stress of the patient.

18. A composition for use in a method of reducing a patient's left ventricular wall stress, wherein the composition comprises a therapeutically effective amount of Compound 1 【Chemical Formula 9】 or a pharmaceutically acceptable salt thereof, and the patient has obstructive hypertrophic cardiomyopathy (oHCM).

19. The composition according to claim 1, wherein the therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is selected by adjusting the daily dose of Compound 1 or a pharmaceutically acceptable salt thereof administered to the patient.

20. A composition for use in a method of treating oHCM in a patient in need of treatment for obstructive hypertrophic cardiomyopathy (oHCM), wherein the composition comprises a therapeutically effective amount of Compound 1 【Chemical 10】 or a pharmaceutically acceptable salt thereof, and the therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is selected by adjusting the daily dose of Compound 1 or a pharmaceutically acceptable salt thereof administered to the patient.

21. The composition according to claim 19, wherein the dose is adjusted once during the course of treatment.

22. The composition according to claim 19, wherein the dose is adjusted two or more times during the course of treatment.

23. The composition according to claim 19, wherein the daily dose is administered to the patient in a constant amount for about two weeks before the amount of the daily dose is adjusted.

24. The composition according to claim 1, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 5 mg to about 30 mg.

25. The composition according to claim 24, wherein the daily dose is about 5 mg, about 10 mg, about 15 mg, about 20 mg, or about 30 mg.

26. A composition for use in a method of treating oHCM in a patient in need of treatment for obstructive hypertrophic cardiomyopathy (oHCM), wherein the composition comprises Compound 1 【Chemical 11】 or a pharmaceutically acceptable salt thereof, the method comprising administering to the patient a first daily dose of Compound 1 or a pharmaceutically acceptable salt thereof over a first period; and administering to the patient a second daily dose of Compound 1 or a pharmaceutically acceptable salt thereof over a second period or discontinuing administration of Compound 1 or a pharmaceutically acceptable salt thereof to the patient, based on one or more components of a first echocardiogram of the patient obtained after the first period, a composition comprising the same. **Claim 27** The composition according to claim 26, wherein the method comprises selecting a second daily dose of the Compound 1 or a pharmaceutically acceptable salt thereof based on the one or more components of the first echocardiogram. **Claim 28** The one or more components of the first echocardiogram are a) Biphasic plane LV EF, b) Post-Valsalva LVOT-G, c) Resting LVOT-G, d) Biphasic plane LV EF and post-Valsalva LVOT-G, or e) Biphasic plane LV EF, post-Valsalva LVOT-G, and resting LVOT-G The composition according to claim 26, comprising the same. **Claim 29** The one or more components of the first echocardiogram include biphasic plane LV EF, wherein when the biphasic plane LV EF of the first echocardiogram is below a predetermined biphasic plane LV EF threshold, the second daily dose of Compound 1 【Chemical Formula 12】 or a pharmaceutically acceptable salt thereof is lower than the first daily dose of Compound 1 or a pharmaceutically acceptable salt thereof, the composition according to claim 26. **Claim 30** The one or more components of the first echocardiogram include biphasic plane LV EF, wherein when the biphasic plane LV EF of the first echocardiogram is below a predetermined biphasic plane LV EF threshold, administration of Compound 1 or a pharmaceutically acceptable salt thereof to the patient is discontinued, the composition according to claim 26. **Claim 31** The one or more components of the first echocardiogram include biphasic plane LV EF, resting LVOT-G, and post-Valsalva LVOT-G, Here, when the biplane LVEF of the first echocardiogram is equal to or higher than the predetermined biplane LVEF threshold value, the resting LVOT-G of the first echocardiogram is lower than the predetermined resting LVOT-G threshold value, and the post-Valsalva LVOT-G of the first echocardiogram is lower than the predetermined post-Valsalva LVOT-G threshold value, the second daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is the same as the first daily dose of Compound 1 or a pharmaceutically acceptable salt thereof. The composition according to claim 26.

32. The one or more components of the first echocardiogram include biplane LVEF, resting LVOT-G, and post-Valsalva LVOT-G. Here, the following conditions in the first echocardiogram: (1) The biplane LVEF is equal to or higher than the predetermined biplane LVEF threshold value, and the resting LVOT-G is equal to or higher than the predetermined resting LVOT-G threshold value, or (2) The biplane LVEF is equal to or higher than the predetermined biplane LVEF threshold value, the resting LVOT-G is lower than the predetermined resting LVOT-G threshold value, and the post-Valsalva LVOT-G is equal to or higher than the predetermined post-Valsalva LVOT-G threshold value. When either of the above is satisfied, the second daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is more than the first daily dose of Compound 1 or a pharmaceutically acceptable salt thereof. The composition according to claim 26.

33. The one or more components of the first echocardiogram include biplane LVEF and post-Valsalva LVOT-G. Here, the following conditions in the first echocardiogram: (1) The biplane LVEF is equal to or higher than the predetermined biplane LVEF threshold value and lower than a second predetermined biplane LVEF threshold value, or (2) The biplane LVEF is equal to or higher than the second predetermined biplane LVEF threshold value, and the post-Valsalva LVOT-G of the first echocardiogram is lower than the second predetermined post-Valsalva LVOT-G threshold value. When either of the above is satisfied, the second daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is the same as the first daily dose of Compound 1 or a pharmaceutically acceptable salt thereof. The composition according to claim 26.

34. The one or more components of the first echocardiogram include biplane LVEF and post-Valsalva LVOT-G. Here, when the biplane LVEF of the first echocardiogram exceeds the second predetermined biplane LVEF threshold value and the post-Valsalva LVOT-G of the first echocardiogram is equal to or greater than the second predetermined post-Valsalva LVOT-G threshold value, the second daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is greater than the first daily dose of Compound 1. The composition according to claim 26.

35. The composition according to claim 26, wherein the first daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 5 mg of Compound 1.

36. The composition according to claim 35, wherein the second daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg of Compound 1.

37. The composition according to claim 26, wherein the method further comprises measuring the one or more components of the first echocardiogram.

38. The composition according to claim 26, wherein the first period is about 2 weeks.

39. The composition according to claim 26, wherein the second period is about 2 weeks.

40. The second daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient over the second period. The composition according to claim 26, wherein the method further comprises administering a third daily dose of Compound 1 or a pharmaceutically acceptable salt thereof to the patient over a third period or discontinuing the administration of Compound 1 or a pharmaceutically acceptable salt thereof to the patient based on one or more components of the second echocardiogram of the patient obtained after the second period and the second daily dose.

41. The composition according to claim 40, wherein the method comprises selecting a third daily dose of Compound 1 or a pharmaceutically acceptable salt thereof based on the one or more components of the second echocardiogram and the second daily dose.

42. The one or more components of the second echocardiogram are (a) biplane LVEF, (b) post-Valsalva LVOT-G, (c) resting LVOT-G, (d) biplane LVEF and post-Valsalva LVOT-G, or (e) biplane LVEF, post-Valsalva LVOT-G, and resting LVOT-G The composition according to claim 40.

43. The one or more components of the second echocardiogram include biplane LVEF, when the biplane LVEF of the second echocardiogram is below the predetermined biplane LVEF threshold, the third daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is lower than the second daily dose of Compound 1 or a pharmaceutically acceptable salt thereof, or administration of Compound 1 or a pharmaceutically acceptable salt thereof to the patient is discontinued, the composition according to claim 40.

44. when the biplane LVEF of the second echocardiogram is below the predetermined biplane LVEF threshold and the second daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is the same as or lower than the first daily dose of Compound 1, administration of Compound 1 or a pharmaceutically acceptable salt thereof to the patient is discontinued, the composition according to claim 40.

45. when the second daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is higher than the first daily dose of Compound 1 or a pharmaceutically acceptable salt thereof and the biplane LVEF of the second echocardiogram is below the predetermined biplane LVEF threshold, the third daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is the same as the first daily dose of Compound 1 or a pharmaceutically acceptable salt thereof, the composition according to claim 40.

46. The one or more components of the second echocardiogram include biplane LVEF, resting LVOT-G, and post-Valsalva LVOT-G, wherein when the biplane LVEF of the second echocardiogram is at or above the predetermined biplane LVEF threshold, the resting LVOT-G of the second echocardiogram is below the predetermined resting LVOT-G threshold, and the post-Valsalva LVOT-G of the second echocardiogram is below the predetermined post-Valsalva LVOT-G threshold, the third daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is the same as the second daily dose of Compound 1 or a pharmaceutically acceptable salt thereof, the composition according to claim 40.

47. The one or more components of the second echocardiogram include biplane LVEF, resting LVOT-G, and post-Valsalva LVOT-G, wherein the following conditions in the second echocardiogram: (1) The biphasic plane LVEF is equal to or greater than the predetermined biphasic plane LVEF threshold value, and the resting LVOT-G is equal to or greater than the predetermined resting LVOT-G threshold value, or (2) The biphasic plane LVEF is equal to or greater than the predetermined biphasic plane LVEF threshold value, the resting LVOT-G is less than the predetermined resting LVOT-G threshold value, and the LVOT-G after Valsalva is equal to or greater than the predetermined LVOT-G threshold value after Valsalva. When any of the above is satisfied, the third daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is greater than the second daily dose of Compound 1 or a pharmaceutically acceptable salt thereof. The composition according to claim 40.

48. One or more components of the second echocardiogram include biphasic plane LVEF and LVOT-G after Valsalva. Here, the following conditions in the second echocardiogram: (1) The biphasic plane LVEF is equal to or greater than the predetermined biphasic plane LVEF threshold value and less than the second predetermined biphasic plane LVEF threshold value, or (2) The biphasic plane LVEF is equal to or greater than the second predetermined biphasic plane LVEF threshold value, and the LVOT-G after Valsalva is less than the second predetermined LVOT-G threshold value after Valsalva. When any of the above is satisfied, the third daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is the same as the second daily dose of Compound 1 or a pharmaceutically acceptable salt thereof. The composition according to claim 40.

49. One or more components of the second echocardiogram include biphasic plane LVEF and LVOT-G after Valsalva. Here, when the biphasic plane LVEF of the second echocardiogram exceeds the second predetermined biphasic plane LVEF threshold value and the LVOT-G after Valsalva of the second echocardiogram is equal to or greater than the second predetermined LVOT-G threshold value after Valsalva, the third daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is greater than the second daily dose of Compound 1 or a pharmaceutically acceptable salt thereof. The composition according to claim 40.

50. The first daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 5 mg of Compound 1. The second daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg of Compound 1. The third daily dose of the compound 1 or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, or about 15 mg of compound 1, The composition according to claim 40.

51. The composition according to claim 40, wherein the method further comprises measuring one or more components of the second echocardiogram.

52. The composition according to claim 40, wherein the third period is about two weeks.

53. The third daily dose of the compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient over the third period, The method is based on one or more components of the third echocardiogram of the patient obtained after the third period and the third daily dose of the compound or a pharmaceutically acceptable salt thereof, and a fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient over a fourth period, or further comprising terminating the administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient, the composition according to claim 40.

54. The composition according to claim 53, wherein the method comprises selecting a fourth daily dose of the compound 1 or a pharmaceutically acceptable salt thereof based on the one or more components of the third echocardiogram and the third daily dose.

55. The one or more components of the third echocardiogram are (a) Biphasic plane LVEF, (b) Post-Valsalva LVOT-G, (c) Resting LVOT-G, (d) Biphasic plane LVEF and post-Valsalva LVOT-G, or (e) Biphasic plane LVEF, post-Valsalva LVOT-G, and resting LVOT-G The composition according to claim 53, comprising.

56. The one or more components of the third echocardiogram include biphasic plane LVEF, When the biphasic plane LVEF of the third echocardiogram is below the predetermined biphasic plane LVEF threshold, the fourth daily dose of the compound 1 or a pharmaceutically acceptable salt thereof is lower than the third daily dose of the compound 1 or a pharmaceutically acceptable salt thereof, or the administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient is terminated, the composition according to claim 53.

57. If the biplane LVEF in the third echocardiogram is below the predetermined biplane LVEF threshold value, and the third daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is the same as or lower than the first daily dose of Compound 1 or a pharmaceutically acceptable salt thereof, the administration of Compound 1 or a pharmaceutically acceptable salt thereof to the patient is discontinued. The composition according to claim 53.

58. If the third daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is higher than the second daily dose of Compound 1 or a pharmaceutically acceptable salt thereof, and the biplane LVEF in the third echocardiogram is below the predetermined biplane LVEF threshold value, then the fourth daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is the same as the second daily dose of Compound 1 or a pharmaceutically acceptable salt thereof; or If the third daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is the same as the second daily dose of Compound 1 or a pharmaceutically acceptable salt thereof, and the biplane LVEF in the third echocardiogram is below the predetermined biplane LVEF threshold value, then the fourth daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is the same as the first daily dose of Compound 1 or a pharmaceutically acceptable salt thereof. The composition according to claim 53.

59. The one or more components of the third echocardiogram include biplane LVEF, resting LVOT-G, and post-Valsalva LVOT-G, wherein if the biplane LVEF in the third echocardiogram is greater than or equal to the predetermined biplane LVEF threshold value, the resting LVOT-G in the third echocardiogram is below the predetermined resting LVOT-G threshold value, and the post-Valsalva LVOT-G in the third echocardiogram is below the predetermined post-Valsalva LVOT-G threshold value, then the fourth daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is the same as the third daily dose of Compound 1 or a pharmaceutically acceptable salt thereof. The composition according to claim 53.

60. The one or more components of the third echocardiogram include biplane LVEF, resting LVOT-G, and post-Valsalva LVOT-G, wherein the following conditions in the third echocardiogram: (1) the biphasic plane LVEF is equal to or greater than the predetermined biphasic plane LVEF threshold value, and the resting LVOT-G is equal to or greater than the predetermined resting LVOT-G threshold value, or (2) the biphasic plane LVEF is equal to or greater than the predetermined biphasic plane LVEF threshold value, the resting LVOT-G is less than the predetermined resting LVOT-G threshold value, and the post-Valsalva LVOT-G is equal to or greater than the predetermined post-Valsalva LVOT-G threshold value, When either of the above is satisfied, the fourth daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is greater than the third daily dose of Compound 1 or a pharmaceutically acceptable salt thereof. The composition according to claim 53.

61. The one or more components of the third echocardiogram include biphasic plane LVEF and post-Valsalva LVOT-G, Here, the following conditions in the third echocardiogram: (1) the biphasic plane LVEF is equal to or greater than the predetermined biphasic plane LVEF threshold value and less than the second predetermined biphasic plane LVEF threshold value, or (2) the biphasic plane LVEF is equal to or greater than the second predetermined biphasic plane LVEF threshold value and the post-Valsalva LVOT-G is less than the second predetermined post-Valsalva LVOT-G threshold value, When either of the above is satisfied, the fourth daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is the same as the third daily dose of Compound 1 or a pharmaceutically acceptable salt thereof. The composition according to claim 53.

62. The one or more components of the third echocardiogram include biphasic plane LVEF and post-Valsalva LVOT-G, Here, when the biphasic plane LVEF of the third echocardiogram exceeds the second predetermined biphasic plane LVEF threshold value and the post-Valsalva LVOT-G of the third echocardiogram is equal to or greater than the second predetermined post-Valsalva LVOT-G threshold value, the fourth daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is greater than the third daily dose of Compound 1 or a pharmaceutically acceptable salt thereof. The composition according to claim 53.

63. The first daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 5 mg of Compound 1, The second daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg of Compound 1, The third daily dose of the compound 1 or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, or about 15 mg of compound 1, The fourth daily dose of the compound 1 or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, about 15 mg, or about 20 mg of compound 1, The composition according to claim 53.

64. The composition according to claim 53, wherein the method further comprises measuring the one or more components of the third echocardiogram.

65. The composition according to claim 53, wherein the fourth period is about two weeks.

66. (a) The predetermined biplane LVEF threshold is 50%; (b) The predetermined biplane LVEF threshold is 50%, the predetermined resting LVOT-G threshold is 30 mmHg, and the predetermined post-Valsalva LVOT-G threshold is 50 mmHg; or (c) The predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the second predetermined post-Valsalva LVOT-G threshold is 30 mmHg, The composition according to claim 29.

67. Before administration of compound 1 or a pharmaceutically acceptable salt thereof, the patient has (i) a resting LVOT-G of ≧ 50 mmHg; or (ii) a resting LVOT-G of ≧ 30 mmHg and < 50 mmHg with a post-Valsalva LVOT-G of ≧ 50 mmHg The composition according to any one of claims 1 to 66.

68. Before administration of compound 1 or a pharmaceutically acceptable salt thereof, the patient has a left ventricular ejection fraction (LVEF) of ≧ 60%. The composition according to any one of claims 1 to 66.

69. The composition according to any one of claims 1 to 66, wherein the patient is not administered disopyramide during treatment with compound 1 or a pharmaceutically acceptable salt thereof.

70. The composition according to any one of claims 1 to 66, wherein the patient is administered disopyramide during treatment with compound 1 or a pharmaceutically acceptable salt thereof.

71. The composition according to any one of claims 1 to 66, wherein the patient has not been treated with disopyramide or an antiarrhythmic drug having a negative inotropic effect within four weeks prior to treatment with compound 1 or a pharmaceutically acceptable salt thereof.

72. The composition according to any one of claims 1 to 66, wherein the patient is administered an antiarrhythmic agent during treatment with compound 1 or a pharmaceutically acceptable salt thereof.

73. The composition according to any one of claims 1 to 66, wherein the patient is a CYP2D6 poor metabolizer.

74. The composition according to any one of claims 1 to 66, wherein the patient is in a fasting state when administered compound 1 or a pharmaceutically acceptable salt thereof.

75. The composition according to any one of claims 1 to 66, wherein the patient is in a postprandial state when administered compound 1 or a pharmaceutically acceptable salt thereof.

76. The composition according to any one of claims 1 to 66, wherein the method does not include collecting a blood sample from the patient.

77. The composition according to any one of claims 1 to 66, wherein the method does not include analyzing a blood sample from the patient.

78. The composition according to any one of claims 1 to 66, wherein the patient is administered a beta blocker during treatment with compound 1 or a pharmaceutically acceptable salt thereof.

79. The composition according to any one of claims 1 to 66, wherein the method results in one or more of the following: improvement of mitral regurgitation, improvement of cardiac relaxation, beneficial cardiac remodeling, cardiac reverse remodeling, beneficial cardiac structural remodeling, beneficial cardiac functional remodeling, reversal of harmful cardiac remodeling, reduction of mean left ventricular myocardial mass index (LVMI), improvement of left ventricular (LV) filling pressure, reduction of left atrial volume index (LAVI), reduction of the categorical assessment of systolic anterior motion of the mitral valve leaflet, reduction of systolic anterior motion of the mitral valve leaflet, reduction of the frequency of eccentric mitral regurgitation, reduction of mitral regurgitation, reduction of lateral wall E / e', reduction of lateral wall E / E, reduction of brain natriuretic peptide (BNP), and reduction of the N-terminal prohormone of brain natriuretic peptide (NT-proBNP).

80. The composition according to any one of claims 1 to 66, wherein the method results in one or more of the following: improvement in exercise ability, improvement in maximum oxygen uptake, improvement in maximum oxygen uptake (pVO2) by cardiopulmonary exercise stress test (CPET), Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OSS), improvement in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in quality of life, improvement in quality of life measured by PRO questionnaire, improvement in one or more (multiple possible) classes of NYHA functional classification, improvement in left ventricular outflow tract gradient (LVOT-G) after Valsalva, and improvement in total workload during CPET.

81. wherein the method is (a) making the change amount from the baseline of pVO2 ≥ 1.5 mL / kg / min and improving the NYHA functional class by one or more (multiple possible) classes (b) making the change amount from the baseline of pVO2 ≥ 3.0 mL / kg / min and not worsening the NYHA functional class, the composition according to claim 80.

82. The composition according to claim 80, wherein the method improves KCCQ-OSS or KCCQ-CSS by at least 5 points, at least 10 points, or at least 20 points.

83. The composition according to claim 80, wherein the method makes the resting LVOT-G < 30 mmHg and the LVOT-G after Valsalva < 50 mmHg and improves the NYHA functional class by one or more (multiple possible) classes.

84. The composition according to any one of claims 1 to 66, wherein the method reduces myocardial injury in the patient.

85. (a) the daily dose is administered as a single daily dose, or (b) the daily dose is administered in two divided doses, characterized in that the composition according to any one of claims 1 to 66.

86. The composition according to any one of claims 1 to 66, wherein the administration of compound 1 or a pharmaceutically acceptable salt thereof has a sustained effect over at least 10 weeks, 12 weeks, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years.

87. The composition according to claim 79, wherein one or more of the results of the treatment occur within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks from the start of treatment with compound 1 or a pharmaceutically acceptable salt thereof.

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