Methods for treating non-obstructive hypertrophic cardiomyopathy

Abstract

Described herein are methods for treating non-obstructive hypertrophic cardiomyopathy or hypertrophic cardiomyopathy accompanied by ventricular midsection obstruction (MVO). The methods of treatment comprise the administration of a cardiac coaguloprotein inhibitor (CK-3773274, also known as CK-274 or aficotan) and may comprise the daily dose of titration administration based on a component of echocardiography. The daily dose may be increased, maintained, or decreased, or terminated based on the echocardiography.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 368,967 filed on July 20, 2022; U.S. Provisional Application No. 63 / 375,026 filed on September 8, 2022; U.S. Provisional Application No. 63 / 486,594 filed on February 23, 2023; U.S. Provisional Application No. 63 / 491,010 filed on March 17, 2023; U.S. Provisional Application No. 63 / 495,966 filed on April 13, 2023; and U.S. Provisional Application No. 63 / 501,088 filed on May 9, 2023; the contents of which are hereby incorporated by reference in their entirety for all purposes. Technical Field

[0003] The present disclosure relates to the treatment of non-obstructive hypertrophic cardiomyopathy or hypertrophic cardiomyopathy with mid-ventricular obstruction, and compounds and compositions useful for treating non-obstructive hypertrophic cardiomyopathy. Background Art

[0004] Hypertrophic cardiomyopathy (HCM) is a disease in which the heart muscle (myocardium) becomes abnormally thick (hypertrophy). The thickening of the heart muscle causes the interior of the left ventricle to become smaller and stiffer, and therefore the ventricle becomes less able to relax and fill with blood. 30% of HCM patients do not have left ventricular outflow tract (LVOT) obstruction either at rest or under physiological stimulation (i.e., Valsalva maneuver or exercise); these patients are classified as non-obstructive HCM (nHCM). Compared with patients with resting oHCM, nHCM patients have a similar risk of heart failure and all-cause mortality, but have a higher burden of life-threatening ventricular arrhythmias (sustained ventricular tachycardia or ventricular fibrillation) compared to patients with resting or underlying obstruction. Therefore, there is a need for therapies to address this condition. Summary of the invention

[0005] Methods and compositions for treating non-obstructive hypertrophic cardiomyopathy are described herein. Cardiac myosin inhibitor (CK-3773274, also known as CK-274 or aficontan) or a pharmaceutically acceptable salt thereof can be used to treat non-obstructive hypertrophic cardiomyopathy or hypertrophic cardiomyopathy with mid-ventricular obstruction. As further described herein, the daily dose of CK-274 can be titrated based on the results of an echocardiogram.

[0006] A method of treating non-obstructive hypertrophic cardiomyopathy (nHCM) or HCM with mid-ventricular obstruction (MVO, also referred to as "mid-cavity obstruction") in a patient in need thereof may include administering to the patient a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof is selected by titrating the daily dose of CK-274 or a pharmaceutically 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. Prior to titrating the daily dose, the daily dose may be administered to the patient at a constant amount for about two weeks.

[0007] In some implementations of the above methods, CK-274 or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 5 mg to about 20 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. As understood by those skilled in the art and described herein, unless otherwise indicated, an amount (e.g., in a dose) is the amount of CK-274 free base, or when a non-free base, such as a pharmaceutically acceptable salt, is administered, the corresponding amount of CK-274 free base.

[0008] In some implementations, the daily dose is administered as a single dose per day. In some implementations, the daily dose is administered in 2 divided doses.

[0009] In some embodiments, as described herein, methods, such as methods for treating non-obstructive hypertrophic cardiomyopathy (nHCM) or HCM with mid-ventricular obstruction (MVO) in patients in need, or methods for reducing the frequency of angina pectoris include administering a first daily dose of CK-274 or a pharmaceutically acceptable salt thereof to the patient in a first period, and administering a second daily dose of CK-274 or a pharmaceutically acceptable salt thereof to the patient in a second period. In some embodiments, the first daily dose and the second daily dose are different. In some embodiments, the second daily dose is lower than the first daily dose. In some embodiments, the second daily dose is higher than the first daily dose. In some embodiments, the second daily dose is the same as the first daily dose. In some embodiments, the method further includes administering a third daily dose in a third period described herein. In some embodiments, the method further includes administering a fourth daily dose in a fourth period described herein. Various techniques and criteria, such as the biplane LVEF component of an echocardiogram after a daily dose over a period of time, can be used to select the next daily dose. In some embodiments, the daily dose is about 15 mg CK-274 (e.g., as the third or fourth daily dose).

[0010] In some embodiments, a method for treating non-obstructive hypertrophic cardiomyopathy (nHCM) or HCM with mid-ventricular obstruction (MVO) in a patient in need thereof comprises: administering a first daily dose of CK-274 or a pharmaceutically acceptable salt thereof to the patient for a first period of time; and administering a second daily dose of CK-274 or a pharmaceutically acceptable salt thereof to the patient for a second period of time based on the biplane LVEF component of the first echocardiogram of the patient obtained after the first period of time, or terminating the administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient. The method may include selecting a second daily dose of CK-274 or a pharmaceutically acceptable salt thereof based on the biplane LVEF component of the first echocardiogram. In some embodiments of the methods described herein, the patient undergoes two or more echocardiograms within the first period of time, and the second daily dose is selected based on the combined results of the two or more echocardiograms obtained within the first period of time.

[0011] In some implementations of the above method, when the biplane LVEF of the first echocardiogram is lower than a predetermined biplane LVEF threshold, the administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient is terminated or interrupted. For example, the predetermined biplane LVEF threshold may be 50%. For example, the predetermined biplane LVEF threshold may be 40%.

[0012] In some implementations of the above method, when the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is lower than the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof. For example, the predetermined biplane LVEF threshold may be 50%.

[0013] In some implementations of the above methods, when the biplane LVEF of the first echocardiogram is within a predetermined biplane LVEF threshold, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof. In some embodiments, the predetermined biplane LVEF threshold is: biplane LVEF ≥ 50% and biplane LVEF < 55%. In some embodiments, the predetermined biplane LVEF threshold is: biplane LVEF ≥ 50% and biplane LVEF < 60%.

[0014] In some implementations of the above method, when the biplane LVEF of the first echocardiogram is equal to or above a predetermined biplane LVEF threshold, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is greater than the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof. In some embodiments, the predetermined biplane LVEF threshold is 55%. In some embodiments, the predetermined biplane LVEF threshold is 60%.

[0015] In some implementations of the above methods, the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg CK-274. In some embodiments, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg CK-274.

[0016] In some implementations of the above methods, the first period of time is about 2 weeks. In some embodiments, the second period of time is about 2 weeks.

[0017] In some implementations of the above methods, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient for the second period, and the method further comprises administering a third daily dose of CK-274 or a pharmaceutically acceptable salt thereof to the patient for the third period, or terminating the administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient, based on the biplane LVEF of the second echocardiogram of the patient obtained after the second period and the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises selecting a third daily dose of CK-274 or a pharmaceutically acceptable salt thereof based on the biplane LVEF of the second echocardiogram and the second daily dose. In some embodiments of the methods described herein, the patient undergoes two or more echocardiograms during the second period, and the third daily dose is selected based on the combined results of the two or more echocardiograms obtained during the second period.

[0018] In some embodiments of the above methods, when the biplane LVEF of the second echocardiogram is below a predetermined biplane LVEF threshold, the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is lower than the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof, or administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient is terminated. In some embodiments, the predetermined biplane LVEF threshold is 50%.

[0019] In some embodiments of the above methods, when the biplane LVEF of the second echocardiogram is below a predetermined biplane LVEF threshold and the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof, the administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient is terminated. In some embodiments, the predetermined biplane LVEF threshold is 50%. For example, if the method includes treating the patient with a first daily dose of about 5 mg CK-274 and a second daily dose of about 5 mg CK-274, and if the biplane LVEF of the second echocardiogram is below a biplane LVEF threshold of 50%, the administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient is terminated.

[0020] In some embodiments of the above methods, when the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is higher than the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof, and the biplane LVEF of the second echocardiogram is below a predetermined biplane LVEF threshold, the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof. In some embodiments, the predetermined biplane LVEF threshold is 50%. For example, if the method includes treating the patient with a first daily dose of about 5 mg CK-274 and a second daily dose of about 10 mg CK-274, and if the biplane LVEF of the second echocardiogram is below a biplane LVEF threshold of 50%, the third daily dose of CK-274 is restored to 5 mg CK-274.

[0021] In some embodiments of the above methods, when the biplane LVEF of the second echocardiogram is within a predetermined biplane LVEF threshold, the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof. In some embodiments, the predetermined biplane LVEF threshold is: biplane LVEF ≥ 50% and biplane LVEF < 55%. In some embodiments, the predetermined biplane LVEF threshold is: biplane LVEF ≥ 50% and biplane LVEF < 60%.

[0022] In some embodiments of the above methods, the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is greater than the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof when the biplane LVEF of the second echocardiogram is equal to or greater than a predetermined biplane LVEF threshold. In some embodiments, the predetermined biplane LVEF threshold is 55%. In some embodiments, the predetermined biplane LVEF threshold is 60%.

[0023] In some embodiments of the above methods, the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg CK-274, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg CK-274, and the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, or about 15 mg CK-274.

[0024] In some embodiments of the above method, the method further comprises measuring a second echocardiographic component.

[0025] In some embodiments of the above methods, the third period of time is about 2 weeks.

[0026] In some embodiments of the above methods, the third daily dose of CK-274 or a pharmaceutically 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 CK-274 or a pharmaceutically acceptable salt thereof to the patient for a fourth period of time, or terminating administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient, based on the component of the third echocardiogram of the patient obtained after the third period of time and the third daily dose of the compound or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises selecting a fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof based on the biplane LVEF of the third echocardiogram and the third daily dose. In some embodiments of the methods described herein, the patient undergoes two or more echocardiograms within the third period of time, and the fourth daily dose is selected based on the combined results of the two or more echocardiograms obtained within the third period of time.

[0027] In some embodiments of the above methods, when the biplane LVEF of the third echocardiogram is lower than a predetermined biplane LVEF threshold, the fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof is lower than the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof, or administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient is terminated.

[0028] In some embodiments, when the biplane LVEF of the third echocardiogram is below a predetermined biplane LVEF threshold and the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as or lower than the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof, administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient is terminated. In some embodiments, the predetermined biplane LVEF threshold is 50%.

[0029] In some embodiments of the above methods, when the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is higher than the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof, and the biplane LVEF of the third echocardiogram is equal to or higher than a predetermined biplane LVEF threshold, the fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof; or, when the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof, and the biplane LVEF of the third echocardiogram is equal to or higher than a predetermined biplane LVEF threshold, the fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof. In some embodiments, the predetermined biplane LVEF threshold is 50%.

[0030] In some embodiments of the above methods, the fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof is greater than the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof when the biplane LVEF of the third echocardiogram is equal to or greater than a predetermined biplane LVEF threshold. In some embodiments, the predetermined biplane LVEF threshold is 55%. In some embodiments, the predetermined biplane LVEF threshold is 60%.

[0031] In some embodiments of the above methods, the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg CK-274, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg CK-274, the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg or about 15 mg CK-274, and the fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg or about 15 mg CK-274.

[0032] In some embodiments, the daily dose is about 15 mg CK-274. In some embodiments, the third daily dose is about 15 mg CK-274. In some embodiments, the fourth daily dose is about 15 mg CK-274. In some embodiments, the daily dose is about 20 mg CK-274. In some embodiments, the fourth daily dose is about 20 mg CK-274. In some embodiments, the daily dose is administered in the form of tablets. In some embodiments, the amount of CK-274 (which can exist in a variety of forms (e.g., free form, pharmaceutically acceptable salt form, polymorph form, etc.)) in the tablet is about the daily dose described herein. In some embodiments, the amount of CK-274 in the tablet is about 5 mg. In some embodiments, the amount of CK-274 in the tablet is about 10 mg. In some embodiments, the amount of CK-274 in the tablet is about 15 mg. In some embodiments, the amount of CK-274 in the tablet is about 20 mg. In some embodiments, the amount of CK-274 in the tablet is about half of the daily dose described herein. In some embodiments, the amount of CK-274 in the tablet is about 2.5 mg. In some embodiments, the amount of CK-274 in the tablet is about 5 mg. In some embodiments, the amount of CK-274 in the tablet is about 7.5 mg. In some embodiments, the amount of CK-274 in the tablet is about 10 mg.

[0033] In some embodiments of the above methods, the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg CK-274, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg CK-274, the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, or about 15 mg CK-274, and the fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, about 15 mg, or about 20 mg CK-274.

[0034] In some embodiments of the above methods, the method further comprises measuring a biplane LVEF of a third echocardiogram.

[0035] In some embodiments of the above methods, the fourth period of time is about 2 weeks.

[0036] In some implementations, a method for treating non-obstructive hypertrophic cardiomyopathy (nHCM) or HCM with mid-ventricular obstruction (MVO) in a patient in need thereof comprises: administering a first daily dose of CK-274 or a pharmaceutically acceptable salt thereof to the patient for a first period of time; and based on a first echocardiogram of the patient obtained after the first period of time including a biplane LVEF, administering a second daily dose of CK-274 or a pharmaceutically acceptable salt thereof to the patient for a second period of time, or terminating administration of CK-274 to the patient, wherein: if the biplane LVEF of the first echocardiogram is less than a first predetermined biplane LVEF, the biplane LVEF of the patient is less than a first predetermined biplane LVEF of the patient. LVEF threshold, then terminate the administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient; if the biplane LVEF of the first echocardiogram is equal to or higher than the first predetermined biplane LVEF threshold and lower than the second predetermined biplane LVEF threshold, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof; and if the biplane LVEF of the first echocardiogram is equal to or higher than the second predetermined biplane LVEF threshold, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is greater than the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments of the above methods, the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg CK-274, and the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg CK-274.

[0038] In some embodiments of the above methods, the method further comprises measuring a biplane LVEF of the first echocardiogram.

[0039] In some embodiments of the above methods, the first period of time is about 2 weeks.

[0040] In some embodiments of the above methods, the second period of time is about 2 weeks.

[0041] In some embodiments of the above methods, a second daily dose of CK-274 or a pharmaceutically 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 CK-274 or a pharmaceutically acceptable salt thereof to the patient for a third period of time, or terminating administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient based on a second echocardiogram of the patient comprising a biplane LVEF obtained after the second period of time and the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof, wherein: if the biplane LVEF of the second echocardiogram is below a first predetermined biplane LVEF threshold and the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof, then administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient is terminated; if the second echocardiogram comprises a biplane LVEF, then administration of CK-274 or a pharmaceutically acceptable salt thereof is terminated; if the biplane LVEF of the second echocardiogram is lower than a first predetermined biplane LVEF threshold and the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is higher than the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof, the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is lower than the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof; if the biplane LVEF is equal to or higher than the first predetermined biplane LVEF threshold and lower than a second predetermined biplane LVEF threshold, the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof; and if the biplane LVEF of the second echocardiogram is higher than the second predetermined biplane LVEF threshold, the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is greater than the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments of the above methods, the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg CK-274, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg CK-274, and the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, or about 15 mg CK-274.

[0043] In some embodiments of the above methods, the method further comprises measuring a biplane LVEF of a second echocardiogram.

[0044] In some embodiments of the above methods, the third period of time is about 2 weeks.

[0045] In some embodiments of the above methods, a third daily dose of CK-274 or a pharmaceutically 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 CK-274 or a pharmaceutically acceptable salt thereof to the patient for a fourth period of time, or terminating administration of CK-274 to the patient based on a third echocardiogram of the patient obtained after the third period of time and comprising a biplane LVEF and a third dose of CK-274 or a pharmaceutically acceptable salt thereof, wherein: if the biplane LVEF of the third echocardiogram is below a first predetermined biplane LVEF threshold and the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof, then administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient is terminated; if the biplane LVEF of the third echocardiogram is below a first predetermined biplane LVEF threshold, then administration of CK-274 or a pharmaceutically acceptable salt thereof is terminated; If the biplane LVEF of the third echocardiogram is equal to or higher than the first predetermined biplane LVEF threshold and the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is higher than the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof, the fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof is lower than the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof; if the biplane LVEF is equal to or higher than the first predetermined biplane LVEF threshold and lower than the second predetermined biplane LVEF threshold, the fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof; and if the biplane LVEF of the third echocardiogram is equal to or higher than the second predetermined biplane LVEF threshold, the fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof is greater than the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof. In some embodiments, the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg CK-274, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg CK-274, the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, or about 15 mg CK-274, and the fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, about 15 mg, or about 20 mg CK-274. In some embodiments, the method further comprises measuring the biplane LVEF of the third echocardiogram. In some embodiments, the third period is about 2 weeks.

[0046] In some embodiments of the above methods, the first predetermined biplane LVEF threshold is 50%, and the second predetermined biplane LVEF threshold is 55%.

[0047] In some embodiments of the above methods, the first predetermined biplane LVEF threshold is 50%, and the second predetermined biplane LVEF threshold is 60%.

[0048] In some embodiments of any of the above methods, prior to administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient has end-diastolic left ventricular (LV) wall thickness of ≥15 mm in one or more myocardial segments. In some embodiments of any of the above methods, prior to administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient has end-diastolic left ventricular (LV) wall thickness of ≥13 mm in one or more wall segments and a known pathogenic gene mutation or a positive family history of HCM.

[0049] In some embodiments of any of the methods described above, prior to administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient has a resting and post-Valsalien maneuver LVOT-G of <30 mmHg.

[0050] In some embodiments of any of the above methods, prior to administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient has a resting LVOT-G of <30 mmHg. In some embodiments of any of the above methods, prior to administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient has a post-Valsalvarg LVOT-G of <50 mmHg. In some embodiments of any of the above methods, prior to administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient has a resting LVOT-G of <30 mmHg and a post-Valsalvarg LVOT-G of <50 mmHg.

[0051] In some embodiments of any of the methods described above, the patient has a KCCQ-CSS score of ≥30 and ≤85 prior to administration of CK-274 or a pharmaceutically acceptable salt thereof.

[0052] In some embodiments of any of the above methods, prior to the administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient has elevated NT-proBNP. In some such embodiments of any of the above methods, prior to the administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient has an NT-proBNP level of >300 pg / mL. In some such embodiments of any of the above methods, prior to the administration of CK-274 or a pharmaceutically acceptable salt thereof, if the patient suffers from atrial fibrillation or atrial flutter, the patient has an NT-proBNP level of ≥900 pg / mL. In some such embodiments of any of the above methods, prior to the administration of CK-274 or a pharmaceutically acceptable salt thereof, if the patient suffers from atrial fibrillation or atrial flutter, the patient has an NT-proBNP level of ≥225 pg / mL or an NT-proBNP level of ≥675 pg / mL.

[0053] In some embodiments of any of the methods described above, prior to administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient has a left ventricular ejection fraction (LVEF) of ≥ 60%.

[0054] In some embodiments of any of the methods described above, disopyramide is not administered to the patient during treatment with CK-274 or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments of any of the methods described above, the patient has not been treated with disopyramide or an antiarrhythmic drug with negative cardiotonic activity within 4 weeks prior to treatment with CK-274 or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments of any of the methods described above, the patient is a CYP2D6 poor metabolizer.

[0057] In some embodiments of any of the methods described above, the patient is fasting when administering CK-274 or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments of any of the methods described above, the patient is eating when CK-274 or a pharmaceutically acceptable salt thereof is administered.

[0059] In some embodiments of any of the methods described above, the method does not comprise collecting a blood sample from the patient.

[0060] In some embodiments of any of the methods described above, the method does not comprise analyzing a blood sample from the patient.

[0061] In some embodiments of any of the above methods, during treatment with CK-274 or a pharmaceutically acceptable salt thereof, a beta-blocker is administered to the patient. In some embodiments of any of the above methods, one or more of a beta-blocker, verapamil, diltiazem, and ranolazine is administered to the patient.

[0062] In some embodiments, the patient is obese. In some embodiments, the patient is not obese. In some embodiments, the patient has a body mass index (BMI) of 30 or greater. In some embodiments, the patient has a body mass index (BMI) of less than 30.

[0063] Also provided herein is a method of treating non-obstructive hypertrophic cardiomyopathy (nHCM) or HCM with midventricular obstruction (MVO) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments of any of the above methods, the method results in any one or more of the following: improved cardiac relaxation, beneficial cardiac remodeling, reverse cardiac remodeling, beneficial cardiac structural remodeling, beneficial cardiac functional remodeling, reversal of adverse cardiac remodeling, reduced mean left ventricular mass index (LVMI), improved left ventricular (LV) filling pressure, reduced left atrial volume index (LAVI), reduced category assessment of systolic anterior motion of the mitral leaflets, reduced systolic anterior motion of the mitral leaflets, reduced frequency of eccentric mitral regurgitation, reduced mitral regurgitation, reduced lateral E / e', reduced lateral E / E, reduced brain natriuretic peptide (BNP), and reduced N-terminal prohormone of brain natriuretic peptide (NT-proBNP).

[0065] In some embodiments, one or more results of the treatment occur within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks of initiating treatment with CK-274 or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments of any of the methods above, the patient has a reduced left ventricular mass index (LVMI).

[0067] In some embodiments of any of the methods described above, the patient has a reduced left artery volume index (LAVI).

[0068] In some embodiments of any of the methods described above, the patient's e' is reduced.

[0069] In some embodiments of any of the methods described above, the patient has a reduced lateral E / e'.

[0070] In some embodiments of any of the methods described above, the likelihood of systolic anterior motion of the mitral valve leaflets is reduced.

[0071] In some embodiments of any of the methods described above, the patient has reduced levels of brain natriuretic peptide or N-terminal prohormone of brain natriuretic peptide (NT-proBNP).

[0072] In some embodiments of any of the methods described above, the level of cardiac troponin I is reduced in the patient.

[0073] In some embodiments of any of the methods described above, the patient has reduced left ventricular wall stress.

[0074] In some embodiments of any of the methods described above, the patient has reduced myocardial damage.

[0075] In some embodiments of any of the above methods, the patient's heart failure symptoms are reduced, for example, the method can lower the patient's NYHA classification.

[0076] In some embodiments of any of the methods described above, the extent of mid-ventricular obstruction is reduced.

[0077] In some embodiments of any of the methods described above, the method produces a sustained effect of at least 10 weeks, 12 weeks, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years.

[0078] In some embodiments of any of the above methods, the second, third, or fourth period of administration 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 administration can indicate: administration until the patient no longer requires treatment; administration until there is no effect of further treatment; or administration until there is no reason for further treatment.

[0079] In some embodiments, the method results in a decrease in the patient's NYHA classification by one or more categories, and / or a decrease in NT-proBNP, and / or a decrease in troponin I (eg, cardiac troponin I) levels.

[0080] In some embodiments of any of the above methods, CK-274 or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, CK-274 or a pharmaceutically acceptable salt thereof is administered as a tablet. In some embodiments, the tablet comprises one or more carriers or excipients selected from the group consisting of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, the tablet comprises: (i) about 1% to about 50% by weight of CK-274 or a pharmaceutically acceptable salt thereof; (ii-1) about 10% to about 60% by weight of mannitol; (ii-2) about 5% to about 45% by weight of microcrystalline cellulose; (iii) about 0.1% to about 10% by weight of hydroxypropyl cellulose; (iv) about 1% to about 10% by weight of croscarmellose sodium; (v) about 0.1% to about 10% by weight of sodium lauryl sulfate; and vi) about 0.1% to about 10% by weight of magnesium stearate, wherein the weight % does not include the weight of the coating (if present). In some embodiments, CK-274 or a pharmaceutically acceptable salt thereof comprises one or more of polymorphic Form I, Form II, Form III, Form IV, Form V, and Form VI of CK-274. BRIEF DESCRIPTION OF THE DRAWINGS

[0081] Figure 1 An exemplary method for treating non-obstructive hypertrophic cardiomyopathy (nHCM) or HCM with mid-ventricular obstruction (MVO) in a patient comprising titrating a daily dose of CK-274 or a pharmaceutically acceptable salt thereof is illustrated.

[0082] Figure 2 A schematic overview of the Phase 1 clinical study of CK-274 (also known as aficontan) is shown. The study included a SAD cohort, a MAD cohort, a CYP2D6-PM cohort, and a food effect cohort. The MAD and CYP2D6-PM cohorts were initiated when a tolerated pharmacologically active dose (approximately 5% decrease in LVEF) was determined in the SAD cohort. The food effect cohort was initiated after the last SAD cohort was completed. The SAD 75-mg dose cohort met the criteria for stopping dose escalation, and the remaining patients in this cohort received 50 mg. Subsequently, the final SAD cohort was completed with 40 mg aficontan. CYP2D6-PM = cytochrome P450 2D6 poor metabolizer phenotype; d = day; LVEF = left ventricular ejection fraction; MAD = multiple ascending doses; qd = once a day; SAD = single ascending dose.

[0083] Figure 3A The mean (SE) maximum plasma concentrations (C ) of aficontan were shown to increase in a dose-proportional manner after single oral doses between 1 mg and 50 mg. 最大 ). Figure 3B The exposure of aficontan (AUC 24 )(B). AUC 24 = Area under the plasma drug concentration-time curve from 0 to 24 h; C 最大 = maximum plasma concentration; SE = standard error.

[0084] Figure 4 Plasma concentrations of aficontan over time for multiple doses according to an exemplary clinical trial are shown. Mean (SE) aficontan plasma concentrations are shown. Data points are offset for clarity. Aficontan plasma concentrations increased between the 5-mg dose and the 2 higher doses; however, as of day 2, there was no difference between the mean concentrations of the 7.5-mg and 10-mg doses. The clearance rates for the 5-mg and 10-mg doses were similar, and the cumulative ratios for all 3 doses were similar. For days 7, 8, 10, 11, 12, and 13, only trough measurements are shown. For the 5-mg and 10-mg cohorts, the dosing period was 14 days, and follow-up was 3 days. For the 7.5-mg cohort, dosing was extended to 17 days, and follow-up was 3 days, and steady state was confirmed to be reached after 10 to 12 days. SE = standard error.

[0085] Figure 5A The SAD cohort of an exemplary aficontin clinical trial is shown and Figure 5BThe MAD cohort of an exemplary aficontin clinical trial is shown. The mean (SE) change in LVEF from baseline is shown. Data points are offset for clarity. In the SAD and MAD cohorts, a decrease in LVEF within the target range was observed (5% to 15% decrease). In the SAD cohort, LVEF was generally slightly reduced, with an average maximum decrease of 5.8% (1.5h after dosing) in the 50-mg group. In the MAD cohort, the maximum mean decrease in LVEF from baseline occurred in the 10-mg group (with an average change of 5.0% 1.5h after dosing on Day 14). LVEF = left ventricular ejection fraction; MAD = multiple ascending doses; qd, once a day; SAD = single ascending dose; SE = standard error.

[0086] Fig. 6A An analysis of the SAD cohort from an exemplary clinical trial is shown and shows that there is a trend toward a decrease in LVEF with increasing plasma concentrations of aficontan. Figure 6B An analysis of the MAD cohort of an exemplary clinical trial is shown and shows minimal suppression of LVEF for most participants at plasma aficontan concentrations of ≤180 ng / ml. CI = confidence interval; LVEF = left ventricular ejection fraction; MAD = multiple ascending dose; SAD = single ascending dose.

[0087] Figure 7 The design of an exemplary clinical trial of CK-274 (Aficontan) is shown.

[0088] Figure 8 Shown is the design of an open-label extension of an exemplary clinical trial of CK-274 (Aficontan).

[0089] Fig. 9 Shown are the mean left ventricular ejection fractions of patients during the titration period of an exemplary clinical trial of aficontan (Example 2, interim results).

[0090] Fig.10 Shown are the dose levels achieved by patients at the end of the titration period of an exemplary clinical trial of aficontan (Example 2, interim results).

[0091] Fig.11 Shown are mean NT-proBNP levels of patients over time during an exemplary clinical trial of aficontan (Example 2, interim results).

[0092] Fig.12 Shown are mean hs-cTnI levels of patients over time during an exemplary clinical trial of aficontan (Example 2, interim results).

[0093] Fig.13The proportion of patients with each NYHA functional class over time during an exemplary clinical trial of aficontan is shown (Example 2, interim results).

[0094] Fig.14 Shown are the median KCCQ-CSS and SAQ-AF values ​​for patients over time during an exemplary clinical trial of aficontan (Example 2, interim results).

[0095] Fig.15 The proportion of patients with a change in category on the KCQ-CSS at week 10 in an exemplary clinical trial of aficontan is shown (Example 2, interim results).

[0096] Fig.16 The design of an exemplary clinical trial of aficontan is shown (Example 4).

[0097] Fig.17 The left ventricular ejection fraction of patients during the treatment period of an exemplary clinical trial of aficontan is shown (Example 2, second interim results).

[0098] Fig.18 Shown are the mean KCCQ-CSS of patients over time during an exemplary clinical trial of aficontan (Example 2, second interim results).

[0099] Fig.19 The proportion of patients with a change in category on the KCQ-CSS at week 10 in an exemplary clinical trial of aficontan is shown (Example 2, second interim results).

[0100] Fig. 20 The proportion of patients with each NYHA functional class over time during an exemplary clinical trial of aficontan is shown (Example 2, Second Interim Results).

[0101] Fig.21 Shown are the mean SAQ-AF of patients over time during an exemplary clinical trial of aficontan (Example 2, second interim results).

[0102] Fig. 22 The proportional changes in NT-proBNP levels and hs-cTnI levels of patients over time compared to baseline during an exemplary clinical trial of aficontan are shown (Example 2, second interim results).

[0103] Fig.23A A responder analysis of patients with a BMI <30 or >30 in an exemplary clinical trial of aficontan is shown (Example 2, second interim results).

[0104] Fig. 23BA responder analysis of patients treated with or without beta-blockers in an exemplary clinical trial of aficontan is shown (Example 2, second interim results).

[0105] Fig.23C A responder analysis of patients with elevated TnI or E / e'>13 or without elevated TnI or E / e' in an exemplary clinical trial of aficontan is shown (Example 2, second interim results).

[0106] Fig.23D A responder analysis of patients with or without a genetic or family history of HCM in an exemplary clinical trial of aficontan is shown (Example 2, second interim results).

[0107] Fig.24 It was shown that patients with mid-ventricular obstruction in an exemplary clinical trial of aficontan had reduced NT-proBNP and hs-troponin I levels and improved symptoms (Example 2, second interim results).

[0108] Fig.25 Shown are changes in Doppler measures of diastolic function in patients in an exemplary clinical trial of aficontan (Example 2, second interim results).

[0109] Fig.26A Experimental X-ray powder diffraction (XRPD) pattern of polymorph Form I of CK-274 is shown.

[0110] Fig.26B Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) graphs of polymorph Form I of CK-274 are shown.

[0111] Fig.26C A dynamic vapor sorption (DVS) graph of polymorph Form I of CK-274 is shown.

[0112] Fig.27A The experimental XRPD pattern of polymorph Form II of CK-274 is shown.

[0113] Fig.27B DSC and TGA graphs of polymorph Form II of CK-274 are shown.

[0114] Fig.28A Shown is an experimental XRPD pattern of a mixture of polymorphic Forms I and III of CK-274.

[0115] Fig.28B Shown are DSC and TGA graphs of a mixture of polymorphic Forms I and III of CK-274.

[0116] Fig.29AExperimental XRPD pattern of polymorph Form IV of CK-274 is shown.

[0117] Fig.29B Shown are DSC and TGA graphs of polymorph Form IV of CK-274.

[0118] Fig.30 The experimental XRPD pattern and two simulated patterns of polymorph Form V of CK-274 are shown (from top to bottom: simulated at 223 K; simulated at 273 K; experimental).

[0119] Fig.31A Two experimental XRPD patterns of polymorph Form VI of CK-274 are shown: (a) top, XRPD of Form VI taken before drying; and (b) bottom, after drying (oven, vacuum, 24 hours, 25°C).

[0120] Fig.31B and Fig.31C Shown is a TGA graph of polymorph Form VI of CK-274. Fig.31B The weight loss of an oven dried sample (oven, vacuum, overnight, 25°C) of Form VI is shown in the range of 25-300°C. Fig.31C TGA graph showing a sample of Form VI in the range of 25-300 °C which was oven dried (oven, vacuum, overnight, 25 °C) and further heated at 150 °C prior to thermogravimetric analysis.

[0121] Fig.31D and Fig.31E Shown is the DSC graph of polymorph Form VI of CK-274. Fig.31D Shown is a DSC trace of an oven dried sample (oven, vacuum, overnight, 25°C) of Form VI in the range of 25-300°C. Fig.31E DSC plot showing a sample of Form VI in the range of 25-300°C which was oven dried (oven, vacuum, overnight, 25°C) and further heated at 150°C prior to thermogravimetric analysis. DETAILED DESCRIPTION

[0122] Described herein are cardiac myosin inhibitors (CK-3773274, also referred to as CK-274 or aficontan) and various methods, for example, for treating non-obstructive hypertrophic cardiomyopathy or hypertrophic cardiomyopathy with mid-ventricular obstruction using cardiac myosin inhibitors. Therapeutic methods may include adjusting the dose based on the results of one or more biplane left ventricular ejection fraction (LVEF) measurements, for example, to increase, decrease, or maintain the dose. These measurements may be performed, for example, using echocardiography.

[0123] CK-3773274 (CK-274) is a small molecule cardiac myosin inhibitor having the structure shown below.

[0124]

[0125] 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. The small molecule inhibitor can be administered orally to a patient to treat non-obstructive hypertrophic cardiomyopathy (nHCM) or HCM with MVO, for example.

[0126] CK-274 has been described in WO 2019 / 144041, which is incorporated herein by reference. CK-274 or a pharmaceutically acceptable salt thereof can be obtained following the methods described therein. The CK-274 used in the disclosed methods may exist in the form of a pharmaceutically acceptable salt, solvate, hydrate, polymorph, or a combination thereof, and may be formulated into any suitable pharmaceutical formulation. CK-274 may also exist in its free base form. Polymorphs of CK-274 have been described in WO 2021 / 011807, which is incorporated herein by reference. Formulations of CK-274 have been described in WO 2021 / 011808, which is incorporated herein by reference. CK-274 is designed to reduce hypercontractility associated with hypertrophic cardiomyopathy (HCM). Without being limited by theory, in preclinical models, CK-274 reduces myocardial contractility by directly binding to cardiac myosin at a unique and selective binding site, thereby preventing myosin from entering a force-producing state. CK-274 reduces the number of active actin-myosin cross-bridges per cardiac cycle and thus reduces myocardial contractility. This mechanism of action may be therapeutically effective in disorders characterized by excessive hypercontractility (such as HCM, e.g., non-obstructive HCM, also known as nHCM; or HCM with MVO).

[0127] definition

[0128] As used in this specification, the following words and phrases are generally intended to have the meanings as set forth below, unless otherwise indicated in the context in which they are used.

[0129] Throughout this application, unless the context indicates otherwise, reference to CK-3773274, CK-274 or aphicontan includes its amorphous form or polymorphs thereof, including any of polymorphic forms I, II, III, IV, V or VI as described, or mixtures thereof.

[0130] References herein to "about" a value or parameter include (and describe) the value or parameter itself and any value or parameter that is 5% higher or 5% lower than the parameter. For example, description of "about X" includes description of "X" and "X + / - 5%".

[0131] "NYHA classification" or "NYHA class" refers to the New York Heart Association functional classification of heart failure symptoms. A description of each of NYHA classes I, II, III, and IV can be found in "Classes of Heart Failure", American Heart Association, http: / / www.heart.org / en / health-topics / heart-failure / what-is-heart-failure / classes-of-heart-failure, adapted from: 1) Dolgin M, Association NYH, Fox A C, Gorlin R, Levin RI, New York Heart Association. Criteria Committee. "Nomenclature and criteria for diagnosis of diseases of the heart and blood vessels", 9th ed., Boston, MA: Lippincott Williams and Wilkins; March 1, 1994; and 2) Criteria Committee, New York Heart Association, Inc. Diseases of the Heart and Blood Vessels. Nomenclature and Criteria for diagnosis, 6th ed., Boston, Little, Brown and Co. 1964, p. 114. Briefly, NYHA Class I indicates that the patient has no limitations in physical activity; ordinary physical activity does not cause undue fatigue, palpitations, dyspnea (shortness of breath). NYHA Class II indicates that the patient has mild limitations in physical activity; is comfortable at rest; ordinary physical activity causes fatigue, palpitations, dyspnea (shortness of breath). NYHA Class III indicates that the patient has significant limitations in physical activity; is comfortable at rest; less than ordinary physical activity causes fatigue, palpitations, or dyspnea. NYHA Class IV indicates that the patient cannot perform any physical activity comfortably; has symptoms of heart failure at rest; and discomfort increases if any physical activity is performed.

[0132] The term "pharmaceutically acceptable salt" refers to a salt of any compound herein that is known to be non-toxic and commonly used in the medical literature. In some embodiments, a pharmaceutically acceptable salt of a compound retains the biological effectiveness of the compound 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 using inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed using inorganic bases and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines, including naturally occurring substituted amines; cyclic amines; and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0133] If the compounds described herein are obtained in the form of acid addition salts, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the compound is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced according to conventional methods for preparing acid addition salts from base compounds by dissolving the free base in a suitable organic solvent and treating the solution with an acid (see, e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19). Those skilled in the art will recognize various synthetic methods that can be used to prepare pharmaceutically acceptable addition salts.

[0134] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in the pharmaceutical composition is contemplated. Supplementary active ingredients may also be incorporated into the pharmaceutical composition.

[0135] The terms "patient," "individual," and "subject" refer to animals, such as mammals. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows, and humans. In some embodiments, the patient or subject is a human, such as a human who has been or will become the subject of treatment, observation, or experiment. The compounds, compositions, and methods described herein can be used for both human therapy and veterinary applications.

[0136] 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 the treatment as defined herein when administered to a patient in need of treatment. A therapeutically effective amount of a compound may be an amount sufficient to treat a disease responsive to modulation of cardiac myotomes. The therapeutically effective amount will vary depending, for example, on the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the specific compound, the dosing regimen to be followed, the time of administration, 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 determined experimentally, for example by measuring the blood concentration of the chemical entity, or theoretically, by calculating the bioavailability.

[0137] "Treatment" (and related terms such as "treat," "treated," "treating") includes one or more of: inhibiting a disease or condition; slowing or preventing the development of clinical symptoms of a disease or condition; and / or alleviating a disease or condition (i.e., causing relief or regression from clinical symptoms). The term encompasses complete and partial reduction or prevention of a disease or condition and complete or partial reduction of clinical symptoms of a disease or condition. Thus, the compounds described and / or disclosed herein can prevent an existing disease or condition from worsening, help manage a disease or condition, or reduce or eliminate a disease or condition.

[0138] Reference to any dose of a compound described herein or a pharmaceutically acceptable salt thereof (eg, 5 mg, 10 mg, 20 mg, etc. of CK-274) refers to the amount of the compound without any salt (ie, equivalent mass).

[0139] Treatment of non-obstructive hypertrophic cardiomyopathy

[0140] As further described herein, a therapeutically effective amount of CK-274 may be administered to a patient to treat non-obstructive hypertrophic cardiomyopathy. CK-274 may be administered at a constant dose level. CK-274 may be administered at a titrated dose level. For example, the dose of CK-274 may be adjusted based on the patient's response to the drug. That is, the dose of CK-274 may be periodically increased, decreased, maintained, or suspended based on one or more of a measurement of drug response, such as a left ventricular biplane left ventricular ejection fraction (LVEF) measurement.

[0141] CK-274 is administered in a therapeutically effective dose (e.g., a dose sufficient to provide treatment for a disease state). For humans, the daily dose may be between about 1 mg and about 50 mg. For example, the daily dose may 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 may be, but is not limited to, administered every day, every other day, every week, every 2 weeks, every month, or at different intervals. In some embodiments, the administration period of the daily dose is between one day and a lifetime of the subject. 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 2, 3, or 4 divided doses. In some embodiments, the daily dose is administered in 2 divided doses.

[0142] In one example, the patient is treated for non-obstructive hypertrophic cardiomyopathy by administering to the patient a daily dose of about 5 mg to about 15 mg of CK-274. In one example, the patient is treated for non-obstructive 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 non-obstructive 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 non-obstructive 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 non-obstructive hypertrophic cardiomyopathy by administering to the patient a daily dose of about 20 mg of CK-274.

[0143] In some embodiments, a method for treating non-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 some embodiments, the non-obstructive hypertrophic cardiomyopathy is refractory non-obstructive hypertrophic cardiomyopathy. In some embodiments, a method for treating non-obstructive hypertrophic cardiomyopathy, refractory hypertrophic cardiomyopathy, or refractory non-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.

[0144] During the course of treatment of non-obstructive hypertrophic cardiomyopathy, the dosage of CK-274 administered to the patient can be titrated, for example, by increasing, reducing, maintaining or suspending the dosage. Titration can be performed once during treatment, or can be repeated at intervals of a period of time. For example, in some implementations, the dosage of CK-274 is titrated twice or more (e.g., 3 times, 4 times, 5 times or more) during the course of treatment. In some embodiments, before titrating the daily dose, a new daily dose is applied to the patient in a constant amount for about 1 week to about 8 weeks (or about 2 weeks to about 6 weeks, or about 4 weeks). In some embodiments, before titration, a new daily dose is applied to the patient in a constant amount for about 2 weeks. For example, the first daily dose can be applied to the patient before the first titration for about 2 weeks, wherein the daily dose is increased, reduced or maintained. Then a second titration can be performed about 2 weeks after the first titration. The titration of the dose allows the dose to be personalized for the patient's response to the drug, thereby maximizing the potential therapeutic effect of the patient.

[0145] Dose titration can be based on a biplane left ventricular ejection fraction (LVEF) measured in a patient. One or more measurements can be determined, for example, using an echocardiogram. The echocardiogram can be performed 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 performed about 2 hours after administration of the daily dose.

[0146] In some embodiments, the patient is administered an initial daily dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, or about 30 mg CK-274, or any amount therebetween. After a period of time (e.g., about 2 weeks), the biplane LVEF is measured by echocardiography, for example, after the administration of the dose (e.g., about 1-3 hours or about 2 hours after the administration of the dose). If the biplane LVEF is equal to or higher than a predetermined biplane LVEF threshold (e.g., about 40% or greater, about 45% or greater, about 50% or greater, about 55% or greater, or about 60% or greater), the daily dose is increased. In some embodiments, if the biplane LVEF is equal to or higher than a predetermined biplane LVEF threshold of about 55%, the daily dose is increased. In some embodiments, if the biplane LVEF is equal to or higher than a predetermined biplane LVEF threshold of about 60%, the daily dose is increased. If the biplane LVEF is lower than the biplane LVEF threshold, the dose may be reduced or terminated. In some embodiments, the biplane LVEF threshold is about 50%.

[0147] After a period of time (eg, about 2 weeks) of administering the first titrated dose to the patient, the dose may be again titrated (ie, increased, decreased, or maintained) or withheld based on the patient's biplane LVEF, eg, using the same threshold parameters as discussed above.

[0148] Provided herein is a method for treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient who is eligible for septal reduction therapy (SRT), comprising administering a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof to the patient. Also provided herein is a method for treating nHCM in a patient who needs SRT, comprising administering a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof to the patient, wherein the method does not require SRT in the patient. In some embodiments, the SRT is myectomy. In some embodiments, the SRT is alcohol septal ablation.

[0149] Further provided herein is a method for treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient with symptoms of heart failure, comprising administering to the patient a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, wherein the method can reduce symptoms of heart failure as assessed by NYHA classification. In some of the foregoing embodiments, the method improves the patient's heart failure symptoms by at least one NYHA category, for example, by one or two NYHA categories. In some of the foregoing embodiments, the method converts the patient from NYHA Class III to Class II or Class I. In some of the foregoing embodiments, the method converts the patient from NYHA Class III to Class II. In some of the foregoing embodiments, the method converts the patient from NYHA Class III to Class I. In some of the foregoing embodiments, the method converts the patient from NYHA Class III to Class I. In some of the foregoing embodiments, the method converts the patient from NYHA Class II to Class I. In some of the foregoing embodiments, the reduction in symptoms of heart failure occurs within 10 weeks of starting treatment with CK-274 or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, the titration of the daily dose of CK-274 or a pharmaceutically acceptable salt thereof is based on the results of the echocardiogram including the biplane LVEF. For example, based on the results of the biplane LVEF, the daily dose of CK-274 or a pharmaceutically acceptable salt thereof may be increased, maintained or decreased (or terminated, for example, if the subject has received the lowest (e.g., first) daily dose). The first daily dose of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient for a first period of time (e.g., about two weeks). The second daily dose of the subject is then selected based on the biplane LVEF of the patient obtained after the first period of time, or the administration of CK-274 or a pharmaceutically acceptable salt thereof is terminated. If the biplane LVEF of the echocardiogram is lower than the first predetermined biplane LVEF threshold (e.g., 50%) and the patient has received the lowest (e.g., first) daily dose, the administration of CK-274 or a pharmaceutically acceptable salt thereof may be terminated. If the biplane LVEF of the echocardiogram is lower than the first predetermined biplane LVEF threshold (e.g., 50%) and the patient has not yet received the lowest 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 above a first predetermined biplane threshold and below a second predetermined biplane LVEF threshold (e.g., 55%), 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 above a second predetermined biplane threshold, the daily dose may be increased (i.e., the second daily dose is greater than the first daily dose). In some embodiments, the second predetermined biplane LVEF threshold is 60%.

[0151] Based on the results of the second echocardiogram of the patient including the biplane LVEF obtained after the second period, before re-titration, the second daily dose is administered to the patient for a second period (e.g., about two weeks). (The second period may be, for example, 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). For example, the third daily dose may be selected based on the second echocardiogram and the second daily dose or the administration may be terminated, or the administration may be terminated. If the second daily dose is equal to (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 is lower than the first predetermined biplane LVEF threshold, administration may be terminated. If the second daily dose is higher than the first daily dose and the biplane LVEF of the second echocardiogram is lower than the first predetermined biplane LVEF threshold, the third daily dose may be reduced relative to the second daily dose, for example, reduced to the amount of the first daily dose. If the biplane LVEF is equal to or higher than the first predetermined biplane LVEF threshold and lower than the second predetermined biplane LVEF threshold, the daily dose can be maintained (i.e., the third daily dose is equal to the second daily dose). If the biplane LVEF of the second echocardiogram is higher than the second predetermined biplane LVEF threshold, the third daily dose can 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). The third period of time can be, for example, 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.

[0152] If necessary, the titration of the daily dose can be repeated for additional rounds to select the fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof or to terminate administration. For example, a third echocardiogram containing a biplane LVEF of the patient can be obtained after the third period, and the fourth daily dose of CK-274 or a pharmaceutically 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 lower than the first predetermined biplane LVEF threshold and the third daily dose is equal to (or lower than) the first daily dose, administration of CK-274 or a pharmaceutically acceptable salt thereof can be terminated. If the third daily dose is higher than the first daily dose and the biplane LVEF of the third echocardiogram is lower than the first predetermined biplane LVEF threshold, the fourth daily dose can be reduced relative to the third daily dose. If the biplane LVEF of the third echocardiogram is lower than the first predetermined biplane LVEF threshold and the third daily dose is equal to (or lower than) the first daily dose (e.g., if the third daily dose is the lowest dose), administration of CK-274 or a pharmaceutically acceptable salt thereof can be terminated. If the third daily dose is higher than the lowest (e.g., first) daily dose, and the biplane LVEF of the third echocardiogram is lower than the first predetermined biplane LVEF threshold, the fourth daily dose can be reduced relative to the third daily dose. If the biplane LVEF of the third echocardiogram is equal to or higher than the predetermined biplane LVEF threshold, the fourth daily dose may be the same as the third daily dose. If the biplane LVEF is equal to or higher than the first predetermined biplane LVEF threshold and lower than the second predetermined biplane LVEF threshold, the daily dose (i.e., the fourth daily dose is equal to the third daily dose) can be maintained. If the biplane LVEF of the second echocardiogram is higher than the second predetermined biplane LVEF threshold, the fourth daily dose can be increased relative to the third daily dose. Then the fourth daily dose is applied to the patient for a fourth period (e.g., two weeks). The fourth period may be, for example, 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.

[0153] Figure 1 An exemplary method for treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient comprising titrating the daily dose of CK-274 or a pharmaceutically acceptable salt thereof is illustrated. Figure 1The exemplary method shown in provides three daily dosage levels, wherein the first daily dosage level is the lowest daily dosage level, but can be easily modified to include additional or less dosage levels, or can be further modified so that the first daily dosage level is not the lowest daily dosage level. At 102, a first daily dosage level (e.g., about 5 mg) of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient. After the first period, at 104, the daily dosage level is increased or maintained, or administration is terminated. It can be selected based on the first echocardiogram obtained from the patient after the first period. If the biplane LVEF of the first echocardiogram is lower than a predetermined biplane LVEF threshold (e.g., 50%), it is possible to select to terminate administration 106, wherein another dose of CK-274 or a pharmaceutically acceptable salt thereof is no longer administered to the patient. When the biplane LVEF is equal to or higher than a predetermined biplane LVEF threshold (e.g., 50%) and lower than a second predetermined biplane LVEF threshold (e.g., 55%), it is possible to select to maintain the first daily dosage level (e.g., about 5 mg). If maintenance is selected, the first daily dose level of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient at 102 for a second period of time, and optionally, the daily dose may be re-titrated after the second period of time at 104. When the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold (e.g., 55%), the daily dose level may be increased to a second daily dose level (e.g., 10 mg). If an increase in the daily dose level is selected, the second daily dose level of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient at 108 for a second period of time.

[0154] If a second daily dose level of CK-274 or a pharmaceutically acceptable salt thereof (e.g., 10 mg) is administered to the patient at 108, the daily dose may be re-titrated (i.e., the daily dose may be selected to increase, decrease, or maintain) based on the echocardiogram at 110. If the biplane LVEF of the echocardiogram is below a predetermined biplane LVEF threshold (e.g., 50%), the daily dose may be reduced to the first daily dose level (e.g., 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. When the biplane LVEF is equal to or above a predetermined biplane LVEF threshold (e.g., 50%) and below a second predetermined biplane LVEF threshold (e.g., 55%), the second daily dose level (e.g., about 10 mg) may be selected to be maintained. If maintenance is selected, the second daily dose level of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient at 108 for an additional period of time, and optionally, the daily dose may be re-titrated at 110 after the period of time. When the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold (e.g., 55%), the daily dosage level may be increased to a third daily dosage level (e.g., 15 mg). If the daily dosage level is increased, then at 112, the second daily dosage level of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient for the period.

[0155] If the patient is administered a third daily dose level of CK-274 or a pharmaceutically acceptable salt thereof (e.g., 10 mg) at 112, the daily dose may be re-titrated (i.e., the daily dose may be selected to be reduced or maintained) based on the echocardiogram at 114. If the biplane LVEF of the echocardiogram is below a predetermined biplane LVEF threshold (e.g., 50%), the daily dose may be reduced to a second daily dose level (e.g., 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. When the biplane LVEF is equal to or above a predetermined biplane LVEF threshold (e.g., 50%), the third daily dose level (e.g., about 15 mg) may be selected to be maintained. If maintenance is selected, the patient is administered a third daily dose level of CK-274 or a pharmaceutically acceptable salt thereof at 112 for another period of time, and optionally, the daily dose may be re-titrated at 114 after the period of time.

[0156] exist Figure 1 In the exemplary method shown, the first daily dose level is the minimum dose and therefore cannot be further reduced. However, in other embodiments, if the biplane LVEF of the echocardiogram is below a predetermined biplane LVEF threshold (e.g., 50%), the first daily dose level may not be the minimum dose and therefore may be reduced to a lower dose level (e.g., 10 mg to 5 mg).

[0157] exist Figure 1In the exemplary method shown in , the third daily dosage level is the maximum dosage, and therefore cannot be further increased. However, in other embodiments, additional dosage levels can be obtained and the daily dosage at 114 can be further increased. Figure 1 In the method shown, at 114, a selection is made based on the echocardiogram to maintain the third daily dose level or reduce the daily dose level. If the biplane LVEF of the echocardiogram is lower than the predetermined biplane LVEF threshold (e.g., 50%), the daily dose may be reduced to the second daily dose level (e.g., 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. When the biplane LVEF is equal to or higher than the predetermined biplane LVEF threshold (e.g., 50%), the third daily dose level (e.g., about 15 mg) may be selected to be maintained. If maintenance is selected, the third daily dose level of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient at 112 for another period of time, and optionally, the daily dose may be re-titrated at 114 after the period of time. In embodiments where additional dose levels are available and the daily dose may be further increased at 114, if the biplane LVEF is equal to or higher than the second predetermined biplane LVEF threshold (e.g., 60%), the daily dose may be increased to the fourth daily dose level (e.g., about 20 mg).

[0158] Exemplary daily dose increases include an increase from about 5 mg to about 10 mg CK-274, or an increase from about 10 mg to about 15 mg CK-274. Other exemplary daily dose increases include an increase from about 5 mg to about 10 mg CK-274, an increase from about 10 mg to about 15 mg CK-274, or an increase from about 15 mg to about 20 mg CK-274. Other dose increases can be easily envisioned, for example, a given initial daily dose increase of 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 reductions include a decrease from about 15 mg to about 10 mg, or a decrease from about 10 mg to about 5 mg. Other exemplary daily dose reductions include a decrease from about 20 mg to about 15 mg, a decrease from about 15 mg to about 10 mg, or a decrease from about 10 mg to about 5 mg. Other dosage reductions can be readily envisioned, for example, a given initial daily dosage reduction by about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 10 mg, or any amount therebetween.

[0159] Exemplary embodiments of the methods described herein include administering a first daily dose or dose 1 (e.g., a first daily dose of between about 1 mg and 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) of CK-274, or a pharmaceutically acceptable salt thereof, 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 administration of a first daily dose or dose 1 (e.g., a first daily dose of between about 1 mg and 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, 12 weeks, or any length of time therebetween) of CK-274, or a pharmaceutically acceptable salt thereof, 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) based on the patient's The biplane LVEF is maintained at a daily dose, reduced (e.g., the daily dose is reduced by about 1 mg to about 10 mg, for example, the daily dose is reduced 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), increased (e.g., the daily dose is increased by about 1 mg to about 10 mg, for example, the daily dose is increased 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 administration is terminated to reach a second daily dose. Another exemplary embodiment of the methods described herein comprises administering a first daily dose of CK-274 or a pharmaceutically acceptable salt thereof for about two weeks, followed by maintaining the daily dose, reducing the daily dose by about 5 mg, increasing the daily dose by about 5 mg, or administration is terminated based on the patient's biplane LVEF to reach a second daily dose. Another exemplary embodiment of the methods described herein includes administering a first daily dose of CK-274 or a pharmaceutically acceptable salt thereof for about three weeks, followed by maintaining the daily dose based on the patient's biplane LVEF, reducing the daily dose by about 5 mg, increasing the daily dose by about 5 mg, or terminating administration to reach a second daily dose. Another exemplary embodiment of the methods described herein includes administering a first daily dose of CK-274 or a pharmaceutically acceptable salt thereof for about two weeks, followed by maintaining the daily dose based on the patient's biplane LVEF, reducing the daily dose by about 10 mg, increasing the daily dose by about 10 mg, or terminating administration to reach a second daily dose. Another exemplary embodiment of the methods described herein includes administering a first daily dose of CK-274 or a pharmaceutically acceptable salt thereof for about three weeks, followed by maintaining the daily dose based on the patient's biplane LVEF, reducing the daily dose by about 10 mg, increasing the daily dose by about 10 mg, or terminating administration to reach a second daily dose. Another exemplary embodiment of the methods described herein comprises administering a first daily dose of CK-274, or a pharmaceutically acceptable salt thereof, for about 2 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 terminating administration based on the patient's biplane LVEF to achieve a second daily dose.

[0160] Treatment of non-obstructive hypertrophic cardiomyopathy can improve the exercise capacity and / or alleviate the symptoms of patients with hyperdynamic ventricular contraction caused by non-obstructive hypertrophic cardiomyopathy. In some embodiments, the method includes administering a therapeutically effective daily dose of CK-274 or a pharmaceutically acceptable salt thereof to an individual suffering from non-obstructive hypertrophic cardiomyopathy, thereby improving the individual's exercise capacity. In some embodiments, exercise capacity can be measured by one or more cardiopulmonary exercise test (CPET) parameters, or a combination of one or more CPET parameters. In some embodiments, exercise capacity can be measured by peak oxygen uptake (pVO2) (maximum exercise capacity) and / or minute ventilation / carbon dioxide production (VE / VCO2) slope (submaximal exercise capacity). In some embodiments, the method includes administering a therapeutically effective daily dose of CK-274 or a pharmaceutically acceptable salt thereof to an individual suffering from non-obstructive hypertrophic cardiomyopathy, thereby producing a pVO2 change of ≥1.0 mL / kg / min compared to baseline, and the individual's NYHA functional class is improved by ≥1 class. 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 non-obstructive hypertrophic cardiomyopathy, thereby producing a change in pVO2 of ≥2.0 mL / kg / min compared to baseline, and no worsening of NYHA functional class. 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 non-obstructive hypertrophic cardiomyopathy, thereby alleviating one or more symptoms of hyperdynamic ventricular contraction.

[0161] In some embodiments, a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof is administered to a patient with non-obstructive hypertrophic cardiomyopathy to treat non-obstructive hypertrophic cardiomyopathy, wherein a biplane LVEF is maintained at or above 50%. In some embodiments, in response to the administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, the biplane LVEF decreases by less than about 20%, less than about 15%, less than about 10%, or less than about 5%. The maintenance interval of the biplane LVEF may 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 of daily dose administration.

[0162] In some embodiments, a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof is administered to a patient with non-obstructive hypertrophic cardiomyopathy, thereby reducing the patient's left ventricular mass index (LVMI). In response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, the LVMI may be reduced by about 1 g / m 2 or larger, about 1.5g / m 2 or larger, about 2g / m 2or larger, about 2.5g / m 2 or larger, about 3g / m 2 or larger, about 3.5g / m 2 or larger, or about 4g / m 2 In some embodiments, in response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, LVMI is reduced by about 1 g / m 2 About 10g / m 2 mmHg, for example, a decrease of about 1 g / m 2 About 6g / m 2 , or about 2g / m 2 About 5g / m 2 The reduction in LVMI can occur after about 1 week, after about 2 weeks, after about 3 weeks, after about 4 weeks, after about 5 weeks, after about 6 weeks, after about 8 weeks, or after about 10 weeks of daily dose administration.

[0163] In some embodiments, a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof is administered to a patient with non-obstructive hypertrophic cardiomyopathy, thereby reducing the patient's left arterial volume index (LAVI). In response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, LAVI may be reduced by about 0.5 mL / m 2 or greater, about 1 mL / m 2 or greater, about 1.5 mL / m 2 or greater, about 2 mL / m 2 or greater, or about 2.5 mL / m 2 In some embodiments, in response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, LAVI is reduced by about 0.5 mL / m 2 To about 5mL / m 2 mmHg, for example, a decrease of about 0.5 mL / m 2 About 4g / m 2 , or about 1 mL / m 2 To about 3mL / m 2 The reduction in LAVI can occur after 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 of daily dose administration.

[0164] In some embodiments, a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof is administered to a patient with non-obstructive hypertrophic cardiomyopathy, thereby reducing the patient's e' value. In response to the administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, the e' value may be reduced by about 0.1 cm / s or greater, about 0.15 cm / s or greater, about 0.2 cm / s or greater, or about 0.25 cm / s or greater. In some embodiments, in response to the administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, the e' value is reduced by about 0.05 cm / s to about 0.3 cm / s, for example, by about 0.1 cm / s to about 0.25 cm / s, or about 0.15 cm / s to about 0.25 cm / s. The reduction in the e' value may occur after 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 of daily dose administration.

[0165] In some embodiments, a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof is administered to a patient suffering from non-obstructive hypertrophic cardiomyopathy, thereby reducing the patient's lateral E / e' ratio. In response to the administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, the lateral E / e' ratio may be reduced 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 the administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, the lateral E / e' ratio is reduced by about 0.5 to about 2, for example, by about 1 to about 1.8, or by about 1.5 to about 1.8. The reduction in the lateral E / e' ratio may occur after 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 of daily dose administration.

[0166] In some embodiments, a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof is administered to a patient suffering from non-obstructive hypertrophic cardiomyopathy, thereby reducing the likelihood of systolic anterior motion (SAM) of the patient's mitral valve leaflets.

[0167] In some embodiments, a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof is administered to a patient with non-obstructive hypertrophic cardiomyopathy, thereby reducing the level of brain natriuretic peptide or N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in the patient. The reduction in the level of brain natriuretic peptide or N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in the patient may occur after 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 of daily dose administration.

[0168] In some embodiments, a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof is administered to a patient with non-obstructive hypertrophic cardiomyopathy, thereby reducing the level of cardiac troponin I. The reduction in the level of cardiac troponin I in the patient can occur after 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 of daily dose administration.

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

[0170] In some embodiments of any of the methods disclosed herein, the method results in a decrease in the NYHA classification of the patient by one or more categories, and / or a decrease in NT-proBNP, and / or a decrease in the level of troponin I (e.g., cardiac troponin I). In some embodiments, the method results in a decrease in the NYHA classification of the patient by one or more categories, or a decrease in NT-proBNP, or a decrease in the level of troponin I (e.g., cardiac troponin I). In some embodiments, the method results in a decrease in the NYHA classification of the patient by one or more categories, and a decrease in NT-proBNP. In some embodiments, the method results in a decrease in the NYHA classification of the patient by one or more categories, and a decrease in NT-proBNP. In some embodiments, the method results in a decrease in the NYHA classification of the patient by one or more categories, and a decrease in the level of troponin I (e.g., cardiac troponin I). In some embodiments, the method results in a decrease in NT-proBNP and a decrease in the level of troponin I (e.g., cardiac troponin I). In some embodiments, the method results in a decrease in the NYHA classification of the patient by one or more categories, a decrease in NT-proBNP, and a decrease in the level of troponin I (e.g., cardiac troponin I).

[0171] In some embodiments of any of the foregoing, administration of CK-274 or a pharmaceutically acceptable salt thereof to a patient with non-obstructive hypertrophic cardiomyopathy further reduces left ventricular wall stress and / or reduces myocardial damage in the patient. The reduction in left ventricular wall stress and / or reduction in myocardial damage in the patient may occur after 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 of daily dose administration.

[0172] In some embodiments of any of the foregoing, administration of CK-274 or a pharmaceutically acceptable salt thereof to a patient with non-obstructive hypertrophic cardiomyopathy may improve the patient's health status. In some embodiments of any of the foregoing, administration of CK-274 or a pharmaceutically acceptable salt thereof to a patient with hypertrophic cardiomyopathy may improve the patient's health status, as determined by changes in the Short Form 36 Physical Function Subscale (SF-36-PFS). In some embodiments of any of the foregoing, administration of CK-274 or a pharmaceutically acceptable salt thereof to a patient with hypertrophic cardiomyopathy may improve the patient's health status, as determined by changes in the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS). In some embodiments, administration of CK-274 or a pharmaceutically acceptable salt thereof to a patient with hypertrophic cardiomyopathy may improve KCCQ-CSS by 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 pharmaceutically acceptable salt thereof to a patient with hypertrophic cardiomyopathy may improve patient health status and health-related quality of life as measured by the PRO questionnaire, as determined by changes in responses to the EuroQol 5 Dimensions 5 Levels Instrument (EQ-5D-5L). In some embodiments of any of the foregoing, administration of CK-274 or a pharmaceutically acceptable salt thereof to a patient with hypertrophic cardiomyopathy may improve patient health status as determined by changes in the Seattle Angina Questionnaire-Angina Frequency (SAQ-AF). In some embodiments of any of the foregoing, administration of CK-274 or a pharmaceutically acceptable salt thereof to a patient with hypertrophic cardiomyopathy may improve patient health status as determined by changes in the Seattle Angina Questionnaire-7 (SAQ-7).

[0173] In some embodiments, administration of CK-274 or a pharmaceutically acceptable salt thereof to a patient with non-obstructive hypertrophic cardiomyopathy produces a sustained effect of 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 pharmaceutically acceptable salt thereof to a patient with non-obstructive hypertrophic cardiomyopathy produces a sustained effect of at least 6 months. In some embodiments, administration of CK-274 or a pharmaceutically acceptable salt thereof to a patient with hypertrophic cardiomyopathy produces a sustained effect of at least 1 year. In some embodiments, administration of CK-274 or a pharmaceutically acceptable salt thereof to a patient with non-obstructive hypertrophic cardiomyopathy produces a sustained effect of at least 5 years.

[0174] The administration of the compounds and compositions disclosed and / or described herein can be via any accepted mode of administration of the therapeutic agent, 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 compound or composition is administered orally or intravenously. In some embodiments, the compound or composition disclosed and / or described herein is administered orally.

[0175] Pharmaceutically acceptable compositions include solid, semisolid, liquid and aerosol dosage forms, such as tablets, capsules, powders, liquids, suspensions, suppositories and aerosol forms. The compounds disclosed and / or described herein can also be administered in the following forms: sustained or controlled release dosage forms (e.g., controlled / sustained release pills, depot injections, osmotic pumps or transdermal (including electrotransport) patch forms) for extended administration, and / or pulse administration at a predetermined rate. In some embodiments, the composition is provided in a unit dosage form suitable for single administration of a precise dose.

[0176] CK-274 can be administered alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, cross-linked sodium carboxymethyl cellulose, glucose, gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical composition may also contain a small amount of non-toxic auxiliary substances, such as wetting agents, emulsifiers, solubilizers, pH buffers, etc. (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate). Typically, depending on the intended mode of administration, the pharmaceutical composition will contain about 0.005% to 95% by weight, or about 0.5% to 50% by weight of the compounds disclosed and / or described herein. Actual methods for preparing such dosage forms are known or will be apparent to those skilled in the art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania. Suitable formulations of CK-274 have been described in WO 2021 / 011808, which is incorporated herein by reference in its entirety.

[0177] In some embodiments, CK-274 is provided in a formulation comprising: (i) CK-274 or a pharmaceutically acceptable salt thereof; (ii) a filler; (iii) a binder; (iv) a disintegrant; (v) a surfactant; and (vi) a lubricant. In some embodiments, CK-274 is provided in a formulation comprising: (i) CK-274; (ii) a filler; (iii) a binder; (iv) a disintegrant; (v) a surfactant; and (vi) a lubricant.

[0178] In some embodiments, the filler is selected from the group consisting of powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, kaolin, corn starch, maize starch, starch derivatives, pregelatinized starch, calcium phosphate, dibasic calcium phosphate, dicalcium phosphate, tricalcium phosphate, compressible sugars, sugar alcohols, mannitol, sorbitol, maltitol, xylitol, lactitol, lactose, dextrose, maltose, sucrose, glucose, fructose, sucrose, raffinose, dextrates, trehalose, maltodextrin, and mixtures of any of the foregoing.

[0179] In some embodiments, the binder is selected from the group consisting of gum arabic, gum acacia, alginates, alginic acid, corn starch, copovidone, polyvinyl pyrrolidone, gelatin, glyceryl behenate, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, methyl cellulose, hydroxypropyl methyl cellulose, lactose, polyvinyl alcohol, povidone, polyethylene oxide, polyacrylate, potato starch, pregelatinized starch, sodium alginate, sodium starch, sodium carboxymethyl cellulose, starch, and a mixture of any of the foregoing.

[0180] In some embodiments, the disintegrant is selected from the group consisting of alginic acid, cross-linked sodium carboxymethylcellulose, cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, cross-linked polyvidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, polacrilin potassium, pregelatinized starch, partially hydrolyzed starch, sodium carboxymethyl starch, starch, sodium alginate, sodium carboxymethyl cellulose, and a mixture of any of the foregoing.

[0181] In some embodiments, the surfactant is selected from the group consisting of cetylpyridinium chloride, heptadecaethyleneoxycetanol, lecithin, polyoxyethylene stearate, nonoxynol 9, nonoxynol 10, octoxynol 9, sorbitan fatty acid esters, Span 20, Span 40, Span 60, Span 80, Span 85, polysorbate, polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, sodium salt of fatty alcohol sulfate, sodium lauryl sulfate, sodium salt of sulfosuccinic acid, dioctyl sodium sulfosuccinate, partial esters of fatty acids and alcohols, glyceryl monostearate, glyceryl monooleate, ethers of fatty alcohols and polyoxyethylene, esters of fatty acids and polyoxyethylene, copolymers of ethylene oxide and propylene oxide Benzalkonium chloride, ethoxylated triglycerides, and mixtures of any of the foregoing.

[0182] In some embodiments, the lubricant is selected from the group consisting of hydrogenated castor oil, magnesium stearate, glyceryl monostearate, calcium stearate, glyceryl behenate, glyceryl distearate, glyceryl dipalmitostearate, behenyl polyoxyl-8 glyceride, sodium stearyl fumarate, stearic acid, talc, zinc stearate, mineral oil, polyethylene glycol, poloxamer, sodium lauryl sulfate, and mixtures of any of the foregoing.

[0183] In some embodiments, the formulation comprises: (i) about 1 weight % to about 80 weight % of CK-274 or a pharmaceutically acceptable salt thereof; (ii) about 15 weight % to about 90 weight % of a filler; (iii) about 0.1 weight % to about 10 weight % of a binder; (iv) about 1 weight % to about 10 weight % of a disintegrant; (v) about 0.1 weight % to about 10 weight % of a surfactant; and (vi) about 0.1 weight % to about 10 weight % of a lubricant.

[0184] In some embodiments, the formulation comprises: (i) about 1 weight % to about 50 weight % of CK-274 or a pharmaceutically acceptable salt thereof; (ii) about 40 weight % to about 80 weight % of a filler; (iii) about 0.5 weight % to about 5 weight % of a binder; (iv) about 2 weight % to about 8 weight % of a disintegrant; (v) about 0.5 weight % to about 5 weight % of a surfactant; and (vi) about 0.5 weight % to about 5 weight % of a lubricant.

[0185] In some embodiments, the formulation comprises: (i) about 10% to about 30% by weight of CK-274 or a pharmaceutically acceptable salt thereof; (ii) about 60% to about 80% by weight of a filler; (iii) about 1% to about 3% by weight of a binder; (iv) about 4% to about 6% by weight of a disintegrant; (v) about 1% to about 3% by weight of a surfactant; and (vi) about 0.5% to about 1.5% by weight of a lubricant.

[0186] In some embodiments, the formulation comprises: (i) about 1 weight % to about 10 weight % of CK-274 or a pharmaceutically acceptable salt thereof; (ii) about 70 weight % to about 90 weight % of a filler; (iii) about 1 weight % to about 3 weight % of a binder; (iv) about 4 weight % to about 6 weight % of a disintegrant; (v) about 1 weight % to about 3 weight % of a surfactant; and (vi) about 0.5 weight % to about 1.5 weight % of a lubricant.

[0187] In some embodiments, the formulation comprises: (i) about 5 weight % CK-274 or a pharmaceutically acceptable salt thereof; (ii) about 85 weight % filler; (iii) about 2 weight % binder; (iv) about 5 weight % disintegrant; (v) about 2 weight % surfactant; and (vi) about 1 weight % lubricant.

[0188] In some embodiments, the formulation comprises: (i) about 10 weight % CK-274 or a pharmaceutically acceptable salt thereof; (ii) about 80 weight % filler; (iii) about 2 weight % binder; (iv) about 5 weight % disintegrant; (v) about 2 weight % surfactant; and (vi) about 1 weight % lubricant.

[0189] In some embodiments, the formulation comprises: (i) about 1 weight % to about 50 weight % of CK-274 or a pharmaceutically acceptable salt thereof; (ii-1) about 10 weight % to about 60 weight % of mannitol; (ii-2) about 5 weight % to about 45 weight % of microcrystalline cellulose; (iii) about 0.1 weight % to about 10 weight % of hydroxypropyl cellulose; (iv) about 1 weight % to about 10 weight % of cross-linked sodium carboxymethyl cellulose; (v) about 0.1 weight % to about 10 weight % of sodium lauryl sulfate; and (vi) about 0.1 weight % to about 10 weight % of magnesium stearate.

[0190] In some embodiments, the formulation comprises: (i) about 10% to about 30% by weight of CK-274 or a pharmaceutically acceptable salt thereof; (ii-1) about 40% to about 50% by weight of mannitol; (ii-2) about 20% to about 30% by weight of microcrystalline cellulose; (iii) about 1% to about 3% by weight of hydroxypropyl cellulose; (iv) about 4% to about 6% by weight of cross-linked sodium carboxymethyl cellulose; (v) about 1% to about 3% by weight of sodium lauryl sulfate; and (vi) about 0.5% to about 1.5% by weight of magnesium stearate.

[0191] In some embodiments, the formulation comprises: (i) about 1 weight % to about 10 weight % of CK-274 or a pharmaceutically acceptable salt thereof; (ii-1) about 50 weight % to about 60 weight % of mannitol; (ii-2) about 25 weight % to about 35 weight % of microcrystalline cellulose; (iii) about 1 weight % to about 3 weight % of hydroxypropyl cellulose; (iv) about 4 weight % to about 6 weight % of cross-linked sodium carboxymethyl cellulose; (v) about 1 weight % to about 3 weight % of sodium lauryl sulfate; and (vi) about 0.5 weight % to about 1.5 weight % of magnesium stearate.

[0192] In some embodiments, the formulation comprises: (i) about 20 weight % CK-274 or a pharmaceutically acceptable salt thereof; (ii-1) about 44 weight % mannitol; (ii-2) about 26 weight % microcrystalline cellulose; (iii) about 2 weight % hydroxypropyl cellulose; (iv) about 5 weight % cross-linked sodium carboxymethyl cellulose; (v) about 2 weight % sodium lauryl sulfate; and (vi) about 1 weight % magnesium stearate.

[0193] In some embodiments, the formulation comprises: (i) about 10 weight % CK-274 or a pharmaceutically acceptable salt thereof; (ii-1) about 50 weight % mannitol; (ii-2) about 30 weight % microcrystalline cellulose; (iii) about 2 weight % hydroxypropyl cellulose; (iv) about 5 weight % cross-linked sodium carboxymethyl cellulose; (v) about 2 weight % sodium lauryl sulfate; and (vi) about 1 weight % magnesium stearate.

[0194] In some embodiments, the formulation comprises: (i) about 5 weight % CK-274 or a pharmaceutically acceptable salt thereof; (ii-1) about 54 weight % mannitol; (ii-2) about 31 weight % microcrystalline cellulose; (iii) about 2 weight % hydroxypropyl cellulose; (iv) about 5 weight % cross-linked sodium carboxymethyl cellulose; (v) about 2 weight % sodium lauryl sulfate; and (vi) about 1 weight % magnesium stearate.

[0195] In some embodiments, the aforementioned formulations are in tablet form. In some embodiments, the tablet further comprises a coating (e.g., a film coating as described elsewhere herein). In such embodiments, the weight percentages herein are provided relative to the core tablet, excluding the weight of the coating.

[0196] In some embodiments, CK-274 or a pharmaceutical composition containing CK-274 will take 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, acacia gum, polyvinyl pyrrolidine, gelatin, cellulose, cellulose derivatives) and a compound disclosed and / or described herein. Other solid dosage forms include powders, pellets (marume), solutions or suspensions (e.g., in propylene carbonate, vegetable oils, or triglycerides) encapsulated in gelatin capsules.

[0197] In some embodiments, CK-274 is provided in the form of a tablet comprising: (i) a core, the total weight of which comprises: (a) an intragranular component comprising: (ai) CK-274 or a pharmaceutically acceptable salt thereof; (a-ii) an intragranular filler; (a-iii) an intragranular binder; (a-iv) an intragranular disintegrant; and (av) an intragranular surfactant; and (b) an extragranular component comprising: (bi) an extragranular filler; (b-ii) an extragranular disintegrant; and (b-iii) an extragranular lubricant; and optionally (ii) a coating layer comprising a coating agent.

[0198] In some embodiments, the intragranular filler is selected from the group consisting of powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, kaolin, corn starch, maize starch, starch derivatives, pregelatinized starch, calcium phosphate, dibasic calcium phosphate, dicalcium phosphate, tricalcium phosphate, compressible sugars, sugar alcohols, mannitol, sorbitol, maltitol, xylitol, lactitol, lactose, dextrose, maltose, sucrose, glucose, fructose, sucrose, raffinose, dextrose binders, trehalose, maltodextrin, and mixtures of any of the foregoing.

[0199] In some embodiments, the intragranular binder is selected from the group consisting of gum arabic, gum acacia, alginates, alginic acid, corn starch, copovidone, polyvinyl pyrrolidone, gelatin, glyceryl behenate, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, methyl cellulose, hypromellose, lactose, polyvinyl alcohol, povidone, polyethylene oxide, polyacrylate, potato starch, pregelatinized starch, sodium alginate, sodium starch, sodium carboxymethyl cellulose, starch, and mixtures of any of the foregoing.

[0200] In some embodiments, the intragranular disintegrant is selected from the group consisting of alginic acid, cross-linked sodium carboxymethylcellulose, cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, cross-linked polyvidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, polacrilin potassium, pregelatinized starch, partially hydrolyzed starch, sodium carboxymethyl starch, starch, sodium alginate, sodium carboxymethyl cellulose, and a mixture of any of the foregoing.

[0201] In some embodiments, the intragranular surfactant is selected from the group consisting of: cetylpyridinium chloride, heptadecaethyleneoxycetanol, lecithin, polyoxyethylene stearate, nonoxynol 9, nonoxynol 10, octoxynol 9, sorbitan fatty acid esters, Span 20, Span 40, Span 60, Span 80, Span 85, polysorbate, polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, sodium salt of fatty alcohol sulfate, sodium lauryl sulfate, sodium salt of sulfosuccinic acid, dioctyl sodium sulfosuccinate, partial esters of fatty acids and alcohols, glyceryl monostearate, glyceryl monooleate, ethers of fatty alcohols and polyoxyethylene, esters of fatty acids and polyoxyethylene, copolymers of ethylene oxide and propylene oxide Benzalkonium chloride, ethoxylated triglycerides, and mixtures of any of the foregoing.

[0202] In some embodiments, the extragranular filler is selected from the group consisting of powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, kaolin, corn starch, maize starch, starch derivatives, pregelatinized starch, calcium phosphate, dibasic calcium phosphate, dicalcium phosphate, tricalcium phosphate, compressible sugars, sugar alcohols, mannitol, sorbitol, maltitol, xylitol, lactitol, lactose, dextrose, maltose, sucrose, glucose, fructose, sucrose, raffinose, dextrose binders, trehalose, maltodextrin, and mixtures of any of the foregoing.

[0203] In some embodiments, the extragranular disintegrant is selected from the group consisting of alginic acid, cross-linked sodium carboxymethylcellulose, cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, cross-linked polyvidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, polacrilin potassium, pregelatinized starch, partially hydrolyzed starch, sodium carboxymethyl starch, starch, sodium alginate, sodium carboxymethylcellulose, and a mixture of any of the foregoing.

[0204] In some embodiments, the extragranular lubricant is selected from the group consisting of hydrogenated castor oil, magnesium stearate, glyceryl monostearate, calcium stearate, glyceryl behenate, glyceryl distearate, glyceryl dipalmitostearate, behenyl polyoxyl-8 glyceride, sodium stearyl fumarate, stearic acid, talc, zinc stearate, mineral oil, polyethylene glycol, poloxamer, sodium lauryl sulfate, and mixtures of any of the foregoing.

[0205] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 1% to about 80% of CK-274 or a pharmaceutically acceptable salt thereof, based on the total weight of the core; (a-ii) about 10% to about 80% of an intragranular filler, based on the total weight of the core; (a-iii) about 0.1% to about 10% of an intragranular binder, based on the total weight of the core; (a-iv) about 0.1% to about 5% of an intragranular disintegrant, based on the total weight of the core; and (av) about 0.1% to about 5% of an intragranular surfactant, based on the total weight of the core; and (b) an extragranular component comprising: (bi) about 5% to about 15% of an extragranular filler, based on the total weight of the core; (b-ii) about 0.1% to about 5% of an extragranular disintegrant, based on the total weight of the core; and (b-iii) about 0.1% to about 5% of an extragranular lubricant, based on the total weight of the core. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0206] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 1% to about 80% of CK-274 or a pharmaceutically acceptable salt thereof, based on the total weight of the core; (a-ii) about 10% to about 80% of an intragranular filler, based on the total weight of the core; (a-iii) about 0.1% to about 10% of an intragranular binder, based on the total weight of the core; (a-iv) about 0.1% to about 5% of an intragranular disintegrant, based on the total weight of the core; and (av) about 0.1% to about 5% of an intragranular surfactant, based on the total weight of the core; and (b) an extragranular component comprising: (bi) about 5% to about 15% of an extragranular filler, based on the total weight of the core; (b-ii) about 0.1% to about 5% of an extragranular disintegrant, based on the total weight of the core; and (b-iii) about 0.1% to about 5% of an extragranular lubricant, based on the total weight of the core. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0207] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 1% to about 50% of CK-274 or a pharmaceutically acceptable salt thereof, based on the total weight of the core; (a-ii) about 40% to about 80% of an intragranular filler, based on the total weight of the core; (a-iii) about 1% to about 5% of an intragranular binder, based on the total weight of the core; (a-iv) about 1% to about 5% of an intragranular disintegrant, based on the total weight of the core; and (av) about 1% to about 5% of an intragranular surfactant, based on the total weight of the core; and (b) an extragranular component comprising: (bi) about 5% to about 15% of an extragranular filler, based on the total weight of the core; (b-ii) about 1% to about 5% of an extragranular disintegrant, based on the total weight of the core; and (b-iii) about 0.1% to about 2% of an extragranular lubricant, based on the total weight of the core. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0208] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 10% to about 30% of CK-274 or a pharmaceutically acceptable salt thereof, based on the total weight of the core; (a-ii) about 50% to about 70% of an intragranular filler, based on the total weight of the core; (a-iii) about 1% to about 3% of an intragranular binder, based on the total weight of the core; (a-iv) about 2% to about 4% of an intragranular disintegrant, based on the total weight of the core; and (av) about 1% to about 3% of an intragranular surfactant, based on the total weight of the core; and (b) an extragranular component comprising: (bi) about 5% to about 15% of an extragranular filler, based on the total weight of the core; (b-ii) about 1% to about 3% of an extragranular disintegrant, based on the total weight of the core; and (b-iii) about 0.1% to about 1.5% of an extragranular lubricant, based on the total weight of the core. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0209] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 1% to about 10% CK-274 or a pharmaceutically acceptable salt thereof, based on the total weight of the core; (a-ii) about 60% to about 80% of an intragranular filler, based on the total weight of the core; (a-iii) about 1% to about 3% of an intragranular binder, based on the total weight of the core; (a-iv) about 2% to about 4% of an intragranular disintegrant, based on the total weight of the core; and (av) about 1% to about 3% of an intragranular surfactant, based on the total weight of the core; and (b) an extragranular component comprising: (bi) about 5% to about 15% of an extragranular filler, based on the total weight of the core; (b-ii) about 1% to about 3% of an extragranular disintegrant, based on the total weight of the core; and (b-iii) about 0.1% to about 1.5% of an extragranular lubricant, based on the total weight of the core. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0210] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 5% of CK-274 or a pharmaceutically acceptable salt thereof by weight of the core; (a-ii) about 74% of the total weight of the core by weight of an intragranular filler; (a-iii) about 2% of the total weight of the core by weight of an intragranular binder; (a-iv) about 3% of the total weight of the core by weight of an intragranular disintegrant; and (av) about 2% of the total weight of the core by weight of an intragranular surfactant; and (b) an extragranular component comprising: (bi) about 11% of the total weight of the core by weight of an extragranular filler; (b-ii) about 2% of the total weight of the core by weight of an extragranular disintegrant; and (b-iii) about 1% of the total weight of the core by weight of an extragranular lubricant. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0211] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 10% of CK-274 or a pharmaceutically acceptable salt thereof by weight of the core; (a-ii) about 69% of the total weight of the core by weight of an intragranular filler; (a-iii) about 2% of the total weight of the core by weight of an intragranular binder; (a-iv) about 3% of the total weight of the core by weight of an intragranular disintegrant; and (av) about 2% of the total weight of the core by weight of an intragranular surfactant; and (b) an extragranular component comprising: (bi) about 11% of the total weight of the core by weight of an extragranular filler; (b-ii) about 2% of the total weight of the core by weight of an extragranular disintegrant; and (b-iii) about 1% of the total weight of the core by weight of an extragranular lubricant. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0212] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 20% of the total weight of the core of CK-274 or a pharmaceutically acceptable salt thereof; (a-ii) about 59% of the total weight of the core of an intragranular filler; (a-iii) about 2% of the total weight of the core of an intragranular binder; (a-iv) about 3% of the total weight of the core of an intragranular disintegrant; and (av) about 2% of the total weight of the core of an intragranular surfactant; and (b) an extragranular component comprising: (bi) about 11% of the total weight of the core of an extragranular filler; (b-ii) about 2% of the total weight of the core of an extragranular disintegrant; and (b-iii) about 1% of the total weight of the core of an extragranular lubricant. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0213] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 1% to about 50% CK-274 or a pharmaceutically acceptable salt thereof, based on the total weight of the core; (a-ii-1) about 40% to about 60% mannitol, based on the total weight of the core; (a-ii-2) about 10% to about 30% microcrystalline cellulose, based on the total weight of the core; (a-iii) about 1% to about 5% hydroxypropyl cellulose, based on the total weight of the core; (a-iv) about 1% to about 5% cross-linked sodium carboxymethyl cellulose, based on the total weight of the core; and (av) about 1% to about 5% sodium lauryl sulfate, based on the total weight of the core; and (b) an extragranular component comprising: (bi) about 5% to about 15% microcrystalline cellulose, based on the total weight of the core; (b-ii) about 1% to about 5% cross-linked sodium carboxymethyl cellulose, based on the total weight of the core; and (b-iii) about 0.1% to about 2% extragranular lubricant, based on the total weight of the core. In some embodiments, the extragranular lubricant is magnesium stearate. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0214] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 10% to about 30% CK-274 or a pharmaceutically acceptable salt thereof, based on the total weight of the core; (a-ii-1) about 40% to about 50% mannitol, based on the total weight of the core; (a-ii-2) about 10% to about 20% microcrystalline cellulose, based on the total weight of the core; (a-iii) about 1% to about 3% hydroxypropyl cellulose, based on the total weight of the core; (a-iv) about 2% to about 4% cross-linked sodium carboxymethyl cellulose, based on the total weight of the core; and (av) about 1% to about 3% sodium lauryl sulfate, based on the total weight of the core; and (b) an extragranular component comprising: (bi) about 5% to about 15% microcrystalline cellulose, based on the total weight of the core; (b-ii) about 1% to about 3% cross-linked sodium carboxymethyl cellulose, based on the total weight of the core; and (b-iii) about 0.1% to about 1.5% extragranular lubricant, based on the total weight of the core. In some embodiments, the extragranular lubricant is magnesium stearate. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0215] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 1 weight % to about 10% CK-274 or a pharmaceutically acceptable salt thereof, based on the total weight of the core; (a-ii-1) about 50% to about 60% mannitol, based on the total weight of the core; (a-ii-2) about 15% to about 25% microcrystalline cellulose, based on the total weight of the core; (a-iii) about 1% to about 3% hydroxypropyl cellulose, based on the total weight of the core; (a-iv) about 2% to about 4% cross-linked sodium carboxymethyl cellulose, based on the total weight of the core; and (av) about 1% to about 3% sodium lauryl sulfate, based on the total weight of the core; and (b) an extragranular component comprising: (bi) about 5% to about 15% microcrystalline cellulose, based on the total weight of the core; (b-ii) about 1% to about 3% cross-linked sodium carboxymethyl cellulose, based on the total weight of the core; and (b-iii) about 0.1% to about 1.5% extragranular lubricant, based on the total weight of the core. In some embodiments, the extragranular lubricant is magnesium stearate. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0216] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 20% of CK-274 or a pharmaceutically acceptable salt thereof by weight of the core; (a-ii-1) about 44% of mannitol by weight of the core; (a-ii-2) about 15% of microcrystalline cellulose by weight of the core; (a-iii) about 2% of hydroxypropyl cellulose by weight of the core; (a-iv) about 3% of croscarmellose sodium by weight of the core; and (av) about 2% of sodium lauryl sulfate by weight of the core; and (b) an extragranular component comprising: (bi) about 11% of microcrystalline cellulose by weight of the core; (b-ii) about 2% of croscarmellose sodium by weight of the core; and (b-iii) about 1% of an extragranular lubricant by weight of the core. In some embodiments, the extragranular lubricant is magnesium stearate. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0217] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 10% of CK-274 or a pharmaceutically acceptable salt thereof by weight of the core; (a-ii-1) about 50% of mannitol by weight of the core; (a-ii-2) about 19% of microcrystalline cellulose by weight of the core; (a-iii) about 2% of hydroxypropyl cellulose by weight of the core; (a-iv) about 3% of croscarmellose sodium by weight of the core; and (av) about 2% of sodium lauryl sulfate by weight of the core; and (b) an extragranular component comprising: (bi) about 11% of microcrystalline cellulose by weight of the core; (b-ii) about 2% of croscarmellose sodium by weight of the core; and (b-iii) about 1% of an extragranular lubricant by weight of the core. In some embodiments, the extragranular lubricant is magnesium stearate. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0218] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 5% by weight of CK-274 or a pharmaceutically acceptable salt thereof; (a-ii-1) about 54% by weight of mannitol; (a-ii-2) about 20% by weight of microcrystalline cellulose; (a-iii) about 2% by weight of hydroxypropyl cellulose; (a-iv) about 3% by weight of cross-linked sodium carboxymethyl cellulose; and (av) about 2% by weight of sodium lauryl sulfate; and (b) an extragranular component comprising: (bi) about 11% by weight of microcrystalline cellulose; (b-ii) about 2% by weight of cross-linked sodium carboxymethyl cellulose; and (b-iii) about 1% by weight of an extragranular lubricant. In some embodiments, the extragranular lubricant is magnesium stearate. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0219] In some embodiments, the tablet comprises a coating layer containing a coating agent. In some embodiments, the coating layer surrounds the entire core of the tablet. In some embodiments, the coating agent is selected from the group consisting of Opadry QX White 21A180025, Opadry I and Opadry II. In some embodiments, the coating agent is Opadry QX White 21A180025. In some embodiments, the tablet comprises about 0.5% to about 10% of the total weight of the core coating agent. In some embodiments, the tablet comprises about 1% to about 5% of the total weight of the core coating agent. In some embodiments, the tablet comprises about 2% to about 4% of the total weight of the core coating agent. In some embodiments, the tablet comprises about 3% of the total weight of the core coating agent. In some embodiments, the tablet comprises about 0.5% to about 10% of the total weight of the core Opadry QX White 21A180025. In some embodiments, the tablet comprises about 1% to about 5% of the total weight of the core Opadry QX White 21A180025. In some embodiments, the tablet comprises about 2% to about 4% of the total weight of the core Opadry QX White 21A180025. In some embodiments, the tablet comprises about 3% of the total weight of the core Opadry QX White 21A180025.

[0220] In some embodiments, the amount of CK-274 (which may be present in various forms) in a formulation (e.g., tablet) is about the daily dose described herein, for example, about 5 mg, about 10 mg, about 15 mg, or about 20 mg CK-274. In some embodiments, the amount of CK-274 (which may be present in various forms) in a formulation (e.g., tablet) is about half of the daily dose described herein. In some embodiments, the amount of CK-274 in a formulation (e.g., tablet) is about 2.5 mg, about 5 mg, about 7.5 mg, or about 10 mg CK-274.

[0221] In some embodiments, CK-274 is present in its free base form in various formulations, such as tablets. In some embodiments, methods, such as those described in the Examples, use such tablets.

[0222] Liquid pharmaceutical compositions can be prepared, for example, by dissolving, dispersing or suspending the compounds disclosed and / or described herein and optional pharmaceutical additives in a carrier (e.g., water, saline, aqueous dextrose solution, glycerol, glycol, ethanol, etc.) to form a solution or suspension. Injectables can be prepared in conventional form, in a liquid solution or suspension, in an emulsion, or in a solid form suitable for dissolving or suspending in a liquid before injection. The percentage of the compound contained in such parenteral compositions depends on, for example, the physical properties of the compound, the activity of the compound, and the needs of the subject. However, a percentage of 0.01% to 10% active ingredient can be used in the solution, and if the composition is a solid that will be diluted to another concentration subsequently, the percentage can be higher. In some embodiments, the composition will contain about 0.2% to 2% of the compound disclosed and / or described herein in the solution.

[0223] Pharmaceutical compositions of the compounds disclosed and / or described herein may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a finely divided powder for insufflation, 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.

[0224] Additionally, pharmaceutical compositions may include a compound disclosed and / or described herein and one or more other pharmaceutical agents, medicaments, adjuvants, etc. Suitable pharmaceutical agents include those described herein.

[0225] Treatment of hypertrophic cardiomyopathy with mid-ventricular obstruction

[0226] In some embodiments of any of the foregoing methods, non-obstructive HCM is HCM with mid-ventricular obstruction (MVO). For example, in some embodiments, the methods disclosed herein include administering a therapeutically effective amount of CK-274 to a patient to treat hypertrophic cardiomyopathy with mid-ventricular obstruction (MVO), as described herein for treating non-obstructive hypertrophic cardiomyopathy. For example, in some embodiments, a patient in need suffers from HCM with mid-ventricular obstruction. It should be understood that the term "mid-ventricular obstruction" (MVO) can be used interchangeably with "mid-cavity obstruction" in the embodiments disclosed herein.

[0227] Reduce the frequency of angina

[0228] In some embodiments, the present disclosure provides a method for reducing the frequency of angina pectoris in a subject as described herein, the method comprising administering or delivering CK-274 as described herein to a subject. In some embodiments, the subject is a human subject suffering from non-obstructive hypertrophic cardiomyopathy. In some embodiments, CK-274 is administered or delivered as a free base. In some embodiments, CK-274 is administered or delivered as a pharmaceutically acceptable salt. In some embodiments, CK-274 is administered as a tablet, such as a tablet comprising about a daily dose or half of a daily dose, as described herein. In some embodiments, the daily dose is about 5 mg, about 10 mg, about 15 mg, or about 20 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.

[0229] Polymorph

[0230] In some embodiments, CK-274 is in the form of a polymorph of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Suitable polymorphs of CK-274 include those disclosed in WO 2021 / 011807 and can be prepared according to WO 2021 / 011807, which is incorporated herein by reference in its entirety. Polymorphs may have properties suitable for medical or pharmaceutical uses, such as bioavailability and stability under certain conditions. Changes in the crystal structure of a drug substance may affect the dissolution rate of the drug product (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ease of purification, ability to consistently prepare doses of known strength, etc.), and stability (e.g., thermal stability, shelf life (including resistance to degradation), etc.). Such changes may affect the preparation or formulation of pharmaceutical compositions of different doses or delivery forms (e.g., solid oral dosage forms, including tablets and capsules). Compared with other forms such as non-crystalline or amorphous forms, polymorphs can provide desired or suitable hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, reproducibility and / or process control. Therefore, polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide can provide stability or storage of the drug product form of the active agent or have the advantages of being suitable for the bioavailability and / or stability of the active agent. In some embodiments, the CK-274 in the preparation, such as the tablet, is one or a combination of polymorphic forms I, II, III, IV, V or VI. In some embodiments, CK-274 is one of polymorphic Form I, Form II, Form III, Form IV, Form V, or Form VI. In some embodiments, CK-274 is polymorphic Form I or Form IV. In some embodiments, CK-274 is polymorphic Form I. In some embodiments, CK-274 is polymorphic Form IV.

[0231] Form I

[0232] In some embodiments, CK-274 is a polymorphic Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. The 2-θ angles and relative peak intensities of Form I observable using XRPD are shown in Table P-1. In some embodiments, Form I has substantially Fig.26A XRPD pattern shown.

[0233] Table P-1

[0234]

[0235]

[0236] In some embodiments, polymorph Form I has an XRPD pattern that exhibits at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks at 2-theta angles with maximum intensity in the XRPD pattern, substantially as described herein. Fig.26A As shown or as provided in Table P-1. It should be understood that relative intensities may vary according to a variety of factors, including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum. Relative peak intensities and peak attributions may vary within experimental error. In some embodiments, the peak attributions listed herein (including polymorphic form I) may vary by about ± 0.6 °, ± 0.4 °, ± 0.2 °, or ± 0.1 ° 2-θ.

[0237] In some embodiments, polymorph Form I has a molecular weight comprising 3.7±0.2, 11.2±0.2, 12.9±0.2, 13.5±0.2, 14.4±0.2, 14.9±0.2, 16.6±0.2, 17.8±0.2, 18.6±0.2, 21.6±0.2, 22.2±0.2, 22.4±0.2, 22.8±0.2, 23.2±0.2, 23.9±0. XRPD pattern of peaks at 2-θ angles of 2, 24.4±0.2, 24.7±0.2, 25.0±0.2, 25.8±0.2, 26.1±0.2, 28.6±0.2, 29.0±0.2, 29.4±0.2, 29.9±0.2, 30.6±0.2, 33.8±0.2, 36.1±0.2, 36.8±0.2, 37.8±0.2, and 39.8±0.2°. In some embodiments, polymorph Form I has an XRPD pattern comprising peaks at 2-θ angles of 3.7 ± 0.2, 11.2 ± 0.2, 12.9 ± 0.2, 13.5 ± 0.2, 14.4 ± 0.2, 18.6 ± 0.2, 22.4 ± 0.2, 24.7 ± 0.2, 25.0 ± 0.2, and 26.1 ± 0.2°. In some embodiments, polymorph Form I has an XRPD pattern comprising peaks at 2-θ angles of 3.7 ± 0.2, 11.2 ± 0.2, 12.9 ± 0.2, 14.4 ± 0.2, and 22.4 ± 0.2°. It should be understood that in addition to the XRPD pattern, peaks at 2-θ angles of 2. Fig.26A Additional peaks beyond those shown in or provided in Table P-1 may be due, for example, to the presence of impurities, solvents or other polymorphs or amorphous forms in the tested samples.

[0238] In some embodiments, Form I has substantially Fig.26B Differential DSC graph shown. In some embodiments, Form I is characterized by an endotherm with an onset of about 199°C, as determined by DSC. In some embodiments, Form I is characterized by an endotherm with an onset of 199±2°C (e.g., 199±1.9°C, 199±1.8°C, 199±1.7°C, 199±1.6°C, 199±1.5°C, 199±1.4°C, 199±1.3°C, 192±1.2°C, 199±1°C, 199±0.9°C, 199±0.8°C, 199±0.7°C, 199±0.6°C, 199±0.5°C, 199±0.4°C, 199±0.3°C, 199±0.2°C, or 199±0.1°C), as determined by DSC.

[0239] In some embodiments, Form I has substantially Fig.26B TGA graph shown.

[0240] In some embodiments, Form I has substantially Fig.26C The DVS diagram shown.

[0241] In some embodiments of Form I, at least one, at least two, at least three, at least four, at least five, or all of the following (a)-(f) apply:

[0242] (a) Form I has an XRPD pattern comprising peaks at 2-θ angles of 3.7±0.2, 11.2±0.2, 12.9±0.2, 14.4±0.2, and 22.4±0.2°; an XRPD pattern comprising peaks at 2-θ angles of 3.7±0.2, 11.2±0.2, 12.9±0.2, 13.5±0.2, 14.4±0.2, 18.6±0.2, 22.4±0.2, 24.7±0.2, 25.0±0.2, and 26.1±0.2°; or an XRPD pattern comprising peaks at 2-θ angles of 3.7±0.2, 11.2±0.2, 12.9±0.2, 13.5±0.2, 14.4±0.2, XRPD pattern of peaks at 2-θ angles of 16.6±0.2, 17.8±0.2, 18.6±0.2, 21.6±0.2, 22.2±0.2, 22.4±0.2, 22.8±0.2, 23.2±0.2, 23.9±0.2, 24.4±0.2, 24.7±0.2, 25.0±0.2, 25.8±0.2, 26.1±0.2, 28.6±0.2, 29.0±0.2, 29.4±0.2, 29.9±0.2, 30.6±0.2, 33.8±0.2, 36.1±0.2, 36.8±0.2, 37.8±0.2, and 39.8±0.2;

[0243] (b) Form I has substantially Fig.26A The XRPD pattern shown in;

[0244] (c) Form I has substantially Fig.26B The DSC diagram shown in;

[0245] (d) Form I is characterized by an endotherm onset at about 199°C as determined by DSC;

[0246] (e) Form I has substantially Fig.26B The TGA graph shown in ; and

[0247] (f) Form I has substantially Fig.26C The DVS diagram shown in .

[0248] Form II

[0249] In some embodiments, CK-274 is a polymorphic Form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. The 2-θ angles and relative peak intensities of Form II observable using XRPD are shown in Table P-2. In some embodiments, Form II has substantially Fig.27A XRPD pattern shown in .

[0250] Table P-2

[0251]

[0252] In some embodiments, polymorph Form II has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks at °2-θ with maximum intensity in the XRPD pattern, substantially as Fig.27A As shown or as provided in Table P-2. It should be understood that relative intensity can vary according to a variety of factors, including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum. Relative peak intensity and peak attribution can vary within the experimental error range. In some embodiments, the peak attribution listed herein (including polymorphic form II) can vary by about ± 0.6 °, ± 0.4 °, ± 0.2 ° or ± 0.1 ° 2-θ.

[0253] In some embodiments, polymorph Form II has an XRPD pattern comprising peaks at 2-theta angles of 3.7±0.2, 7.4±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, 13.5±0.2, 14.4±0.2, 14.7±0.2, 16.1±0.2, 17.0±0.2, 18.5±0.2, 20.4±0.2, 21.6±0.2, 22.3±0.2, 23.3±0.2, 24.0±0.2, 24.3±0.2, 24.8±0.2, 25.8±0.2, 27.4±0.2, 28.8±0.2, 29.5±0.2, and 30.5±0.2°. In some embodiments, polymorph Form II has an XRPD pattern comprising peaks at 2-θ angles of 3.7 ± 0.2, 9.8 ± 0.2, 11.1 ± 0.2, 12.8 ± 0.2, 14.7 ± 0.2, 16.1 ± 0.2, 18.5 ± 0.2, 20.4 ± 0.2, 22.3 ± 0.2, and 23.3 ± 0.2°. In some embodiments, polymorph Form II has an XRPD pattern comprising peaks at 2-θ angles of 3.7 ± 0.2, 9.8 ± 0.2, 11.1 ± 0.2, 12.8 ± 0.2, and 20.4 ± 0.2°. It should be understood that in addition to the XRPD pattern, it can also be observed that Fig.27A Additional peaks beyond those shown in or provided in Table P-2 may be due, for example, to the presence of impurities, solvents or other polymorphs or amorphous forms in the tested samples.

[0254] In some embodiments, Form II has substantially Fig.27B In some embodiments, Form II is characterized by an endothermic onset at about 199°C, as determined by DSC. In some embodiments, Form II is characterized by an endothermic onset at about 199±2°C (e.g., 199±1.9°C, 199±1.8°C, 199±1.7°C, 199±1.6°C, 199±1.5°C, 199±1.4°C, 199±1.3°C, 199±1.2°C, 199±1°C, 199±0.9°C, 199±0.8°C, 199±0.7°C, 199±0.6°C, 199±0.5°C, 199±0.4°C, 199±0.3°C, 199±0.2°C, or 199±0.1°C), as determined by DSC.

[0255] In some embodiments, Form II has substantially Fig.27B TGA graph shown in .

[0256] In some embodiments of Form II, at least one, at least two, at least three, at least four, or all of the following (a)-(e) apply:

[0257] (a) Form II has an XRPD pattern comprising peaks at 2-θ angles of 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, and 20.4±0.2°; an XRPD pattern comprising peaks at 2-θ angles of 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, 14.7±0.2, 16.1±0.2, 18.5±0.2, 20.4±0.2, 22.3±0.2, and 23.3±0.2°; or an XRPD pattern comprising peaks at 2-θ angles of 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, 14.7±0.2, 16.1±0.2, 18.5±0.2, 20.4±0.2, 22.3±0.2, and 23.3±0.2°. 0.2, 11.1±0.2, 12.8±0.2, 13.5±0.2, 14.4±0.2, 14.7±0.2, 16.1±0.2, 17.0±0.2, 18.5±0.2, 20.4±0.2, 21.6±0.2, 22.3±0.2, 23.3±0.2, 24.0±0.2, 24.3±0.2, 24.8±0.2, 25.8±0.2, 27.4±0.2, 28.8±0.2, 29.5±0.2, and 30.5±0.2 degrees;

[0258] (b) Form II has substantially Fig.27A The XRPD pattern shown in;

[0259] (c) Form II has substantially Fig.27B The DSC diagram shown in;

[0260] (d) Form II is characterized by a melting endotherm with an onset of about 199°C as determined by DSC; and

[0261] (e) Form II has substantially Fig.27B TGA graph shown in .

[0262] Form III

[0263] In some embodiments, CK-274 is a polymorphic form III of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. The 2-θ angles and relative peak intensities of the mixture of forms I and III observable using XRPD are shown in Table P-3. In some embodiments, the mixture of forms I and III has substantially Fig.28A XRPD pattern shown in .

[0264] Table P-3

[0265]

[0266]

[0267] In some embodiments, polymorph Form III has an XRPD pattern comprising peaks at 2-θ angles of 9.6 ± 0.2, 10.9 ± 0.2, 15.8 ± 0.2, and 18.1 ± 0.2°. In some embodiments, polymorph Form III has an XRPD pattern comprising peaks at 2-θ angles of 9.6 ± 0.2, 10.9 ± 0.2, 14.5 ± 0.2, 15.8 ± 0.2, and 18.1 ± 0.2°. In some embodiments, polymorph Form III has an XRPD pattern comprising peaks at 2-θ angles of 9.6 ± 0.2, 10.9 ± 0.2, 14.5 ± 0.2, 15.8 ± 0.2, 18.1 ± 0.2, and 20.2 ± 0.2°. It should be understood that relative intensities may vary according to a variety of factors, including sample preparation, mounting, and the instrument and analysis procedures and settings used to obtain the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein (including polymorph Form III) may vary by about ±0.6°, ±0.4°, ±0.2°, or ±0.1° 2-θ.

[0268] In some embodiments, the mixture of polymorphic forms I and III has substantially Fig.28B DSC graph shown in .

[0269] In some embodiments, the mixture of polymorphic forms I and III has substantially Fig.28B TGA graph shown in .

[0270] Form IV

[0271] In some embodiments, CK-274 is a polymorphic form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. The 2-θ angles and relative peak intensities of Form IV observable using XRPD are shown in Table P-4. In some embodiments, Form IV has substantially Fig.29A XRPD pattern shown in .

[0272] Table P-4

[0273]

[0274]

[0275] In some embodiments, polymorph Form IV has an XRPD pattern that exhibits at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks at 2-theta angles with maximum intensity in the XRPD pattern, substantially as Fig.29A As shown or as provided in Table P-4. It should be understood that relative intensities may vary according to a variety of factors, including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum. Relative peak intensities and peak attributions may vary within experimental error. In some embodiments, the peak attributions listed herein (including polymorphic form IV) may vary by about ± 0.6 °, ± 0.4 °, ± 0.2 °, or ± 0.1 ° 2-θ.

[0276] In some embodiments, polymorph Form IV has a density comprising 3.7±0.2, 7.7±0.2, 11.1±0.2, 12.4±0.2, 12.8±0.2, 13.5±0.2, 14.3±0.2, 15.5±0.2, 16.6±0.2, 17.9±0.2, 18.5±0.2, 18.6±0.2, 19.1±0.2, 19.9±0.2, 20.9±0.2, 21.5±0.2, 21.6±0.2, 21.9±0.2, 22.3±0.2, 22.4±0.2, 22.8±0.2, 23.1±0.2, 23.5±0.2, 23.9±0. 2, 24.4±0.2, 24.8±0.2, 25.0±0.2, 25.3±0.2, 25.8±0.2, 26.2±0.2, 27.1±0.2, 27.4±0.2, 28.0±0.2, 28.6±0.2, 29.0±0.2, 30.0±0.2, 30.5±0.2, 30.8±0.2, 31.0±0.2, 31.4±0.2, 33.8±0.2, 35.0±0.2, 35.7±0.2, 36.1±0.2, 36.7±0.2, 37.9±0.2, 38.1±0.2, and 39.8±0.2. In some embodiments, polymorph Form IV has an XRPD pattern comprising peaks at 2-θ angles of 3.7 ± 0.2, 11.1 ± 0.2, 12.8 ± 0.2, 13.5 ± 0.2, 21.9 ± 0.2, 22.8 ± 0.2, 23.1 ± 0.2, 23.5 ± 0.2, 24.4 ± 0.2, and 24.8 ± 0.2°. In some embodiments, polymorph Form IV has an XRPD pattern comprising peaks at 2-θ angles of 11.1 ± 0.2, 12.8 ± 0.2, 13.5 ± 0.2, 22.8 ± 0.2, and 24.4 ± 0.2°. It should be understood that in addition to the XRPD pattern, peaks at 2-θ angles of 24.4 ± 0.2° may also be observed. Fig.29A Additional peaks beyond those shown in or provided in Table P-4 may be due, for example, to the presence of impurities, solvents or other polymorphs or amorphous forms in the tested samples.

[0277] In some embodiments, Form IV has substantially Fig.29BIn some embodiments, Form IV is characterized by an endothermic onset at about 200°C, as determined by DSC. In some embodiments, Form IV is characterized by an endothermic onset at about 200±2°C (e.g., 200±1.9°C, 200±1.8°C, 200±1.7°C, 200±1.6°C, 200±1.5°C, 200±1.4°C, 200±1.3°C, 200±1.2°C, 200±1, 200±0.9°C, 200±0.8°C, 200±0.7°C, 200±0.6°C, 200±0.5°C, 200±0.4°C, 200±0.3°C, 200±0.2°C, or 200±0.1°C), as determined by DSC.

[0278] In some embodiments, Form IV has substantially Fig.29B TGA graph shown in .

[0279] In some embodiments of Form IV, at least one, at least two, at least three, at least four, or all of the following (a)-(e) apply:

[0280] (a) Form IV has an XRPD pattern having peaks at 2-θ angles of 11.1±0.2, 12.8±0.2, 13.5±0.2, 22.8±0.2, and 24.4±0.2°; and peaks at 2-θ angles of 3.7±0.2, 11.1±0.2, 12.8±0.2, 13.5±0.2, 21.9±0.2, 22.8±0.2, 23.1±0.2, 23.5±0.2, 24.4±0.2, and 24. or an XRPD pattern comprising a peak at a 2-θ angle of 8±0.2°; or a peak at a 2-θ angle of 3.7±0.2, 7.7±0.2, 11.1±0.2, 12.4±0.2, 12.8±0.2, 13.5±0.2, 14.3±0.2, 15.5±0.2, 16.6±0.2, 17.9±0.2, 18.5±0.2, 18.6±0.2, 19.1±0.2, 19.9±0.2, 20.9±0.2 , 21.5±0.2, 21.6±0.2, 21.9±0.2, 22.3±0.2, 22.4±0.2, 22.8±0.2, 23.1±0.2, 23.5±0.2, 23.9±0.2, 24.4±0.2, 24.8±0.2, 25.0±0.2, 25.3±0.2, 25.8±0.2, 26.2±0.2, 27.1±0.2, 27.4±0.2, 28 XRPD pattern of peaks at 2-θ angles of .0±0.2, 28.6±0.2, 29.0±0.2, 30.0±0.2, 30.5±0.2, 30.8±0.2, 31.0±0.2, 31.4±0.2, 33.8±0.2, 35.0±0.2, 35.7±0.2, 36.1±0.2, 36.7±0.2, 37.9±0.2, 38.1±0.2, 39.8±0.2°;

[0281] (b) Form IV has substantially Fig.29A The XRPD pattern shown in;

[0282] (c) Form IV has substantially Fig.29B The DSC diagram shown in;

[0283] (d) Form IV is characterized by a melting endotherm with an onset of about 200°C as determined by DSC; and

[0284] (e) Form IV has substantially Fig.29B TGA graph shown in .

[0285] Form V

[0286] In some embodiments, CK-274 is a polymorphic Form V of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. The 2-θ angles and relative peak intensities of Form V observable using XRPD are shown in Table P-5. In some embodiments, Form V has substantially Fig.30 XRPD pattern shown in .

[0287] Table P-5

[0288]

[0289]

[0290] In some embodiments, polymorph Form V has an XRPD pattern that exhibits at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks at 2-theta angles with maximum intensity in the XRPD pattern, substantially as described herein. Fig.30 As shown or as provided in Table P-5. It should be understood that relative intensity can vary according to a variety of factors, including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum. Relative peak intensity and peak attribution can vary within the experimental error range. In some embodiments, the peak attribution listed herein (including polymorph form V) can vary by about ± 0.6 °, ± 0.4 °, ± 0.2 ° or ± 0.1 ° 2-θ.

[0291] In some embodiments, polymorph Form V has an XRPD pattern comprising peaks at the following 2-theta angles: 5.7±0.2, 8.3±0.2, 11.5±0.2, 13.8±0.2, 15.5±0.2, 15.8±0.2, 16.3±0.2, 16.6±0.2, 17.2±0.2, 17.8±0.2, 18.5±0.2, 18.9±0.2, 19.1±0.2, 19.8±0.2, 20.0±0.2, 20.2 ±0.2, 20.7±0.2, 21.2±0.2, 21.6±0.2, 23.0±0.2, 23.1±0.2, 23.3±0.2, 24.0±0.2, 24.2±0.2, 24.3±0.2, 24.6±0.2, 24.7±0.2, 25.2±0.2, 25.6±0.2, 26.7±0.2, 27.1±0.2, 27.3±0.2, 27.5±0.2, 27.9±0.2, 28.1±0.2 .2, 28.4±0.2, 28.9±0.2, 29.2±0.2, 29.7±0.2, 29.8±0.2, 29.9±0.2, 30.4±0.2, 30.6±0.2, 31.1±0.2, 31.3±0.2, 31.5±0.2, 32.0±0.2, 32.9±0.2, 33.0±0.2, 33.2±0.2, 33.5±0.2, 34.4±0.2, 34.6±0.2, 34.9±0.2 , 35.3±0.2, 35.7±0.2, 36.0±0.2, 36.2±0.2, 36.5±0.2, 36.6±0.2, 37.0±0.2, 37.1±0.2, 37.5±0.2, 37.8±0.2, 37.9±0.2, 38.3±0.2, 38.4±0.2, 38.7±0.2, 38.8±0.2, 39.3±0.2, 39.4±0.2, 39.6±0.2, and 39.9±0.2°. In some embodiments, polymorph Form V has an XRPD pattern comprising peaks at 2-theta angles of 5.7±0.2, 8.3±0.2, 11.5±0.2, 16.3±0.2, 17.2±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 20.7±0.2, 21.2±0.2, 23.3±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, 26.7±0.2, 28.1±0.2, 29.2±0.2, 29.7±0.2, 29.9±0.2, and 31.1±0.2.In some embodiments, polymorph Form V has an XRPD pattern comprising peaks at 2-θ angles of 11.5 ± 0.2, 16.3 ± 0.2, 19.1 ± 0.2, 20.0 ± 0.2, 20.2 ± 0.2, 21.2 ± 0.2, 24.0 ± 0.2, 24.7 ± 0.2, 25.6 ± 0.2, and 26.7 ± 0.2°. In some embodiments, polymorph Form V has an XRPD pattern comprising peaks at 2-θ angles of 11.5 ± 0.2, 16.3 ± 0.2, 20.0 ± 0.2, 21.2 ± 0.2, and 24.7 ± 0.2°. It should be understood that in addition to the XRPD pattern, it may also be observed. Fig.30 Additional peaks beyond those shown in or provided in Table P-5 may be due, for example, to the presence of impurities, solvents or other polymorphs or amorphous forms in the tested samples.

[0292] In some embodiments of Form V, at least one or both of the following (a)-(b) apply:

[0293] (a) Form V has an XRPD pattern comprising peaks at 2-θ angles of 11.5±0.2, 16.3±0.2, 20.0±0.2, 21.2±0.2, and 24.7±0.2°; an XRPD pattern comprising peaks at 2-θ angles of 11.5±0.2, 16.3±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 21.2±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, and 26.7±0.2°; or an XRPD pattern comprising peaks at 2-θ angles of 5.7±0.2 , 8.3±0.2, 11.5±0.2, 16.3±0.2, 17.2±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 20.7±0.2, 21.2±0.2, 23.3±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, 26.7±0.2, 28.1±0.2, 29.2±0.2, 29.7±0.2, 29.9±0.2, and 31.1±0.2 degrees; and

[0294] (b) Form V has substantially Fig.30 XRPD pattern shown in .

[0295] Form VI

[0296] In some embodiments, CK-274 is a polymorphic form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. The 2-θ angles and relative peak intensities of Form VI observable using XRPD are shown in Table P-6. In some embodiments, Form VI has substantially Fig.31A XRPD pattern shown in .

[0297] Table P-6

[0298]

[0299]

[0300]

[0301] In some embodiments, polymorph Form VI has an XRPD pattern that exhibits at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks at 2-θ angles with maximum intensity in the XRPD pattern, substantially as Fig.31A As shown or as provided in Table P-6. It should be understood that relative intensity can vary according to a variety of factors, including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum. Relative peak intensity and peak attribution can vary within the experimental error range. In some embodiments, the peak attribution listed herein (including polymorphic form VI) can vary by about ± 0.6 °, ± 0.4 °, ± 0.2 ° or ± 0.1 ° 2-θ.

[0302] In some embodiments, polymorph Form VI has a molecular weight comprising 3.0±0.2, 5.0±0.2, 5.4±0.2, 5.9±0.2, 7.2±0.2, 8.1±0.2, 8.9±0.2, 9.6±0.2, 9.9±0.2, 10.6±0.2, 12.1±0.2, 13.3±0.2, 14.0±0.2, 14.4 ±0.2, 14.7±0.2, 15.0±0.2, 15.4±0.2, 16.1±0.2, 16.5±0.2, 17.8±0.2, 18.9±0.2, 19.0±0.2, 19.2±0.2, 19.6±0.2, 20.0±0.2, 20.3±0.2, 20.7±0.2, 21.1±0.2, 1.9±0.2, 22.6±0.2, 22.9±0.2, 23.6±0.2, 23.8±0.2, 24.4±0.2, 24.8±0.2, 25.5±0.2, 26.4±0.2, 26.7±0.2, 27.3±0.2, 27.6±0.2, 28.2±0.2, 28.5±0.2, 29.0±0. In some embodiments, polymorph Form VI has an XRPD pattern comprising peaks at 2-θ angles of 5.4±0.2, 5.9±0.2, 8.1±0.2, 9.6±0.2, 10.6±0.2, 12.1±0.2, 14.0±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2°. In some embodiments, polymorph Form VI has an XRPD pattern comprising peaks at 2-θ angles of 10.6 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 16.1 ± 0.2, and 17.8 ± 0.2°. It should be understood that peaks at 2-θ angles other than 10.6 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 16.1 ± 0.2, and 17.8 ± 0.2° may also be observed in the XRPD pattern. Fig.31A Additional peaks beyond those shown in or provided in Table P-6 may be due, for example, to the presence of impurities, solvents or other polymorphs or amorphous forms in the tested samples.

[0303] In some embodiments, Form VI has substantially Fig.31B The TGA diagram shown in or substantially as Fig.31C The TGA graph shown in . In some embodiments, Form VI exhibits a weight loss of about 2% ± 0.5% between 25°C and 200°C as determined by TGA.

[0304] In some embodiments, Form VI has substantially Fig.31D The DSC diagram shown in or substantially as shown in Fig.31E In some embodiments, Form VI is characterized by an endothermic onset at about 200±2°C (e.g., 200±1.9°C, 200±1.8°C, 200±1.7°C, 200±1.6°C, 200±1.5°C, 200±1.4°C, 200±1.3°C, 200±1.2°C, 200±1, 200±0.9°C, 200±0.8°C, 200±0.7°C, 200±0.6°C, 200±0.5°C, 200±0.4°C, 200±0.3°C, 200±0.2°C, or 200±0.1°C), as determined by DSC. In some embodiments, Form VI is characterized by a temperature of about 200 ± 2°C (e.g., 200 ± 1.9°C, 200 ± 1.8°C, 200 ± 1.7°C, 200 ± 1.6°C, 200 ± 1.5°C, 200 ± 1.4°C, 200 ± 1.3°C, 200 ± 1.2°C, 200 ± 1, 200 ± 0.9°C, 200 ± 0.8°C, 200 ± 0.7°C). , 200±0.6°C, 200±0.5°C, 200±0.4°C, 200±0.3°C, 200±0.2°C or 200±0.1°C), and begins to absorb heat at about 115±2°C (e.g., 115±1.9°C, 115±1.8°C, 115±1.7°C, 115±1.6°C, 115±1.5°C, 115±1.4°C, 115±1.3°C). , 115±1.2°C, 115±1, 115±0.9°C, 115±0.8°C, 115±0.7°C, 115±0.6°C, 115±0.5°C, 115±0.4°C, 115±0.3°C, 115±0.2°C or 115±0.1°C), or at about 41±2°C (e.g., 41±1.9°C, 41±1.8°C, 41±1 .7℃, 41±1.6℃, 41±1.5℃, 41±1.4℃, 41±1.3℃, 41±1.2℃, 41±1, 41±0.9℃, 41±0.8℃, 41±0.7℃, 41±0.6℃, 41±0.5℃, 41±0.4℃, 41±0.3℃, 41±0.2℃ or 41±0.1℃), or any combination thereof.

[0305] In some embodiments of Form VI, at least one, at least two, at least three, at least four, at least five, at least six, or all of the following (a)-(g) apply:

[0306] (a) Form VI has an XRPD pattern comprising peaks at 2-θ angles of 10.6±0.2, 12.1±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2°; an XRPD pattern comprising peaks at 2-θ angles of 5.4±0.2, 5.9±0.2, 8.1±0.2, 9.6±0.2, 10.6±0.2, 12.1±0.2, 14.0±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2°. D figure; or including 3.0±0.2, 5.0±0.2, 5.4±0.2, 5.9±0.2, 7.2±0.2, 8.1±0.2, 8.9±0.2, 9.6±0.2, 9.9±0.2, 10.6±0.2, 12.1±0.2, 13.3±0.2, 14.0±0.2, 14.4±0.2, 14.7±0.2, 15.0±0.2, 15.4±0.2, 16.1±0.2, 16.5±0.2, 17.8 ±0.2, 18.9±0.2, 19.0±0.2, 19.2±0.2, 19.6±0.2, 20.0±0.2, 20.3±0.2, 20.7±0.2, 21.1±0.2, 21.9±0.2, 22.6±0.2, 22.9±0.2, 23.6±0.2, 23.8±0.2, 24.4±0.2, 24.8±0.2, 25.5±0.2, 26.4±0.2, 26.7±0.2, 27.3±0. XRPD pattern of peaks at 2-θ angles of 0.2, 27.6 ± 0.2, 28.2 ± 0.2, 28.5 ± 0.2, 29.0 ± 0.2, 29.6 ± 0.2, 29.9 ± 0.2, 30.4 ± 0.2, 30.9 ± 0.2, 31.6 ± 0.2, 32.2 ± 0.2, 32.6 ± 0.2, 33.1 ± 0.2, 33.3 ± 0.2, 34.5 ± 0.2, 35.0 ± 0.2, 35.5 ± 0.2, and 38.5 ± 0.2;

[0307] (b) Form VI has substantially Fig.31A The XRPD pattern shown in;

[0308] (c) Form VI has substantially Fig.31B or Fig.31C TGA graph shown in .

[0309] (d) Form VI has a weight loss of about 2% ± 0.5% between 25°C and 200°C as determined by TGA;

[0310] (e) Form VI has substantially Fig.31D or Fig.31E The DSC graph shown in ; and

[0311] (f) Form IV is characterized by a melting endotherm with an onset of about 200°C as determined by DSC; and

[0312] (g) Form VI is characterized by having an endotherm with an onset at about 200°C, an exotherm with an onset at about 115°C, or an endotherm with an onset at about 41°C, or any combination thereof, as determined by DSC.

[0313] Pill Box

[0314] Also provided are articles and kits containing any of the compounds or pharmaceutical compositions provided herein. The articles may include containers with labels. Suitable containers include, for example, bottles, vials, and test tubes. The containers may be formed of a variety of materials, such as glass or plastic. The containers may hold the pharmaceutical compositions provided herein. The labels on the containers may indicate that the pharmaceutical compositions are used to prevent, treat, or inhibit the disorders described herein, and may also indicate instructions for in vivo or in vitro use.

[0315] In one aspect, provided herein are kits containing a compound or composition as described herein and instructions for use. The kit may contain instructions for treating a heart disease in an individual or subject in need thereof. The kit may additionally contain any materials or equipment that can be used to administer the compound or composition, such as vials, syringes, or IV bags. The kit may also contain sterile packaging.

[0316] In some embodiments, the present disclosure provides a method for manufacturing a medicament comprising CK-274, the method comprising:

[0317] manufacturing a first batch of tablets in which the amount of CK-274 (which may be present in various forms) is about the first daily dose or about half of the first daily dose;

[0318] manufacturing a second batch of tablets wherein the amount of CK-274 (which may be present in various forms) is about the second daily dose or about half of the second daily dose;

[0319] Optionally manufacturing a third batch of tablets wherein the amount of CK-274 (which may be present in various forms) is about the third daily dose or about half of the third daily dose; and

[0320] Optionally, a fourth batch of tablets is produced in which the amount of CK-274 (which may be present in various forms) is about the fourth daily dose or about half the fourth daily dose.

[0321] In some embodiments, the method comprises manufacturing a third batch of tablets, wherein the amount of CK-274 (which may be present in various forms) is about the third daily dose or about half of the third daily dose. In some embodiments, the method comprises manufacturing a fourth batch of tablets, wherein the amount of CK-274 (which may be present in various forms) is about the fourth daily dose or about half of the fourth daily dose.

[0322] In some embodiments, the present disclosure provides a method for manufacturing a medicament comprising CK-274, the method comprising:

[0323] manufacturing a first batch of tablets in which the amount of CK-274 (which may be present in various forms) is approximately the first daily dose;

[0324] manufacturing a second batch of tablets in which the amount of CK-274 (which may be present in various forms) is approximately the second daily dose;

[0325] Optionally manufacturing a third batch of tablets wherein the amount of CK-274 (which may be present in various forms) is about the third daily dose; and

[0326] Optionally, a fourth batch of tablets is produced in which the amount of CK-274 (which may be present in various forms) is about the fourth daily dose.

[0327] In some embodiments, the method comprises manufacturing a third batch of tablets, wherein the amount of CK-274 (which may be present in various forms) is about the third daily dose. In some embodiments, the method comprises manufacturing a fourth batch of tablets, wherein the amount of CK-274 (which may be present in various forms) is about the fourth daily dose.

[0328] Various first, second, third and fourth daily doses are described herein. In some embodiments, the daily dose is about 5 mg CK-274. In some embodiments, the first daily dose is about 5 mg CK-274. In some embodiments, the daily dose is about 10 mg CK-274. In some embodiments, the daily dose is about 15 mg CK-274. In some embodiments, the daily dose is about 20 mg CK-274. In some embodiments, tablets with at least two different daily doses are manufactured. In some embodiments, tablets in which the amount of CK-274 (which can exist in various forms) is about 15 mg are manufactured. In some embodiments, tablets in which the amount of CK-274 (which can exist in various forms) is about 2.5 mg are manufactured. In some embodiments, tablets in which the amount of CK-274 (which can exist in various forms) is about 7.5 mg are manufactured. It will be appreciated by those skilled in the art that, in addition to CK-274, tablets may also include various other components described herein, such as fillers, binders, disintegrants, surfactants, lubricants, etc. In some embodiments, the tablets are film coated.

[0329] Example

[0330] The application can be better understood by reference to the following non-limiting examples, which are provided as exemplary embodiments of the application. The following examples are presented to more fully illustrate the embodiments, however, they should never be construed as limiting the wide scope of the application. Although some embodiments of the application have been shown and described herein, it should be apparent that such embodiments are provided only by way of example. Without departing from the spirit and scope of the present invention, those skilled in the art may make many changes, modifications and substitutions. It should be understood that various alternatives to the embodiments described herein may be adopted when practicing the methods described herein.

[0331] Example 1

[0332] This first-in-human study of aficontan (also known as CK-274) was conducted to evaluate its safety, pharmacokinetic, and pharmacodynamic profile, including the effects of food or the CYP2D6 poor metabolizer (CYP2D6-PM) phenotype. Aficontan is a selective cardiac myosin inhibitor that reduces preclinical measures of left ventricular contractility 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 to 55 years to receive single ascending doses or multiple ascending doses (14 or 17 days) of aficontan or placebo. 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). At single doses of ≤50 mg and multiple doses of ≤10 mg of aficontan, adverse events were generally mild and no more frequent than with placebo. In the single ascending dose cohort, plasma concentrations of aficontan increased in a dose-proportional manner; the half-life of aficontan is 75 to 85 h. Neither food nor CYP2D6-PM phenotype had a clinically significant effect on pharmacokinetics. With a single 50-mg dose, the mean left ventricular ejection fraction (LVEF) was reduced by 5.5% compared to baseline (p=0.0001). With multiple doses, a mean LVEF reduction of 5.0% was observed after 10 mg of aficontan once daily for 14 days. At the doses evaluated, aficontan appears to be safe and well tolerated. The pharmacodynamic effect on LVEF was demonstrated, which provides support for further clinical studies of aficontan.

[0333] method

[0334] Study Overview and Ethics. The study used a randomized, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) design ( Figure 2The study was not designed to determine a maximum tolerated dose, but rather to determine a pharmacologically active dose range, defined as giving an absolute decrease in left ventricular ejection fraction (LVEF) from baseline within the range of 5% to 15% (e.g., a decrease from a baseline LVEF value of 70% to between 55% and 65%). Dose escalation should be stopped when this range is reached, or when a non-tolerated dose is determined (if earlier).

[0335] Participants and Treatments. To be eligible for this study, participants should be healthy adults aged 18 to 55 years with a body mass index of 18.0 to 32.0 kg / m 2 , with normal electrocardiogram (ECG) and clinical laboratory values, or only mild abnormalities that were considered clinically insignificant. Participants also had to have normal cardiac structure and function, LVEF ≥ 60% for the first 4 SAD cohorts, LVEF ≥ 65% for the subsequent SAD cohorts, all MAD cohorts, and food effect cohorts, and LVEF ≥ 55% for the CYP2D6-PM cohort. Participants were not allowed to use any prescription medications within 14 days, over-the-counter medications (except acetaminophen) within 7 days, or tobacco or nicotine within 3 months before the study; in addition, they were not allowed to consume alcohol, caffeine, or grapefruit within 48 hours before study enrollment.

[0336] The randomization schedule was generated centrally for each cohort and treatment period. In all cohorts, aficontan or matching placebo was administered in granular form as capsules containing approximately 240 ml of water. Study medication was administered after an overnight fast, except during the fed period in the food effect cohort.

[0337] Single ascending dose (SAD) cohorts. The SAD portion of the study used a randomized, double-blind, placebo-controlled, sequential, ascending dose design in which participants received single ascending oral doses of study medication. The 7 cohorts were dosed sequentially ( Figure 2 Of the 8 participants within each cohort, the first 2 were randomized (1:1) to aficontan or placebo and followed for a minimum of 2 days before dosing the remaining participants in the group. The remaining 6 participants were then randomized (5:1) to receive a single oral dose of aficontan (1 mg, 3 mg, 10 mg, 25 mg, 40 mg, 50 mg, or 75 mg) or placebo.

[0338] The initial dose of aficontan was selected using criteria based on previous animal studies and United States Food and Drug Administration guidelines with a safety margin of ≥10-fold. Dose escalation will be stopped when results determine a pharmacologically active dose range that results in a 5% to 15% decrease in LVEF or a non-tolerable dose, whichever occurs first.

[0339] Recommendations for dose escalation for the SAD cohort and the MAD cohort described below were made by the treating investigator (who was blinded to treatment group) and approved or disapproved by the unblinded Dose Level Review Committee (DLRC). Decisions were made when ≥6 participants had been treated and followed for ≥3 days, including the collection of clinical, laboratory, ECG, and telemetry data and appropriate assessment of maximum plasma drug concentrations (C 最大 ) echocardiogram of LV function at the time of escalation. Escalation criteria included no more than 2 participants in a dose group experiencing LVEF <50% and no individual experiencing LVEF <45%. Dose escalation criteria were as follows: (1) the individual did not have ongoing cardiac serious adverse events related to study drug; (2) 2 individuals did not experience similar non-cardiac serious adverse events in the same organ system that appeared to be related to study drug; (3) 2 individuals treated with afibactam did not experience a decrease in left ventricular ejection fraction (LVEF) >15% compared to the last pre-dose value (determined by the Dose Level Review Committee [DLRC]); (4) no individual experienced LVEF <45% (unless determined by the DLRC and treating investigator to be unrelated to study drug); and (5) the treating investigator and DLRC approved the escalation and next dose level based on their clinical judgment.

[0340] Multiple ascending dose (MAD) cohort. The MAD cohort also uses a randomized, double-blind, placebo-controlled, sequential design. When the SAD cohort determines that a single oral dose is well tolerated and associated with the observed PD effect, the MAD cohort is enrolled. Each of the 3 MAD cohorts includes 8 participants, who are randomly assigned (6:2) to aficontan or placebo. Participants receive a once-daily oral dose of the study drug for 14 days (in the cohorts comparing 5 or 10 mg aficontan to placebo) or 17 days (for the cohorts comparing 7.5 mg aficontan to placebo).

[0341] CYP2D6 Poor Metabolizer Cohort. A separate cohort was enrolled to evaluate the potential impact of CYP2D6 genetic variants on the PK properties of aficontan. The CYP2D6 gene encodes the cytochrome P450 2D6 enzyme, which is described as the most extensively characterized polymorphic drug-metabolizing enzyme, and previous in vitro studies have implicated CYP2D6 as a potential metabolizer of aficontan.

[0342] CYP2D6 genotype was determined at screening of 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. Figure 2 Each participant received a single dose of aficontan (10 mg) or placebo. Nine participants were randomized (7:2), with the sentinel dosing group consisting of the first 2 participants treated.

[0343] Food Effect Cohort. To assess the effect of food on the PK of aficontan, a separate cohort was enrolled after completion of the last SAD cohort, with a planned enrollment of 8 to 12 participants. Participants received 2 single doses of 10 mg aficontan, ≥14 days apart, in an open-label, 2-way crossover design. Participants were randomized in a 1:1 ratio to 1 of 2 sequences: fasted / fed or fed / fasted. During the fasting period, aficontan was administered after an overnight fast; during the fed period, aficontan was administered 30 minutes after the start of a high-fat breakfast.

[0344] Evaluate

[0345] Safety and tolerability. Safety is assessed according to the incidence of adverse events (AE) and the incidence of reduced LVEF. Treatment-emergent AE (TEAE) is defined as an AE that begins or increases after the study drug is administered. All AEs are coded using the Medical Dictionary for Regulatory Activities 21.1 version and graded using the National Cancer Institute Common Terminology Criteria for AE (4.03 version) 5-point severity scale. Each AE is judged by the treating investigator to be related or unrelated to the study drug. Clinical laboratory tests are obtained at regular intervals in all cohorts.

[0346] For safety monitoring, participants in all cohorts underwent periodic echocardiograms evaluated by cardiologists. In the SAD and MAD cohorts, echocardiograms were also reviewed by the echocardiography core laboratory for PD assessment, as described below. In addition, participants in all cohorts were monitored using a Holter monitor with continuous 12-lead ECG recordings. For safety monitoring, a single 12-lead ECG was extracted periodically at screening, before dosing, and throughout follow-up and interpreted by the investigator. In the SAD, MAD, and CYP2D6-PM cohorts, cardiac dynamics ECGs (triplicate 10-second, 12-lead ECG recordings) were obtained before the corresponding PK blood and ECG intervals quantified by qualified readers.

[0347] Pharmacokinetic Analysis. For all study groups, blood samples were obtained for PK assessments before dosing, up to 12 times daily on Day 1, and then at regular intervals throughout the study. Blood samples were collected according to the following schedule: SAD Cohort: Day 1: before and after dosing at 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h, 36 h, 48 h, 72 h, 96 h, and 216 h. MAD cohort (14-day dosing): Day 1: before and 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, and 12 h after dosing; Days 2, 4, 5, 6, and 9: before dosing (corresponding to trough samples after dosing on Days 1, 3, 4, 5, and 8) and 1.5 h after dosing; Days 3, 7, 8, Days 10, 11, 12 and 13: before dosing (corresponding to trough samples after dosing on days 2, 6, 7, 9, 10, 11 and 12); Day 14: before dosing and 0.25h, 0.5h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h, 48h, 72h and 168h after dosing. MAD cohort (17 days of dosing): Day 1: before and 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, and 12 h after dosing; Days 2, 4, 5, 6, and 9: before dosing (corresponding to trough samples after dosing on Days 1, 3, 4, 5, and 8) and 1.5 h after dosing; Days 3, 7, 8, 10, and 12 h after dosing Day 11, Day 12, Day 13, Day 14, Day 15, and Day 16: Pre-dose (corresponding to trough samples after dosing on Days 2, 6, 7, 9, 10, 11, and 12); Day 17: Pre-dose and 0.25h, 0.5h, 1.5h, 2h, 2.5h, 3h, 5h, 7h, 9h, 12h, 24h, 36h, 48h, 72h, and 168h. CYPD6-PM Cohort: Day 1: Pre-dose and 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h, 48h, 72h, 96h, 216h, 312h, and 552h. Food effect cohort: Day 1: before and 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h, 48h, 72h, 96h, 144h, and 216h after dosing. Version 7.0 uses a standard non-compartmental approach to calculate PK parameters; actual sample collection times are used.

[0348] Plasma concentrations of aficontan were measured using a high performance liquid chromatography-tandem mass spectrometry method, the accuracy, precision, linearity, sensitivity and specificity of which were validated at Celerion (Lincoln, Nebraska). The analytical range (lower limit of quantitation to upper limit) of aficontan was 1.00 ng / ml to 500 ng / ml.

[0349] Echocardiograms. For PD assessment of LVEF, echocardiograms for the SAD and MAD cohorts were interpreted by an echocardiography core laboratory and used for all data analyses and dose level review decisions, with immediate local interpretation of echocardiograms performed for safety monitoring. In the SAD cohort receiving 1 mg, 3 mg, or 10 mg aficontan, echocardiograms were obtained on Day -1, predose on Day 1, and at 1.5 h, 4 h, and 24 h postdose. For the SAD cohort receiving 25 mg, 40 mg, 50 mg, or 75 mg aficontan, echocardiograms were obtained on Day -1, predose on Day 1, and at 1.5 h, 6 h, and 24 h postdose. If the 24-h LVEF had not returned to near or above baseline, as determined by the investigator, an echocardiogram was obtained only on Day 3 (48 h postdose). In the MAD cohort, echocardiograms were obtained on day −1, predose on day 1, and 1.5 h postdose on days 2, 4, and 9, and 1.5 h, 24 h, and 72 h postdose on day 14 (for the 5-mg and 10-mg cohorts) or 1.5 h, 24 h, and 72 h postdose on day 17 (for the 7.5-mg cohort). If the participant's prior LVEF was not close to or above baseline, as determined by the investigator, an echocardiogram was obtained only 3 days after the last dose (day 17 or day 20).

[0350] Statistical Analysis. The sample size selected for this study was based on a precedent set of other first-in-human PK studies of similar nature and not on a power calculation. All participants who received ≥1 dose of study drug (aficontan or placebo) were included in the safety analysis. All participants who received ≥1 dose of study drug and had ≥1 evaluable PK plasma profile were included in the PK analysis set.

[0351] The PK analysis was designed to evaluate single-dose kinetics, multiple-dose (steady-state) kinetics, the effects of CYP2D6 phenotype on the absorption and elimination of aficontan, and the effects of food on the absorption and elimination of aficontan. For the SAD cohort, a power model was used to evaluate dose proportionality of aficontan on day 1. For the MAD cohort, a power model was used to evaluate dose proportionality on day 1 and day 14 or day 17. Several considerations were taken into account when evaluating dose proportionality of a drug, such as results from statistical analysis of the power model (e.g., slope estimates and width of 2-sided 95% confidence intervals [CIs]), qualitative assessments of PK specific to the drug, and clinical relevance. For the SAD cohort, the parameter used to evaluate dose proportionality was the time from time 0 to the last measurable concentration (AUC 末次 ) of the plasma drug concentration-time curve (AUC), the AUC extrapolated from time 0 to infinity (AUC inf ), AUC from 0 to 24 h (AUC 24 ) and maximum plasma concentration (C 最大 ). For the MAD cohort, the parameter is AUC 24 and C on day 1 最大 , plus the AUC at the end of the dosing period (AUC tau ) and C on day 14 or 17 最大 By including the secondary (ln dose) 2 and three times (ln dose) 3 The statistical linear relationship between the ln-converted PK parameter and the ln-converted dose was verified by using the effect. A statistical linear relationship was established if the quadratic and cubic effects were not statistically significant using the 5% significance level, or if the effects were statistically significant but were of such small magnitude that they were not clinically relevant. PROC MIXED performed a dose-proportional analysis. A dose proportionality was established if a statistically linear relationship was shown and if the 2-sided 95% CI around the slope estimate parameter included a value of 1 for the dose-dependent parameter.

[0352] In the MAD cohort, Helmert contrast was used to compare ln-transformed plasma trough concentrations (C 谷 ) values ​​were used to perform steady-state analysis of aficontan. Analysis of variance (ANOVA) models were performed separately for each dose level; day was included as a fixed effect. Hemetic contrasts were developed so that the mean of each time point was compared to the mean of subsequent time points. Steady-state was established at the time point where no statistical difference (α=5%, 2-sided) was observed using subsequent time points.

[0353] All participants who received ≥1 dose of study drug and had ≥1 pre-dose and ≥1 post-dose echocardiogram measurements were included in the PD analysis set. Descriptive analyses included absolute decrease in LVEF from baseline and categorical LVEF response (proportion of participants with LVEF decrease from baseline of ≥5%, ≥10%, and >15% and proportion of participants with LVEF <50% and <45%). Version 9.3 or higher generates descriptive statistics of echocardiographic parameters.

[0354] Dose-response analysis was performed using analysis of covariance (ANCOVA) to determine the least square mean difference (Afecontan minus placebo). To analyze the effect of drug dose on echocardiographic parameters in the SAD and MAD cohorts, a linear mixed model using repeated measures analysis of covariance (ANCOVA) was used to perform inferential analysis on the PD analysis set. ANCOVA used baseline values ​​as covariates, including treatment, time point, and time point-treatment interactions as fixed effects, and changes compared to baseline as dependent variables. Unstructured variance-covariance structure was used, and the model took into account repeated measurements at time points. ANCOVA analysis was performed separately for each study section and each PD parameter. The least square mean, the difference of the least square mean (active minus placebo) and the relevant 2-sided 95% CI were presented for each comparison.

[0355] Analyses of concentration 'bins' and exposure responses were also performed using ANCOVA. PROC MIXED performed all comparative analyses. Another inferential analysis was implemented in the SAD and MAD cohorts to evaluate the relationship between the concentration of aficontan and the LVEF of participants in the PK / PD analysis set. Concentration bin ANCOVA was implemented using a linear mixed model for repeated measures analysis, using the concentration bin group as a fixed effect, the baseline PD parameter as a covariate, the change compared to the baseline as the dependent variable, and a random intercept for adjusting repeated measures. An unstructured variance-covariance structure was used. The plasma concentration of aficontan was paired with consistent PD parameters. ANCOVA compared the changes in PD parameters between each bin and the pooled placebo group. The least square mean, the difference of the least square mean (bin group minus placebo) and the relevant 2-sided 95% CI were presented for each comparison. ANCOVA analysis was performed separately for each study section. For all time points where PK data and PD measurements were available, the time points were pooled for analysis. In each part of the study, the concentration of aficontan with time-matched PD data was pooled and sorted in ascending order. The data were then divided into 5 groups of observations ('bins') from minimum to maximum, each consisting of 20% of the data points. Each bin was treated as a separate group. The concentration bins consisted of the placebo group and 5 bin groups based on the concentration pooled across all time points of aficontan treatment.

[0356] The above analysis was then repeated using concentration as a continuous variable to estimate exposure-response trends. Random intercept effects and random concentration effects were added to the ANCOVA. Estimates of the concentration slope and corresponding 2-sided 95% CIs are presented along with the ANCOVA analysis for each study part.

[0357] For all time points for which PK data and PD measures were available, the time points were pooled for analysis.A nominal significance level of 5% was used for statistical comparisons, without adjustment for multiplicity.

[0358] result

[0359] 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 food effect cohort. All participants completed the study. The mean age of each cohort was between 32 and 40 years old, and most participants were male (Table 1).

[0360] Table 1: Baseline characteristics

[0361]

[0362] Values ​​are mean (range), n (%) or mean ± SD. BMI = body mass index; LVEF = left ventricular ejection fraction; MAD = multiple ascending dose; CYP2D6-PM = cytochrome P450 2D6 poor metabolizer; SAD = single ascending dose; SD = standard deviation.

[0363] For the SAD cohort, there were no safety issues that prohibited dose escalation between 1 mg and 25 mg. With the next planned dose (50 mg), 1 participant had a post-dose LVEF <50% (46.2%); however, this did not meet the dose escalation stopping rule and the 75-mg cohort was started. The sentinel participant in the 75-mg cohort had a post-dose LVEF <45%; therefore, other participants were not dosed at 75 mg. Therefore, the 50-mg group was expanded and the other 5 participants in this cohort were dosed. After expansion, 1 participant in the 50-mg dose group experienced an LVEF <45%, which also decreased by >15%. Therefore, other participants were not dosed at ≥50 mg. The DLRC determined that the dose appropriate for the final single-dose cohort was 40 mg.

[0364] Following the results of the 1-mg to 25-mg SAD cohort, the first MAD cohort was initiated with 5 mg aficontan once daily for 14 days. There were no safety issues, and the next cohort was initiated with 10 mg once daily for 14 days. In this cohort, 2 participants met stopping criteria based on echocardiographic findings. The DLRC decided that the next treatment level should be 7.5 mg to better characterize the PK at steady state; therefore, the dosing period was expanded from 14 to 17 days to ensure that PK had reached steady state by the last day of dosing.

[0365] Safety and tolerability. There were no serious AEs, and no participant discontinued the study due to AEs. For single-dose and multiple-dose administration, the observed TEAEs were generally mild (grade 1), and aficontan was no more frequent than placebo (Tables 2 and 3). In summary, in both the SAD and MAD cohorts, the most common TEAE was headache (Tables 2 and 3).

[0366]

[0367]

[0368] Echocardiographic-related AEs of decreased ejection fraction <45% based on study echocardiography expert assessment were reported in 3 participants: 1 each in the SAD 40-mg cohort, 50-mg cohort, and 75-mg cohort (Table 4). All AEs were grade 1 and resolved at the time of the next echocardiographic assessment (within 2.5h to 4.6h). A single participant receiving 75mg afecontan had an LVEF of 34.6% at 1.5h post-dose, a 31.5% decrease in LVEF and concluded that dose escalation in the SAD portion of the study was as discussed above. At the follow-up assessment 2.5h later, the LVEF had returned to 51.9%. No AEs of decreased ejection fraction <45% were reported in the MAD, CYP2D6-PM, or food effect cohorts.

[0369] In all cohorts, the average safety ECG parameters at the assessed time points were within normal limits. No clinically significant changes from baseline were observed in any parameter. The QT interval (QTcF) corrected for heart rate using the Fridericia's formula did not exceed 450ms at baseline or at any assessment during the dosing interval, except for 2 individuals whose baseline QTcF was ≥440ms and whose QTcF values ​​increased by 3ms and 13ms, respectively. In all cohorts, the QTcF interval of >30ms did not increase, except for 1 participant in the SAD placebo group whose QTcF interval increased by 33ms (427ms to a baseline value of 394ms) on day 5. In the cardiac dynamics assessment, the category analysis of ECG parameters did not reveal cardiac safety issues, and there was no evidence of a positive QT effect after a single or multiple doses of afecontan.

[0370] 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.

[0371] Table 4: Echocardiographically related AEs in patients with reduced ejection fraction <45%

[0372]

[0373] *Time after drug administration. LVEF values ​​used for safety assessment were determined by the study cardiologist. In the SAD cohort, postdose echocardiograms were performed at 1.5 h, 4 h, 6 h, 24 h, and 48 h after dosing. AE = adverse event; LVEF = left ventricular ejection fraction; SAD = single ascending dose.

[0374] Pharmacokinetics

[0375] Single-dose kinetics. The plasma profiles of aficantan were generally well characterized at all dose levels, except for the lowest dose of 1 mg (due to concentrations approaching the lower limit of quantitation) and the highest dose of 75 mg (administered to only 1 participant), as discussed above. Over the dose range of 1 mg to 50 mg, mean maximum plasma concentrations and exposures increased in a dose-proportional manner, as shown in Table 1. 最大 and the area under the plasma concentration-time curve (AUC 24 ) increased with increasing doses. Figure 3A-3B and Table 5). The mean clearance and distribution volume were similar at each dose. The median time of maximum concentration was observed to be between 0.5h and 2.8h, with a maximum time of 4.0h for all participants. The mean half-life ranged from 75h to 85h.

[0376]

[0377] Multiple-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); however, by day 2, there was little difference between the mean concentrations of the 7.5-mg and 10-mg doses ( Figure 4 ). The plasma PK parameters are shown in Table 6. By the end of the treatment period (Day 14 or Day 17), the mean plasma concentrations were between 2 and 2.5 times the plasma concentrations on Day 1. The terminal elimination half-life estimates for each dose were consistent, ranging between 77 h and 86 h. The clearance rates for the 5-mg and 10-mg doses were similar, and the accumulation ratios for the three doses were similar. Consistent with the observed terminal elimination half-life estimates, steady state was reached after 10 to 12 days ( Figure 4 ).

[0378] Table 6: Summary of plasma aficantan pharmacokinetics following multiple oral doses

[0379]

[0380] CYP2D6 poor metabolizer cohort. The mean half-life was prolonged to 110 h in CYP2D6-PM compared with 85 h in the extensive metabolizers (i.e., 10-mg SAD cohort); however, no increase in AUC was observed in this group, and the geometric mean AUC was 679 ng·h / ml (geometric CV % 35) compared with 679 ng·h / ml (geometric CV % 35) in the extensive metabolizers (Table 5). 24 The clearance of CYP2D6-PM was 495 ng·h / ml (geometric coefficient of variation % [CV%] 19) (Table 7). CYP2D6-PM did not appear to have a reduced clearance that would produce a clinically meaningful difference in exposure.

[0381] Table 7: Summary of plasma afecontan pharmacokinetics in the CYP2D6 poor metabolizer cohort

[0382]

[0383] The dose of aficantan was 10 mg. AUC and C 最大 Values ​​are presented as geometric mean and geometric CV%, T 最大 Values ​​are presented as median (range), and all other parameters are presented as arithmetic mean ± standard deviation. AUC 24 = Area under the plasma drug concentration-time curve from time 0 to 24 h; AUC inf = AUC extrapolated from time 0 to infinity; CL / F = apparent total body clearance; C 最大 = maximum plasma concentration; CV% = coefficient of variation %; PK = pharmacokinetics; t 1 / 2 = half-life; T最大 = time to reach maximum plasma concentration; Vz / F = apparent volume of distribution.

[0384] Food Effect. The PK parameters of aficontan in the food effect cohort are shown in Table 8. When taken with food, the C 最大 The increase was approximately 30% and the time to reach the maximum observed concentration was shortened (1.5 vs. 2.3 h). However, food had a minimal effect on AUC, and the geometric mean AUC in the fasting state was 24 (Geometric CV%) was 601 (33) ng·h / ml versus 631 (25) ng·h / ml in the fed state.

[0385] Table 8: Summary of Plasma Aficontan Pharmacokinetics in the Food Effect Cohort

[0386]

[0387]

[0388] Aficontan dose was 10 mg in each cohort. *For AUC inf ,t 1 / 2 , CL / F and Vz / F, n=4. For AUC inf ,t 1 / 2 , CL / F and Vz / F, n = 7. AUC and C 最大 Values ​​are presented as geometric mean and geometric CV%, T 最大 The median (range) is presented, and all other parameters are presented as the arithmetic mean ± standard deviation. 24 = Area under the plasma drug concentration-time curve from 0 to 24 hours; AUC inf = AUC extrapolated from time 0 to infinity; CL / F = apparent total body clearance; C 最大 = maximum plasma concentration; CV% = coefficient of variation %; t 1 / 2 = half-life; T 最大 = time to reach maximum plasma concentration; Vz / F = apparent volume of distribution.

[0389] Pharmacodynamics

[0390] Left ventricular ejection fraction. At baseline, the mean LVEF ranged from 61.0% to 67.5% across the cohorts (Table 1). In the SAD cohort, a mean decrease in LVEF was observed in the group receiving the highest dose of afibactam ( Figure 5A). The maximum mean decrease from baseline was seen in the 50-mg cohort at 1.5 h after dosing (least square mean difference 5.5%, p=0.0001). LVESV and LVEDV increased statistically significantly by 8.1 mL and 6.6 mL, respectively (Table 9). There were no significant changes in other echocardiographic parameters such as stroke volume, cardiac output, cardiac time intervals, and measures reflecting diastolic function (Table 9). A single participant receiving 75 mg of aficontan demonstrated a 31.5% decrease in LVEF 1.5 h after dosing, which resolved by 2.5 h after initiation but concluded that dose escalation in the SAD portion of the study was appropriate, as discussed above. In the MAD cohort, a significant decrease in LVEF occurred with continued dosing in the 10-mg cohort ( Figure 5B The maximum mean maximum % reduction from baseline was 5.0% ( 1.5 h after dosing) seen on Day 14 in the 10-mg cohort. Figure 5B The placebo-corrected reduction (least square mean difference) of 3.2% did not reach statistical significance (p=0.21), which may be attributed to lack of statistical power in this subgroup comparison.

[0391] Table 9: Echocardiographic parameters

[0392]

[0393] The table compares the placebo data with the data of 50 mg aficontan (the highest well tolerated single dose) for echocardiographic parameters at baseline and 1.5 h (the time of echocardiography closest to peak plasma concentration of aficontan). A = Peak A wave velocity, bpm = beats per minute, CFB = change from baseline, CO = cardiac output, E = Peak E wave velocity, EDV = end-systolic volume, ESV = end-systolic volume, ET = ejection time, e' lateral = tissue Doppler velocity of the lateral wall, IVCT = isovolumetric contraction time, IVRT = isovolumetric relaxation time, LAV = left atrial volume, LVEF = left ventricular ejection fraction, NS = not significant (p>0.05), SD = standard deviation, SV = stroke volume

[0394] Category LVEF Response. In the SAD cohort, an absolute decrease in LVEF of ≥5% from baseline was observed in 1 of 15 participants (7%) in the placebo cohort, 1 of 6 participants (17%) in the 3-mg cohort, 2 of 6 participants (33%) in the 40-mg cohort, 7 of 11 participants (64%) in the 50-mg cohort, and 1 of 1 participant (100%) in the 75-mg cohort, whereas no participant in the 1-mg, 10-mg, or 25-mg cohort had a decrease of ≥5%. An absolute decrease in LVEF of ≥10% occurred in 1 of 6 participants (17%) in the 40-mg cohort, 2 of 11 participants (18%) in the 50-mg cohort, and 1 of 75-mg cohort (100%). A decrease in LVEF to <50% was observed in 2 of 11 participants (18%) in the 50-mg cohort (48.2% and 45.5% based on core laboratory assessment) and in 1 of 1 participant in the 75-mg cohort (100%). Only participants in the 75-mg cohort experienced LVEF <45%.

[0395] In the MAD cohort, an absolute decrease in LVEF from baseline of ≥5% was observed in 4 participants: 1 of 6 participants receiving placebo (17%), 1 of 6 participants receiving 7.5 mg aficontan once daily (17%), and 2 of 6 participants receiving 10 mg aficontan once daily (33%). Among these participants, 2 participants in the 10-mg cohort had a decrease of ≥10%. No decrease in LVEF to <50% was observed in any of the MAD cohorts based on core laboratory assessment.

[0396] The PK / PD relationship of aficontan was illustrated by plotting the plasma concentration of aficontan versus the change in LVEF in the SAD and MAD cohorts. Fig. 6A and Figure 6B ). In the SAD cohort, there was a trend toward decreased LVEF with increasing plasma concentrations of aficontan. The relationship between LVEF and plasma aficontan concentration was statistically significant in bin concentration analysis (122 ng / ml to 524 ng / ml, p<0.0001) and concentration-slope analysis (p=0.0027) in the highest plasma concentration bin. In the MAD cohort, the relationship between LVEF and plasma aficontan did not reach statistical significance in either bin concentration analysis or linear regression analysis, which may be attributed to the more limited range of plasma concentrations explored and the smaller group size.

[0397] Discussion

[0398] This Phase 1, first-in-human study has established that aficontan is physiologically effective in reducing LVEF and doses (up to 50 mg as a single oral dose or up to 10 mg after multiple dosing) are well tolerated in healthy participants, thereby determining the pharmacologically active dose that will be used as the starting dose for studies in patients with HCM. In addition, a single oral dose of 10 mg was well tolerated in individuals with the CYP2D6-PM phenotype and food had no significant effect on the PK of aficontan. Together, these observations support continued development of aficontan for patients with HCM and provide a roadmap for Phase 2 studies.

[0399] Safety of Aficontan. No serious AEs were observed in the study and all participants completed the intended dosing as planned. In general, AEs were mild and of similar frequency between participants treated with Aficontan and placebo. Importantly, participants whose LVEF fell below 50% had no relevant symptoms or adverse changes in vital signs, and the LVEF in these cases returned to baseline within 24h. This study was not intended to find the maximum tolerated dose, and therefore dose escalation was immediately stopped once a significant PD effect was observed in the SAD and MAD parts of the study; therefore, the dose that was intolerant due to AEs was not determined.

[0400] Effect on LVEF. In the SAD cohort, a dose of 50 mg produced a mean LVEF reduction of 5.8%, whereas in the MAD cohort, 10 mg once daily for 14 days produced a mean absolute LVEF reduction of approximately 5%. The proportion of participants with an absolute reduction 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 had an absolute reduction in LVEF of ≥10% from baseline. In the SAD cohort, there was a statistically significant reduction in LVEF with increasing plasma concentrations of aficontan when the widest exposure range of aficontan was explored. Thus, the study met its secondary objectives of identifying a pharmacologically active dose and describing its PK / PD relationship.

[0401] Three participants had a decrease in LVEF to <50%, which was rapidly reversed after discontinuation of study drug. After a single dose of 50 mg, 2 (18%) participants experienced LVEF <50% (48.2% and 45.5%). After a single dose of 75 mg, 1 participant experienced a decrease in LVEF to 34.1%. In all cases, events were noted approximately 1.5 h after dosing, and LVEF recovered to >50% by 4 h to 6 h after dosing. SAD results provide information for dose selection for other parts of the study, and there were no echocardiographic AEs in the MAD, CYP2D6-PM, or food effect cohorts.

[0402] Implications of PK Results. Aficontan exhibited linear kinetics over the dose range of 1 mg to 50 mg; half-life was independent of concentration, and clearance was independent of dose. Steady state was reached by the end of day 10 with the 10-mg dose and by the end of day 12 with the 5-mg and 7.5-mg doses. There were no effects of food suggesting a need for a change in dosing. These findings support once-daily dosing in the fasted or fed state.

[0403] The relationship between plasma concentration and LVEF suggests a wide therapeutic index that will facilitate optimization of individual doses in patients with HCM who are expected to be titrated through an increasing range of doses until the desired PD effect is achieved. In addition, the half-life of aficontan (75 to 85 h after a single dose; 77 to 86 h after multiple doses) and the observed reversibility of the effect offer the potential advantage that steady state is achieved within 2 weeks and excessive effects on LVEF are easily reversed.

[0404] Conclusions. Aficontan demonstrated a favorable safety profile in healthy participants, with no serious AEs or meaningful changes in laboratory tests, ECG, or health assessments. Any decrease in LVEF to a value <50% was reversible within 6 h after a single dose. A pharmacologically active dose of aficontan was determined that could be used as a starting dose for studies in patients with HCM.

[0405] Example 2

[0406] A multicenter, randomized, placebo-controlled, double-blind, dose-finding Phase 2 clinical trial of CK-274 was conducted in patients with symptomatic non-obstructive HCM (nHCM) or HCM with MVO. The primary objectives of the trial were to determine the safety and tolerability of CK-274. Secondary objectives were to describe the concentration-response relationship of CK-274 on resting left ventricular ejection fraction (LVEF) as measured by echocardiography during the 10-week treatment period, to describe the dose-response relationship of CK-274, and to evaluate the plasma concentration of CK-274 in patients with nHCM.

[0407] Patients receiving disopyramide were excluded from the study. All patients received up to three escalating doses of CK-274 based on echocardiographic guidelines. Overall, treatment duration was 10 weeks, with a 4-week follow-up period after the last dose.

[0408] Because patient characteristics vary widely in this disease, dose titration is individualized based on pharmacodynamic (PD) response. This includes maintaining LVEF >55% to maximize efficacy and safety.

[0409] Patients were eligible for inclusion in the study only if all of the following criteria applied: 1. Able to understand and willing to sign the informed consent form (ICF) and willing to comply with all study procedures and restrictions for the duration; 2. Males and females aged between 18 and 85 years at screening; 3. Weight ≥45 kg at screening; 4. Diagnosed with HCM according to the following criteria: (a) LV hypertrophy and non-dilated LV chamber in the absence of other heart disease; and (b) Minimum wall thickness ≥15 mm (for a positive family history of HCM or a known pathogenic gene mutation, a minimum wall thickness ≥13 mm is acceptable); 5. Adequate echocardiographic acoustic window; 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 should have been taking a stable dose for >4 weeks and were expected to remain on the same medication regimen during the study. 10. Male patients are eligible to participate in the study if they agree to the following conditions during the study and for at least 10 weeks after the last dose: (a) not to donate sperm; plus (b) (i) not to use heterosexual intercourse as their preferred and usual lifestyle (long-term and lasting abstinence) and agree to maintain abstinence; or (b) (i) must agree to use male condoms and, if their female partners are women of childbearing potential, have their female partners use highly effective contraceptive methods; 11. Female patients are eligible to participate in the study if they are not pregnant or breastfeeding and at least one of the following conditions applies: (a) (i) not women of childbearing potential, or (a) (ii) women of childbearing potential who use highly effective contraceptive methods during the study and for at least 4 weeks after the last dose; and (b) women of childbearing potential must have a negative pregnancy test (urine or serum as required by local regulations) within 3 days before the first dose of the study intervention; 12. Able to complete all screening procedures.

[0410] Patients were excluded from the study if any of the following criteria applied: 1. Aortic stenosis or fixed subaortic occlusion; 2. Infiltrative or storage conditions known to cause cardiac hypertrophy that mimic HCM (e.g., Noonan syndrome, Fabry disease, disease, amyloidosis); 3. History of left ventricular (LV) systolic dysfunction (LVEF < 45%) at any time during their clinical course; 4. Documented history of current obstructive coronary artery disease (stenosis of one or more epicardial coronary arteries > 70%) or documented history of myocardial infarction; 6. Previous treatment with cardiotoxic agents (e.g., doxorubicin or similar drugs); 7. Treatment with disopyramide or antiarrhythmic drugs with negative cardiotonic activity within 4 weeks prior to screening; 8. Any ECG abnormality that the investigator believes poses a risk to patient safety (e.g., second-degree type II atrioventricular block); 9. Documented paroxysmal atrial fibrillation or flutter during the screening period; 10. Paroxysmal or permanent heart failure requiring rhythm-restoring therapy (e.g., direct current cardioplegia, ablation procedures, or antiarrhythmic therapy) ≤ 6 months prior to screening. Atrial fibrillation, but this clause does not apply if atrial fibrillation has been treated with anticoagulation and the heart rate has been adequately controlled for >6 months; 11. History of syncope or sustained rapid arrhythmia during exercise within 6 months before screening; 12. Placement of an implantable cardioverter-defibrillator (ICD) within 3 months before screening or plan to place an ICD during the study; 13. History of appropriate ICD shock for life-threatening ventricular arrhythmia within 6 months before screening; 14. Receiving a major organ transplant (such as heart, lung, liver, bone marrow, kidney) or expected to be transplanted within 12 months of randomization); 15. Liver damage, defined as total bilirubin (TBL) ≥1.5× upper limit of normal (ULN) at screening, or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3×ULN, only documented Gilbert syndrome (Gilbert syndrome) is allowed syndrome) and TBL ≥ 1.5 × ULN due to unconjugated hyperbilirubinemia without other liver diseases; 16. Any other clinically significant condition, malignancy, active infection, other illness or disease history or evidence, in the opinion of the investigator or medical monitor, the disease will pose a risk to patient safety or interfere with study evaluation, 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(by modified Diet in Renal Disease equation); 19. Currently participating in another investigational device or drug study or receiving an investigational device or drug <1 month (or 5 half-lives of the drug, whichever is longer) prior to screening; 20. Previously received or currently receiving mavacamten treatment; 21. Known allergy to any excipient in CK-3773274 film-coated tablets (e.g., mannitol, microcrystalline cellulose, cross-linked carboxymethyl cellulose, hydroxypropyl cellulose, sodium lauryl sulfate, magnesium stearate, Opadry QX White 21A180025).

[0411] In the study, patients received up to three ascending doses of CK-274 as shown in Table 11. Each patient received Dose 1 once daily for 2 weeks. At Week 2, patients underwent an echocardiogram 2 hours after administration of their dose. If the biplane LVEF was ≥55%, the patient was titrated up to Dose 2. Otherwise, the patient continued on Dose 1. If the LVEF was <50% at Week 2, treatment was discontinued. The dose adjustment algorithm is shown in Table 10 below.

[0412] After taking the assigned dose for an additional 2 weeks (i.e., Week 4), each patient will undergo an echocardiogram 2 hours after their dose. If the biplane LVEF is ≥55%, the patient will be escalated to the next higher dose. Otherwise, the patient remains on the same dose. If the LVEF is <50% at Week 4, the patient is returned to the previous dose level, or if the patient is taking Dose 1, treatment is stopped.

[0413] After taking an additional 2 weeks of the assigned dose (i.e., Week 6), each patient underwent an echocardiogram 2 hours after their dose. If LVEF was <50% at Week 6, the patient was titrated down to the previous dose level or, if the patient was taking Dose 1, treatment was discontinued.

[0414] Table 10: Dose adjustment algorithm

[0415]

[0416] Table 11: Dosage regimen

[0417] Dose 1 Dose 2 Dose 3 5mg 10mg 15mg

[0418] Echocardiograms obtained on treatment day 1, treatment weeks 2, 4, 6, and 10, and two weeks after the last dose were analyzed for several key structural and physiological parameters; measurements of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and cardiac troponin I were also monitored. Ambulatory cardiac monitoring was performed one week before treatment day 1 and at week 9.

[0419] Health Status and Health-Related Quality of Life: If available, patients completed patient-reported outcome (PRO) questionnaires prior to dosing, at Day 1, Week 6, Week 10, and Week 12. The following instruments were used at these visits: Short Form 36 Physical Functioning Subscale (SF-36-PFS), Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), SAQ7, PGI-C (Week 10 only), and CGI (Week 10 only).

[0420] Primary Safety Endpoint

[0421] The primary safety endpoints were: (i) the incidence of AEs reported from the first dose to the safety follow-up; (ii) the incidence of SAEs reported from the first dose to the safety follow-up; and (iii) the incidence of LVEF < 50% from the first dose to the safety follow-up.

[0422] Safety follow-up was defined as 4 weeks after the last dose.

[0423] Exploratory safety endpoints

[0424] Exploratory safety endpoints from the first IP dose to safety follow-up included: (i) the incidence of drug-related AEs in patients, AEs leading to IP discontinuation, and AE severity; (ii) observed values ​​and changes from baseline in clinical laboratory data, vital signs, and ECG parameters (e.g., heart rate, PR interval, QRS interval, QT interval, and QTc interval [Bazett correction and Fridericia correction]); (iii) categorical safety variables, including: (a) the number of patients (%) with LVEF <40% at each scheduled assessment point and at any time during the study; (b) the number of patients (%) with QTc in the following categories at each scheduled ECG assessment time: absolute value >450ms, >480ms, or >500ms; increase >30ms, >60ms compared to baseline; (c) clinically significant changes in clinical laboratory test values ​​and ECG parameters; and (d) the incidence of arrhythmias within a 1-week period reported at baseline before dosing and at Week 10 as assessed by an ambulatory cardiac monitoring device.

[0425] Pharmacokinetic endpoints

[0426] The secondary PK endpoint was the C of CK-274 observed during the dosing period at the time points listed in Table 12. 最大 and C 谷 PK was also assessed via development of a population PK model.

[0427] Table 12: Summary of PK and echocardiographic time points

[0428]

[0429] a The visit occurred at least 14 days but no more than 17 days after the last visit.

[0430] Pharmacodynamic endpoints

[0431] The secondary PD endpoint of the study was the slope of the relationship between plasma concentration of CK-3773274 and the change from baseline in resting LVEF.

[0432] Core laboratory echocardiographic parameters were evaluated at baseline and during treatment at weeks 2, 4, 6, and 10, and at week 12 (follow-up) after a 2-week washout.

[0433] Exploratory pharmacodynamic endpoints

[0434] Exploratory PD endpoints included, but were not limited to: (i) the relationship of the plasma concentration range of CK-3773274 to LVEF, LVFS, and global longitudinal strain (GLS); (ii) the observed values ​​and changes from baseline in the echocardiographic parameters described in Table 13 and assessed by the core laboratory at Weeks 2, 4, 6, 10, and 12 during treatment; (iii) the change from baseline to Week 10 in NT-proBNP; (iv) the change from baseline to Week 10 in hs-cTnI; and (v) the proportion of patients with LVEF > 50% and a ≥ 50% decrease in NT-proBNP from baseline.

[0435] For selected PD measures where the statistical distribution may deviate from normal, proportional changes from baseline were assessed.

[0436] Table 13: Echocardiographic parameters measured

[0437] Resting LVOT-G LVEDV IVST LVOT-G after Valsalva maneuver LVESD IVCT LVEF LVESV IVRT LVFS LVCO E / E' Ratio GLS LV stroke volume LAV LVEDD LVOT VTI

[0438] GLS = global longitudinal strain; IVCT = isovolumetric contraction time; IVRT = isovolumetric relaxation time; IVST = interventricular septum thickness; LAV = left atrial volume; LVCO = left ventricular cardiac output; LVEDD = left ventricular end-diastolic diameter; LVEDV = left ventricular end-diastolic volume; LVESD = left ventricular end-systolic diameter; LVESV = left ventricular end-systolic volume; VTI = velocity time integral.

[0439] Other exploratory endpoints

[0440] Other exploratory endpoints included: (i) change in NYHA functional class from baseline to week 10; and (ii) the percentage of patients with baseline NYHA class III disease who improved to NYHA class I or II disease at week 10.

[0441] Exploratory health status and health-related quality of life endpoints included, but were not limited to, the change from baseline to week 10 and the slope of change from baseline to week 10 for each of the following: (i) T scores on the PROMIS Dyspnea Severity Short Form 10a, PROMIS Dyspnea Severity Short Form 10a with two additional items, PROMIS Fatigue Short Form 7a, and PROMIS Physical Function Short Form 8b; (ii) normative-based T scores on the SF-36 Physical Function subscale; (iii) individual responses to the HCM Global Impression of Condition questionnaire at baseline, week 6, and week 10; (iv) individual responses to the HCM Global Impression of Change questionnaire at week 6 and week 10; (v) change in KCCQ score from baseline to week 10; and (vi) change in SAQ7 score from baseline to week 10.

[0442] Interim results

[0443] 41 patients were enrolled. Baseline characteristics are shown in Table 14.

[0444] During the titration period (weeks 0-6), LVEF decreased modestly; no LVEF was less than 50% during the titration period (see Fig. 9 ). Thirty-five patients (85%) achieved a daily dose of 15 mg of aphicontin; 6 patients (15%) achieved 10 mg (see Fig.10 ).

[0445] Geometric mean NT-proBNP (%CV) decreased at each scheduled visit, with proportional changes from baseline being highly statistically significant (see Fig.11 , #P<0.0001); a significant decrease of 56% was achieved at the end of treatment (week 10) (p<0.0001). hs-cTnI also decreased significantly proportionally to baseline at each study visit (*p<0.05) and reached a significant decrease of 21% at the end of treatment (week 10) (p<0.05); after a 2-week washout, both cardiac biomarkers rebounded upward after drug treatment (see Fig.12 ). NYHA class improved during treatment. Twenty-two of 41 patients (54%) experienced a change of ≥1 NYHA class, with 12 patients improving from class III to class II; 4 patients improving from class III to class I; and 8 patients improving from class II to class I (see Fig.13 ).

[0446] The KCCQ-CSS score improved by 7.3 (-1.0, 18.8) points from a median baseline value (IQR) of 69.8 (56.8, 83.9), and 21 patients (54%) improved by ≥5 points ( Fig.14 and Fig.15Fourteen patients (34%) with symptomatic angina (SAQ-AF ≤ 80) at baseline had an improved response to treatment, with a mean (SD) change in SAQ-AF from baseline to week 10 of 14.3 (± 16.0) (p = 0.005) ( Fig.14 ).

[0447] Table 14: Baseline Characteristics

[0448]

[0449]

[0450] Medium-term safety

[0451] 85% of the cohort reached the 15 mg dose by week 6 (see Fig.10 ). 66% of patients had at least 1 TEAE (see Table 15). There were no discontinuations due to AEs. One patient had a dose reduction to 10 mg at week 9 due to the AE fatigue. One patient had a 2-day dose interruption due to the AE palpitations (which resolved). Three patients had SAEs: bronchitis, new-onset atrial fibrillation, cardiac arrest. None of these were considered by the investigator to be related to afibactam.

[0452] Three patients (7.3%) had an LVEF <50% at Week 10. Two occurred in patients with permanent AF, one of whom reported palpitations requiring adjustment of rate control medication. No AEs of heart failure were reported. All three patients had returned to baseline LVEF by Week 12.

[0453] Table 15: Safety

[0454]

[0455]

[0456] *The patient voluntarily interrupted IP for 2 days due to palpitations (AE) in the setting of an upper respiratory tract infection (AE). The patient restarted IP per site instructions. The palpitations resolved.

[0457] Second interim results

[0458] 41 patients were enrolled. Baseline characteristics are shown in Table 16.

[0459] There was a modest and reversible decrease in LVEF from baseline to week 10 of -5.5% (9.9) Fig.17 There were no treatment interruptions or down-titration events related to LVEF <50%, and no events related to LVEF <40%.

[0460] At week 10, the mean KCCQ-CSS improved by 10.6 points (p<0.0001 for change from baseline to week 10) ( Fig.18 , data presented as means and standard deviations). 58% of all patients experienced a clinical reduction in symptom burden, with almost half reporting moderate and great-very great improvements ( Fig.19 ).

[0461] NYHA class improved during treatment. 28% of patients achieved NYHA class 1 (asymptomatic) by week 10 ( Fig. 20 ), and 56% of all patients showed an improvement in function of ≥1 NYHA class. The change from baseline to Week 10 showed p=0.011 compared to the assumed 37% placebo effect.

[0462] Fourteen patients (34% of patients) with symptomatic angina (SAQ-AF ≤ 80) at baseline had an improved response to treatment, with a mean (SD) change in SAQ-AF from baseline to week 10 of 14.3 (± 16.0) (p = 0.005) ( Fig.21 ).

[0463] Median NT-proBNP (IQR) decreased at each scheduled visit, with proportional changes from baseline being highly statistically significant (see Fig. 22 , ***P<0.0001). At the end of treatment (week 10), the mean (SE) decrease was -870 pg / mL (155.3) or 55% (p<0.0001). The median hs-cTnI (IQR) also decreased significantly proportionally to baseline at each study visit (*p<0.05; **p<0.005) (see Fig. 22 At the end of treatment (week 10), the mean (SE) reduction was significant -24.8 ng / L (11.8) or 21% (p<0.05). After a 2-week washout, both cardiac biomarkers rebounded upward after drug treatment (see Fig. 22 ).

[0464] Exploratory responder analyses were performed to consider treatment effects in certain patient subgroups. Responders were defined as those who demonstrated (a) a >50% reduction in NT-proBNP, (b) a ≥1 improvement in NYHA class, (c) a ≥5-point improvement in KCCQ, or (d) a combination of the foregoing. Potential differential treatment effects were observed in patients with a BMI ≥30 compared with those with a BMI <30. Fig.23A A consistent treatment effect was observed in other patient subgroups: patients who received beta-blockers had a significantly higher risk of developing leukopenia compared with those who did not ( Fig. 23B); patients with elevated TnI or E / e' (>13) compared with patients without elevated TnI or E / e' ( Fig.23C ); Patients with a genetic or family history of HCM compared to patients without a genetic or family history ( Fig.23D ).

[0465] Patients showed overall improvement in Doppler measures of diastolic function (lateral e'; lateral E / e'; septal E / e') from baseline to week 10 ( Fig.25 , showing mean values ​​and 95% CI).

[0466] Of the 41 patients enrolled, 7 with midventricular obstruction (MVO) were studied. MVO patients represent a subgroup of nHCM patients who are often excluded from other studies but suffer from severely limiting symptoms. All patients in this subgroup showed symptom improvement and reductions in NT-proBNP and hs-troponin I levels ( Fig.24 ).

[0467] Table 16: Baseline Characteristics

[0468]

[0469]

[0470] Second Interim Safety

[0471] Three patients (7.3%) had LVEF <50% at week 10 (EOT). No LVEF <40% occurred. All LVEFs normalized after 2-week washout (week 12) and there were no associated SAEs. Four patients (9.8%) experienced SAEs, including one death. None of the SAEs were attributed to afibactam.

[0472] in conclusion

[0473] Aficontin was generally well tolerated, with a modest targeted reduction in LVEF in response to aficontin within 10 weeks. Heart failure burden improved significantly in most non-obstructive patients during open-label therapy, along with improvements in cardiac biomarkers. Significant improvements were also achieved in angina. The mean reduction in the angina frequency score, meaning angina frequency decreased from once a day or week to once a week or month, was 14.3 points. Trends in markers of diastolic function suggest that longer exposure at the target dose may produce favorable echocardiographic evidence of improved myocardial relaxation.

[0474] Example 3

[0475] An open-label extension clinical trial of CK-274 is being conducted in patients with symptomatic nHCM or HCM with MVO. The duration of treatment is expected to be multi-year. The primary goal of the trial is to determine the safety and tolerability of CK-274 over a 5-year period.

[0476] Approximately 25 patients may be enrolled in this study. After a screening period of (up to) 56 days, eligible patients are administered a daily dose of aficontan. The highest maximum tolerated dose is derived from other ongoing studies of aficontan. Each patient starts at the lowest pre-specified dose and undergoes echocardiographically guided dose titration to the maximum tolerated dose (not to exceed the highest pre-specified dose). Dose adjustments should not be made more frequently than every 2 weeks.

[0477] Patients who completed the study as described in Example 2 and did not already have atrial fibrillation were eligible for inclusion in the study. Echocardiographically guided dose titration based on field readings was controlled by the investigator and could be performed at any time during the trial, as described below.

[0478] Study Design

[0479] On day 1, each patient underwent an echocardiogram; each patient received dose 1 of CK-274 once daily for 2 weeks. At week 2, each patient underwent a truncated echocardiogram 2 hours after administration of their dose. If biplane LVEF was ≥55%, the patient was titrated up to dose 2. Otherwise, the patient remained on 5 mg of CK-274. If LVEF was <50%, treatment was discontinued.

[0480] At Weeks 4, 6, 12, and every 12 weeks thereafter, each patient will undergo an echocardiogram or truncated echocardiogram 2 hours after administration of their dose (truncated echocardiogram at Weeks 4 and 6; and echocardiogram at Week 12 and every 12 weeks thereafter) to determine if additional dose titration is needed (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 Tables 17 and 18.) Figure 8 ). If the patient has an LVEF <40% after the Week 2 visit, a repeat echocardiogram may be performed to confirm the initial findings (preferably within 24 hours). If the echocardiographic findings are confirmed, the patient will receive a ≥2-day drug holiday. Once a regional echocardiogram shows an LVEF ≥55%, the patient may continue to take CK-274 at a reduced, previously tolerated dose.

[0481] Table 17: Dose adjustment algorithm

[0482]

[0483] Table 18: Dosage regimen

[0484] Dose 1 Dose 2 Dose 3 Dose 4 5mg 10mg 15mg 20mg

[0485] Echocardiography

[0486] The echocardiographic parameters to be measured include at least left ventricular parameters (resting left ventricular outflow tract pressure gradient (LVOT-G), LVOT-G after Valsalva maneuver, LVEF, LVFS, left ventricular strain, left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), LV stroke volume), ventricular septum and free wall thickness, E / e', E / A, LA volume.

[0487] Cardiac MRI

[0488] The cardiac magnetic resonance (CMR) imaging substudy evaluates the effects of long-term administration of aficontan doses on cardiac morphology, function, and fibrosis in HCM patients who are eligible and choose to participate. CMR is performed at baseline at any time during the screening period and can be performed within 8 weeks before the first dose of aficontan is given on Day 1. Patients who fail the screening and are rescreened do not need to repeat the baseline CMR. If the subject has been selected for the Example 5 CMR substudy, there is no need to repeat the baseline CMR. Patients with eGFR<30mL / min / 1.73m2 or allergic to gadolinium can only receive non-contrast CMR. Patients can also choose only non-contrast CMR evaluation for any other reason. Subsequent CMR studies are performed within ±30 days of the 48th and 144th week visits, or within 60 days before the 240th week or end of treatment (EOT) visit.

[0489] NYHA functional class was recorded. If available, patients completed patient-reported outcome (PRO) questionnaires: Kansas City Cardiomyopathy Questionnaire (KCCQ), Seattle Angina Questionnaire-7 (SAQ-7), EuroQol 5 Dimensions 5 Levels Instrument (EQ-5D-5L), Patient Global Impression of Change (PGI-C) scale, Clinical Global Impression (CGI) scale, SF-36 Physical Functioning subscale (SF-36PFS), as specified in Table 19.

[0490] Table 19: Health status and health-related quality of life planning form

[0491]

[0492] Primary End Point

[0493] The primary endpoints were: (i) the incidence of patient-reported adverse events (AEs); (ii) the incidence of patient-reported serious adverse events (SAEs); and (iii) the incidence of patients with left ventricular ejection fraction (LVEF) < 50%.

[0494] Exploratory End Points

[0495] The exploratory objectives of the study included (i) evaluating the steady-state pharmacokinetics of aficontan during chronic administration, as measured by C 谷 (ii) to evaluate the long-term effects of aficontan on cardiac biomarkers, as assessed by changes from baseline in NT-proBNP, hs-cTnI, Galectin-3, PINP, TIMP-1, CITP, soluble ST2, and other biomarkers at 12-week intervals until the end of participation; (iii) to evaluate the effects on functional outcomes, such as changes from baseline in NYHA functional class at 12-week intervals until the end of participation; and (iv) to evaluate the effects on symptoms of nHCM, such as by EQ-5D-5L, PGI-C at 12-week intervals. (v) to assess the pharmacodynamic effects of afibactam on cardiac function and structure, as assessed by changes from baseline to end of participation in the following echocardiographic measures of cardiac function and structure at 12-week intervals: LVEF; left ventricular fractional shortening (LVFS); left ventricular stroke volume (LVSV); left ventricular end-systolic volume and end-diastolic volume (LVESV and LVEDV, respectively); ventricular septum, free wall, and maximum wall thickness; left atrial volume; left ventricular strain (longitudinal, circumferential, radial); diastolic indices: E / e', E / A; (vi) to evaluate the effect of aficontan on electrocardiographic indices of abnormal myocardial repolarization, as assessed by the change from baseline to the end of participation in the proportion of patients with an LV strain pattern on ECG at 12-week intervals; (vii) to evaluate the effect of aficontan on cardiac structure, as assessed by the change from baseline to 1, 3, and 5 years and to the end of participation in the following measures of cardiac morphology and structure, assessed by cardiac magnetic resonance (CMR) imaging: RV and LV mass; ventricular septum, free wall, and maximum wall thickness; left atrial volume; diastolic indices: E / e', E / A; (vi) to evaluate the effect of aficontan on electrocardiographic indices of abnormal myocardial repolarization, as assessed by the change from baseline to 1, 3, and 5 years and to the end of participation in the following measures of cardiac morphology and structure, as assessed by cardiac magnetic resonance (CMR) imaging (viii) to assess the effect of aficontan on cardiac function as assessed by the change from baseline to 1, 3 and 5 years and at the end of participation in the following biventricular function assessed by CMR imaging: stroke volume (SV); ejection fraction (EF); cardiac output (CO); (ix) to assess the effect of aficontan on cardiac fibrosis as assessed by the change from baseline to 1, 3 and 5 years and at the end of participation in the following CMR parameters with late gadolinium enhancement (LGE): LGE mass (g), LGE mass % (as % of LV mass).

[0496] Example 4

[0497] This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled trial in participants with symptomatic nHCM. This Phase 3 trial was designed to further evaluate the effects of aficontan on quality of life, exercise capacity, heart failure symptoms, cardiac biomarkers, cardiac remodeling, and clinical outcomes. In addition, the safety and tolerability of aficontan were evaluated in participants with nHCM.

[0498] Approximately 420 eligible participants were randomly assigned in a 1:1 ratio to receive afibactam or placebo. Doses of 5 mg, 10 mg, 15 mg, or 20 mg of afibactam or matching placebo were administered in an ascending manner using echocardiography-guided dose titration. Randomization was stratified according to persistent atrial fibrillation and the presence or absence of intracavitary obstruction.

[0499] The study consisted of 2 parts: Part 1, which included Day 1 to Week 36; and Part 2, Week 36 to Week 72. All participants completed Part 1. At the end of Part 1, participants continued into Part 2 until the last randomized participant completed Part 1 (Week 36). At that time, all remaining active study participants in Part 2 had an End-of-Treatment Visit followed by an End-of-Study Visit.

[0500] Enrollment was limited so that approximately <10% of participants had persistent or permanent atrial fibrillation and approximately <10% of participants had a body mass index in the range of >35 to <40 kg / m2. Participants who completed the study had the option of transferring into a long-term open-label extension study.

[0501] A cardiovascular magnetic resonance imaging substudy was conducted in up to 100 participants.

[0502] Abbreviations: AE = adverse event; CGI = clinical global impression; CPET = cardiopulmonary exercise testing; EQ-5D-5L = EuroQol 5 dimensions 5 levels instrument; hs-cTnI = high-sensitivity cardiac troponin I; KCCQ = Kansas City Cardiomyopathy Questionnaire; KCCQ-CSS = KCCQ-clinical summary score; KCCQ-OSS = KCCQ-global summary score; LAVI = left atrial volume index; LVEF = left ventricular ejection fraction; LVMI = left ventricular mass index; MRI = magnetic resonance imaging; nHCM = nonobstructive hypertrophic cardiomyopathy; NT-proBNP = N-terminal prohormone brain natriuretic peptide; NYHA = New York Heart Association; PGI-C = patient global impression of change; PK = pharmacokinetic; PRO = patient-reported outcome; pVO2 = peak oxygen uptake; SAQ-7 = Seattle Angina Questionnaire-7; SBP = systolic blood pressure; VAT = ventilatory anaerobic threshold; VE / VCO2 = minute ventilation / carbon dioxide production.

[0503] Eligibility

[0504] Inclusion criteria: Participants who met all of the following criteria at screening were included in the trial: (1) aged 18-85 years. (2) body mass index <40 kg / m 2 . (3) Diagnosed with nHCM and screened by echocardiogram with the following results: (i) end-diastolic left ventricular (LV) wall thickness ≥15 mm in one or more myocardial segments, or ≥13 mm in one or more wall segments, and known pathogenic gene mutation or positive family history of HCM, and (ii) resting LVOT-G <30 mmHg and Valsalva maneuver LVOT-G <50 mmHg; and (iii) LVEF ≥60%; it should be noted that participants with a history of mid-cavity or apical obstruction were eligible in the absence of LVOT obstruction. (4) NYHA class II or III. (5) Respiratory exchange ratio ≥1.00 at screening cardiopulmonary exercise testing (CPET) and peak oxygen uptake (pVO2) ≤90% predicted for age and gender. (6) KCCQ-CSS score ≥30 and ≤85. (7) NT-proBNP: (a) NT-proBNP ≥ 300 pg / mL or NT-proBNP ≥ 900 pg / mL (if presenting with atrial fibrillation or atrial flutter), or (b) for black participants, NT-proBNP ≥ 225 pg / mL or NT-proBNP ≥ 675 pg / mL if presenting with atrial fibrillation or atrial flutter. (8) Hemoglobin ≥ 10 g / dL. (9) Participants taking beta-blockers, verapamil, diltiazem, or ranolazine should have been taking a stable dose for ≥ 2 weeks prior to baseline CPET and are expected to remain on the same medication regimen during the study. (10) Male participants were eligible to participate if they agreed to: a) refrain from sperm donation during the trial and for at least 10 weeks after the last IP dose, and b) during the trial and for 4 weeks after the last IP dose: (i) abstain from heterosexual intercourse as their preferred and customary lifestyle (long-term and continuous abstinence) and agree in writing to maintain abstinence, or (ii) must agree to use male condoms if their female partner is a woman of childbearing potential and have their female partner use highly effective contraceptive methods. (11) Female participants were eligible to participate if they were not pregnant, not breastfeeding, or planning to donate eggs and met at least one of the following criteria: a) were not women of childbearing potential, or b) were WOCBP and used highly effective contraceptive methods and their male partner agreed to use condoms during the trial and for at least 4 weeks after the last IP dose, or c) the WOCBP had a negative pregnancy test result (urine or serum, as required by local regulations) on Day 1, before the first dose of the study IP

[0505] Exclusion Criteria: Participants who met any of the following criteria were excluded from the trial: (1) Significant valvular heart disease (according to the investigator's judgment): (a) moderate or greater aortic stenosis or fixed subaortic obstruction, (b) moderate or greater mitral regurgitation. (2) Known or suspected infiltrative, genetic, or storage conditions that cause cardiac hypertrophy similar to nHCM (e.g., Noonan syndrome, Fabry disease, amyloidosis). (3) Known coronary artery stenosis ≥70%. (4) History of left ventricular systolic dysfunction (LVEF <45%) or stress cardiomyopathy. (5) Inability to exercise on a treadmill or bicycle (e.g., orthopedic restrictions). (6) Room air oxygen saturation readings <90% recorded at screening, or a history of significant chronic obstructive pulmonary disease or severe / significant pulmonary hypertension. (7) History of syncope, symptomatic ventricular arrhythmias, or exercise-induced sustained ventricular tachyarrhythmias within 3 months prior to screening. (8) History of resistant hypertension (persistently elevated blood pressure despite maximum doses of 3 or more classes of hypertension control medications). (9) Screening diastolic blood pressure > 100 mmHg. (10) Previous treatment with afibactam. (11) Treatment with marvacattan within 3 months prior to screening (must be discussed with the medical monitor prior to screening). (12) Receiving septal reduction therapy < 6 months prior to screening. (13) Considering or possibly considering heart transplantation or left ventricular assist device placement during the study period. (14) Paroxysmal or permanent atrial fibrillation was excluded only if the following conditions were met: (a) rhythm-restoring therapy (e.g., direct current cardioversion, atrial fibrillation ablation surgery, or antiarrhythmic therapy) was required within ≤ 3 months prior to screening, and (b) heart rate control and anticoagulation were not achieved for at least 3 months prior to screening.

[0506] Exclusion criteria for the cardiac MRI sub-study were: (1) inability to tolerate cardiac MRI. (2) presence of an implantable cardioverter-defibrillator (ICD). (3) presence of a pacemaker.

[0507] program

[0508] Participants randomized to receive aficontan may receive up to four escalating doses of IP during the initial 6 weeks of the trial, as shown in Tables 20 and 21 below. For participants randomized to receive aficontan, the initial dose of aficontan was 5 mg (Dose 1). Each participant received Dose 1 once daily for 2 weeks. At the Week 2 visit, participants underwent an echocardiogram approximately 2 hours after administration of their dose of study product (IP). If the LVEF read on the echocardiogram site was ≥60%, the participant had the dose titrated upward to 10 mg (Dose 2); otherwise, the participant remained on the same dose.

[0509] After taking the assigned dose for another 2 weeks (week 4), each participant underwent an echocardiogram approximately 2 hours after administration of their IP dose. If the LVEF on echocardiogram was ≥ 60%, the participant was titrated up to the next higher dose; otherwise, the participant remained on the same dose.

[0510] After taking the assigned dose for another 2 weeks (Week 6), each participant underwent an echocardiogram approximately 2 hours after administration of their IP dose. If the LVEF on echocardiogram was ≥ 60%, the participant was titrated up to the next higher dose; otherwise, the participant remained on the same dose.

[0511] After taking the assigned dose for an additional 2 weeks, at the Week 8 visit, each participant underwent an echocardiogram 2 hours after their IP dose to ensure LVEF ≥ 50%. If LVEF was < 50% at Week 8, participants were down-titrated to the next lower dose, or if participants were taking 5 mg (Dose 1), down-titrated to placebo.

[0512] If LVEF <50% on echocardiogram at any time point in the study, the participant was returned to the previous dose level or, if taking 5 mg, the IP was switched to placebo, in which case the participant remained on placebo for the remainder of the study. If the scheduled echocardiogram showed LVEF <40% at any time, study drug was temporarily withheld. Once LVEF recovered to ≥60%, treatment could be restarted at the next lower dose level after discussion with the medical monitor.

[0513] The maximum duration of treatment was 72 weeks, with a 4-week follow-up period after the last dose (Weeks 72 to 76). All participants were followed through at least Week 36 or Part 1 of the study. Participants who completed Week 36 continued in the double-blind, placebo-controlled study until Week 72 (following end of treatment [EOT] at Week 76) or until the last randomized participant in Part 1 completed Week 36. When the last randomized participant completed Week 36, all remaining active study participants had an End-of-Treatment Visit (within 4 weeks) followed by a 4-week follow-up End-of-Study Visit. Active time is expressed in Fig.16 middle.

[0514] Table 20: Titration period, dose titration

[0515]

[0516] *Echocardiographic criteria for scheduled dose titration

[0517] Table 21: Echocardiographic criteria for scheduled dose titration

[0518]

[0519]

[0520] Table 22: Key echocardiographic LV parameters to be measured

[0521] LVMI LVEDV IVST Medial and lateral e′ LVESD IVCT LVEF LVESV IVRT LVFS LVCO E / e′ ratio (septal and lateral) GLS LV stroke volume LAVI LVEDD LVOT VTI Maximum LVWT

[0522] E / e' = ratio of early mitral inflow velocity to early mitral annular diastolic velocity; GLS = global longitudinal strain; IVCT = isovolumetric contraction time; IVRT = isovolumetric relaxation time; IVST = interventricular septum thickness; LAVI = left atrial volume index; LV = left ventricle; LVCO = left ventricular cardiac output; LVEDD = left ventricular end-diastolic dimension; LVEDV = left ventricular end-diastolic volume; LVEF = left ventricular ejection fraction; LVESD = left ventricular end-systolic dimension; LVESV = left ventricular end-systolic volume; LVFS = left ventricular fractional shortening; LVMI = left ventricular mass index; LVOT VTI = left ventricular outflow tract velocity time integral; LVWT = left ventricular wall thickness

[0523] Table 23: Health status and health-related quality of life planning form

[0524]

[0525] CGI = Clinical Global Impression scale; d = day; ED = premature discontinuation; EOS = end of study; EOT = end of treatment; EQ-5D-5L = EuroQol 5 dimensions 5 levels instrument; KCCQ = Kansas City Cardiomyopathy Questionnaire; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; PGI-C = Patient Global Impression of Change scale; SAQ-7 = Seattle Angina Questionnaire-7.

[0526] Pharmacokinetics

[0527] Approximately 4 mL of blood samples were collected for measurement of plasma concentrations of aficontan, as specified in Table 24. Samples were used to evaluate the PK of aficontan and its potential metabolites

[0528] Table 24. PK time points

[0529] Visit PK time point Week 2 Before and 2 hours after administration Week 4 Before and 2 hours after administration Week 8 Before and 2 hours after administration Week 36 Before and 2 hours after administration Stopping medication early Irregular

[0530] Cardiac MRI sub-study

[0531] A cardiac MRI substudy will evaluate the effects of dosed aficontan on cardiac morphology, function, and fibrosis in up to 100 eligible and consenting participants with nHCM. Cardiac MRI will be performed during screening and at Weeks 36 and 72. Cardiac MRI should be performed after CPET if the assessment is performed on the same day. Participants with eGFR < 30 mL / min / 1.73 m2 or allergy to gadolinium may undergo non-contrast cardiac MRI. Participants who fail screening and are rescreened do not need to have a repeat cardiac MRI.

[0532] Statistical methods

[0533] Assuming a 5-point difference in change from baseline in KCCQ-CSS for afibactam compared with placebo, a standard deviation of 15, and 10% of participants missing change from baseline data for the primary endpoint, a sample size of 420 participants (210 participants / treatment group) provided greater than 90% power to detect a difference in mean KCCQ-CSS change from baseline to Week 36 with a two-sided type I error of 0.05.

[0534] During the study, the pooled SD of the change from baseline in KCCQ-CSS at Week 36 was monitored blindly and regularly. If the pooled SD was larger than expected, the sample size could be increased to maintain the expected power.

[0535] Efficacy analysis will be performed on the full analysis set (FAS). The primary analysis tested the null hypothesis that there was no treatment difference in the primary endpoint between participants randomly assigned to receive placebo or afecontan. A mixed model repeated measures model was used to analyze the changes in KCCQ-CSS compared to baseline, with treatment group, randomization stratification factor, visit, baseline visit and treatment group visit interaction as fixed effects, and baseline KCCQ-CSS as a covariate. A two-sample t-test was performed to compare the composite z score of the first secondary endpoint between treatment groups. The proportion of responders was analyzed using the Cochran-Mantel-Haenszel (CMH) test stratified by randomization stratification factor. Other changes compared to the baseline endpoint were analyzed using the same model as the primary endpoint. The event time endpoint was analyzed using the Kaplan-Meier estimator and Cox regression model.

[0536] Security analysis is performed on the security analysis set.

[0537] The number and percentage of participants reporting any treatment-emergent adverse event were tabulated by Medical Dictionary for Regulatory Activities (MedDRA) system organ class and priority term.

[0538] Table 25. Populations used for analysis.

[0539]

[0540]

[0541] end

[0542] Primary endpoint: To evaluate the effect of aficontin compared with placebo on participants' health status as measured by the change from baseline to week 36 on the KCCQ-CSS.

[0543] Secondary endpoints: (1) to evaluate the effect of aficontan compared with placebo on maximal and submaximal exercise capacity, as measured by the change from baseline to week 36 in two composite Z scores of CPET parameters: pVO2 (maximal exercise capacity) and VE / VCO2 slope (submaximal exercise capacity); (2) to evaluate the effect of aficontan compared with placebo on NYHA functional class, as measured by the proportion of participants with an improvement of ≥1 category in NYHA functional class from baseline to week 36; and (3) to evaluate the effect of aficontan compared with placebo on cardiac wall stress biomarkers. (4) to evaluate the effect of afibactam compared with placebo on echocardiographic measures of structural remodeling, as measured by the change in LAVI from baseline to week 36; and (5) to evaluate the effect of afibactam compared with placebo on cardiovascular events, as measured by the time to first occurrence of cardiovascular death, heart transplant or left ventricular assist device, discontinuation of sudden cardiac death, nonfatal stroke, hospitalization for heart failure, or arrhythmia requiring treatment or hospitalization (atrial fibrillation or ventricular tachyarrhythmia).

[0544] Safety endpoints: To evaluate the safety and tolerability of aficontan compared to placebo in participants with nHCM as measured by each of the following: (1) the incidence of AEs in participants; (2) the incidence of participants with LVEF <50% and a combination of each of the following: (a) signs and symptoms of heart failure and / or (b) an increase in NT-proBNP from baseline at the time of LVEF assessment; and (3) the incidence of participants with LVEF <40%.

[0545] Exploratory endpoints: (1) To evaluate the effect of aficontan compared with placebo on exercise capacity and functional class, as measured by the number of participants taking aficontan who achieved either: (a) a change in pVO2 of ≥1.0 mL / kg / min and an improvement in NYHA functional class of ≥1 grade from baseline, or (b) a change in pVO2 of ≥2.0 mL / kg / min from baseline at Week 36.0 mL / kg / min and no worsening of NYHA functional class; (2) to evaluate the effect of aficontan compared with placebo on participant-reported health status as measured by each of the following: (a) change from baseline to Week 36 and Week 72 in KCCQ-OSS, (b) change from baseline to Week 72 in KCCQ-CSS, (c) proportion of participants with improvements of >5, 10, 15, and 20 points in KCCQ-CSS and KCCQ-OSS at Week 36 and Week 72, (d) time to improvement of ≥5 points from baseline in KCCQ-CSS, and (e) change from baseline to Week 36 and Week 72 in SAQ-7; (3) to evaluate the effect of aficontan compared with placebo on echocardiographic measures of left ventricular structure, compliance, and filling, as measured by each of the following: (a) change from baseline to Week 36 and Week 72 in LVMI, (b) mean medial and lateral e' from baseline to Week 36 and Week 72; (4) to evaluate the effects of aficontan compared with placebo on echocardiographic measures of left ventricular structure, compliance, and filling, as measured by each of the following: (a) change in LVMI from baseline to Week 36 and Week 72, (b) change in mean medial and lateral e' from baseline to Week 36 and Week 72; (5) to evaluate the effects of aficontan compared with placebo on biomarkers of myocardial injury, as measured by change in hs-cTnI from baseline to Week 36 and Week 72; (6) to evaluate the effects of aficontan compared with placebo on motor symptoms and CPET parameters, as measured by change from baseline to Week 36 in each of the following: (a) circulatory power (VO2×SBP), (b) O2 pulse, (c) VAT, (d) total workload (Watts), (e) heart rate response, (f) Borg scale ( scale); (7) to evaluate the effect of aficontan compared with placebo on health status and health-related quality of life as measured by the PRO questionnaire, as measured by the change from baseline to Week 36 and Week 72 in the individual responses to CGI, PGI-C, and EQ-5D-5L; (8) to evaluate the PK of aficontan and its metabolites, as measured by pharmacokinetic parameters up to Week 36; (9) to evaluate the effect of aficontan on myocardial remodeling assessed by cardiac MRI, as measured by the change from baseline to Week 36 and Week 72 in each of the following: (a) LVMI, (b) ventricular septum, free wall, and maximum wall thickness, (c) myocardial fibrosis, (d) LAVI and left atrial function, (e) left ventricular end-systolic volume, and (f) left ventricular end-diastolic volume.

[0546] Security analysis will be performed on the security analysis set.

[0547] Pharmacokinetic endpoints: Plasma concentrations and PK parameters of aficantan (maximum observed plasma concentration [C 最大 ] and trough plasma concentration [C 谷 ]).

[0548] Example 5

[0549] The polymorphic forms I, II, III, IV, V and VI of CK-274 were characterized by various analytical techniques, including XRPD, DSC, TGA and DVS, as described in WO 2021 / 011807.

Claims

1. A method of treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof is selected by titrating the daily dose of CK-274 or a pharmaceutically acceptable salt thereof administered to the patient.

2. The method of claim 1, wherein the dose is titrated once during the course of treatment.

3. The method of claim 1, wherein the dose is titrated two or more times during the course of treatment.

4. The method of any one of claims 1-3, wherein the daily dose is administered to the patient in a constant amount for about two weeks prior to titrating the daily dose.

5. The method of any one of claims 1-4, wherein CK-274 or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 5 mg to about 20 mg.

6. The method of claim 5, wherein the daily dose is about 5 mg.

7. The method of claim 5, wherein the daily dose is about 10 mg.

8. The method of claim 5, wherein the daily dose is about 15 mg.

9. The method of claim 5, wherein the daily dose is about 20 mg.

10. The method of any one of claims 1-9, wherein the daily dose is administered daily as a single dose.

11. The method of any one of claims 1-9, wherein the daily dose is administered in 2 divided doses.

12. A method of treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient in need thereof, the method comprising: The patient is administered a first daily dose of CK-274 or a pharmaceutically acceptable salt thereof, for a first period of time; as well as Based on the component of the patient's first echocardiogram obtained after the first period of time, administering a second daily dose of CK-274 or a pharmaceutically acceptable salt thereof to the patient for a second period of time, or terminating administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient.

13. The method of claim 12, comprising selecting the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof based on the component of the first echocardiogram.

14. The method of claim 12 or 13, wherein the component of the first echocardiogram comprises a biplane LVEF.

15. The method of any one of claims 12-14, wherein the component of the first echocardiogram comprises a biplane LVEF, and when the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is lower than the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof.

16. The method of any one of claims 12-14, wherein the component of the first echocardiogram comprises a biplane LVEF, and when the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold, administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient is terminated.

17. The method of claim 15 or 16, wherein the predetermined biplane LVEF threshold is 50%.

18. The method of any one of claims 12-14, wherein the component of the first echocardiogram comprises a biplane LVEF, and wherein when the biplane LVEF of the first echocardiogram is equal to or above a predetermined biplane LVEF threshold and below a second predetermined biplane LVEF threshold, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof.

19. The method of any one of claims 12-14, wherein the component of the first echocardiogram comprises a biplane LVEF, and wherein the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is greater than the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof when the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold.

20. The method of claim 18 or 19, wherein the predetermined biplane LVEF threshold is 50% and the second predetermined biplane LVEF threshold is 55%.

21. The method of any one of claims 12-20, wherein the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg CK-274.

22. The method of claim 21, wherein the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg CK-274.

23. The method of any one of claims 12-22, further comprising measuring the component of the first echocardiogram.

24. The method of any one of claims 12-23, wherein the first period of time is about 2 weeks.

25. The method of any one of claims 12-24, wherein the second period of time is about 2 weeks.

26. The method of any one of claims 12-25, wherein the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient for the second period of time, the method further comprising administering a third daily dose of CK-274 or a pharmaceutically acceptable salt thereof to the patient for a third period of time, or terminating administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient based on a component of a second echocardiogram of the patient obtained after the second period of time and the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof.

27. The method of claim 26, comprising selecting the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof based on the component of the second echocardiogram and the second daily dose.

28. The method of claim 26 or 27, wherein the component of the second echocardiogram comprises a biplane LVEF.

29. The method of any one of claims 26-28, wherein the component of the second echocardiogram comprises a biplane LVEF, and when the biplane LVEF of the second echocardiogram is below the predetermined biplane LVEF threshold, the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is lower than the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof, or administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient is terminated.

30. The method of claim 29, wherein administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient is terminated when the biplane LVEF of the second echocardiogram is below the predetermined biplane LVEF threshold and the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as or lower than the first daily dose of CK-274.

31. The method of claim 29, wherein when the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is higher than the first daily dose of CK-274 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 CK-274 or a pharmaceutically acceptable salt thereof is the same as the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof.

32. The method of any one of claims 15-31, wherein the predetermined biplane LVEF threshold is 50%.

33. The method of any one of claims 26-28, wherein the component of the second echocardiogram comprises a biplane LVEF, and wherein when the biplane LVEF of the second echocardiogram is equal to or above the predetermined biplane LVEF threshold and below the second predetermined biplane LVEF, the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof.

34. The method of any one of claims 26-28, wherein the component of the second echocardiogram comprises a biplane LVEF, and wherein the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is greater than the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof when the biplane LVEF of the second echocardiogram is equal to or above the second predetermined biplane LVEF threshold.

35. The method of claim 33 or 34, wherein the predetermined biplane LVEF threshold is 50% and the second predetermined biplane LVEF threshold is 55%.

36. The method of any one of claims 26-35, wherein the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg CK-274, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg CK-274, and the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, or about 15 mg CK-274.

37. The method of any one of claims 26-36, further comprising measuring the component of the second echocardiogram.

38. The method of any one of claims 26-37, wherein the third period of time is about 2 weeks.

39. The method of any one of claims 26-38, wherein the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient for the third period of time, the method further comprising administering a fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof to the patient for a fourth period of time, or terminating administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient based on a component of a third echocardiogram of the patient obtained after the third period of time and the third daily dose of the compound or a pharmaceutically acceptable salt thereof.

40. The method of claim 39, comprising selecting the fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof based on the component of the third echocardiogram and the third daily dose.

41. The method of claim 39 or 40, wherein the component of the third echocardiogram comprises biplane LVEF.

42. The method of any one of claims 39-41, wherein the component of the third echocardiogram comprises a biplane LVEF, and when the biplane LVEF of the third echocardiogram is below the predetermined biplane LVEF threshold, the fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof is lower than the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof, or administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient is terminated.

43. The method of claim 42, wherein administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient is terminated when the biplane LVEF of the third echocardiogram is below the predetermined biplane LVEF threshold and the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as or lower than the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof.

44. The method of claim 42 or 43, wherein: When the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is higher than the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof, and the biplane LVEF of the third echocardiogram is below the predetermined biplane LVEF threshold, the fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof; or When the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof, and the biplane LVEF of the third echocardiogram is lower than the predetermined biplane LVEF threshold, the fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof.

45. The method of any one of claims 42-44, wherein the predetermined biplane LVEF threshold is 50%.

46. ​​The method of any one of claims 39-41, wherein the component of the third echocardiogram comprises a biplane LVEF, and wherein when the biplane LVEF of the third echocardiogram is equal to or above the predetermined biplane LVEF threshold and below the second predetermined biplane LVEF, the fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof.

47. The method of any one of claims 39-41, wherein the component of the third echocardiogram comprises a biplane LVEF, and wherein when the biplane LVEF of the third echocardiogram is equal to or above the second predetermined biplane LVEF threshold, the fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as or greater than the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof.

48. The method of claim 46 or 47, wherein the predetermined biplane LVEF threshold is 50% and the second predetermined biplane LVEF threshold is 55%.

49. The method of any one of claims 39-48, wherein the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg CK-274, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg CK-274, the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg or about 15 mg CK-274, and the fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, about 15 mg or about 20 mg CK-274.

50. The method of any one of claims 39-49, wherein the fourth period of time is about 2 weeks.

51. A method of treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient in need thereof, the method comprising: The patient is administered a first daily dose of CK-274 or a pharmaceutically acceptable salt thereof, for a first period of time; as well as Based on a first echocardiogram of the patient obtained after the first period that includes a biplane LVEF, administering a second daily dose of CK-274 or a pharmaceutically acceptable salt thereof to the patient for a second period, or terminating administration of CK-274 to the patient, wherein: terminating administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient if the biplane LVEF of the first echocardiogram is below a first predetermined biplane LVEF threshold; If the biplane LVEF is equal to or above the first predetermined biplane LVEF threshold and below a second predetermined biplane LVEF threshold, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof; and If the biplane LVEF of the first echocardiogram is above the second predetermined biplane LVEF threshold, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is greater than the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof.

52. The method of claim 51, wherein the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg CK-274, and the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg CK-274.

53. The method of claim 51 or 52, further comprising measuring the biplane LVEF of the first echocardiogram.

54. The method of any one of claims 51-53, wherein the first period of time is about 2 weeks.

55. The method of any one of claims 51-54, wherein the second period of time is about 2 weeks.

56. The method of claims 51-55, wherein the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient for the second period of time, the method further comprising administering a third daily dose of CK-274 or a pharmaceutically acceptable salt thereof to the patient for a third period of time, or terminating administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient based on a second echocardiogram of the patient comprising a biplane LVEF obtained after the second period of time and the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof, wherein: terminating administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient if the biplane LVEF of the second echocardiogram is less than the first predetermined biplane LVEF threshold and the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof; if the biplane LVEF of the second echocardiogram is below the first predetermined biplane LVEF threshold and the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is higher than the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof, the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is lower than the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof; If the biplane LVEF is equal to or above the first predetermined biplane LVEF threshold and below the second predetermined biplane LVEF threshold, the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof; and If the biplane LVEF of the second echocardiogram is above the second predetermined biplane LVEF threshold, the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is greater than the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof.

57. The method of claim 56, wherein the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg CK-274, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg CK-274, and the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, or about 15 mg CK-274.

58. The method of claim 56 or 57, further comprising measuring the biplane LVEF of the second echocardiogram.

59. The method of any one of claims 56-58, wherein the third period of time is about 2 weeks.

60. The method of any one of claims 56-59, wherein the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient for the third period of time, the method further comprising administering a fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof to the patient for a fourth period of time, or terminating administration of CK-274 to the patient based on a third echocardiogram of the patient comprising a biplane LVEF and the third dose of CK-274 or a pharmaceutically acceptable salt thereof obtained after the third period of time, wherein: terminating administration of CK-274 or a pharmaceutically acceptable salt thereof to said patient if said biplane LVEF on said third echocardiogram is below said first predetermined biplane LVEF threshold and said third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as said first daily dose of CK-274 or a pharmaceutically acceptable salt thereof; if said biplane LVEF of said third echocardiogram is below said first predetermined biplane LVEF threshold and said third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is higher than said first daily dose of CK-274 or a pharmaceutically acceptable salt thereof, said fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof is lower than said third daily dose of CK-274 or a pharmaceutically acceptable salt thereof; If the biplane LVEF is equal to or above the first predetermined biplane LVEF threshold, the fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as or higher than the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof.

61. The method of claim 60, wherein the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg CK-274, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg CK-274, the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg or about 15 mg CK-274, and the fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, about 15 mg or about 20 mg CK-274.

62. The method of claim 60 or 61 further comprising measuring the biplane LVEF of the third echocardiogram.

63. The method of any one of claims 60-62, wherein the third period of time is about 2 weeks.

64. The method of any one of claims 51-63, wherein the first predetermined biplane LVEF threshold is 50% and the second predetermined biplane LVEF threshold is 55%.

65. A method of treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient in need thereof, the method comprising: (1) administering a first daily dose ("dose 1") of CK-274 to the patient or a pharmaceutically acceptable salt thereof, for a first period of time; (2) after the first period of time, performing a first echocardiogram on the patient to determine the patient's biplane LVEF ("LVEF1"); and (a) if the patient's LVEF1 is <50%, then terminating the administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient; or (b) if the patient's LVEF1 is ≥55%, administering to the patient a second daily dose ("Dose 2") of CK-274 or a pharmaceutically acceptable salt thereof for a second period of time, wherein Dose 2 is greater than Dose 1; or (c) if the patient's LVEF1 is ≥50% and <55%, administering to the patient a dose of CK-274 or a pharmaceutically acceptable salt thereof for a second period of time that is the same as the dose administered for the first period of time; and optionally (3) after the second period of time, performing a second echocardiogram on the patient to determine the patient's biplane LVEF ("LVEF2"); and (a) if the patient receives Dose 1 during the second period and the patient's LVEF2 is <50%, terminating administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient; or (b) if the patient received dose 2 during the second period and the patient's LVEF2 is <50%, administering dose 1 of CK-274 or a pharmaceutically acceptable salt thereof to the patient for a third period; or (c) if the patient received Dose 1 during the second period and the patient's LVEF2 is ≥ 55%, administering to the patient a larger daily dose ("Dose 2") of CK-274 or a pharmaceutically acceptable salt thereof for a third period; or (d) if the patient received Dose 2 during the second period and the patient's LVEF2 is ≥ 55%, administering to the patient a third daily dose ("Dose 3") of CK-274 or a pharmaceutically acceptable salt thereof for a third period, wherein Dose 3 is greater than Dose 2; or (e) if the patient's LVEF2 is ≥50% and <55%, administering to the patient a dose of CK-274 or a pharmaceutically acceptable salt thereof that is the same as the dose administered during the second period for a third period; and optionally (4) after the third period of time, performing a third echocardiogram on the patient to determine the patient's biplane LVEF ("LVEF3"); and (a) if the patient receives dose 1 during the third period and the patient's LVEF3 is <50%, terminating administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient; or (b) if the patient received dose 2 during the third period and the patient's LVEF3 is <50%, administering dose 1 of CK-274 or a pharmaceutically acceptable salt thereof to the patient for a fourth period; or (c) if the patient received dose 3 during the third period and the patient's LVEF3 is <50%, administering dose 2 of CK-274 or a pharmaceutically acceptable salt thereof to the patient for a fourth period; or (d) if the patient received dose 1 during the third period and the patient's LVEF3 is ≥ 55%, administering dose 2 of CK-274 or a pharmaceutically acceptable salt thereof to the patient for a fourth period; (e) if the patient received dose 2 during the third period and the patient's LVEF3 is ≥ 55%, administering dose 3 of CK-274 or a pharmaceutically acceptable salt thereof to the patient for a fourth period; (f) if the patient received Dose 3 during the third period and the patient's LVEF3 is ≥ 55%, administering to the patient a fourth daily dose ("Dose 4") of CK-274 or a pharmaceutically acceptable salt thereof for a fourth period, wherein Dose 4 is greater than Dose 3; or (5) If the patient's LVEF3 is ≥50% and <55%, administering to the patient a dose of CK-274 or a pharmaceutically acceptable salt thereof that is the same as the dose administered during the third period for a fourth period.

66. The method of claim 65, wherein the first period of time is about 2 weeks.

67. The method of any one of claims 65-66, wherein the second period of time is 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.

68. The method of any one of claims 65-67, wherein the third period of time is 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.

69. The method of any one of claims 65-68, wherein the fourth period of time is 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.

70. The method of any one of claims 65-69, wherein Dose 1 is about 5 mg.

71. The method of any one of claims 65-70, wherein Dose 2 is about 10 mg.

72. The method of any one of claims 65-71, wherein dose 3 is about 15 mg.

73. The method of any one of claims 65-72, wherein dose 4 is about 20 mg.

74. The method of any one of claims 65-73, wherein each of Dose 1, Dose 2, Dose 3, and Dose 4 is administered daily as a single dose.

75. The method of any one of claims 65-73, wherein each of Dose 1, Dose 2, Dose 3, and Dose 4 is administered in 2 divided doses.

76. The method of any one of claims 1-75, wherein when the patient is receiving the highest allowed dose and the patient's LVEF is > 55%, then the patient continues to receive the same highest dose for the next period.

77. The method of any one of claims 1-76, wherein administration of CK-274 or a pharmaceutically acceptable salt thereof is terminated or suspended when the patient's LVEF is <40%.

78. The method of any one of claims 1-77, wherein administration of CK-274 or a pharmaceutically acceptable salt thereof is terminated or suspended when an unplanned echocardiogram shows LVEF <50% and the patient has symptoms of low cardiac output.

79. The method of any one of claims 1-78, wherein prior to administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient has a resting and post-Valsalgar maneuver LVOT-G of less than 30 mmHg.

80. The method of any one of claims 1-79, wherein the patient has a left ventricular ejection fraction (LVEF) of ≥ 60% prior to administration of CK-274 or a pharmaceutically acceptable salt thereof.

81. The method of any one of claims 1-80, wherein the patient has a NT-proBNP level greater than 300 pg / mL prior to administration of CK-274 or a pharmaceutically acceptable salt thereof.

82. The method of any one of claims 1-81, wherein disopyramide is not administered to the patient during treatment with CK-274 or a pharmaceutically acceptable salt thereof.

83. The method of any one of claims 1-82, wherein the patient has not been treated with disopyramide or an antiarrhythmic drug with negative cardiotonic activity within 4 weeks prior to treatment with CK-274 or a pharmaceutically acceptable salt thereof.

84. The method of any one of claims 1-83, wherein the patient has undergone septal narrowing therapy (SRT) prior to initiating treatment with CK-274 or a pharmaceutically acceptable salt thereof.

85. The method of any one of claims 1-84, wherein the patient is a CYP2D6 poor metabolizer.

86. The method of any one of claims 1-85, wherein the patient is fasting when administering CK-274 or a pharmaceutically acceptable salt thereof.

87. The method of any one of claims 1-85, wherein the patient is eating when CK-274 or a pharmaceutically acceptable salt thereof is administered.

88. The method of any one of claims 1-87, wherein the method does not comprise collecting a blood sample from the patient.

89. The method of any one of claims 1-87, wherein the method does not comprise analyzing a blood sample from the patient.

90. The method of any one of claims 1-89, wherein a beta-blocker is administered to the patient during treatment with CK-274 or a pharmaceutically acceptable salt thereof.

91. A method of treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof.

92. A method of treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, wherein prior to administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient has a resting left ventricular ejection fraction of at least 60%.

93. A method of treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, wherein prior to administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient has a resting left ventricular ejection fraction of at least 60% and a resting and post-Valsalien maneuver left ventricular outflow tract pressure gradient (LVOT-G) of less than 30 mmHg.

94. The method of any one of claims 91-93, wherein the therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof is selected by titrating the daily dose of CK-274 or a pharmaceutically acceptable salt thereof administered to the patient.

95. The method of claim 94, wherein the dose is titrated once during a course of treatment.

96. The method of claim 94, wherein the dose is titrated two or more times during a course of treatment.

97. The method of any one of claims 95-96, wherein the daily dose is administered to the patient in a constant amount for about two weeks prior to titrating the daily dose.

98. The method of any one of claims 95-97, wherein CK-274 or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 5 mg to about 20 mg.

99. The method of claim 98, wherein the daily dose is about 5 mg.

100. The method of claim 98, wherein the daily dose is about 10 mg.

101. The method of claim 98, wherein the daily dose is about 15 mg.

102. The method of claim 98, wherein the daily dose is about 20 mg.

103. The method of any one of claims 98-102, wherein the daily dose is administered daily as a single dose.

104. The method of any one of claims 98-102, wherein the daily dose is administered in 2 divided doses.

105. The method of any one of claims 1-104, wherein the patient is classified as NYHA class III when administration of CK-274 or a pharmaceutically acceptable salt thereof is initiated.

106. The method of any one of claims 1-104, wherein the patient is classified as NYHA class II when administration of CK-274 or a pharmaceutically acceptable salt thereof is initiated.

107. The method of any one of claims 1-106, wherein the administration results in an improvement in health status as measured by one or more of the Short Form 36 Physical Functioning Subscale (SF-36-PFS), the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), SAQ7, PGI-C, or CGI.

108. The method of any one of claims 1-107, wherein administration of CK-274 reduces left ventricular wall stress.

109. The method of any one of claims 1-108, wherein administration of CK-274 or a pharmaceutically acceptable salt thereof has a sustained effect of at least 6 months.

110. The method of any one of claims 1-108, wherein administration of CK-274 or a pharmaceutically acceptable salt thereof has a sustained effect of at least 5 years.

111. The method of any one of claims 1-108, wherein administration of CK-274 or a pharmaceutically acceptable salt thereof has a sustained effect of at least 10 weeks, 12 weeks, 1 year, 2 years, 3 years, or 4 years.

112. A method of treating HCM with midventricular obstruction (MVO) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof is selected by titrating the daily dose of CK-274 or a pharmaceutically acceptable salt thereof administered to the patient.

113. A method of treating hypertrophic cardiomyopathy with midventricular obstruction (MVO) in a patient in need thereof, the method comprising: The patient is administered a first daily dose of CK-274 or a pharmaceutically acceptable salt thereof, for a first period of time; and Based on the component of the patient's first echocardiogram obtained after the first period of time, administering a second daily dose of CK-274 or a pharmaceutically acceptable salt thereof to the patient for a second period of time, or terminating administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient.

114. The method of any one of claims 1-113, wherein the method causes the patient to achieve one or more of the following: a) refine the NYHA functional classification into one or more categories; and / or b) a decrease in mean NT-proBNP; and / or c) Decreased cardiac troponin I.

115. The method of any one of claims 1-113, wherein the method causes the patient to achieve one or more of the following: a) refine the NYHA functional classification into one or more categories; and / or b) a decrease in mean NT-proBNP; and / or c) decreased cardiac troponin I; and / or d) Improvement in health status as measured by the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS); and / or e) Improvement in health status as measured by the Seattle Angina Questionnaire-Angina Frequency (SAQ-AF).

116. The method of claim 18 or 19, wherein the predetermined biplane LVEF threshold is 50% and the second predetermined biplane LVEF threshold is 60%.

117. The method of claim 33 or 34, wherein the predetermined biplane LVEF threshold is 50% and the second predetermined biplane LVEF threshold is 60%.

118. The method of claim 46 or 47, wherein the predetermined biplane LVEF threshold is 50% and the second predetermined biplane LVEF threshold is 60%.

119. The method of any one of claims 51-63, wherein the first predetermined biplane LVEF threshold is 50% and the second predetermined biplane LVEF threshold is 60%.

120. A method of treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient in need thereof, the method comprising: (1) administering a first daily dose ("dose 1") of CK-274 to the patient or a pharmaceutically acceptable salt thereof, for a first period of time; (2) after the first period of time, performing a first echocardiogram on the patient to determine the patient's biplane LVEF ("LVEF1"); and (a) if the patient's LVEF1 is <50%, then terminating the administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient; or (b) if the patient's LVEF1 is ≥ 60%, administering to the patient a second daily dose ("Dose 2") of CK-274 or a pharmaceutically acceptable salt thereof for a second period of time, wherein Dose 2 is greater than Dose 1; or (c) if the patient's LVEF1 is ≥50% and <60%, administering to the patient a dose of CK-274 or a pharmaceutically acceptable salt thereof for a second period of time that is the same as the dose administered for the first period of time; and optionally (3) after the second period of time, performing a second echocardiogram on the patient to determine the patient's biplane LVEF ("LVEF2"); and (f) if the patient receives Dose 1 during the second period and the patient's LVEF2 is <50%, terminating administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient; or (g) if the patient received dose 2 during the second period and the patient's LVEF2 is <50%, administering dose 1 of CK-274 or a pharmaceutically acceptable salt thereof to the patient for a third period; or (h) administering to the patient the second daily dose ("dose 2") of CK-274 or a pharmaceutically acceptable salt thereof for a third period if the patient received dose 1 during the second period and the patient's LVEF2 is ≥ 60%; or (i) if the patient received Dose 2 during the second period and the patient's LVEF2 is ≥ 60%, administering to the patient a third daily dose ("Dose 3") of CK-274 or a pharmaceutically acceptable salt thereof for a third period, wherein Dose 3 is greater than Dose 2; or (j) if the patient's LVEF2 is ≥50% and <60%, administering to the patient a dose of CK-274 or a pharmaceutically acceptable salt thereof that is the same as the dose administered during the second period for a third period; and optionally (4) after the third period of time, performing a third echocardiogram on the patient to determine the patient's biplane LVEF ("LVEF3"); and (a) if the patient receives Dose 1 during the third period and the patient's LVEF3 is <50%, terminating administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient; or (g) if the patient received dose 2 during the third period and the patient's LVEF3 is <50%, administering dose 1 of CK-274 or a pharmaceutically acceptable salt thereof to the patient for a fourth period; or (h) if the patient received dose 3 during the third period and the patient's LVEF3 is <50%, administering dose 2 of CK-274 or a pharmaceutically acceptable salt thereof to the patient for a fourth period; or (i) if the patient received dose 1 during the third period and the patient's LVEF3 is ≥ 60%, administering dose 2 of CK-274 or a pharmaceutically acceptable salt thereof to the patient for a fourth period; (j) if the patient received dose 2 during the third period and the patient's LVEF3 is ≥ 60%, administering dose 3 of CK-274 or a pharmaceutically acceptable salt thereof to the patient for a fourth period; (k) if the patient received Dose 3 during the third period and the patient's LVEF3 is ≥ 60%, administering to the patient a fourth daily dose ("Dose 4") of CK-274 or a pharmaceutically acceptable salt thereof for a fourth period, wherein Dose 4 is greater than Dose 3; or (5) If the patient's LVEF3 is ≥50% and <60%, administering to the patient a dose of CK-274 or a pharmaceutically acceptable salt thereof that is the same as the dose administered during the third period for a fourth period.

121. The method of claim 120, wherein the first period of time is about 2 weeks.

122. The method of any one of claims 120-121, wherein the second period is 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.

123. The method of any one of claims 120-122, wherein the third period is 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.

124. The method of any one of claims 120-123, wherein the fourth period is 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.

125. The method of any one of claims 120-124, wherein Dose 1 is about 5 mg.

126. The method of any one of claims 120-125, wherein Dose 2 is about 10 mg.

127. The method of any one of claims 120-126, wherein dose 3 is about 15 mg.

128. The method of any one of claims 120-127, wherein dose 4 is about 20 mg.

129. The method of any one of claims 120-128, wherein each of Dose 1, Dose 2, Dose 3, and Dose 4 is administered daily as a single dose.

130. The method of any one of claims 120-128, wherein each of Dose 1, Dose 2, Dose 3, and Dose 4 is administered in 2 divided doses per day.

131. The method of any one of claims 116-130, wherein when the patient is receiving the highest allowed dose and the patient's LVEF is ≥ 60%, then the patient continues to receive the same highest dose for the next period.

132. The method of any one of claims 116-131, wherein administration of CK-274 or a pharmaceutically acceptable salt thereof is terminated or suspended when the patient's LVEF is <40%.

133. The method of any one of claims 116-132, wherein administration of CK-274 or a pharmaceutically acceptable salt thereof is terminated or suspended when an unplanned echocardiogram shows LVEF <50% and the patient has symptoms of low cardiac output.

134. The method of any one of claims 116-133, wherein the patient has a resting LVOT-G of less than 30 mmHg prior to administration of CK-274 or a pharmaceutically acceptable salt thereof.

135. The method of any one of claims 116-134, wherein prior to administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient has a LVOT-G after Valsalva maneuver of less than 50 mmHg.

136. The method of any one of claims 116-135, wherein the patient has a left ventricular ejection fraction (LVEF) of ≥ 60% prior to administration of CK-274 or a pharmaceutically acceptable salt thereof.

137. The method of any one of claims 116-136, wherein the patient has a NT-proBNP level greater than 300 pg / mL prior to administration of CK-274 or a pharmaceutically acceptable salt thereof.

138. The method of any one of claims 116-137, wherein disopyramide is not administered to the patient during treatment with CK-274 or a pharmaceutically acceptable salt thereof.

139. The method of any one of claims 116-138, wherein the patient has not been treated with disopyramide or an antiarrhythmic drug with negative cardiotonic activity within 4 weeks prior to treatment with CK-274 or a pharmaceutically acceptable salt thereof.

140. The method of any one of claims 116-139, wherein the patient has undergone septal narrowing therapy (SRT) prior to initiating treatment with CK-274 or a pharmaceutically acceptable salt thereof.

141. The method of any one of claims 116-140, wherein the patient is a CYP2D6 poor metabolizer.

142. The method of any one of claims 116-141, wherein the patient is fasting when administering CK-274 or a pharmaceutically acceptable salt thereof.

143. The method of any one of claims 116-141, wherein the patient is eating when CK-274 or a pharmaceutically acceptable salt thereof is administered.

144. The method of any one of claims 116-143, wherein the method does not comprise collecting a blood sample from the patient.

145. The method of any one of claims 116-143, wherein the method does not comprise analyzing a blood sample from the patient.

146. The method of any one of claims 116-144, wherein a beta-blocker is administered to the patient during treatment with CK-274 or a pharmaceutically acceptable salt thereof.

147. The method of any one of claims 116-146, wherein the patient is classified as NYHA class III when administration of CK-274 or a pharmaceutically acceptable salt thereof is initiated.

148. The method of any one of claims 116-146, wherein the patient is classified as NYHA class II when administration of CK-274 or a pharmaceutically acceptable salt thereof is initiated.

149. The method of any one of claims 116-148, wherein the administration results in an improvement in health status as measured by one or more of the Short Form 36 Physical Functioning Subscale (SF-36-PFS), the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), SAQ7, PGI-C, or CGI.

150. The method of any one of claims 116-149, wherein administration of CK-274 reduces left ventricular wall stress.

151. The method of any one of claims 116-150, wherein administration of CK-274 or a pharmaceutically acceptable salt thereof has a sustained effect of at least 6 months.

152. The method of any one of claims 116-150, wherein administration of CK-274 or a pharmaceutically acceptable salt thereof has a sustained effect of at least 5 years.

153. The method of any one of claims 116-150, wherein administration of CK-274 or a pharmaceutically acceptable salt thereof has a sustained effect of at least 10 weeks, 12 weeks, 1 year, 2 years, 3 years, or 4 years.

154. The method of any one of claims 1-153, wherein the patient is obese.

155. The method of any one of claims 1-153, wherein the patient is not obese.

156. The method of any one of claims 1-153, wherein the patient has a body mass index of 30 or greater.

157. The method of any one of claims 1-153, wherein the patient has a body mass index of less than 30.

158. The method of any one of claims 1-157, wherein the CK-274 or a pharmaceutically acceptable salt thereof is administered orally.

159. The method of claim 158, wherein the CK-274 or a pharmaceutically acceptable salt thereof is administered as a tablet.

160. The method of claim 159, wherein the tablet comprises one or more carriers or excipients selected from the group consisting of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, and magnesium carbonate.

161. The method of claim 159, wherein the tablet comprises: (i) about 1% to about 50% by weight of said CK-274 or a pharmaceutically acceptable salt thereof; (ii-1) from about 10% to about 60% by weight of mannitol; (ii-2) about 5% to about 45% by weight of microcrystalline cellulose; (iii) from about 0.1% to about 10% by weight hydroxypropyl cellulose; (iv) from about 1% to about 10% by weight of croscarmellose sodium; (v) from about 0.1% to about 10% by weight sodium lauryl sulfate; and (vi) from about 0.1% to about 10% by weight of magnesium stearate, The weight % stated does not include the weight of any coating that may be present.

162. The method of any one of claims 1-161, wherein the CK-274 or a pharmaceutically acceptable salt thereof comprises one or more of polymorphic Form I, Form II, Form III, Form IV, Form V, and Form VI of CK-274.

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