Method for treating non-obstructive hypertrophic cardiomyopathy

Abstract

Methods for treating non-obstructive hypertrophic cardiomyopathy or mid-ventricular obstructive (MVO) hypertrophic cardiomyopathy are described herein. The treatment methods include administration of a myocardial myosin inhibitor (CK-274 or CK-3773274, also referred to as aficamten), and may include adjusting the daily dose administered based on components of an echocardiogram. The daily dose may be increased, maintained, decreased, or terminated based on the echocardiogram. In some embodiments, the dose is adjusted once during the course of treatment. In some embodiments, the dose is adjusted two or more times during the course of treatment. The daily dose may be administered to the patient in a constant amount for about two weeks before the amount of the daily dose is adjusted.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority to U.S. Provisional Application No. 63 / 368,967, filed Jul. 20, 2022; U.S. Provisional Application No. 63 / 375,026, filed Sep. 8, 2022; U.S. Provisional Application No. 63 / 486,594, filed Feb. 23, 2023; U.S. Provisional Application No. 63 / 491,010, filed Mar. 17, 2023; U.S. Provisional Application No. 63 / 495,966, filed Apr. 13, 2023; and U.S. Provisional Application No. 63 / 501,088, filed May 9, 2023, the contents of all of these U.S. provisional applications are hereby incorporated by reference in their entireties for all purposes.

[0002] The disclosure herein relates to the treatment of non - obstructive hypertrophic cardiomyopathy or mid - ventricular obstructive hypertrophic cardiomyopathy, and to compounds and compositions useful for the treatment of non - obstructive hypertrophic cardiomyopathy.

Background Art

[0003] Hypertrophic cardiomyopathy (HCM) is a disease in which the heart muscle (myocardium) becomes abnormally thick (hypertrophied). When the myocardium hypertrophies, the inside of the left ventricle becomes small and stiff, so that the ventricle cannot relax and cannot be filled with blood. 30% of HCM patients do not develop left ventricular outflow tract (LVOT) obstruction at rest or with physiological provocation (i.e., Valsalva maneuver or exercise). These patients are classified as having non - obstructive HCM (nHCM). nHCM patients have a similar risk of developing heart failure and all - cause mortality compared to patients with HCM at rest, but have a greater burden of life - threatening ventricular arrhythmias (sustained ventricular tachycardia or ventricular fibrillation) compared to patients with rest or latent obstruction. Therefore, treatments for this condition are needed.

Summary of the Invention

[0004] Methods and compositions for treating non-obstructive hypertrophic cardiomyopathy are described herein. A myocardial myosin inhibitor (CK-274, also known as aficamten or CK-3773274), or a pharmaceutically acceptable salt thereof, can be used for the treatment of non-obstructive hypertrophic cardiomyopathy or mid-ventricular obstructive hypertrophic cardiomyopathy. Further, as described herein, the daily dose of CK-274 can be adjusted based on the results of echocardiograms.

[0005] A method of treating non-obstructive hypertrophic cardiomyopathy (nHCM) or mid-ventricular obstructive (MVO, also known as "mid-cavitary obstruction") HCM in a patient in need thereof can 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 adjusting the daily dose of CK-274 or a pharmaceutically acceptable salt thereof administered to the patient. In some embodiments, the dose is adjusted once during the course of treatment. In some embodiments, the dose is adjusted two or more times during the course of treatment. The daily dose can be administered to the patient at a constant amount for about two weeks before the amount of the daily dose is adjusted.

[0006] In some embodiments of the above method, CK-274 or a pharmaceutically acceptable salt thereof is administered at 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. It will be understood by those skilled in the art that, as described herein, unless otherwise specified, for example, the amount of the dose is the amount of the CK-274 free base, or, when a non-free base form, for example, a pharmaceutically acceptable salt, is administered, it is the amount of the corresponding CK-274 free base.

[0007] In some embodiments, the daily dose is administered as a single dose daily. In some embodiments, the daily dose is administered as two divided doses.

[0008] In some embodiments, as described herein, a method, for example, a method of treating non-obstructive hypertrophic cardiomyopathy (nHCM) or mid-ventricular obstructive (MVO) HCM in a patient in need of treatment for nHCM or MVO HCM, or a method for reducing the frequency of angina in a patient in need of reducing the frequency of angina, comprises administering to the patient a first daily dose of CK-274 or a pharmaceutically acceptable salt thereof over a first period of time and administering to the patient a second daily dose of CK-274 or a pharmaceutically acceptable salt thereof over a second period of time. In some embodiments, the first daily dose and the second daily dose are different. In some embodiments, the second daily dose is less than the first daily dose. In some embodiments, the second daily dose is greater 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 comprises administering a third daily dose over a third period of time, as described herein. In some embodiments, the method further comprises administering a fourth daily dose over a fourth period of time, as described herein. Various techniques and criteria can be utilized to select the next daily dose, for example, using the biplane LVEF component of an echocardiogram after a period of time following a previous daily dose. In some embodiments, the daily dose (e.g., as the third or fourth daily dose) is about 15 mg of CK-274.

[0009] In some embodiments, a method of treating non-obstructive hypertrophic cardiomyopathy (nHCM) or mid-ventricular obstructive (MVO) HCM in a patient in need of treatment for nHCM or MVO HCM comprises administering to the patient a first daily dose of CK-274 or a pharmaceutically acceptable salt thereof over a first period, and based on the biplane LVEF component of a first echocardiogram of the patient obtained after the first period, administering to the patient a second daily dose of CK-274 or a pharmaceutically acceptable salt thereof over a second period, or terminating the administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient. The method may include selecting the 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 receives two or more echocardiograms during the first period, and the second daily dose is selected based on the combined results of the two or more echocardiograms obtained during the first period.

[0010] In some embodiments of the above method, when the biplane LVEF of the first echocardiogram is below 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 can be 50%. For example, the predetermined biplane LVEF threshold can be 40%.

[0011] In some embodiments 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 less than the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof. For example, the predetermined biplane LVEF threshold can be 50%.

[0012] In some embodiments of the above method, 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%.

[0013] In some embodiments of the above method, when the biplane LVEF of the first echocardiogram is above a predetermined biplane LVEF threshold, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is more 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%.

[0014] In some embodiments of the above method, the first daily dose of CK-274, or a pharmaceutically acceptable salt thereof, is about 5 mg of 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 of CK-274.

[0015] In some embodiments of the above method, the first period is about two weeks. In some embodiments, the second period is about two weeks.

[0016] In some embodiments of the above method, a second once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient over a second period, and the method is based on the biplane LVEF of the patient's second echocardiogram obtained after the second period and the second once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof, further comprising administering to the patient a third once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof over a third period, or terminating the administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient. In some embodiments, the method includes selecting a third once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof based on the biplane LVEF of the second echocardiogram and the second once-daily dose. In some embodiments of the methods described herein, the patient receives two or more echocardiograms within the second period, and the third once-daily dose is selected based on the combined results of the two or more echocardiograms obtained within the second period.

[0017] In some embodiments of the above method, when the biplane LVEF of the second echocardiogram is below a predetermined biplane LVEF threshold, the third once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof is less than the second once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof, or 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%.

[0018] In some embodiments of the above method, 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 a patient with a first daily dose of about 5 mg of CK-274 and a second daily dose of about 5 mg of CK-274, and the biplane LVEF of the second echocardiogram is below the biplane LVEF threshold of 50%, the administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient is terminated.

[0019] In some embodiments of the above method, when the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is more 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 a patient with a first daily dose of about 5 mg of CK-274 and a second daily dose of about 10 mg of CK-274, and the biplane LVEF of the second echocardiogram is below the biplane LVEF threshold of 50%, the third daily dose of CK-274 is returned to 5 mg of CK-274.

[0020] In some embodiments of the above method, 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%.

[0021] In some embodiments of the above method, when the biplane LVEF of the second echocardiogram is greater than or equal to a predetermined biplane LVEF threshold, the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is more than the second 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%.

[0022] In some embodiments of the above method, the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg of CK-274, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg of 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 of CK-274.

[0023] In some embodiments of the above method, the method further includes measuring components of the second echocardiogram.

[0024] In some embodiments of the above method, the third period is about two weeks.

[0025] In some embodiments of the above method, a third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is administered to a patient over a third period, and the method is based on a third echocardiogram component of the patient obtained after the third period and a third daily dose of the ★compound★ or a pharmaceutically acceptable salt thereof, administering to the patient a fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof over a fourth period, or terminating the administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient. In some embodiments, the method further includes 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 receives two or more echocardiograms during the third period, and the fourth daily dose is selected based on the integrated results of the two or more echocardiograms obtained during the third period.

[0026] In some embodiments of the above method, when the biplane LVEF of the third echocardiogram is below a predetermined biplane LVEF threshold, the fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof is less than the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof, or the administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient is terminated.

[0027] 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 less than 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%.

[0028] In some embodiments of the above method, when the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is more than the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof, and the biplane LVEF of the third echocardiogram is greater than or equal to 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 greater than or equal to 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%.

[0029] In some embodiments of the above method, when the biplane LVEF of the third echocardiogram is greater than or equal to a predetermined biplane LVEF threshold, the fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof is more than the third 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%.

[0030] In some embodiments of the above method, the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg of CK-274, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg of 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 of 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 of CK-274.

[0031] In some embodiments, the daily dose is about 15 mg of CK-274. In some embodiments, the third daily dose is about 15 mg of CK-274. In some embodiments, the fourth daily dose is about 15 mg of CK-274. In some embodiments, the daily dose is about 20 mg of CK-274. In some embodiments, the fourth daily dose is about 20 mg of CK-274. In some embodiments, the daily dose is administered as a tablet. In some embodiments, the amount of CK-274 in a tablet, which may exist in multiple forms (e.g., free form, pharmaceutically acceptable salt form, polymorphic form, etc.), is approximately the daily dose described herein. In some embodiments, the amount of CK-274 in a tablet is about 5 mg. In some embodiments, the amount of CK-274 in a tablet is about 10 mg. In some embodiments, the amount of CK-274 in a tablet is about 15 mg. In some embodiments, the amount of CK-274 in a tablet is about 20 mg. In some embodiments, the amount of CK-274 in a tablet is approximately half of the daily dose described herein. In some embodiments, the amount of CK-274 in a tablet is about 2.5 mg. In some embodiments, the amount of CK-274 in a tablet is about 5 mg. In some embodiments, the amount of CK-274 in a tablet is about 7.5 mg. In some embodiments, the amount of CK-274 in a tablet is about 10 mg.

[0032] In some embodiments of the above method, the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg of CK-274, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg of 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 of 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 of CK-274.

[0033] In some embodiments of the above method, the method further includes measuring the biplane LVEF of the third echocardiogram.

[0034] In some embodiments of the above method, the fourth period is about two weeks.

[0035] In some embodiments, a method of treating non-obstructive hypertrophic cardiomyopathy (nHCM) or mid-ventricular obstructive (MVO) HCM in a patient in need of treatment for nHCM or MVO HCM comprises administering to the patient a first daily dose of CK-274 or a pharmaceutically acceptable salt thereof over a first period, and based on a first echocardiogram comprising the patient's biplane LVEF obtained after the first period, administering to the patient a second daily dose of CK-274 or a pharmaceutically acceptable salt thereof over a second period, or terminating the administration of CK-274 to the patient, wherein when the biplane LVEF of the first echocardiogram is below a first predetermined biplane LVEF threshold, the administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient is terminated, and when the biplane LVEF is greater than or equal to 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 when the biplane LVEF of the first echocardiogram is greater than or equal to 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.

[0036] In some embodiments of the above method, the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg of CK-274, and the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg of CK-274.

[0037] In some embodiments of the above method, the method further comprises measuring the biplane LVEF for the first echocardiogram.

[0038] In some embodiments of the above method, the first period is about two weeks.

[0039] In some embodiments of the above method, the second period is about two weeks.

[0040] In some embodiments of the above method, a second once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient over the second period, and the method further comprises administering to the patient a third once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof over a third period, or terminating the administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient, based on a second echocardiogram comprising the patient's biplane LVEF obtained after the second period and the second once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof; wherein the 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 a first predetermined biplane LVEF threshold and the second once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the first once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof; the third once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof is less than the second once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof when the biplane LVEF of the second echocardiogram is below a first predetermined biplane LVEF threshold and the second once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof is more than the first once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof; the third once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the second once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof when the biplane LVEF is equal to or greater than the first predetermined biplane LVEF threshold and below a second predetermined biplane LVEF threshold; and the third once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof is more than the second once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof when the biplane LVEF of the second echocardiogram is above the second predetermined biplane LVEF threshold.

[0041] In some embodiments of the above method, the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg of CK-274, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg of 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 of CK-274.

[0042] In some embodiments of the above method, the method further comprises measuring the biplane LVEF for a second echocardiogram.

[0043] In some embodiments of the above method, the third period is about two weeks.

[0044] In some embodiments of the above method, a third once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient over a third period, and the method further comprises administering to the patient a fourth once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof over a fourth period, or terminating the administration of CK-274 to the patient, based on a third echocardiogram including the patient's biplane LVEF obtained after the third period and the third once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof. When the biplane LVEF of the third echocardiogram is below a first predetermined biplane LVEF threshold and the third once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the first once-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. When the biplane LVEF of the third echocardiogram is below a first predetermined biplane LVEF threshold and the third once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof is more than the first once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof, the fourth once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof is less than the third once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof. When the biplane LVEF is equal to or greater than the first predetermined biplane LVEF threshold and less than a second predetermined biplane LVEF threshold, the fourth once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof is the same as the third once-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 the second predetermined biplane LVEF threshold, the fourth once-daily dose of CK-274 or a pharmaceutically acceptable salt thereof is more than the third once-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 of CK-274, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg of 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 of 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 of CK-274. In some embodiments, the method further comprises measuring the biplane LVEF for the third echocardiogram. In some embodiments, the third period is about two weeks.

[0045] In some embodiments of the above method, the first predetermined biplane LVEF threshold is 50% and the second predetermined biplane LVEF threshold is 55%.

[0046] In some embodiments of the above method, the first predetermined biplane LVEF threshold is 50% and the second predetermined biplane LVEF threshold is 60%.

[0047] In some embodiments of any of the above methods, prior to administration of CK-274 or a pharmaceutically acceptable salt thereof, the left ventricular (LV) end-diastolic wall thickness in one or more myocardial segments of the patient is 15 mm or more. 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 left ventricular (LV) end-diastolic wall thickness of 13 mm or more in one or more wall segments and a known gene mutation causing the disease or a positive family history of HCM.

[0048] In some embodiments of any of the above methods, prior to administration of CK-274 or a pharmaceutically acceptable salt thereof, the LVOT-G at rest and after Valsalva in the patient is less than 30 mmHg.

[0049] In some embodiments of any of the above methods, before administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient's resting LVOT-G is less than 30 mmHg. In some embodiments of any of the above methods, before administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient's post-Valsalva LVOT-G is less than 50 mmHg. In some embodiments of any of the above methods, before administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient's resting LVOT-G is less than 30 mmHg and the patient's post-Valsalva LVOT-G is less than 50 mmHg.

[0050] In some embodiments of any of the above methods, before administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient's KCCQ-CSS score is 30 or more and 85 or less.

[0051] In some embodiments of any of the above methods, before administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient's NT-proBNP is elevated. In some embodiments of any of the above methods, before administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient's NT-proBNP level exceeds 300 pg / mL. In some embodiments of any of the above methods, in the case of atrial fibrillation or atrial flutter before administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient's NT-proBNP level is 900 pg / mL or more. In some embodiments of any of the above methods, in the case of atrial fibrillation or atrial flutter before administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient's NT-proBNP level is 225 pg / mL or more or 675 pg / mL or more.

[0052] In some embodiments of any of the above methods, before administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient's left ventricular ejection fraction (LVEF) is 60% or more.

[0053] In some embodiments of any of the above methods, the patient is not administered disopyramide during treatment with CK-274 or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments of any of the above methods, the patient has not been treated with disopyramide or an antiarrhythmic agent having a negative inotropic effect within 4 weeks prior to treatment with CK-274 or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments of any of the above methods, the patient is a CYP2D6 poor metabolizer.

[0056] In some embodiments of any of the above methods, the patient is in a fasting state when administered CK-274 or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments of any of the above methods, the patient is in a postprandial state when administered CK-274 or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments of any of the above methods, the method does not include collecting a blood sample from the patient.

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

[0060] In some embodiments of any of the above methods, the patient is administered a beta blocker during treatment with CK-274 or a pharmaceutically acceptable salt thereof. In some embodiments of any of the above methods, the patient is administered one or more of a beta blocker, verapamil, diltiazem, and ranolazine.

[0061] 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.

[0062] Also provided herein is a method of treating non-obstructive hypertrophic cardiomyopathy (nHCM) or mid-ventricular obstructive (MVO) HCM 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.

[0063] In some embodiments of any of the above methods, the method results in one or more of the following: improvement of cardiac relaxation, beneficial cardiac remodeling, cardiac reverse remodeling, beneficial cardiac structural remodeling, beneficial cardiac functional remodeling, reversal of detrimental cardiac remodeling, reduction of mean left ventricular myocardial mass index (LVMI), improvement of left ventricular (LV) filling pressure, reduction of left atrial volume index (LAVI), reduction of categorical assessment regarding systolic anterior motion of the mitral valve leaflet, reduction of systolic anterior motion of the mitral valve leaflet, reduction of the frequency of eccentric mitral regurgitation, reduction of mitral regurgitation, reduction of lateral wall E / e’, reduction of lateral wall E / E, reduction of brain natriuretic peptide (BNP), and reduction of N-terminal prohormone of brain natriuretic peptide (NT-proBNP).

[0064] In some embodiments, one or more of the results of the treatment occur within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks from the start of treatment with CK-274 or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments of any of the above methods, the patient's left ventricular myocardial mass index (LVMI) is reduced.

[0066] In some embodiments of any of the above methods, the patient's left arterial volume index (LAVI) is reduced.

[0067] In some embodiments of any of the above methods, the patient's e’ is reduced.

[0068] In some embodiments of any of the above methods, the patient's lateral wall E / e’ is reduced.

[0069] In some embodiments of any of the above methods, the possibility of systolic anterior motion of the mitral valve tip is reduced.

[0070] In some embodiments of any of the above methods, the level of the patient's brain natriuretic peptide or the N-terminal prohormone of brain natriuretic peptide (NT-proBNP) is reduced.

[0071] In some embodiments of any of the above methods, the level of the patient's cardiac troponin I is reduced.

[0072] In some embodiments of any of the above methods, the left ventricular wall stress of the patient is decreased.

[0073] In some embodiments of any of the above methods, the myocardial injury of the patient is reduced.

[0074] In some embodiments of any of the above methods, the heart failure symptoms of the patient are reduced, for example, the method reduces the NYHA classification of the patient.

[0075] In some embodiments of any of the above methods, the degree of midventricular obstruction is reduced.

[0076] In some embodiments of any of the above methods, the method provides a sustained effect(s) over at least 10 weeks, 12 weeks, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years.

[0077] In some embodiments of any of the above methods, administration over a second period, a third period, or a fourth period can be, for example, administration over 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 administration on an irregular basis. As used herein, administration on an irregular basis can indicate administering until the patient no longer requires further treatment, administering until there is no further therapeutic effect, or administering until there is no further reason to treat.

[0078] In some embodiments, the method results in a reduction of at least 1 class in the patient's NYHA classification and / or a reduction in NT-proBNP and / or a reduction in the level of troponin I (e.g., cardiac troponin I).

[0079] 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 wt% to about 50 wt% of CK-274 or a pharmaceutically acceptable salt thereof, (ii-1) about 10 wt% to about 60 wt% of mannitol, (ii-2) about 5 wt% to about 45 wt% of microcrystalline cellulose, (iii) about 0.1 wt% to about 10 wt% of hydroxypropylcellulose, (iv) about 1 wt% to about 10 wt% of croscarmellose sodium, (v) about 0.1 wt% to about 10 wt% of sodium lauryl sulfate, and (vi) about 0.1 wt% to about 10 wt% of magnesium stearate, provided that wt% excludes the weight thereof when a coating is present. In some embodiments, CK-274 or a pharmaceutically acceptable salt thereof comprises one or more of polymorphic forms I, II, III, IV, V, and VI of CK-274.

Brief Description of the Drawings

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Mode for Carrying Out the Invention

[0121] This specification describes various methods for treating, for example, non-obstructive hypertrophic cardiomyopathy or mid-ventricular obstructive hypertrophic cardiomyopathy, using a cardiac myosin inhibitor (also referred to as CK-274 or aficamten, CK-3773274) and a cardiac myosin inhibitor. The treatment methods may include adjusting the dose, for example, increasing, decreasing, or maintaining the dose, based on the results of one or more biplane left ventricular ejection fraction (LVEF) measurements. These measurements can be obtained, for example, using echocardiograms.

[0122] CK-3773274 (CK-274) is a small molecule cardiac myosin inhibitor having the structure shown below.

Chemical formula

[0123] The chemical name of CK-274 is (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. This small molecule inhibitor can be orally administered to patients, for example, for the treatment of non-obstructive hypertrophic cardiomyopathy (nHCM) or MVOHCM.

[0124] CK-274 is described in WO2019 / 144041, which is incorporated herein by reference. CK-274 or a pharmaceutically acceptable salt thereof can be obtained according to the methods described therein. CK-274 used in the disclosed methods can exist as a pharmaceutically acceptable salt, solvate, hydrate, polymorph, or a combination thereof, and can be formulated into any suitable pharmaceutical formulation. CK-274 can also exist in its free base form. The polymorphs of CK-274 are described in WO2021 / 011807, which is incorporated herein by reference. The formulations of CK-274 are described in WO2021 / 011808, which is incorporated herein by reference. CK-274 is designed to reduce the hypercontractility associated with hypertrophic cardiomyopathy (HCM). Without being bound by theory, in preclinical models, CK-274 reduces myocardial contractility by directly binding to cardiac myosin at a unique and selective allosteric binding site, thereby preventing myosin from entering the force-generating state. CK-274 reduces the number of active actin-myosin cross-bridges during each cardiac cycle, resulting in a reduction in myocardial contractility. This mechanism of action can be therapeutically effective in conditions characterized by excessive hypercontractility, such as HCM (e.g., non-obstructive HCM, also referred to as nHCM, or MVOHCM).

[0125] Definitions As used herein, the following words and phrases are generally intended to have the meanings set forth below, unless otherwise indicated in the context in which they are used.

[0126] Throughout this application, unless the context otherwise indicates, references to CK-3773274, CK-274, or aficamten include its amorphous form or its polymorphs, including any one of polymorphic forms I, II, III, IV, V, or VI described herein, or a mixture thereof.

[0127] References to a value or parameter “about” in this specification include (and describe) that value or parameter itself and any value or parameter that is 5% more or 5% less than the parameter. For example, a description of “about X” includes descriptions of “X” and “X + / - 5%”.

[0128] "NYHA classification" or "NYHA class" refers to the New York Heart Association functional classification of heart failure symptoms. For descriptions of each of NYHA classes I, II, III, and IV, see 1) Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart Association. Criteria Committee. “Nomenclature and criteria for diagnosis of diseases of the heart and great vessels”. 9th ed. Boston, MA: Lippincott Williams and Wilkins; March 1, 1994; and 2) Criteria Committee, New York Heart Association, Inc. Diseases of the Heart and Blood Vessels. Nomenclature and Criteria for diagnosis, 6th edition Boston, Little, Brown and Co. 1964, p 114, adopted from "Classes of Heart Failure", American Heart Association, https: / / www.heart.org / en / health-topics / heart-failure / what-is-heart-failure / classes-of-heart-failure. Briefly stated, NYHA class I indicates that the patient has no limitation in physical activity and no excessive fatigue, palpitations, or dyspnea (shortness of breath) during normal physical activity. NYHA class II indicates that the patient has a mild limitation in physical activity, no complaints at rest, but fatigue, palpitations, or dyspnea during normal physical activity. NYHA class III indicates that the patient has a marked limitation in physical activity, no complaints at rest, but fatigue, palpitations, or dyspnea during usual physical activity below a certain level. NYHA class IV indicates that the patient has complaints with any physical activity, symptoms of heart failure are seen at rest, and the complaints increase with any physical activity.

[0129] The term "pharmaceutically acceptable salt" refers to any salt of a compound herein that is known to be non-toxic and is commonly used in the pharmaceutical literature. In some embodiments, the pharmaceutically acceptable salts of the compounds retain the biological effectiveness of the compounds described herein and are not undesirable biologically or otherwise. 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 and organic acids. Examples of inorganic acids from which the salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids from which the 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 and organic bases. Examples of inorganic bases from which the salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Examples of organic bases from which the salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines such as naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salts are selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0130] When the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the compound is a free base, addition salts, particularly pharmaceutically acceptable addition salts, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds (see, e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January, 1977, 66(1), 1-19). Those skilled in the art will recognize the various synthetic methods that can be used to prepare pharmaceutically acceptable addition salts.

[0131] The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include 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 pharmaceutical active substances is well known in the art. The use thereof in pharmaceutical compositions is contemplated, except where any conventional media or agent is incompatible with the active ingredient. Auxiliary active ingredients can also be incorporated into the pharmaceutical compositions.

[0132] 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 human, e.g., for purposes of treatment, observation, or experimentation, or is the human for whom it is intended. The compounds, compositions, and methods described herein may be useful in both human therapy and veterinary applications.

[0133] The terms "therapeutically effective amount" or "effective amount" refer to the amount of a compound disclosed and / or described herein that, when administered to a patient in need of the treatment as defined herein, is sufficient to affect such treatment. The therapeutically effective amount of a compound can be an amount sufficient to treat a disease responsive to modulation of myocardial segments. The therapeutically effective amount will vary, for example, depending on the subject and condition being treated, the subject's weight and age, the severity of the condition, the particular compound, the dosing regimen to be followed, the timing of administration, and the mode of administration, all of which can be readily determined by one of ordinary skill in the art. The therapeutically effective amount can be confirmed experimentally, for example, by assaying the blood concentration of the chemical substance, or theoretically, by calculating bioavailability.

[0134] "Treatment" (and related terms such as "treat," "treated," "treating," etc.) includes one or more of inhibiting a disease or disorder, delaying or preventing the occurrence of clinical symptoms of a disease or disorder, and / or alleviating a disease or disorder (i.e., causing remission or regression of clinical symptoms). The term encompasses both complete and partial reduction or prevention of a condition or disorder and complete or partial reduction of clinical symptoms of a disease or disorder. Thus, the compounds described and / or disclosed herein can prevent the worsening of an existing disease or disorder, assist in the management of a disease or disorder, or reduce or eliminate a disease or disorder.

[0135] Reference to any dosage amount of a compound described herein or a pharmaceutically acceptable salt thereof (e.g., 5 mg, 10 mg, 20 mg, etc. of CK-274) refers to the amount of the compound without any salt (i.e., the equivalent mass). Treatment of non-obstructive hypertrophic cardiomyopathy

[0136] As further described herein, a therapeutically effective amount of CK-274 can be administered to a patient for the treatment of non-obstructive hypertrophic cardiomyopathy. CK-274 can be administered at a fixed dosage level. CK-274 can be administered at a dosage-adjusted level. For example, the dosage of CK-274 can be adjusted according to the patient's response to the drug. That is, the dosage of CK-274 can be periodically increased, decreased, maintained, or temporarily interrupted according to measurements of drug response such as one or more of the left ventricular biplane left ventricular ejection fraction (LVEF) measurements.

[0137] CK-274 is administered at a therapeutically effective dosage, for example, a dosage sufficient to effect treatment of the disease state. In the case of humans, the daily dosage can be from about 1 mg to about 50 mg. For example, the daily dosage can be about 5 mg, about 10 mg, about 15 mg, about 20 mg, or about 30 mg, or any amount in between. The daily dosage refers to the total amount administered in a day. The daily dosage can be administered, but is not limited to, daily, every other day, weekly, every two weeks, monthly, or at various intervals. In some embodiments, the daily dosage is administered for a period ranging from one day to the lifetime of the subject. In some embodiments, the daily dosage is administered once a day. In some embodiments, the daily dosage is administered in multiple divided dosages, such as two, three, or four divided dosages. In some embodiments, the daily dosage is administered in two divided dosages.

[0138] In one example, administering a daily dosage of about 5 mg to about 15 mg of CK-274 to a patient treats the patient's non-obstructive hypertrophic cardiomyopathy. In one example, administering a daily dosage of about 5 mg of CK-274 to a patient treats the patient's non-obstructive hypertrophic cardiomyopathy. In one example, administering a daily dosage of about 10 mg of CK-274 to a patient treats the patient's non-obstructive hypertrophic cardiomyopathy. In one example, administering a daily dosage of about 15 mg of CK-274 to a patient treats the patient's non-obstructive hypertrophic cardiomyopathy. In one example, administering a daily dosage of about 20 mg of CK-274 to a patient treats the patient's non-obstructive hypertrophic cardiomyopathy.

[0139] In some embodiments, there is provided a method for treating non-obstructive hypertrophic cardiomyopathy, which comprises 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 treatment-resistant non-obstructive hypertrophic cardiomyopathy. In some embodiments, there is provided a method for treating non-obstructive hypertrophic cardiomyopathy, treatment-resistant hypertrophic cardiomyopathy, or treatment-resistant non-obstructive hypertrophic cardiomyopathy, which comprises administering CK-274, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing CK-274 or a pharmaceutically acceptable salt thereof.

[0140] During the treatment of non-obstructive hypertrophic cardiomyopathy, the dosage of CK-274 administered to a patient can be adjusted, for example, by increasing the dosage, decreasing the dosage, maintaining the dosage, or interrupting the dosage temporarily. The dosage adjustment may be performed once during the treatment, or may be repeated at intervals over a certain period. For example, in some embodiments, the dosage of CK-274 is adjusted more than twice (e.g., 3, 4, 5 or more times) during the treatment. In some embodiments, the amount of the new daily dosage is administered to the patient in a fixed amount for about 1 week to about 8 weeks (or about 2 weeks to about 6 weeks, or about 4 weeks) before the amount of the daily dosage is adjusted. In some embodiments, the amount of the new daily dosage is administered to the patient in a fixed amount for about 2 weeks before the dosage adjustment. For example, the first daily dosage can be administered to the patient for about 2 weeks before the first dosage adjustment, at which time the amount of the daily dosage is increased, decreased, or maintained. Subsequently, a second dosage adjustment can be performed approximately 2 weeks after the first dosage adjustment. By adjusting the dosage of the dosage, the dosage can be individualized according to the patient's response to the drug, thereby maximizing the potential therapeutic effect on the patient.

[0141] Dosage adjustment can be based on the biplane left ventricular ejection fraction (LVEF) measured in the patient. These measurements can be determined, for example, using an echocardiogram. The echocardiogram can be taken after administration of the daily dose, for example, about 1 to about 3 hours, or about 2 hours after dose administration. In some embodiments, the echocardiogram is taken about 2 hours after daily dose administration.

[0142] In some embodiments, an initial daily dose of CK-274 of about 5 mg, about 10 mg, about 15 mg, about 20 mg, or about 30 mg, or any amount in between, is administered to the patient. After a certain period of time (e.g., about 2 weeks) has elapsed, the biplane LVEF is measured, for example, by echocardiogram, after dose administration (e.g., about 1 - 3 hours, or about 2 hours after dose administration). If the biplane LVEF is above a predetermined biplane LVEF threshold (e.g., about 40% or more, about 45% or more, about 50% or more, about 55% or more, or about 60% or more), the daily dose is increased. In some embodiments, the daily dose is increased when the biplane LVEF is above a predetermined biplane LVEF threshold of about 55%. In some embodiments, the daily dose is increased when the biplane LVEF is above a predetermined biplane LVEF threshold of about 60%. If the biplane LVEF is below the biplane LVEF threshold, the dose can be decreased or discontinued. In some embodiments, the biplane LVEF threshold is about 50%.

[0143] After a certain period of time (e.g., about 2 weeks) has elapsed during which the patient has been administered a first dose-adjusted dose, the dose can be adjusted (i.e., increased, decreased, or maintained) again, or temporarily interrupted, based on the patient's biplane LVEF, for example, using the same threshold parameters as described above.

[0144] Disclosed herein is a method for treating non-obstructive hypertrophic cardiomyopathy (nHCM) in patients eligible for septal reduction therapy (SRT), the method comprising administering to the patient a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof. Also disclosed herein is a method for treating nHCM in patients in need of SRT, the method comprising administering to the patient a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, the method eliminating the patient's need for SRT. In some embodiments, SRT is myectomy. In some embodiments, SRT is alcohol septal ablation.

[0145] Further disclosed herein is a method for treating non-obstructive hypertrophic cardiomyopathy (nHCM) in patients having heart failure symptoms, the method comprising administering to the patient a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, the method resulting in a reduction of heart failure symptoms as evaluated by NYHA classification. In some of the foregoing embodiments, the method improves heart failure symptoms by at least one NYHA class of the patient, e.g., by one or two NYHA classes. In some of the foregoing embodiments, the method changes the patient from NYHA class III to class II or class I. In some of the foregoing embodiments, the method changes the patient from NYHA class III to class II. In some of the foregoing embodiments, the method changes the patient from NYHA class III to class I. In some of the foregoing embodiments, the method changes the patient from NYHA class II to class I. In some of the foregoing embodiments, the reduction of heart failure symptoms occurs within 10 weeks from the start of treatment with CK-274 or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, the dosage adjustment of the daily dose of CK-274 or a pharmaceutically acceptable salt thereof is based on the results of an echocardiogram including biplane LVEF. For example, based on the results of the biplane LVEF, the daily dose of CK-274 or a pharmaceutically acceptable salt thereof can be increased, maintained, or decreased (or, for example, discontinued if the subject has already received the minimum (e.g., first) daily dose). The first daily dose of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient over a first period (e.g., about two weeks). Then, the second daily dose or the end of administration of CK-274 or a pharmaceutically acceptable salt thereof to the subject is selected based on the biplane LVEF of the patient obtained after the first period. If the biplane LVEF of the echocardiogram is below a first predetermined biplane LVEF threshold (e.g., 50%) and the patient has already received the minimum (e.g., first) daily dose, the administration of CK-274 or a pharmaceutically acceptable salt thereof can be discontinued. If the biplane LVEF of the echocardiogram is below a first predetermined biplane LVEF threshold (e.g., 50%) and the patient has not yet received the minimum daily dose, the daily dose can be decreased (i.e., the second daily dose is less than the first daily dose). If the biplane LVEF is above the 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 above the second predetermined biplane threshold, the daily dose can be increased (i.e., the second daily dose is more than the first daily dose). In some embodiments, the second predetermined biplane LVEF threshold is 60%.

[0147] The second daily dose can be administered to the patient over a second period (e.g., about two weeks), and then the dose is adjusted again based on the results of a second echocardiogram including the patient's biplane LVEF obtained after the second period. (The second period can be, for example, about two weeks, about ten weeks, about twelve weeks, about six months, about one year, about two years, about three years, about four years, or about five years, or indefinite.) For example, based on the second echocardiogram and the second daily dose, a third daily dose, or the end of administration, may be selected, or administration may be terminated. If the second daily dose is the same as (or lower than) the first daily dose (e.g., if the second daily dose is the minimum dose), and the biplane LVEF of the second echocardiogram is below the first predetermined biplane LVEF threshold, administration may be discontinued. If the second daily dose is higher than the first daily dose and the biplane LVEF of the second echocardiogram is below the first predetermined biplane LVEF threshold, the third daily dose can be decreased relative to the second daily dose (e.g., to the amount of the first daily dose). If the biplane LVEF is equal to or greater than the first predetermined biplane threshold and less than the second predetermined biplane threshold, the daily dose can be maintained (i.e., the third daily dose is the same as the second daily dose). If the biplane LVEF of the second echocardiogram is above 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 over a third period (e.g., two weeks). The third period can be, for example, about two weeks, about ten weeks, about twelve weeks, about six months, about one year, about two years, about three years, about four years, or about five years, or administration over an indefinite period.

[0148] The dosing adjustment of the daily dose can be repeated over additional times, as needed, to select a fourth daily dose or end of administration of CK-274 or a pharmaceutically acceptable salt thereof. For example, for a patient, a third echocardiogram including biplane LVEF is obtained after a third period, and based on the third echocardiogram and the third daily dose, a fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof can be selected. If the biplane LVEF of the third echocardiogram is below a first predetermined biplane LVEF threshold and the third daily dose is the same as (or lower than) the first daily dose, administration of CK-274 or a pharmaceutically acceptable salt thereof can be discontinued. If the third daily dose is higher than the first daily dose and the biplane LVEF of the third echocardiogram is below the first predetermined biplane LVEF threshold, the fourth daily dose is decreased relative to the third daily dose. If the biplane LVEF of the third echocardiogram is below the first predetermined biplane LVEF threshold and the third daily dose is the same as (or lower than) the first daily dose (e.g., if the third daily dose is the minimum dose), administration of CK-274 or a pharmaceutically acceptable salt thereof can be discontinued. If the third daily dose is higher than the lowest (e.g., first) daily dose and the biplane LVEF of the third echocardiogram is below the first predetermined biplane LVEF threshold, the fourth daily dose is decreased relative to the third daily dose. If the biplane LVEF of the third echocardiogram is at or above a predetermined biplane LVEF threshold, the fourth daily dose can be the same as the third daily dose. The daily dose can be maintained if the biplane LVEF is at or above a first predetermined biplane threshold and below a second predetermined biplane threshold (i.e., the fourth daily dose is the same as the third daily dose). If the biplane LVEF of the second echocardiogram exceeds the second predetermined biplane LVEF threshold, the fourth daily dose can be increased relative to the third daily dose. The fourth daily dose is then administered to the patient over a fourth period (e.g., 2 weeks). The fourth period 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 administration can be over an indefinite period.

[0149] Figure 1 shows an exemplary method for treating a patient's non-obstructive hypertrophic cardiomyopathy (nHCM) that includes dose adjustment of a daily dose of CK-274 or a pharmaceutically acceptable salt thereof. The exemplary method shown in Figure 1 provides three daily dose levels, with the first daily dose level being the lowest daily dose level, but can be readily changed to include additional dose levels or fewer dose levels, or further changed such that the first daily dose level is not the lowest daily dose level. At 102, a first daily dose level (e.g., about 5 mg) of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient. After the first period, at 104, the daily dose level is increased or maintained, or administration is terminated. This selection can be based on a first echocardiogram obtained for the patient after the first period. Administration termination 106 can be selected if the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold (e.g., 50%), and the dose of CK-274 or a pharmaceutically acceptable salt thereof will not be administered to the patient any further. If the biplane LVEF is above a predetermined biplane LVEF threshold (e.g., 50%) and below a second predetermined biplane LVEF threshold (e.g., 55%), maintenance of the first daily dose level (e.g., about 5 mg) may be selected. If maintenance is selected, the first daily dose level of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient over a second period at 102, and optionally, the daily dose can be re-dose adjusted at 104 after the second period. If the biplane LVEF is above a second predetermined biplane LVEF threshold (e.g., 55%), the daily dose can 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 over a second period at 108.

[0150] When a second once-daily dose level of CK-274 or a pharmaceutically acceptable salt thereof (e.g., 10 mg) is administered to a patient at 108, the once-daily dose can be re-adjusted (i.e., choose to increase, decrease, or maintain the once-daily dose) based on the echocardiogram at 110. If the biplane LVEF of the echocardiogram is below a predetermined biplane LVEF threshold (e.g., 50%), the once-daily dose can be decreased to the first once-daily dose level (e.g., from 10 mg to 5 mg). When the once-daily dose is decreased to the first once-daily dose level, the first once-daily dose level is administered to the patient at 102. When the biplane LVEF is above a predetermined biplane LVEF threshold (e.g., 50%) and less than a second predetermined biplane LVEF threshold (e.g., 55%), maintenance of the second once-daily dose level (e.g., about 10 mg) may be selected. If maintenance is selected, the second once-daily dose level of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient at 108 over a further period, and optionally, the once-daily dose can be re-adjusted at 110 after the above second period. When the biplane LVEF is above a second predetermined biplane LVEF threshold (e.g., 55%), the once-daily dose can be increased to a third once-daily dose level (e.g., 15 mg). If an increase in the once-daily dose level is selected, the second once-daily dose level of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient over a period at 112.

[0151] When a third once-daily dose level of CK-274 or a pharmaceutically acceptable salt thereof (e.g., 10 mg) is administered to a patient at 112, the once-daily dose can be re-adjusted (i.e., choose to decrease or maintain the once-daily dose) based on the echocardiogram at 114. If the biplane LVEF of the echocardiogram is below a predetermined biplane LVEF threshold (e.g., 50%), the once-daily dose can be decreased to a second once-daily dose level (e.g., from 15 mg to 10 mg). When the once-daily dose is decreased to the second once-daily dose level, the second once-daily dose level is administered to the patient at 108. Maintenance of the third once-daily dose level (e.g., about 15 mg) can be selected when the biplane LVEF is at or above a predetermined biplane LVEF threshold (e.g., 50%). If maintenance is selected, the third once-daily dose level of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient at 112 for a further period, and optionally, the once-daily dose can be re-adjusted at 114 after that period.

[0152] In the exemplary method shown in Figure 1, since the first once-daily dose level is the minimum dose, it is not further decreased. Nevertheless, in other embodiments, since the first once-daily dose level can be other than the minimum dose, it can be decreased to a lower dose level (e.g., from 10 mg to 5 mg) if the biplane LVEF of the echocardiogram is below a predetermined biplane LVEF threshold (e.g., 50%).

[0153] In the exemplary method shown in FIG. 1, since the third once-daily dose level is the maximum dose, it is not further increased. Nevertheless, in other embodiments, additional dose levels may be available and the once-daily dose can be further increased at 114. In the method shown in FIG. 1, at 114, a choice is made to maintain the third once-daily dose level or decrease the once-daily dose level based on the echocardiogram. If the biplane LVEF of the echocardiogram is below a predetermined biplane LVEF threshold (e.g., 50%), the once-daily dose can be decreased to the second once-daily dose level (e.g., from 15 mg to 10 mg). If the once-daily dose is decreased to the second once-daily dose level, the second once-daily dose level is administered to the patient at 108. Maintenance of the third once-daily dose level (e.g., about 15 mg) can be selected when the biplane LVEF is at or above a predetermined biplane LVEF threshold (e.g., 50%). If maintenance is selected, the third once-daily dose level of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient at 112 for a further period, and optionally, the once-daily dose can be re-adjusted at 114 after that period. In embodiments where additional dose levels may be available and the once-daily dose can be further increased at 114, the once-daily dose can be increased to a fourth once-daily dose level (e.g., about 20 mg) when the biplane LVEF is at or above a second predetermined biplane LVEF threshold (e.g., 60%).

[0154] Exemplary increases in the daily dose include an increase in CK-274 from about 5 mg to about 10 mg, or an increase in CK-274 from about 10 mg to about 15 mg. Other exemplary increases in the daily dose include an increase in CK-274 from about 5 mg to about 10 mg, an increase in CK-274 from about 10 mg to about 15 mg, or an increase in CK-274 from about 15 mg to about 20 mg. Other increases in the dose can be readily envisioned, for example, increasing a given initial daily dose by about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 10 mg, or any amount in between. Exemplary decreases in the daily dose include a decrease from about 15 mg to about 10 mg, or a decrease from about 10 mg to about 5 mg. Other exemplary decreases in the daily dose 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 decreases in the dose can be readily envisioned, for example, decreasing a given initial daily dose by about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 10 mg, or any amount in between.

[0155] Exemplary embodiments of the methods described herein administer a first daily dose or dose 1 of CK-274 or a pharmaceutically acceptable salt thereof (e.g., from about 1 mg to about 20 mg, such as 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 the first daily dose) over a first period (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 duration therebetween), and then, based on the patient's biphasic LVEF, maintain the daily dose, decrease the daily dose (e.g., decrease the daily dose by about 1 mg to about 10 mg, such as decrease the daily dose by 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg, or any amount therebetween), increase the daily dose (e.g., increase the daily dose by about 1 mg to about 10 mg, such as increase the daily dose by 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg, or any amount therebetween), or terminate the administration to reach a second daily dose. Another exemplary embodiment of the methods described herein administers a first daily dose of CK-274 or a pharmaceutically acceptable salt thereof for about 2 weeks, and then, based on the patient's biphasic LVEF, maintain the daily dose, decrease the daily dose by about 5 mg, increase the daily dose by about 5 mg, or terminate the administration to reach a second daily dose. Another exemplary embodiment of the methods described herein administers a first daily dose of CK-274 or a pharmaceutically acceptable salt thereof for about 3 weeks, and then, based on the patient's biphasic LVEF, maintain the daily dose, decrease the daily dose by about 5 mg, increase the daily dose by about 5 mg, or terminate the administration to reach a second daily dose. Another exemplary embodiment of the methods described herein administers a first daily dose of CK-274 or a pharmaceutically acceptable salt thereof for about 2 weeks, and then, based on the patient's biphasic LVEF, maintain the daily dose, decrease the daily dose by about 10 mg, increase the daily dose by about 10 mg, or terminate the administration to reach a second daily dose.Another exemplary embodiment of the methods described herein involves administering a first daily dose of CK-274 or a pharmaceutically acceptable salt thereof for about 3 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 the administration to reach a second daily dose, based on the patient's biphasic LVEF. Another exemplary embodiment of the methods described herein involves 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 the administration to reach a second daily dose, based on the patient's biphasic LVEF.

[0156] Treatment of non-obstructive hypertrophic cardiomyopathy can result in improvement of exercise capacity and / or alleviation of symptoms in patients having supraventricular tachycardia resulting from non-obstructive hypertrophic cardiomyopathy. In some embodiments, the method comprises administering to an individual having non-obstructive hypertrophic cardiomyopathy a therapeutically effective daily dose of CK-274 or a pharmaceutically acceptable salt thereof, thereby improving the exercise capacity of the individual. In some embodiments, the exercise capacity can be measured by one or more of the cardiopulmonary exercise test (CPET) parameters, or a combination of one or more CPET parameters. In some embodiments, the exercise capacity can be measured by peak oxygen uptake (pVO2) (peak exercise capacity) and / or minute ventilation / carbon dioxide production (VE / VCO2) slope (peak submaximal exercise capacity). In some embodiments, the method comprises administering to an individual having non-obstructive hypertrophic cardiomyopathy a therapeutically effective daily dose of CK-274 or a pharmaceutically acceptable salt thereof, thereby resulting in a change of 1.0 mL / kg / min or more from the baseline of pVO2 in the individual, and an improvement of 1 class or more in the NYHA functional class. In some embodiments, the method comprises administering to an individual having non-obstructive hypertrophic cardiomyopathy a therapeutically effective daily dose of CK-274 or a pharmaceutically acceptable salt thereof, thereby resulting in a change of 2.0 mL / kg / min or more from the baseline of pVO2 and not worsening the NYHA functional class. In some embodiments, the method comprises administering to an individual having non-obstructive hypertrophic cardiomyopathy a therapeutically effective daily dose of CK-274 or a pharmaceutically acceptable salt thereof, thereby alleviating one or more symptoms of supraventricular tachycardia.

[0157] In some embodiments, a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof is administered to a patient having non-obstructive hypertrophic cardiomyopathy to treat non-obstructive hypertrophic cardiomyopathy, and the biplane LVEF is maintained at 50% or more. In some embodiments, in response to administration of a therapeutically effective amount of CK-274 or a 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 interval during which the biplane LVEF is maintained can be about 1 week or more, about 2 weeks or more, about 3 weeks or more, about 4 weeks or more, about 5 weeks or more, about 6 weeks or more, about 8 weeks or more, or about 10 weeks or more from the daily dose administration.

[0158] In some embodiments, a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof is administered to a patient having non-obstructive hypertrophic cardiomyopathy, whereby the patient's left ventricular myocardial mass index (LVMI) decreases. In response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, the LVMI can decrease by about 1 g / m 2 or more, about 1.5 g / m 2 or more, about 2 g / m 2 or more, about 2.5 g / m 2 or more, about 3 g / m 2 or more, about 3.5 g / m 2 or more, or about 4 g / m 2 or more. In some embodiments, in response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, the LVMI decreases by about 1 g / m 2 to about 10 g / m 2 mmHg, for example, about 1 g / m 2 to about 6 g / m 2 or about 2 g / m 2 to about 5 g / m 2 The decrease in LVMI can occur about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after the daily dose administration.

[0159] In some embodiments, a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof is administered to a patient having non-obstructive hypertrophic cardiomyopathy, whereby the left atrial volume index (LAVI) of the patient is decreased. In response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, the LAVI may decrease by about 0.5 mL / m 2 or more, about 1 mL / m 2 or more, about 1.5 mL / m 2 or more, about 2 mL / m 2 or more, or about 2.5 mL / m 2 or more. In some embodiments, in response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, the LAVI decreases by about 0.5 mL / m 2 to about 5 mL / m 2 mmHg, for example, about 0.5 mL / m 2 to about 4 g / m 2 or about 1 mL / m 2 to about 3 mL / m 2 The decrease in LAVI can occur about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after administration of a daily dose.

[0160] In some embodiments, a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof is administered to a patient having non-obstructive hypertrophic cardiomyopathy, whereby the e' value of the patient is decreased. In response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, the e' value may decrease by about 0.1 cm / s or more, about 0.15 cm / s or more, about 0.2 cm / s or more, or about 0.25 cm / s or more. In some embodiments, in response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, the e' value decreases by about 0.05 cm / s to about 0.3 cm / s, for example, about 0.1 cm / s to about 0.25 cm / s or about 0.15 cm / s to about 0.25 cm / s. The decrease in the e' value can occur about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after administration of a daily dose.

[0161] In some embodiments, a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof is administered to a patient having non-obstructive hypertrophic cardiomyopathy, whereby the lateral wall E / e’ ratio of the patient decreases. In response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, the lateral wall E / e’ ratio may decrease by about 0.5 or more, 1 or more, about 1.2 or more, about 1.5 or more, or about 1.8 or more. In some embodiments, in response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, the lateral wall E / e’ ratio decreases by about 0.5 to about 2, for example, about 1 to about 1.8 or about 1.5 to about 1.8. The decrease in the lateral wall E / e’ ratio may occur about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after administration of the daily dose.

[0162] In some embodiments, a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof is administered to a patient having non-obstructive hypertrophic cardiomyopathy, whereby the likelihood of systolic anterior motion (SAM) of the mitral valve leaflet of the patient decreases.

[0163] In some embodiments, a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof is administered to a patient having non-obstructive hypertrophic cardiomyopathy, whereby the level of brain natriuretic peptide or the N-terminal prohormone of brain natriuretic peptide (NT-proBNP) of the patient decreases. The decrease in the level of brain natriuretic peptide or the N-terminal prohormone of brain natriuretic peptide (NT-proBNP) of the patient may occur about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after administration of the daily dose.

[0164] In some embodiments, a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof is administered to a patient having non-obstructive hypertrophic cardiomyopathy, whereby the level of cardiac troponin I decreases. The decrease in the level of cardiac troponin I of the patient may occur about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after administration of the daily dose.

[0165] In some embodiments of any of the foregoing, a patient having non-obstructive hypertrophic cardiomyopathy is classified as NYHA class III when administration with CK-274 or a pharmaceutically acceptable salt thereof is initiated. In some embodiments, a patient having non-obstructive hypertrophic cardiomyopathy is classified as NYHA class II when administration with CK-274 or a pharmaceutically acceptable salt thereof is initiated.

[0166] In some embodiments of any of the methods disclosed herein, the method results in a reduction of at least 1 class in the NYHA classification of the patient, and / or a reduction in NT-proBNP, and / or a reduction in the level of troponin I (e.g., cardiac troponin I). In some embodiments, the method results in a reduction of at least 1 class in the NYHA classification of the patient, or a reduction in NT-proBNP, or a reduction in the level of troponin I (e.g., cardiac troponin I). In some embodiments, the method results in a reduction of at least 1 class in the NYHA classification of the patient and a reduction in NT-proBNP. In some embodiments, the method results in a reduction of at least 1 class in the NYHA classification of the patient and a reduction in the level of troponin I (e.g., cardiac troponin I). In some embodiments, the method results in a reduction in NT-proBNP and a reduction in the level of troponin I (e.g., cardiac troponin I). In some embodiments, the method results in a reduction of at least 1 class in the NYHA classification of the patient, a reduction in NT-proBNP, and a reduction in the level of troponin I (e.g., cardiac troponin I).

[0167] In some embodiments of any of the foregoing, administration of CK-274 or a pharmaceutically acceptable salt thereof to a patient having non-obstructive hypertrophic cardiomyopathy further results in a reduction of the patient's left ventricular wall stress and / or a reduction of myocardial injury. The reduction of the patient's left ventricular wall stress and / or the reduction of myocardial injury can occur about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after a once-daily dose administration.

[0168] In some embodiments of any of the foregoing, administration of CK-274 or a pharmaceutically acceptable salt thereof to a patient having non-obstructive hypertrophic cardiomyopathy results in an improvement in the patient's health status. In some embodiments of any of the foregoing, administration of CK-274 or a pharmaceutically acceptable salt thereof to a patient having hypertrophic cardiomyopathy results in an improvement in the patient's health status as determined by the amount of change 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 having hypertrophic cardiomyopathy results in an improvement in the patient's health status as determined by the amount of change 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 having hypertrophic cardiomyopathy results in an improvement of 1 point, 2 points, 3 points, 4 points, 5 points, or more than 5 points in the KCCQ-CSS. In some embodiments of any of the foregoing, administration of CK-274 or a pharmaceutically acceptable salt thereof to a patient having hypertrophic cardiomyopathy results in an improvement in the patient's health status and health-related quality of life as measured by a PRO questionnaire, as determined by the amount of change in the responses to the EuroQol 5-Dimension 5-Level Measuring 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 having hypertrophic cardiomyopathy results in an improvement in the patient's health status as determined by the amount of change 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 having hypertrophic cardiomyopathy results in an improvement in the patient's health status as determined by the amount of change in the Seattle Angina Questionnaire - 7 (SAQ-7).

[0169] In some embodiments, administration of CK-274 or a pharmaceutically acceptable salt thereof to a patient having non-obstructive hypertrophic cardiomyopathy results in a sustained effect over 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 having non-obstructive hypertrophic cardiomyopathy results in a sustained effect over at least 6 months. In some embodiments, administration of CK-274 or a pharmaceutically acceptable salt thereof to a patient having hypertrophic cardiomyopathy results in a sustained effect over at least 1 year. In some embodiments, administration of CK-274 or a pharmaceutically acceptable salt thereof to a patient having non-obstructive hypertrophic cardiomyopathy results in a sustained effect over at least 5 years.

[0170] Administration of the compounds and compositions disclosed and / or described herein can be via an acceptable mode of administration of a 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.

[0171] Pharmaceutically acceptable compositions include solid, semi-solid, liquid, and aerosol dosage forms such as tablets, capsules, powders, solutions, suspensions, suppositories, and aerosol forms. The compounds disclosed and / or described herein can also be administered in dosage forms for sustained or controlled release (e.g., controlled release / sustained release pills, depot injections, osmotic pumps, or transdermal (including electrotransport) patches) for long-term timed administration and / or pulsed administration at a predetermined rate. In some embodiments, the composition is provided in unit dosage forms suitable for single administration of precise dosages.

[0172] CK-274 may be administered alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical composition may also contain small amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents, etc. (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate). Generally, the pharmaceutical composition contains from about 0.005% to 95% by weight, or from about 0.5% to 50% by weight, of the compounds disclosed and / or described herein, depending on the intended mode of administration. The actual methods for preparing such dosage forms are known or will be apparent to those skilled in the art. See, for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania. Suitable formulations of CK-274 are disclosed in WO2021 / 011808, which is incorporated herein by reference in its entirety.

[0173] 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.

[0174] In some embodiments, the filler is selected from the group consisting of powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, kaolin, corn starch, corn starch, starch derivatives, pregelatinized starch, calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate, tricalcium phosphate, compressible sugars, sugar alcohols, mannitol, sorbitol, maltitol, xylitol, lactitol, lactose, dextrose, maltose, sucrose, glucose, fructose, saccharose, raffinose, dextrate, trehalose, maltodextrin, and any mixture of the foregoing.

[0175] In some embodiments, the binder is selected from the group consisting of gum arabic, acacia gum, alginates, alginic acid, corn starch, copovidone, polyvinylpyrrolidone, 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, starch sodium, carboxymethyl cellulose sodium, starch, and any mixture of the foregoing.

[0176] In some embodiments, the disintegrant is selected from the group consisting of alginic acid, croscarmellose sodium, cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, potassium polyacrylate, pregelatinized starch, partially hydrolyzed starch, sodium carboxymethyl starch, starch, sodium alginate, carboxymethyl cellulose sodium, and any mixture of the foregoing.

[0177] In some embodiments, the surfactant is selected from the group consisting of cetylpyridinium chloride, heptadecaethyleneoxy cetanol, 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 salts of fatty alcohol sulfates, sodium lauryl sulfate, sodium salts of sulfosuccinic acid, sodium dioctyl sulfosuccinate, partial esters of fatty acids and alcohols, glycerin monostearate, glyceryl monooleate, ethers of polyoxyethylene and fatty alcohols, esters of polyoxyethylene and fatty acids, copolymers of ethylene oxide and propylene oxide (Pluronic®), benzalkonium chloride, ethoxylated triglycerides, and mixtures of any of the foregoing.

[0178] In some embodiments, the lubricant is selected from the group consisting of hydrogenated castor oil, magnesium stearate, glyceryl monostearate, calcium stearate, glyceryl behenate, glycerol distearate, glyceryl dipalmitostearate, behenoyl 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.

[0179] In some embodiments, the formulation comprises (i) about 1 wt% to about 80 wt% of CK-274 or a pharmaceutically acceptable salt thereof, (ii) about 15 wt% to about 90 wt% of a filler, (iii) about 0.1 wt% to about 10 wt% of a binder, (iv) about 1 wt% to about 10 wt% of a disintegrant, (v) about 0.1 wt% to about 10 wt% of a surfactant, and (vi) about 0.1 wt% to about 10 wt% of a lubricant.

[0180] In some embodiments, the formulation comprises (i) from about 1 wt% to about 50 wt% of CK-274 or a pharmaceutically acceptable salt thereof, (ii) from about 40 wt% to about 80 wt% of a filler, (iii) from about 0.5 wt% to about 5 wt% of a binder, (iv) from about 2 wt% to about 8 wt% of a disintegrant, (v) from about 0.5 wt% to about 5 wt% of a surfactant, and (vi) from about 0.5 wt% to about 5 wt% of a lubricant.

[0181] In some embodiments, the formulation comprises (i) from about 10 wt% to about 30 wt% of CK-274 or a pharmaceutically acceptable salt thereof, (ii) from about 60 wt% to about 80 wt% of a filler, (iii) from about 1 wt% to about 3 wt% of a binder, (iv) from about 4 wt% to about 6 wt% of a disintegrant, (v) from about 1 wt% to about 3 wt% of a surfactant, and (vi) from about 0.5 wt% to about 1.5 wt% of a lubricant.

[0182] In some embodiments, the formulation comprises (i) from about 1 wt% to about 10 wt% of CK-274 or a pharmaceutically acceptable salt thereof, (ii) from about 70 wt% to about 90 wt% of a filler, (iii) from about 1 wt% to about 3 wt% of a binder, (iv) from about 4 wt% to about 6 wt% of a disintegrant, (v) from about 1 wt% to about 3 wt% of a surfactant, and (vi) from about 0.5 wt% to about 1.5 wt% of a lubricant.

[0183] In some embodiments, the formulation comprises (i) about 5 wt% of CK-274 or a pharmaceutically acceptable salt thereof, (ii) about 85 wt% of a filler, (iii) about 2 wt% of a binder, (iv) about 5 wt% of a disintegrant, (v) about 2 wt% of a surfactant, and (vi) about 1 wt% of a lubricant.

[0184] In some embodiments, the formulation comprises (i) about 10 wt% of CK-274 or a pharmaceutically acceptable salt thereof, (ii) about 80 wt% of a filler, (iii) about 2 wt% of a binder, (iv) about 5 wt% of a disintegrant, (v) about 2 wt% of a surfactant, and (vi) about 1 wt% of a lubricant.

[0185] In some embodiments, the formulation comprises (i) from about 1% to about 50% by weight of CK-274 or a pharmaceutically acceptable salt thereof, (ii-1) from about 10% to about 60% by weight of mannitol, (ii-2) from about 5% to about 45% by weight of microcrystalline cellulose, (iii) from about 0.1% to about 10% by weight of hydroxypropyl cellulose, (iv) from about 1% to about 10% by weight of croscarmellose sodium, (v) from about 0.1% to about 10% by weight of sodium lauryl sulfate, and (vi) from about 0.1% to about 10% by weight of magnesium stearate.

[0186] In some embodiments, the formulation comprises (i) from about 10% to about 30% by weight of CK-274 or a pharmaceutically acceptable salt thereof, (ii-1) from about 40% to about 50% by weight of mannitol, (ii-2) from about 20% to about 30% by weight of microcrystalline cellulose, (iii) from about 1% to about 3% by weight of hydroxypropyl cellulose, (iv) from about 4% to about 6% by weight of croscarmellose sodium, (v) from about 1% to about 3% by weight of sodium lauryl sulfate, and (vi) from about 0.5% to about 1.5% by weight of magnesium stearate.

[0187] In some embodiments, the formulation comprises (i) from about 1% to about 10% by weight of CK-274 or a pharmaceutically acceptable salt thereof, (ii-1) from about 50% to about 60% by weight of mannitol, (ii-2) from about 25% to about 35% by weight of microcrystalline cellulose, (iii) from about 1% to about 3% by weight of hydroxypropyl cellulose, (iv) from about 4% to about 6% by weight of croscarmellose sodium, (v) from about 1% to about 3% by weight of sodium lauryl sulfate, and (vi) from about 0.5% to about 1.5% by weight of magnesium stearate.

[0188] In some embodiments, the formulation comprises (i) about 20% by weight of CK-274 or a pharmaceutically acceptable salt thereof, (ii-1) about 44% by weight of mannitol, (ii-2) about 26% by weight of microcrystalline cellulose, (iii) about 2% by weight of hydroxypropyl cellulose, (iv) about 5% by weight of croscarmellose sodium, (v) about 2% by weight of sodium lauryl sulfate, and (vi) about 1% by weight of magnesium stearate.

[0189] In some embodiments, the formulation comprises (i) about 10% by weight of CK-274 or a pharmaceutically acceptable salt thereof, (ii-1) about 50% by weight of mannitol, (ii-2) about 30% by weight of microcrystalline cellulose, (iii) about 2% by weight of hydroxypropyl cellulose, (iv) about 5% by weight of croscarmellose sodium, (v) about 2% by weight of sodium lauryl sulfate, and (vi) about 1% by weight of magnesium stearate.

[0190] In some embodiments, the formulation comprises (i) about 5% by weight of CK-274 or a pharmaceutically acceptable salt thereof, (ii-1) about 54% by weight of mannitol, (ii-2) about 31% by weight of microcrystalline cellulose, (iii) about 2% by weight of hydroxypropyl cellulose, (iv) about 5% by weight of croscarmellose sodium, (v) about 2% by weight of sodium lauryl sulfate, and (vi) about 1% by weight of magnesium stearate.

[0191] In some embodiments, the aforementioned formulation is in the form of a tablet. 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 for the core tablet excluding the weight of the coating.

[0192] In some embodiments, CK-274 or a pharmaceutical composition containing CK-274 may be in the form of pills or tablets, and thus the composition may contain, together with the compounds disclosed and / or described herein, a diluent (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesium stearate), and / or a binder (e.g., starch, gum arabic, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives) among one or more of them. Other solid dosage forms include powders encapsulated in gelatin capsules, marume, solutions or suspensions (e.g., in propylene carbonate, vegetable oil, or triglycerides).

[0193] In some embodiments, CK-274 is provided as a tablet comprising (i) a core having a total core weight comprising (a) intragranular components including (a-i) CK-274, or a pharmaceutically acceptable salt thereof, (a-ii) an intragranular filler, (a-iii) an intragranular binder, (a-iv) an intragranular disintegrant, and (a-v) an intragranular surfactant, and (b) extragranular components including (b-i) an extragranular filler, (b-ii) an extragranular disintegrant, and (b-iii) an extragranular lubricant, and optionally (ii) a coating layer comprising a coating agent.

[0194] In some embodiments, the intragranular filler is selected from the group consisting of powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, kaolin, corn starch, corn starch, starch derivatives, pregelatinized starch, calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate, tricalcium phosphate, compressible sugar, sugar alcohol, mannitol, sorbitol, maltitol, xylitol, lactitol, lactose, dextrose, maltose, sucrose, glucose, fructose, saccharose, raffinose, dextrate, trehalose, maltodextrin, and mixtures of any of the foregoing.

[0195] In some embodiments, the intragranular binder is selected from the group consisting of gum arabic, gum acacia, alginate, alginic acid, corn starch, copovidone, polyvinylpyrrolidone, 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, starch sodium, carboxymethyl cellulose sodium, starch, and any mixture of the foregoing.

[0196] In some embodiments, the intragranular disintegrant is selected from the group consisting of alginic acid, croscarmellose sodium, cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, potassium polyacrylate, pregelatinized starch, partially hydrolyzed starch, sodium carboxymethyl starch, starch, sodium alginate, carboxymethyl cellulose sodium, and any mixture of the foregoing.

[0197] In some embodiments, the surfactant within the granules is selected from the group consisting of cetylpyridinium chloride, heptadecaethyleneoxy cetanol, 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 salts of fatty alcohol sulfates, sodium lauryl sulfate, sodium salts of sulfosuccinic acid, sodium dioctyl sulfosuccinate, partial esters of fatty acids and alcohols, glycerin monostearate, glyceryl monooleate, ethers of polyoxyethylene and fatty alcohols, esters of polyoxyethylene and fatty acids, copolymers of ethylene oxide and propylene oxide (Pluronic®), benzalkonium chloride, ethoxylated triglycerides, and mixtures of any of the foregoing.

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

[0199] In some embodiments, the extragranular disintegrant is selected from the group consisting of alginic acid, croscarmellose sodium, cellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, crospovidone, sodium starch glycolate, low-substituted hydroxypropylcellulose, potassium polyacrylate, pregelatinized starch, partially hydrolyzed starch, sodium carboxymethyl starch, starch, sodium alginate, sodium carboxymethylcellulose, and any mixture of the foregoing.

[0200] In some embodiments, the extragranular lubricant is selected from the group consisting of hydrogenated castor oil, magnesium stearate, glyceryl monostearate, calcium stearate, glyceryl behenate, glycerol distearate, glyceryl dipalmityl stearate, behenoyl polyoxyl-8 glyceride, sodium stearyl fumarate, stearic acid, talc, zinc stearate, mineral oil, polyethylene glycol, poloxamer, sodium lauryl sulfate, and any mixture of the foregoing.

[0201] In some embodiments, the core comprises: (a) an intragranular component comprising (a-i) CK-274 or a pharmaceutically acceptable salt thereof at about 1% to about 80% of the total core weight, (a-ii) an intragranular filler at about 10% to about 80% of the total core weight, (a-iii) an intragranular binder at about 0.1% to about 10% of the total core weight, (a-iv) an intragranular disintegrant at about 0.1% to about 5% of the total core weight, and (a-v) an intragranular surfactant at about 0.1% to about 5% of the total core weight; and (b) an extragranular component comprising (b-i) an extragranular filler at about 5% to about 15% of the total core weight, (b-ii) an extragranular disintegrant at about 0.1% to about 5% of the total core weight, and (b-iii) an extragranular lubricant at about 0.1% to about 5% of the total core weight. In some embodiments, the total core weight 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 core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0202] In some embodiments, the core comprises: (a) an intragranular component comprising (a-i) CK-274 or a pharmaceutically acceptable salt thereof at about 1% to about 80% of the total core weight, (a-ii) an intragranular filler at about 10% to about 80% of the total core weight, (a-iii) an intragranular binder at about 0.1% to about 10% of the total core weight, (a-iv) an intragranular disintegrant at about 0.1% to about 5% of the total core weight, and (a-v) an intragranular surfactant at about 0.1% to about 5% of the total core weight; and (b) an extragranular component comprising (b-i) an extragranular filler at about 5% to about 15% of the total core weight, (b-ii) an extragranular disintegrant at about 0.1% to about 5% of the total core weight, and (b-iii) an extragranular lubricant at about 0.1% to about 5% of the total core weight. In some embodiments, the total core weight 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 core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0203] In some embodiments, the core comprises: (a) an intragranular component comprising (a-i) CK-274 or a pharmaceutically acceptable salt thereof at about 1% to about 50% of the total core weight, (a-ii) an intragranular filler at about 40% to about 80% of the total core weight, (a-iii) an intragranular binder at about 1% to about 5% of the total core weight, (a-iv) an intragranular disintegrant at about 1% to about 5% of the total core weight, and (a-v) an intragranular surfactant at about 1% to about 5% of the total core weight; and (b) an extragranular component comprising (b-i) an extragranular filler at about 5% to about 15% of the total core weight, (b-ii) an extragranular disintegrant at about 1% to about 5% of the total core weight, and (b-iii) an extragranular lubricant at about 0.1% to about 2% of the total core weight. In some embodiments, the total core weight 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 core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0204] In some embodiments, the core comprises: (a) an intragranular component comprising (a-i) CK-274 or a pharmaceutically acceptable salt thereof at about 10% to about 30% of the total core weight, (a-ii) an intragranular filler at about 50% to about 70% of the total core weight, (a-iii) an intragranular binder at about 1% to about 3% of the total core weight, (a-iv) an intragranular disintegrant at about 2% to about 4% of the total core weight, and (a-v) an intragranular surfactant at about 1% to about 3% of the total core weight; and (b) an extragranular component comprising (b-i) an extragranular filler at about 5% to about 15% of the total core weight, (b-ii) an extragranular disintegrant at about 1% to about 3% of the total core weight, and (b-iii) an extragranular lubricant at about 0.1% to about 1.5% of the total core weight. In some embodiments, the total core weight 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 core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0205] In some embodiments, the core comprises: (a) an intragranular component including (a-i) CK-274 or a pharmaceutically acceptable salt thereof at about 1% to about 10% of the total core weight, (a-ii) an intragranular filler at about 60% to about 80% of the total core weight, (a-iii) an intragranular binder at about 1% to about 3% of the total core weight, (a-iv) an intragranular disintegrant at about 2% to about 4% of the total core weight, and (a-v) an intragranular surfactant at about 1% to about 3% of the total core weight; and (b) an extragranular component including (b-i) an extragranular filler at about 5% to about 15% of the total core weight, (b-ii) an extragranular disintegrant at about 1% to about 3% of the total core weight, and (b-iii) an extragranular lubricant at about 0.1% to about 1.5% of the total core weight. In some embodiments, the total core weight 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 core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0206] In some embodiments, the core comprises: (a) an intragranular component comprising (a-i) about 5% by total core weight of CK-274 or a pharmaceutically acceptable salt thereof, (a-ii) about 74% by total core weight of an intragranular filler, (a-iii) about 2% by total core weight of an intragranular binder, (a-iv) about 3% by total core weight of an intragranular disintegrant, and (a-v) about 2% by total core weight of an intragranular surfactant; and (b) an extragranular component comprising (b-i) about 11% by total core weight of an extragranular filler, (b-ii) about 2% by total core weight of an extragranular disintegrant, and (b-iii) about 1% by total core weight of an extragranular lubricant. In some embodiments, the total core weight 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 core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0207] In some embodiments, the core comprises (a) an intragranular component comprising (a-i) about 10% by weight of the total core weight of CK-274 or a pharmaceutically acceptable salt thereof, (a-ii) about 69% by weight of the total core weight of an intragranular filler, (a-iii) about 2% by weight of the total core weight of an intragranular binder, (a-iv) about 3% by weight of the total core weight of an intragranular disintegrant, and (a-v) about 2% by weight of the total core weight of an intragranular surfactant, and (b) an extragranular component comprising (b-i) about 11% by weight of the total core weight of an extragranular filler, (b-ii) about 2% by weight of the total core weight of an extragranular disintegrant, and (b-iii) about 1% by weight of the total core weight of an extragranular lubricant. In some embodiments, the total core weight 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 core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0208] In some embodiments, the core comprises: (a) an intragranular component comprising (a-i) about 20% by total core weight of CK-274 or a pharmaceutically acceptable salt thereof, (a-ii) about 59% by total core weight of an intragranular filler, (a-iii) about 2% by total core weight of an intragranular binder, (a-iv) about 3% by total core weight of an intragranular disintegrant, and (a-v) about 2% by total core weight of an intragranular surfactant; and (b) an extragranular component comprising (b-i) about 11% by total core weight of an extragranular filler, (b-ii) about 2% by total core weight of an extragranular disintegrant, and (b-iii) about 1% by total core weight of an extragranular lubricant. In some embodiments, the total core weight 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 core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0209] In some embodiments, the core comprises an intragranular component comprising (a) (a-i) CK-274 or a pharmaceutically acceptable salt thereof at about 1% to about 50% of the total core weight, (a-ii-1) mannitol at about 40% to about 60% of the total core weight, (a-ii-2) microcrystalline cellulose at about 10% to about 30% of the total core weight, (a-iii) hydroxypropyl cellulose at about 1% to about 5% of the total core weight, (a-iv) croscarmellose sodium at about 1% to about 5% of the total core weight, and (a-v) sodium lauryl sulfate at about 1% to about 5% of the total core weight, and (b) an extragranular component comprising (b-i) microcrystalline cellulose at about 5% to about 15% of the total core weight, (b-ii) croscarmellose sodium at about 1% to about 5% of the total core weight, and (b-iii) an extragranular lubricant at about 0.1% to about 2% of the total core weight. In some embodiments, the extragranular lubricant is magnesium stearate. In some embodiments, the total core weight 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 core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0210] In some embodiments, the core comprises an intragranular component containing (a) (a-i) CK-274 or a pharmaceutically acceptable salt thereof at about 10% to about 30% of the total core weight, (a-ii-1) mannitol at about 40% to about 50% of the total core weight, (a-ii-2) microcrystalline cellulose at about 10% to about 20% of the total core weight, (a-iii) hydroxypropyl cellulose at about 1% to about 3% of the total core weight, (a-iv) croscarmellose sodium at about 2% to about 4% of the total core weight, and (a-v) sodium lauryl sulfate at about 1% to about 3% of the total core weight, and (b) (b-i) microcrystalline cellulose at about 5% to about 15% of the total core weight, (b-ii) croscarmellose sodium at about 1% to about 3% of the total core weight, and (b-iii) an extragranular lubricant at about 0.1% to about 1.5% of the total core weight. In some embodiments, the extragranular lubricant is magnesium stearate. In some embodiments, the total core weight 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 core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0211] In some embodiments, the core comprises an intragranular component containing (a) (a-i) about 1 wt% to about 10% of CK-274 or a pharmaceutically acceptable salt thereof based on the total core weight, (a-ii-1) about 50% to about 60% of mannitol based on the total core weight, (a-ii-2) about 15% to about 25% of microcrystalline cellulose based on the total core weight, (a-iii) about 1% to about 3% of hydroxypropyl cellulose based on the total core weight, (a-iv) about 2% to about 4% of croscarmellose sodium based on the total core weight, and (a-v) about 1% to about 3% of sodium lauryl sulfate based on the total core weight, and (b) an extragranular component containing (b-i) about 5% to about 15% of microcrystalline cellulose based on the total core weight, (b-ii) about 1% to about 3% of croscarmellose sodium based on the total core weight, and (b-iii) about 0.1% to about 1.5% of an extragranular lubricant based on the total core weight. In some embodiments, the extragranular lubricant is magnesium stearate. In some embodiments, the total core weight 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 core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0212] In some embodiments, the core comprises (a) an intragranular component comprising (a-i) about 20% by total core weight of CK-274 or a pharmaceutically acceptable salt thereof, (a-ii-1) about 44% by total core weight of mannitol, (a-ii-2) about 15% by total core weight of microcrystalline cellulose, (a-iii) about 2% by total core weight of hydroxypropyl cellulose, (a-iv) about 3% by total core weight of croscarmellose sodium, and (a-v) about 2% by total core weight of sodium lauryl sulfate, and (b) an extragranular component comprising (b-i) about 11% by total core weight of microcrystalline cellulose, (b-ii) about 2% by total core weight of croscarmellose sodium, and (b-iii) about 1% by total core weight of an extragranular lubricant. In some embodiments, the extragranular lubricant is magnesium stearate. In some embodiments, the total core weight 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 core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0213] In some embodiments, the core comprises: (a) an intragranular component comprising (a-i) about 10% by total core weight of CK-274 or a pharmaceutically acceptable salt thereof, (a-ii-1) about 50% by total core weight of mannitol, (a-ii-2) about 19% by total core weight of microcrystalline cellulose, (a-iii) about 2% by total core weight of hydroxypropyl cellulose, (a-iv) about 3% by total core weight of croscarmellose sodium, and (a-v) about 2% by total core weight of sodium lauryl sulfate; and (b) an extragranular component comprising (b-i) about 11% by total core weight of microcrystalline cellulose, (b-ii) about 2% by total core weight of croscarmellose sodium, and (b-iii) about 1% by total core weight of an extragranular lubricant. In some embodiments, the extragranular lubricant is magnesium stearate. In some embodiments, the total core weight 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 core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0214] In some embodiments, the core comprises an intragranular component containing (a) (a-i) 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 croscarmellose sodium, and (a-v) about 2% by weight of sodium lauryl sulfate, and (b) an extragranular component containing (b-i) about 11% by weight of microcrystalline cellulose, (b-ii) about 2% by weight of croscarmellose sodium, 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 core weight 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 core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0215] 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 a coating agent in an amount of about 0.5% to about 10% of the total core weight. In some embodiments, the tablet comprises a coating agent in an amount of about 1% to about 5% of the total core weight. In some embodiments, the tablet comprises a coating agent in an amount of about 2% to about 4% of the total core weight. In some embodiments, the tablet comprises a coating agent in an amount of about 3% of the total core weight. In some embodiments, the tablet comprises Opadry QX White 21A180025 in an amount of about 0.5% to about 10% of the total core weight. In some embodiments, the tablet comprises Opadry QX White 21A180025 in an amount of about 1% to about 5% of the total core weight. In some embodiments, the tablet comprises Opadry QX White 21A180025 in an amount of about 2% to about 4% of the total core weight. In some embodiments, the tablet comprises Opadry QX White 21A180025 in an amount of about 3% of the total core weight.

[0216] In some embodiments, the amount of CK-274 (which may exist in various forms) in a formulation, such as a tablet, is approximately the daily dose described herein, e.g., about 5 mg, about 10 mg, about 15 mg, or about 20 mg of CK-274. In some embodiments, the amount of CK-274 (which may exist in various forms) in a formulation (e.g., a tablet) is approximately half of the daily dose described herein. In some embodiments, the amount of CK-274 in a formulation (e.g., a tablet) is about 2.5 mg, about 5 mg, about 7.5 mg, or about 10 mg of CK-274.

[0217] In some embodiments, CK-274 is present in the free base form in various formulations, such as tablets. In some embodiments, methods, such as those described in the Examples, use such tablets.

[0218] Liquid pharmaceutically administrable compositions can be prepared by forming a solution or suspension, for example, by dissolving, dispersing, or suspending a compound disclosed and / or described herein and an optional pharmaceutical additive in a carrier (such as water, physiological saline, aqueous dextrose, glycerol, glycol, ethanol, etc.). Injectables can be prepared in conventional forms as a liquid solution or suspension, as an emulsion, or in a solid form suitable for dissolving or suspending in a liquid prior to injection. The percentage of the compound contained in such parenteral compositions depends, for example, on the physical properties of the compound, the activity of the compound, and the needs of the subject. However, a percentage of active ingredient of 0.01% to 10% in solution can be used, and higher percentages may be used if the composition is solid and later diluted to another concentration. In some embodiments, the composition contains about 0.2 to 2% of the compound disclosed and / or described herein in solution.

[0219] The pharmaceutical compositions of the compounds disclosed and / or described herein may be administered to the respiratory tract as an aerosol or solution for nebulization, or as an ultrafine powder for insufflation, either alone or in combination with an inert carrier such as lactose. In such cases, the particles of the pharmaceutical composition may have a diameter of less than 50 microns, or in some embodiments less than 10 microns.

[0220] Furthermore, the pharmaceutical composition may contain the compound disclosed and / or described herein, as well as one or more additional agents, pharmaceuticals, adjuvants, etc. Suitable agents and pharmaceuticals include those described herein.

[0221] Treatment of midventricular obstructive hypertrophic cardiomyopathy In some embodiments of any of the foregoing methods, non-obstructive HCM is mid-ventricular obstructive (MVO) HCM. For example, in some embodiments, the methods disclosed herein include administering a therapeutically effective amount of CK-274 to a patient for the treatment of mid-ventricular obstructive (MVO) hypertrophic cardiomyopathy as described herein for the treatment of non-obstructive hypertrophic cardiomyopathy. For example, in some embodiments, the patient in need of treatment has mid-ventricular obstructive HCM. It should be understood that in the embodiments disclosed herein, the term "mid-ventricular obstruction" (MVO) can be used interchangeably with "mid-cavitary obstruction".

[0222] Reduction in angina frequency In some embodiments, the present disclosure provides a method for reducing the frequency of angina in a subject described herein, the method comprising administering or delivering CK-274 to a subject described herein. 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 the 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, for example, a tablet containing 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.

[0223] Polymorph In some embodiments, CK-274 is a polymorphic form 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 WO2021 / 011807 and may be prepared according to this WO2021 / 011807. This document is hereby incorporated by reference in its entirety. Polymorphs can have properties such as bioavailability and stability under specific conditions suitable for medical or pharmaceutical use. Differences in the crystal structure of the active ingredient of a pharmaceutical can affect the dissolution rate of the pharmaceutical (which can affect bioavailability, etc.), manufacturability (e.g., ease of handling, ease of purification, ability to uniformly prepare a dose of known strength, etc.), and stability (e.g., thermal stability, shelf life (including resistance to degradation), etc.). Such differences can affect the preparation or formulation methods of pharmaceutical compositions in different dosage forms or delivery forms such as solid oral dosage forms including tablets and capsules. Compared to other forms such as amorphous or non-crystalline 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. Thus, the polymorphs 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 can have the advantage of improving the manufacturing process of the active ingredient or the stability or storage of the pharmaceutical form of the active ingredient, or having suitable bioavailability and / or stability as an active ingredient. In some embodiments, CK-274 in a formulation, such as a tablet, is one of polymorphic form I, form II, form III, form IV, form V, or form VI, or a combination thereof. 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 in polymorphic form IV.

[0224] Form I In some embodiments, CK-274 is in 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 angles 2θ and relative peak intensities observable for form I using XRPD are shown in Table P-1. In some embodiments, form I has an XRPD pattern substantially shown in FIG. 26A.

Table P1

[0225] In some embodiments, polymorphic form I has an XRPD pattern presenting 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 the angle 2θ having the maximum intensity in the XRPD pattern, substantially as shown in FIG. 26A or as shown in Table P-1. It should be understood that the relative intensities can vary depending on several factors, including the preparation, mounting of the sample, and the equipment and analysis procedures and settings used to acquire the spectrum. The relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed in this document including polymorphic form I may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees at 2θ.

[0226] In some embodiments, polymorphic form I has an XRPD pattern that includes peaks at 2θ angles of 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 ± 0.2, 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 degrees. In some embodiments, polymorphic form I has an XRPD pattern that includes peaks at 2θ 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 degrees. In some embodiments, polymorphic form I has an XRPD pattern that includes peaks at 2θ angles of 3.7 ± 0.2, 11.2 ± 0.2, 12.9 ± 0.2, 14.4 ± 0.2, and 22.4 ± 0.2 degrees. It should be understood that peaks in the XRPD pattern other than those shown in FIG. 26A or given in Table P-1 may be observed, for example, due to the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0227] In some embodiments, Form I has a differential DSC graph substantially as shown in FIG. 26B. In some embodiments, Form I is characterized by having an endothermic onset at about 199° C. as determined by DSC. In some embodiments, Form I is characterized by having an endothermic onset at 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, 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.

[0228] In some embodiments, Form I has a TGA graph substantially as shown in FIG. 26B.

[0229] In some embodiments, Form I has a DVS graph substantially as shown in FIG. 26C.

[0230] 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. Form I has an XRPD pattern that includes peaks at angles 2θ of 3.7 ± 0.2, 11.2 ± 0.2, 12.9 ± 0.2, 14.4 ± 0.2, and 22.4 ± 0.2 degrees, has an XRPD pattern that includes peaks at angles 2θ 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 degrees, or has an XRPD pattern that includes peaks at angles 2θ of 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 ± 0.2, 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 degrees. Form I has an XRPD pattern substantially as shown in Figure 26A. Form I has a DSC graph substantially as shown in Figure 26B. Form I is characterized by having an endothermic onset at about 199 °C as determined by DSC. Form I has a TGA graph substantially as shown in Figure 26B. Form I has a DVS graph substantially as shown in Figure 26C.

[0231] Form II In some embodiments, CK-274 is 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 angles 2θ and relative peak intensities observable for form II using XRPD are shown in Table P-2. In some embodiments, form II has an XRPD pattern substantially as shown in FIG. 27A.

Table P2

[0232] In some embodiments, polymorphic form II has an XRPD pattern presenting 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 the angle 2θ having the maximum intensity in the XRPD pattern, substantially as shown in FIG. 27A or as shown in Table P-2. It should be understood that the relative intensity can vary depending on several factors, including the preparation and mounting of the sample and the equipment, analysis procedures, and settings used to acquire the spectrum. The relative peak intensity and peak assignment may vary within experimental error. In some embodiments, the peak assignments listed in this document for polymorphic form II may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees at 2θ.

[0233] In some embodiments, polymorphic form II has an XRPD pattern that includes peaks at angles 2θ 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 degrees. In some embodiments, polymorphic form II has an XRPD pattern that includes peaks at angles 2θ 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 degrees. In some embodiments, polymorphic form II has an XRPD pattern that includes peaks at angles 2θ of 3.7 ± 0.2, 9.8 ± 0.2, 11.1 ± 0.2, 12.8 ± 0.2, and 20.4 ± 0.2 degrees. It should be understood that peaks in the XRPD pattern other than those shown in FIG. 27A or given in Table P-2 may be observed, for example, due to the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0234] In some embodiments, form II has a DSC graph substantially as shown in FIG. 27B. In some embodiments, form II is characterized by having an endothermic onset at about 199 °C as determined by DSC. In some embodiments, form II is characterized by having 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, 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.

[0235] In some embodiments, Form II has a TGA graph substantially as shown in FIG. 27B.

[0236] 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. (a) Form II has an XRPD pattern including peaks at angles 2θ of 3.7 ± 0.2, 9.8 ± 0.2, 11.1 ± 0.2, 12.8 ± 0.2, and 20.4 ± 0.2 degrees, has an XRPD pattern including peaks at angles 2θ 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 degrees, or has an XRPD pattern including peaks at angles 2θ 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 degrees. (b) Form II has an XRPD pattern substantially as shown in FIG. 27A. (c) Form II has a DSC graph substantially as shown in FIG. 27B. (d) Form II is characterized by having a melting endotherm onset at about 199 °C as determined by DSC. (e) Form II has a TGA graph substantially as shown in FIG. 27B. Form III

[0237] In some embodiments, CK-274 is 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. Table P-3 shows the angles 2θ and relative peak intensities observable for a mixture of form I and form III using XRPD. In some embodiments, the mixture of form I and form III has an XRPD pattern substantially as shown in FIG. 28A.

Table P3

[0238] In some embodiments, polymorphic form III has an XRPD pattern that includes peaks at angles 2θ of 9.6 ± 0.2, 10.9 ± 0.2, 15.8 ± 0.2, and 18.1 ± 0.2 degrees. In some embodiments, polymorphic form III has an XRPD pattern that includes peaks at angles 2θ of 9.6 ± 0.2, 10.9 ± 0.2, 14.5 ± 0.2, 15.8 ± 0.2, and 18.1 ± 0.2 degrees. In some embodiments, polymorphic form III has an XRPD pattern that includes peaks at angles 2θ 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 degrees. It should be understood that the relative intensity can vary depending on several factors, including the preparation and mounting of the sample and the equipment and analytical procedures and settings used to obtain the spectrum. The relative peak intensity and peak assignment may vary within experimental error. In some embodiments, the peak assignments listed in this book for polymorphic form III can vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees at 2θ.

[0239] In some embodiments, the mixture of polymorphic form I and polymorphic form III has a DSC graph substantially as shown in FIG. 28B.

[0240] In some embodiments, the mixture of polymorphic form I and polymorphic form III has a TGA graph substantially as shown in FIG. 28B.

[0241] Form IV In some embodiments, CK-274 is the 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 angles 2θ and relative peak intensities observable for Form IV using XRPD are shown in Table P-4. In some embodiments, Form IV has an XRPD pattern substantially as shown in FIG. 29A. [Table P4-1] [Table P4-2]

[0242] In some embodiments, polymorphic Form IV has an XRPD pattern presenting 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 the angle 2θ having the maximum intensity in the XRPD pattern, substantially as shown in FIG. 29A or as shown in Table P-4. It should be understood that the relative intensities may vary depending on several factors including the preparation, mounting of the sample, and the equipment and analysis procedures and settings used to acquire the spectrum. The relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments recited in this document including polymorphic Form IV may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees at 2θ.

[0243] In some embodiments, polymorph IV has an XRPD pattern having peaks at an angle 2θ 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, 28.0±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 degrees. In some embodiments, polymorphic form IV has an XRPD pattern having peaks at an angle 2θ 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 degrees. In some embodiments, polymorphic form IV has an XRPD pattern having peaks at an angle 2θ of 11.1±0.2, 12.8±0.2, 13.5±0.2, 22.8±0.2, and 24.4±0.2 degrees. It should be understood that peaks in the XRPD pattern other than the peaks shown in FIG. 29A or given in Table P-4 may be observed, for example, due to the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0244] In some embodiments, Form IV has a DSC graph substantially as shown in FIG. 29B. In some embodiments, Form IV is characterized by having an endothermic onset at about 200° C. as determined by DSC. In some embodiments, Form IV is characterized by having a melting 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.

[0245] In some embodiments, Form IV has a TGA graph substantially as shown in FIG. 29B.

[0246] 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. Form IV has an XRPD pattern containing peaks at angles 2θ of 11.1 ± 0.2, 12.8 ± 0.2, 13.5 ± 0.2, 22.8 ± 0.2, and 24.4 ± 0.2 degrees, has an XRPD pattern containing peaks at angles 2θ 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 degrees, or has an XRPD pattern containing peaks at angles 2θ 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, 28.0 ± 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 degrees. Form IV has an XRPD pattern substantially as shown in FIG. 29A. Form IV has a DSC graph substantially as shown in FIG. 29B. Form IV is characterized by having an endothermic melting onset at about 200 °C as determined by DSC. Form IV has a TGA graph substantially as shown in FIG. 29B.

[0247] Form V In some embodiments, CK-274 is 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 angles 2θ and relative peak intensities observable for form V using XRPD are shown in Table P-5. In some embodiments, form V has an XRPD pattern substantially as shown in Figure 30.

Table P5-1

Table P5-2

[0248] In some embodiments, polymorphic form V has an XRPD pattern presenting 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 the angle 2θ having the maximum intensity in the XRPD pattern, substantially as shown in Figure 30 or as shown in Table P-5. It should be understood that the relative intensity may vary depending on several factors including the preparation, mounting of the sample, and the equipment and analysis procedures and settings used to acquire the spectrum. The relative peak intensity and peak assignment may vary within experimental error. In some embodiments, the peak assignment of the peaks enumerated in this document including polymorphic form V may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees at 2θ.

[0249] In some embodiments, polymorphic form V has an XRPD pattern that includes peaks at angles 2θ of 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, 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 degrees. In some embodiments, polymorphic form V has an XRPD pattern that includes peaks at angles 2θ 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.In some embodiments, polymorphic form V has an XRPD pattern that includes peaks at angles 2θ 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 degrees. In some embodiments, polymorphic form V has an XRPD pattern that includes peaks at angles 2θ of 11.5 ± 0.2, 16.3 ± 0.2, 20.0 ± 0.2, 21.2 ± 0.2, and 24.7 ± 0.2 degrees. It should be understood that peaks in the XRPD pattern other than those shown in FIG. 30 or given in Table P-5 may be observed, for example, due to the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0250] In some embodiments of Form V, at least one or both of the following (a) to (b) apply. (a) Form V has an XRPD pattern that includes peaks at angles 2θ of 11.5 ± 0.2, 16.3 ± 0.2, 20.0 ± 0.2, 21.2 ± 0.2, and 24.7 ± 0.2 degrees, has an XRPD pattern that includes peaks at angles 2θ 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 degrees, or has an XRPD pattern that includes peaks at angles 2θ 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. (b) Form V has an XRPD pattern that is substantially the same as that shown in FIG. 30.

[0251] Form VI In some embodiments, CK-274 is 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 angles 2θ and relative peak intensities observable for form VI using XRPD are shown in Table P-6. In some embodiments, form VI has an XRPD pattern substantially as shown in FIG. 31A.

Table P6-1

Table P6-2

[0252] In some embodiments, polymorphic form VI has an XRPD pattern presenting 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 the angle 2θ having the maximum intensity in the XRPD pattern, substantially as shown in FIG. 31A or as shown in Table P-6. It should be understood that the relative intensities can vary depending on several factors including the preparation, mounting of the sample, and the equipment and analytical procedures and settings used to acquire the spectrum. The relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed in this document including polymorphic form VI may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees at 2θ.

[0253] In some embodiments, polymorph VI has an XRPD pattern having peaks at angles 2θ of 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 ± 0.2, 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 degrees. In some embodiments, polymorphic form VI has an XRPD pattern having peaks at angles 2θ 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 degrees. In some embodiments, polymorphic form VI has an XRPD pattern having peaks at angles 2θ of 10.6 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 16.1 ± 0.2, and 17.8 ± 0.2 degrees. It should be understood that peaks in the XRPD pattern other than those shown in FIG. 31A or given in Table P-6 may be observed, for example, due to the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0254] In some embodiments, Form VI has a TGA graph substantially as shown in FIG. 31B or substantially as shown in FIG. 31C. In some embodiments, Form VI exhibits a weight loss of about 2% ± 0.5% at 25°C to 200°C as determined by TGA.

[0255] In some embodiments, Form VI has a DSC graph substantially as shown in FIG. 31D or substantially as shown in FIG. 31E. In some embodiments, Form VI is characterized by having an endothermic melting 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 has 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), an exothermic onset 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 an endothermic onset at about 41±2 °C (e.g., 41±1.9 °C, 41±1.8 °C, 41±1.7 °C, 41±1.6 °C, 41±1.5 °C, 41±1.4 °C, 41±1.3 °C, 41±1.2 °C, 41±1, 41±0.9 °C, 41±0.8 °C, 41±0.7 °C, 41±0.6 °C, 41±0.5 °C, 41±0.4 °C, 41±0.3 °C, 41±0.2 °C, or 41±0.1 °C), or any combination thereof.

[0256] 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. Form VI has an XRPD pattern that includes peaks at angles 2θ of 10.6 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 16.1 ± 0.2, and 17.8 ± 0.2 degrees, has an XRPD pattern that includes peaks at angles 2θ 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 degrees, or has an XRPD pattern that includes peaks at angles 2θ of 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 ± 0.2, 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 degrees. Form VI has an XRPD pattern substantially as shown in Figure 31A. Form VI has a TGA graph substantially as shown in Figure 31B or Figure 31C. Form VI has a weight loss of about 2% ± 0.5% at 25°C to 200°C as determined by TGA. Form VI has a DSC graph substantially as shown in Figure 31D or Figure 31E. Form (f) IV is characterized by having an endothermic melting onset at about 200 °C as determined by DSC. Form (g) VI is characterized by having an endothermic onset at about 200 °C, an exothermic onset at about 115 °C, or an endothermic onset at about 41 °C, as determined by DSC, or any combination thereof.

[0257] Kit Also provided are manufactured articles and kits containing any of the compounds or pharmaceutical compositions provided herein. The product may comprise a labeled container. Suitable containers include, for example, bottles, vials, and test tubes. The container may be formed from a variety of materials such as glass or plastic. The container may hold the pharmaceutical composition provided herein. The label of the container may indicate that the pharmaceutical composition is to be used to prevent, treat, or inhibit the conditions described herein, or may indicate instructions regarding either in vivo or in vitro use.

[0258] In one aspect, provided herein is a kit containing a compound or composition described herein and instructions for use. The kit may include instructions for use in the treatment of a heart disease in an individual or subject in need thereof. The kit may further include any material or device that may be used for administration of the compound or composition, such as a vial, syringe, or IV bag. The kit may also include a sterile package.

[0259] In some embodiments, the disclosure is a method for manufacturing a medicament comprising CK-274, manufacturing a first aggregate of tablets in which the amount of CK-274 (which may exist in various forms) is approximately the first daily dose or approximately half of the first daily dose, manufacturing a second aggregate of tablets in which the amount of CK-274 (which may exist in various forms) is approximately the second daily dose or approximately half of the second daily dose, Optionally, producing a third aggregate of tablets in which the amount of CK-274 (which may exist in various forms) is approximately the third daily dose or approximately half of the third daily dose; Optionally, producing a fourth aggregate of tablets in which the amount of CK-274 (which may exist in various forms) is approximately the fourth daily dose or approximately half of the fourth daily dose; A method comprising is provided. In some embodiments, the method includes producing a third aggregate of tablets in which the amount of CK-274 (which may exist in various forms) is approximately the third daily dose or approximately half of the third daily dose. In some embodiments, the method includes producing a fourth aggregate of tablets in which the amount of CK-274 (which may exist in various forms) is approximately the fourth daily dose or approximately half of the fourth daily dose.

[0260] In some embodiments, the present disclosure is a method for producing a medicament comprising CK-274, producing a first aggregate of tablets in which the amount of CK-274 (which may exist in various forms) is approximately the first daily dose; producing a second aggregate of tablets in which the amount of CK-274 (which may exist in various forms) is approximately the second daily dose; Optionally, producing a third aggregate of tablets in which the amount of CK-274 (which may exist in various forms) is approximately the third daily dose; Optionally, producing a fourth aggregate of tablets in which the amount of CK-274 (which may exist in various forms) is approximately the fourth daily dose; A method comprising is provided.

[0261] In some embodiments, the method includes producing a third aggregate of tablets in which the amount of CK-274 (which may exist in various forms) is approximately the third daily dose. In some embodiments, the method includes producing a fourth aggregate of tablets in which the amount of CK-274 (which may exist in various forms) is approximately the fourth daily dose. This specification describes various first daily dosages, second daily dosages, third daily dosages, and fourth daily dosages. In some embodiments, the daily dosage is about 5 mg of CK-274. In some embodiments, the first daily dosage is about 5 mg of CK-274. In some embodiments, the daily dosage is about 10 mg of CK-274. In some embodiments, the daily dosage is about 15 mg of CK-274. In some embodiments, the daily dosage is about 20 mg of CK-274. In some embodiments, tablets are manufactured with at least two different daily dosages. In some embodiments, tablets are manufactured with an amount of CK-274 (which may exist in various forms) of about 15 mg. In some embodiments, tablets are manufactured with an amount of CK-274 (which may exist in various forms) of about 2.5 mg. In some embodiments, tablets are manufactured with an amount of CK-274 (which may exist in various forms) of about 7.5 mg. Those skilled in the art will understand that, in addition to CK-274, the tablets may contain various other components as described herein, for example, fillers, binders, disintegrants, surfactants, lubricants, etc. In some embodiments, the tablets are film-coated.

Examples

[0262] This application can be better understood by referring to the following non-limiting examples provided as illustrative embodiments of this application. The following examples are presented to more fully illustrate the embodiments but should in no way be construed as limiting the broad scope of this application. Specific embodiments of this application are shown and described herein, but it will be apparent that such embodiments are provided by way of example only. Those skilled in the art will be able to envision numerous variations, modifications, and substitutions without departing from the spirit and scope of the invention. It should be understood that various alternative means to the embodiments described herein may be employed in the practice of the methods described herein.

[0263] Example 1 This first human trial of aficamten (also known as CK-274) was conducted to evaluate its safety, pharmacokinetics, and pharmacodynamics profile, including the effects of diet or CYP2D6 poor metabolizer (CYP2D6-PM) phenotype. Aficamten, a selective myosin inhibitor, may have therapeutic potential for the management of hypertrophic cardiomyopathy because it reduced measures of left ventricular contractility preclinically in vitro and in vivo. In this phase 1, double-blind, randomized, placebo-controlled trial, healthy adults aged 18 to 55 years were enrolled and received single escalating doses or repeated escalating doses of aficamten or placebo (for 14 or 17 days). In addition to standard safety and pharmacokinetic evaluations, pharmacodynamic effects were assessed by echocardiography. A total of 102 participants were enrolled in the trial (57 in the single-dose cohort, 24 in the repeated-dose cohort, 9 in the CYP2D6-PM cohort, and 12 in the diet effect cohort). Adverse events were generally mild at single doses of aficamten up to 50 mg and repeated doses up to 10 mg and were not more frequent than with placebo. In the single escalating dose cohort, plasma concentrations of aficamten increased proportionally with dose, and the half-life of aficamten was 75 to 85 hours. Neither diet nor CYP2D6-PM phenotype had a clinically meaningful effect on pharmacokinetics. At a single dose of 50 mg, the mean left ventricular ejection fraction (LVEF) decreased by 5.5% from baseline (p = 0.0001). With repeated dosing, a mean 5.0% reduction in LVEF was noted 14 days after 10 mg of aficamten once daily. Aficamten appears to be safe and well tolerated at the doses evaluated. The pharmacodynamic effect on LVEF was demonstrated, providing support for further clinical investigation of aficamten.

[0264] Methods Overview and Ethics of the Trial. In this trial, a randomized, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) design was used (Figure 2). This trial was designed not to determine the maximum tolerated dose, but to identify the pharmacologically active dose range that results in an absolute reduction within the range of 5% to 15% from the baseline of the left ventricular ejection fraction (LVEF) (for example, a reduction from a baseline LVEF value of 70% to 55% to 65%). Dose escalation was to be stopped when this range was reached, or earlier if a non-tolerated dose was identified.

[0265] Participants and Treatments. To be eligible for this trial, participants were healthy adults aged 18 to 55 years, with a body mass index of 18.0 to 32.0 kg / m 2 and had normal electrocardiogram (ECG) and clinical test values, or only minor abnormalities that were judged not to be clinically significant. Participants also needed to have normal heart structure and function, with an LVEF of ≥ 60% in the first four SAD cohorts, ≥ 65% in subsequent SAD cohorts, all MAD cohorts, and the meal-effect cohort, and ≥ 55% in the CYP2D6-PM cohort. Use of prescription drugs within 14 days, over-the-counter drugs (except acetaminophen) within 7 days, or tobacco or nicotine within 3 months prior to the trial was prohibited for participants. In addition, intake of alcohol, caffeine, or grapefruit by participants within 48 hours prior to the trial check-in was prohibited.

[0266] For each cohort and treatment period, a randomized schedule was generated centrally. In all cohorts, aficamten or the corresponding placebo was administered in granular form in capsules with approximately 240 ml of water. The study drug was administered after an overnight fast, except during the postprandial period in the meal-effect cohort.

[0267] Single Ascending Dose (SAD) Cohort. In the SAD part of this trial, a randomized, double-blind, placebo-controlled, sequential, dose-escalation design was used, and participants were administered a single ascending oral dose of the investigational drug. They were sequentially dosed in 7 cohorts (Figure 2). Of the 8 participants in each cohort, the first 2 were randomly assigned (1:1) to either aficamten or placebo and followed for at least 2 days before dosing the remaining participants in the group. Thereafter, the remaining 6 participants were randomly assigned (5:1) and administered a single oral dose of either aficamten (1, 3, 10, 25, 40, 50, or 75 mg) or placebo.

[0268] The initial dose of aficamten was selected using criteria based on US Food and Drug Administration guidance from prior animal studies, with a safety margin of more than 10-fold. Dose escalation would stop when a pharmacologically active or non-tolerated dose range that reduced LVEF by 5% to 15% was identified from the results (whichever came first).

[0269] Recommendations regarding dose escalation in the SAD cohort (and the MAD cohort described below) were made by the treating investigator (blinded to the treatment group) and were or were not approved by the unblinded Dose Level Review Committee (DLRC). The decision was made when more than 6 participants had been treated and followed for more than 3 days, which included the collection of clinical data, clinical laboratory data, ECG data, and telemetry data, as well as the maximum plasma drug concentration (C max)It included echocardiograms suitable for evaluating LV function before and after. The incremental criteria included that less than 50% of the LVEF occurred in less than 2 participants in the dose group, and there was no individual with an LVEF of less than 45%. The dose increment criteria were as follows: (1) There was no individual who had experienced a serious cardiac adverse event related to the test drug; (2) No 2 individuals had experienced similar serious non-cardiac adverse events in the same organ system that were considered to be related to the test drug; (3) No 2 individuals treated with aficamten had experienced a decrease in left ventricular ejection fraction (LVEF) exceeding 15% compared to the value immediately before the most recent administration (determined by the Dose Level Review Committee [DLRC]); (4) There was no individual with an LVEF of less than 45% (except when determined by the DLRC and the treating investigator not to be related to the test drug); and (5) Both the treating investigator and the DLRC approved the increment and the next level of dose based on clinical judgment.

[0270] Multiple Ascending Dose (MAD) cohort. The MAD cohort also used randomization, double-blind, placebo-controlled, and sequential designs. Enrollment in the MAD cohort was initiated when a single oral dose associated with well-tolerated and recognized PD effects was identified in the SAD cohort. Each of the three MAD cohorts included 8 participants, who were randomized to aficamten or placebo (6:2). The participants were administered the oral dose of the test drug once daily for 14 days (in the cohort comparing 5 mg or 10 mg of aficamten with placebo) or 17 days (in the cohort comparing 7.5 mg of aficamten with placebo).

[0271] CYP2D6 poor metabolizer cohort. A separate cohort was enrolled to evaluate the potential impact of CYP2D6 gene variants on the PK characteristics of aficamten. The CYP2D6 gene encodes the cytochrome P450 2D6 enzyme, which is described as the most widely characterized polymorphic drug-metabolizing enzyme, and in previous in vitro tests, it was suggested that CYP2D6 is a potential metabolic enzyme for aficamten.

[0272] For all study participants, the CYP2D6 genotype was determined at screening. Participants identified as CYP2D6-PMs were excluded from the SAD and MAD cohorts, but these participants were invited to participate in the CYP2D6-PM cohort. After the SAD 25 mg cohort, the first individual in the CYP2D6-PM cohort was dosed (Figure 2). Each participant received a single dose of aficamten (10 mg) or placebo. Nine participants were randomized (7:2), which included a sentinel dosing group consisting of the first 2 treated participants.

[0273] Diet effect cohort. To evaluate the effect of diet on the PK of aficamten, a separate cohort was enrolled after the completion of the last SAD cohort, and enrollment of 8 - 12 participants was planned. In a non-blind two-way crossover design, participants were to receive two single doses of 10 mg aficamten at least 14 days apart. Participants were randomized 1:1 to one of two sequences, i.e., fasting / postprandial or postprandial / fasting. During the fasting period, aficamten was administered after an overnight fast, and during the postprandial period, aficamten was administered 30 minutes after the start of a high-fat breakfast.

[0274] Evaluation Safety and tolerability. Safety was evaluated by the incidence of adverse events (AEs) and the incidence of reduced LVEF. Treatment-emergent AEs (TEAEs) were defined as AEs that started or increased after administration of the study drug. All AEs were coded using the Medical Dictionary for Regulatory Activities version 21.1 and graded using the 5-level severity scale of the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Each AE was determined by the treating investigator to be either related or not related to the study drug. Clinical laboratory tests were performed at regular intervals in all cohorts.

[0275] For safety monitoring, all cohort participants underwent regular echocardiograms, which were evaluated by a cardiologist. In the SAD and MAD cohorts, echocardiograms were also reviewed by a central echocardiogram facility for PD assessment, as described below. In addition, all cohort participants were monitored with continuous 12-lead ECG recordings using a Holter monitor. For safety monitoring, single 12-lead ECGs were periodically extracted at screening, pre-dose, and throughout the follow-up period and interpreted by the study physician. In the SAD, MAD, and CYP2D6-PM cohorts, hemodynamic ECGs (10 seconds of three 12-lead ECG recordings) were obtained prior to the corresponding PK blood draws, and ECG intervals were quantified by a qualified reader.

[0276] Pharmacokinetic analysis. For all test groups, blood samples for PK evaluation were obtained on Day 1 before dosing and up to 12 times a day at most, and then at regular intervals throughout the study. Blood samples were collected according to the following schedule: SAD cohort: Day 1: before dosing and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, and 216 hours after dosing. MAD cohort (14-day dosing): Day 1: before dosing and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours 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 at 1.5 hours after dosing; Days 3, 7, 8, 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 at 0.25, 0.5, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 168 hours after dosing. MAD cohort (17-day dosing): Day 1: before dosing and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours 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 at 1.5 hours after dosing; Days 3, 7, 8, 10, 11, 12, 13, 14, 15, and 16: before dosing (corresponding to trough samples after dosing on Days 2, 6, 7, 9, 10, 11, and 12); Day 17: before dosing and at 0.25, 0.5, 1.5, 2, 2.5, 3, 5, 7, 9, 12, 24, 36, 48, 72, and 168 hours after dosing. CYP2D6-PM cohort: Day 1: before dosing and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 216, 312, and 552 hours after dosing. Diet effect cohort: Day 1: before dosing and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 216 hours after dosing. Standard non-compartmental methods were used, and PK parameters were calculated using Phoenix® WinNonlin® version 7.0. The actual sample collection times were utilized.

[0277] The plasma concentration of aficamten was measured using high-performance liquid chromatography-tandem mass spectrometry, which had been validated for accuracy, precision, linearity, sensitivity, and specificity at Celerion (Lincoln, Nebraska). The analytical range (lower limit to upper limit of quantification) of aficamten was 1.00 - 500 ng / ml.

[0278] Echocardiogram. For the PD assessment of LVEF, echocardiograms of the SAD and MAD cohorts were interpreted at the central echocardiogram facility and used for all data analysis and determination of dose-level review. On the other hand, for safety monitoring, immediate interpretation of echocardiograms was performed locally. In the SAD cohort administered 1, 3, or 10 mg of aficamten, echocardiograms were obtained on day -1, before dosing on day 1, and at 1.5, 4, and 24 hours after dosing. In the SAD cohort administered 25, 40, 50, or 75 mg of aficamten, echocardiograms were obtained on day -1, before dosing on day 1, and at 1.5, 6, and 24 hours after dosing. Echocardiograms on day 3 (48 hours after dosing) were obtained only at the discretion of the principal investigator of the clinical trial if the LVEF at 24 hours did not return near or above baseline. In the MAD cohort, echocardiograms were obtained on day -1, before dosing on day 1, and at 1.5 hours after dosing on days 2, 4, and 9, and at 1.5, 24, and 72 hours after dosing on day 14 (for the 5 mg and 10 mg cohorts) or day 17 (for the 7.5 mg cohort). Echocardiograms were obtained only at the discretion of the principal investigator of the clinical trial, 3 days after the final dose (day 17 or 20), if the participant's previous LVEF was not near or above baseline.

[0279] Statistical analysis. The sample size selected for this trial was based on the precedent set in other first-in-human PK trials with similar properties and not on a power calculation. All participants who received one or more doses of the study drug (aficamten or placebo) were included in the safety analysis. All participants who received one or more doses of the study drug and had one or more evaluable PK plasma profiles were included in the PK analysis set.

[0280] The PK analysis aimed to evaluate the single-dose kinetics, the kinetics of repeated doses (steady state), the effect of CYP2D6 phenotype on the absorption and excretion of aficamten, and the effect of diet on the absorption and excretion of aficamten. For the SAD cohort, the dose proportionality of aficamten was evaluated using a power model on Day 1. For the MAD cohort, the dose proportionality was evaluated using a power model on Day 1 and on Day 14 or 17. When evaluating the dose proportionality of the drug, several considerations were taken into account, including the results derived from the statistical analysis of the power model (e.g., the estimated value of the slope and the width of the two-sided 95% confidence interval [CI]), the qualitative evaluation specific to the PK of the drug, and the clinical relevance. In the SAD cohort, the parameters used for the evaluation of dose proportionality were the area under the plasma drug concentration-time curve (AUC) from time 0 to the time of the last measurable concentration (AUC last ), the AUC extrapolated from time 0 to infinity (AUC inf ), the AUC from time 0 to 24 hours (AUC 24 ), and the maximum plasma concentration (C max ). In the MAD cohort, the parameters were AUC 24 and C max on Day 1, and in addition on Day 14 or 17, the AUC from the start of dosing to the end of the dosing period (AUC tau ) and C max . The statistical linear relationship between the ln-transformed PK parameters and the ln-transformed dose was verified by including the quadratic (ln dose) 2 and cubic (ln dose) 3 effects. The statistical linear relationship was established using a significance level of 5% when the quadratic and cubic effects were not statistically significant, or when the effects were statistically significant but the magnitude was so small as not to be clinically important. The dose proportionality analysis was performed using SAS® PROCMIXED. Dose proportionality was established when a statistical linear relationship was shown and the two-sided 95% CI around the estimated parameter of the slope included the value of 1 for the dose-dependent parameter.

[0281] In the MAD cohort, steady-state analysis of aficamten was performed on the ln-transformed plasma trough concentration (C trough ) values using the Helmert contrast. A separate analysis of variance (ANOVA) model was performed for each dose level. Days were included as fixed effects. The Helmert contrast was created to compare each time point with the mean of subsequent time points. Steady state was established at the time point when no statistical difference (alpha = 5%, two-sided) was observed with subsequent time points.

[0282] All participants who received one or more doses of the investigational drug and had one or more pre-dose and one or more post-dose echocardiogram measurements were included in the PD analysis set. Descriptive analyses included the absolute reduction in LVEF from baseline and the categorical LVEF responses (the proportions of participants with a reduction in LVEF from baseline of ≥5%, ≥10%, and >15%, and the proportions of participants with an LVEF of <50% and <45%). Descriptive statistics for echocardiogram parameters were generated using SAS® version 9.3 or higher.

[0283] Dose-response analysis was performed using analysis of covariance (ANCOVA) to identify the least-squares mean difference (aficamten - placebo). To analyze the effect of drug dose on echocardiogram parameters in the SAD and MAD cohorts, inferential analysis was performed on the PD analysis set using a linear mixed model for repeated measures analysis of covariance (ANCOVA). In ANCOVA, baseline values were used as covariates, treatment, time point, and the interaction of time point and treatment were included as fixed effects, and the change from baseline was included as the dependent variable. A non-structured variance-covariance structure was used, and the model accounted for repeated measurements over time points. ANCOVA analyses were performed separately for each study part and each PD parameter. For each comparison, the least-squares mean, the difference in least-squares means (active drug - placebo), and the associated two-sided 95% CI were shown.

[0284] Concentration “bins” and exposure-response analyses were also performed using ANCOVA. SAS® PROCMIXED was used for all comparative analyses. Additional inferential analyses were performed in the SAD and MAD cohorts to evaluate the relationship between the concentration of aficamten and LVEF in participants in the PK / PD analysis set. Concentration bin ANCOVA was performed using a linear mixed model for repeated measures, using the concentration bin groups as fixed effects, baseline PD parameters as covariates, the amount of change from baseline as the dependent variable, and a random intercept for adjustment of repeated measures. An unstructured variance-covariance structure was used. Plasma concentrations of aficamten were paired with contemporaneous PD parameters. In ANCOVA, the amount of change in PD parameters between each bin and the placebo pooled group was compared. For each comparison, least squares means, differences in least squares means (bin group - placebo), and associated two-sided 95% CIs were shown. ANCOVA analyses were performed separately for each study part. For all time points at which both PK data and PD measurements were available, time points were pooled for analysis. In each part of the study, aficamten concentrations that included PD data with matching times were pooled and sorted in ascending order. The data were then split into five observation groups (“bins”) from smallest to largest. Each observation group consisted of 20% of the data points. Each bin was treated as a separate group. The concentration bins consisted of the placebo group and five bin groups based on the pooling of concentrations from all time points of aficamten treatment.

[0285] The above analysis was then repeated using concentration as a continuous variable to estimate the exposure-response trend. Both a random intercept effect and a random concentration effect were added to the ANCOVA. For each study part, an estimate of the slope of the concentration and the ANCOVA analysis including the corresponding two-sided 95% CI were shown.

[0286] For all time points at which both PK data and PD measurements were available, time points were pooled for analysis. A nominal significance level of 5% was used for statistical comparisons without adjustment for multiplicity.

[0287] Results Test population. A total of 102 participants (57 in the SAD cohort, 24 in the MAD cohort, 9 in the CYP2D6-PM cohort, and 12 in the diet effect cohort) were enrolled. All participants completed the trial. The average age ranged from 32 to 40 years across the cohorts, and the majority of the participants were male (Table 1). Table 1

[0288] In the SAD cohort, there were no safety concerns precluding dose escalation between 1 mg and 25 mg. At the next planned dose (50 mg), 1 participant had a post-dose LVEF of less than 50% (46.2%), which did not meet the dose escalation stop rule, and the 75 mg cohort was initiated. The sentinel participant in the 75 mg cohort had a post-dose LVEF of less than 45%, and as a result, no further participants were dosed with 75 mg. As a result, the 50 mg group was expanded and 5 additional participants within this cohort were dosed. After expansion, 1 participant in the 50 mg dose group experienced an LVEF of less than 45%. This was also a decrease greater than 15%. Therefore, no further participants were dosed with 50 mg or more. The DLRC determined that the appropriate dose for the final cohort of the single-dose was 40 mg.

[0289] After the results of the 1 mg - 25 mg SAD cohort, the first MAD cohort of aficamten 5 mg once daily for 14 days was initiated. There were no safety concerns, and the next cohort of 10 mg once daily for 14 days was initiated. In this cohort, 2 participants met the stop criteria based on echocardiogram results. The DLRC determined that the next treatment level should be 7.5 mg to better characterize the PK at steady state. Therefore, the dosing period was extended from 14 days to 17 days to ensure that PK reached steady state by the last day of dosing.

[0290] Safety and tolerability. There were no serious AEs, and no participants discontinued the trial due to AEs. The observed TEAEs were generally mild (Grade 1), and aficamten was not more frequent than placebo for either single-dose or repeated-dose administration (Tables 2 and 3). Overall, the most frequently observed TEAE in both the SAD cohort and the MAD cohort was headache (Tables 2 and 3).

Table 2

Table 3

[0291] Echocardiogram-related AEs leading to a decrease in ejection fraction of less than 45% were reported in three participants (one each in the SAD 40 mg cohort, 50 mg cohort, and 75 mg cohort) based on the evaluation by the echocardiogram experts in this trial (Table 4). All were Grade 1 and had all recovered by the next echocardiogram evaluation (within 2.5 - 4.6 hours). One participant who received 75 mg of aficamten had an LVEF of 34.6% 1.5 hours after administration, which was a 31.5% reduction in LVEF, and thus, as described above, the dose escalation in the SAD part of this trial was terminated. At the next evaluation 2.5 hours later, the LVEF had returned to 51.9%. AEs with a decrease in ejection fraction of less than 45% were not reported in the MAD cohort, the CYP2D6-PM cohort, or the diet effect cohort.

[0292] In the entire cohort, the mean of the safety ECG parameters at the time of evaluation was within the normal range. No clinically significant changes from the baseline were observed for any of the parameters. The QT interval corrected for heart rate (QTcF) using Fridericia's formula did not exceed 450 ms at baseline or at any evaluation during the dosing intervals (except for 2 individuals with a baseline QTcF of ≥ 440 ms and an increase in QTcF values by 3 ms and 13 ms, respectively). In the entire cohort, there was no increase in QTcF interval exceeding 30 ms (except for 1 participant in the SAD placebo group with a 33 ms increase in QTcF interval on day 5 (from a baseline value of 394 ms to 427 ms)). In the cardiac dynamics evaluation, categorical analysis of the ECG parameters revealed no safety concerns for the heart, and there was no evidence of a positive QT effect after single or repeated doses of aficamten.

[0293] All vital signs were within the normal range at the time points after dosing. No clinically significant serum chemistry, hematology, or urine test findings were observed during the study.

Table 4

[0294] Pharmacokinetics Single-dose kinetics. The plasma profile of aficamten was generally well-characterized at all dose levels (except for the lowest dose of 1 mg (due to concentrations being close to the lower limit of quantification) and the highest dose of 75 mg administered to only 1 participant as described above). Over the dose range of 1 mg to 50 mg, the mean maximum plasma concentration and exposure were C max and the area under the plasma concentration-time curve from time 0 to 24 hours (AUC 24) increased proportionally with increasing dose, as demonstrated by the increase with increasing dose (Figures 3A - 3B and Table 5). The mean clearance and volume of distribution were similar between doses. The median time to reach the maximum plasma concentration was between 0.5 - 2.8 hours, and the longest time among all participants was 4.0 hours. The mean half - life ranged from 75 - 85 hours.

Table 5

[0295] Pharmacokinetics of repeated doses. With once - daily dosing, the mean plasma concentration increased between the 5 mg dose and the two higher doses (7.5 mg and 10 mg), but there was little difference in the mean concentration between the 7.5 mg and 10 mg doses on day 2 (Figure 4). Plasma PK parameters are shown in Table 6. By the end of the treatment period (day 14 or 17), the mean plasma concentration was 2 - 2.5 times that on day 1. The estimated values of the terminal elimination half - life were consistent between doses and ranged from 77 - 86 hours. Clearance was similar between the 5 mg and 10 mg doses, and the accumulation ratio was similar among the three doses. Consistent with the estimated values of the observed terminal elimination half - life, steady state was reached after 10 - 12 days (Figure 4).

Table 6

[0296] CYP2D6 poor - metabolizer cohort. In CYP2D6 - PM, the mean half - life was prolonged to 110 hours compared to 85 hours in the extensive metabolizer (i.e., the 10 mg SAD cohort), but there was no increase in AUC observed in this group, and the geometric mean AUC 24 was 495 ng·h / ml (19 geometric coefficient of variation percentage [CV%]) compared to 679 ng·h / ml (35 geometric CV%) in the extensive metabolizer (Table 5) (Table 7). CYP2D6 - PM did not appear to have a clinically significant reduction in clearance that would result in a difference in exposure.

Table 7

[0297] Effect of diet. The PK parameters of aficamten in the diet impact cohort are shown in Table 8. When taken with food, the C of aficamten increased by approximately 30%, and the time to reach the maximum plasma concentration was shortened (1.5 hours vs. 2.3 hours). However, diet had little effect on the AUC, with a geometric mean AUC in the fasting state of 601 (33) ng·h / ml compared to 631 (25) in the fed state. max was approximately 30% higher, and the time to reach the maximum plasma concentration was shortened (1.5 hours vs. 2.3 hours). However, diet had little effect on the AUC, with a geometric mean AUC in the fasting state of 601 (33) ng·h / ml compared to 631 (25) in the fed state. 24 (geometric CV%) was 601 (33) ng·h / ml, while it was 631 (25) in the fed state. [Table 8]

[0298] Pharmacodynamics Left ventricular ejection fraction. At baseline, the mean LVEF ranged from 61.0% to 67.5% across the cohort (Table 1). In the SAD cohort, a decrease in mean LVEF was observed in the group receiving the highest dose of aficamten (Figure 5A). The maximum mean reduction from baseline was seen at 1.5 hours after dosing in the 50 mg cohort (least squares mean difference 5.5%, p = 0.0001). LVESV and LVEDV increased significantly by 8.1 mL and 6.6 mL, respectively (Table 9). Other echocardiogram parameters such as stroke volume, cardiac output, cardiac time intervals, and measures reflecting diastolic function did not change significantly (Table 9). One participant receiving 75 mg of aficamten showed a 31.5% reduction in LVEF at 1.5 hours after dosing, which recovered 2.5 hours after onset, but as previously mentioned, this marked the end of the dose escalation in the SAD part of this trial. In the MAD cohort, a clear decrease in LVEF emerged as dosing continued in the 10 mg cohort (Figure 5B). The maximum mean reduction rate of 5.0% from baseline was seen at 1.5 hours after dosing in the 10 mg cohort on day 14 (Figure 5B). The placebo-corrected reduction of 3.2% (least squares mean difference) did not reach statistical significance (p = 0.21). This is likely due to the lack of power in this small group comparison. [Table 9-1]

Table 9-2

[0299] LVEF response by category. In the SAD cohort, an absolute reduction in LVEF of more than 5% from baseline was observed in 1 out of 15 participants (7%) in the placebo cohort, 1 out of 6 (17%) in the 3 mg cohort, 2 out of 6 (33%) in the 40 mg cohort, 7 out of 11 (64%) in the 50 mg cohort, and 1 out of 1 (100%) in the 75 mg cohort. On the other hand, no participants had a reduction of more than 5% in the 1 mg, 10 mg, or 25 mg cohorts. An absolute reduction in LVEF of more than 10% occurred in 1 out of 6 participants (17%) in the 40 mg cohort, 2 out of 11 (18%) in the 50 mg cohort, and 1 (100%) in the 75 mg cohort. A reduction in LVEF to less than 50% was observed in 2 out of 11 participants (18%) in the 50 mg cohort (48.2% and 45.5% according to the central laboratory assessment) and 1 out of 1 (100%) in the 75 mg cohort. Only participants in the 75 mg cohort experienced an LVEF of less than 45%.

[0300] In the MAD cohort, an absolute reduction in LVEF of more than 5% from baseline was observed in 4 participants (1 out of 6 participants (17%) who received placebo, 1 out of 6 (17%) who received 7.5 mg of aficamten once daily, and 2 out of 6 (33%) who received 10 mg of aficamten once daily). Of these, 2 participants in the 10 mg cohort had a reduction of more than 10%. A reduction in LVEF to less than 50% was not observed in any of the MAD cohorts according to the central laboratory assessment.

[0301] Relationship between plasma concentration and change in LVEF. For the SAD and MAD cohorts, the PK / PD relationship of aficamten was illustrated by plotting the plasma concentration of aficamten against the change in LVEF (Figures 6A and 6B). In the SAD cohort, LVEF tended to decrease with an increase in the plasma concentration of aficamten. The relationship between LVEF and the plasma concentration of aficamten was statistically significant in both the bin concentration analysis for the highest plasma concentration bin (122 - 524 ng / ml, p < 0.0001) and the concentration-slope analysis (p = 0.0027). In the MAD cohort, the relationship between LVEF and plasma aficamten did not reach statistical significance in the bin concentration analysis or linear regression analysis. This is likely due to the more limited range of plasma concentrations investigated and the smaller group size.

[0302] Discussion In this first-in-human, first-phase study, a dose of aficamten (up to 50 mg as a single oral dose or up to 10 mg after repeated dosing) that was physiologically effective in reducing LVEF and well tolerated in healthy participants was established, and the pharmacologically active dose that would be the starting dose for the study in patients with HCM was identified. In addition, a single oral dose of 10 mg was well tolerated among individuals with the CYP2D6-PM phenotype, and food had no significant effect on the PK of aficamten. Collectively, these observations support the continued development of aficamten for patients with HCM and provide a roadmap for the phase 2 trial.

[0303] Safety of Africamten. No serious AEs were observed in this trial, and all participants completed the intended dosing as planned. Generally, AEs were mild and occurred with similar frequency between participants treated with Africamten and those treated with placebo. Importantly, for participants in whom LVEF dropped below 50% and returned to baseline within 24 hours, there were no accompanying symptoms or harmful changes in vital signs. This trial was not intended to find the maximum tolerated dose, and thus dosing escalation was stopped when a clear PD effect was observed in the SAD and MAD parts of this trial. Therefore, no dose unacceptable due to AE was identified.

[0304] Effect on LVEF. In the SAD cohort, a mean 5.8% reduction in LVEF occurred at a dose of 50 mg, while in the MAD cohort, an approximate 5% absolute reduction in LVEF occurred with 10 mg once daily for 14 days. The percentage of participants with an absolute reduction in LVEF of more than 5% from baseline increased as the dose increased. In up to 64% of participants in the 50 mg SAD cohort and 33% of participants in the 10 mg MAD cohort, LVEF was reduced by more than 10% from baseline. In the SAD cohort, which explored the widest range of Africamten exposure, LVEF decreased statistically significantly as plasma concentration of Africamten increased. Therefore, this trial achieved the secondary objective of identifying the pharmacologically active dose and describing its PK / PD relationship.

[0305] In three participants, LVEF decreased below 50%, which was rapidly reversible after discontinuation of the study drug. After a single 50 mg dose, two participants (18%) experienced an LVEF below 50% (48.2% and 45.5%). After a single 75 mg dose, one participant experienced a reduction in LVEF to 34.1%. In both cases, the event was observed approximately 1.5 hours after dosing, and LVEF recovered above 50% 4 - 6 hours after dosing. The SAD results informed dose selection for other parts of the trial, and no cardiac echo AEs were seen in the MAD cohort, CYP2D6 - PM cohort, or meal - effect cohort.

[0306] Significance of PK results. Africanum showed linear kinetics over the dose range of 1 mg to 50 mg, with a half-life independent of concentration and clearance independent of dose. Steady state was reached by day 10 at the 10 mg dose, and by day 12 at the 5 mg and 7.5 mg doses. There was no effect of diet suggesting a need for dosing adjustment. These findings support once-daily dosing either in the fasting or fed state.

[0307] The relationship between plasma concentration and LVEF suggests a wide therapeutic index, facilitating the optimization of individual doses in patients with HCM, as it is anticipated that dosing can be adjusted over an increasing dose range until the desired PD effect is achieved. Additionally, the half-life of Africanum (75 - 85 hours after a single dose; 77 - 86 hours after repeated doses) and the reversibility of the observed effects provide potential advantages in reaching steady state within two weeks and the easy reversal of excessive effects on LVEF.

[0308] Conclusion. Africanum showed a favorable safety profile in healthy participants without severe AEs or significant changes in clinical laboratory tests, ECG, or health assessments. When LVEF decreased to values below 50%, it was reversible within 6 hours after a single dose. The pharmacologically active dose of Africanum that could be an initial dose for testing in patients with HCM was identified.

[0309] Example 2 A multicenter, randomized, placebo-controlled, double-blind, dose-escalation Phase 2 clinical trial of CK-274 was conducted in patients with symptomatic non-obstructive HCM (nHCM) or MVOHCM. The primary objective of the trial was to determine the safety and tolerability of CK-274. The secondary objectives were to characterize the concentration-response relationship of CK-274 with respect to the resting left ventricular ejection fraction (LVEF) measured by echocardiogram during 10 weeks of treatment, to characterize the dose-response relationship of CK-274, and to evaluate the plasma concentration of CK-274 in patients with nHCM.

[0310] In this study, patients administered disopyramide were excluded. Based on the guidelines for echocardiography, all patients were administered up to three escalating doses of CK-274. Overall, the treatment period was 10 weeks, and the follow-up period was 4 weeks after the final dose.

[0311] Due to the significant differences in patient characteristics in this disease, dose adjustment with individualized doses for the pharmacodynamics (PD) response was performed. This included maintaining the left ventricular ejection fraction (LVEF) above 55% to maximize efficacy and safety.

[0312] Patients were eligible for inclusion in this trial only if they met all of the following criteria: 1. were able to understand and willing to sign the informed consent form (ICF) and comply with all study procedures and restrictions during the period; 2. were men and women aged 18 - 85 years at screening; 3. had a body weight of 45 kg or more at screening; 4. were diagnosed with HCM according to the following criteria: (a) left ventricular hypertrophy and non - dilated left ventricular cavity were observed in the absence of other heart diseases; and (b) the minimum wall thickness was ≥ 15 mm (a minimum wall thickness of ≥ 13 mm was allowed if the family history of HCM was positive or if they had a known genetic mutation causing the disease); 5. had an acoustic window suitable for echocardiography; 7. had a left ventricular ejection fraction (LVEF) ≥ 60% at screening; 8. were in New York Heart Association (NYHA) class II or III at screening; 9. patients taking beta - blockers, verapamil, diltiazem, or ranolazine had been taking a stable dose for more than 4 weeks and were expected to maintain the same drug regimen during the study; 10. male patients were eligible to participate if they agreed to the following for at least 10 weeks during the study and after the last dose: (a) refrain from sperm donation; in addition, (b)(i) refrain from heterosexual intercourse as a preferred and normal lifestyle (long - term continuous abstinence) and agree to continue abstinence; or (b)(ii) must agree to use a male condom and, if the male patient's female partner is a fertile woman, require the female partner to use a highly effective contraceptive method; 11. female patients were eligible to participate if they were not pregnant or lactating and met at least one of the following conditions: (a)(i) were not a fertile woman, or (a)(ii) were a fertile woman and used a highly effective contraceptive method during the study and for at least 4 weeks after the last dose; and (b) fertile women must have a negative pregnancy test (urine or serum according to local regulatory requirements) within 3 days before the first dose of the study intervention; 12. were able to complete all screening procedures.

[0313] Patients were excluded from this trial if they met any of the following criteria: 1. Aortic valve stenosis or fixed subaortic obstruction; 2. Known infiltrative or storage disorders (e.g., Noonan syndrome, Fabry disease, amyloidosis) that cause cardiac hypertrophy similar to HCM; 3. A history of left ventricular (LV) systolic dysfunction at any point during the clinical course (LVEF < 45%); 4. A proven history of current obstructive coronary artery disease (>70% stenosis in one or more epicardial coronary arteries) or a proven history of myocardial infarction; 6. Previous treatment with cardiotoxic agents such as doxorubicin or similar drugs; 7. Treated with disopyramide or antiarrhythmic drugs with negative inotropic effects within 4 weeks prior to screening; 8. Having any ECG abnormalities (e.g., type II second-degree atrioventricular block) that the principal investigator considers to pose a risk to the patient's safety; 9. Paroxysmal atrial fibrillation or flutter proven during the screening period; 10. Requiring rhythm restoration treatment (e.g., direct current cardioversion, ablation procedure, or antiarrhythmic therapy) for paroxysmal or persistent atrial fibrillation within 6 months prior to screening (this exclusion does not apply if atrial fibrillation is being treated with anticoagulation therapy and the heart rate has been appropriately controlled for more than 6 months); 11. A history of syncope or sustained ventricular tachyarrhythmia during exercise within 6 months prior to screening; 12. Implantable cardioverter-defibrillator (ICD) implantation within 3 months prior to screening or planned ICD implantation during the trial; 13. A history of appropriate ICD shocks for life-threatening ventricular arrhythmias within 6 months prior to screening; 14. Recipients of major organ transplants (e.g., heart, lung, liver, bone marrow, kidney) or those expected to undergo transplantation within 12 months from randomization; 15. Liver function impairment defined by total bilirubin (TBL) being 1.5 times or more above the upper limit of normal (ULN) or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) being 3 times or more above the ULN at the time of screening.However, patients with proven Gilbert's syndrome due to unconjugated hyperbilirubinemia without other liver diseases and having a TBL of more than 1.5 times the ULN are acceptable; 16. Any other clinically significant disorder, malignancy, active infection, previous or evidence of other conditions or diseases that, in the opinion of the principal investigator or medical monitor of the clinical trial, pose a risk to the safety of the participants or interfere with the evaluation, procedure, or completion of the trial; 17. Hemoglobin < 10.0 g / dL at screening; 18. Estimated glomerular filtration rate (eGFR) < 30 mL / min / 1.73 m² at screening. 2 (by the revised MDRD (Modification of Diet in Renal Disease) formula); 19. Currently participating in another clinical trial device or drug trial or having received a clinical trial device or drug less than 1 month before screening (or the longer of 5 half-lives of the drug); 20. Having previously received treatment with or currently being administered mavacamten; 21. Having known hypersensitivity to any of the excipients of the film-coated CK3773274 tablets (e.g., mannitol, microcrystalline cellulose, croscarmellose, hydroxypropyl cellulose, sodium lauryl sulfate, magnesium stearate, Opadry QX White 21A180025).

[0314] In the trial, as shown in Table 11, the three highest escalating doses of CK-274 were administered to the patients. For 2 weeks, Dose 1 was administered to each patient once a day. At the second week, the patients received a cardiac echocardiogram 2 hours after dose administration. If the biplane LVEF was 55% or more, the patients were escalated to Dose 2. Otherwise, the patients continued with Dose 1. If the LVEF was less than 50% at the second week, the treatment was discontinued. The dose adjustment algorithm is shown in Table 10 below.

[0315] After taking the assigned dose for an additional two weeks (i.e., at week 4), each patient underwent a cardiac echocardiogram two hours after dose administration. If the biplane LVEF was 55% or greater, the patient was then up-titrated to the next higher dose. Otherwise, the patient continued on the same dose. If the LVEF was less than 50% at week 4, the patient was either titrated back to the previous dose level or, if the patient was on dose 1, treatment was discontinued.

[0316] After taking the assigned dose for an additional two weeks (i.e., at week 6), each patient underwent a cardiac echocardiogram two hours after dose administration. If the LVEF was less than 50% at week 6, the patient was either tapered back to the previous dose level or, if the patient was on dose 1, treatment was discontinued. [Table 10] [Table 11]

[0317] Echocardiograms obtained on day 1 of treatment, at weeks 2, 4, 6, and 10 of treatment, and two weeks after the last dose were analyzed to resolve several important structural and physiological indices. Measurements of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and cardiac troponin I were also monitored. Outpatient cardiac monitoring was performed one week before day 1 of treatment and at week 9. Health status and health-related quality of life: If available, patients completed patient-reported outcome (PRO) questionnaires before dosing on days 1, 6, 10, and 12. At these visits, the following instruments were used: Short Form 36 Physical Function Subscale (SF-36-PFS), Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), SAQ7, PGI-C (only at week 10), and CGI (only at week 10).

[0318] Primary safety endpoint The main safety evaluation items were as follows: (i) the patient incidence of reported AEs from the first administration to the safety follow-up; (ii) the patient incidence of reported SAEs from the first administration to the safety follow-up; (iii) the patient incidence of LVEF < 50% from the first dose to the safety follow-up.

[0319] Patient incidence. The safety follow-up was defined as 4 weeks after the last dose.

[0320] Exploratory safety endpoints The exploratory safety endpoints from the first dose of the IP to the safety follow-up included the following: (i) the patient incidence of drug-related AEs, AEs leading to IP discontinuation, and the severity of AEs; (ii) the 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 [both Bazett and Fridericia corrections]); (iii) category-specific safety variables including: (a) the number (%) of patients with LVEF < 40% at each scheduled evaluation time point and at any time during the study, (b) the number (%) of patients in the following QTc categories at each scheduled ECG evaluation time: absolute value > 450 ms, > 480 ms, or > 500 ms; increase from baseline > 30 ms, > 60 ms, (c) clinically significant changes in clinical laboratory values and ECG parameters; (d) the reported incidence of cardiac arrhythmias over 1 week evaluated by an outpatient cardiac monitoring device at pre-dose baseline and at week 10.

[0321] Pharmacokinetic endpoints The secondary PK endpoints were observed for Cmax and Ctrough of CK-274 during dosing at the time points listed in Table 12. PK was also evaluated through the development of a population PK model.

Table 12

[0322] The secondary PD endpoints of this trial were as follows: the gradient of the relationship between the plasma concentration of CK-3773274 and the change from baseline in resting LVEF.

[0323] The cardiac echo parameters were evaluated by a central laboratory at baseline, at week 2, week 4, week 6, during dosing at week 10, and after a 2-week washout at week 12 (follow-up visit).

[0324] Exploratory pharmacodynamic endpoints The exploratory PD assessment items included, but were not limited to, the following: (i) the relationship between the plasma concentration range of CK-3773274 and LVEF, LVFS, and global longitudinal strain (GLS); (ii) the observed values and changes from baseline of the cardiac echo parameters evaluated by the central laboratory during treatment at weeks 2, 4, 6, 10, and 12 as described in Table 13; (iii) the change in NT-proBNP from baseline to week 10; (iv) the change in hs-cTnI from baseline to week 10; (v) the proportion of patients with an LVEF above 50% and an NT-proBNP reduction of 50% or more from baseline.

[0325] For selected PD measurements where the statistical distribution was likely to deviate from normal, the proportional change from baseline was evaluated.

Table 13

[0326] Other exploratory endpoints included the following: (i) the change in NYHA functional classification from baseline to week 10; and (ii) for patients with NYHA class III disease at baseline, the proportion who improved to NYHA class I or II disease at week 10.

[0327] Endpoint measures of exploratory health status and health-related quality of life included, but were not limited to, changes from baseline to week 10 and the slopes of the changes from baseline to week 10: (i) T-scores for the PROMIS Dyspnea Intensity Short Form 10a, the PROMIS Dyspnea Intensity Short Form 10a including two additional items, the PROMIS Fatigue Short Form 7a, and the PROMIS Physical Function Short Form 8b; (ii) standard-based T-scores for the SF-36 Physical Function subscale; (iii) an individual's responses to a questionnaire regarding the overall state of HCM at baseline, week 6, and week 10; (iv) an individual's responses to a questionnaire regarding the impression of overall change in HCM at week 6 and week 10; (v) the change in the KCCQ score from baseline to week 10; and (vi) the change in the SAQ7 score from baseline to week 10.

[0328] Intermediate Results Forty-one patients were enrolled. Baseline characteristics are shown in Table 14.

[0329] During the dose adjustment period (0 - 6 weeks), the LVEF decreased gradually and no patient had an LVEF of less than 50% during the dose adjustment period (see Figure 9). Thirty-five patients (85%) achieved a once-daily dose of 15 mg of aficamten and 6 (15%) achieved 10 mg (see Figure 10).

[0330] The geometric mean NT-proBNP (%CV) decreased at each scheduled visit and the proportional change from baseline was highly statistically significant (see Figure 11, #P<0.0001). A significant 56% decrease (p<0.0001) was achieved by the end of treatment (week 10). hs-cTnI also significantly decreased proportionally to baseline at each study visit (*p<0.05), and a significant 21% decrease (p<0.05) was achieved by the end of treatment (week 10); after a 2-week washout, both cardiac biomarkers recovered after discontinuation of drug treatment (see Figure 12). The NYHA class improved during treatment. A change in NYHA class of 1 or more was seen in 22 of 41 (54%) patients, of whom 12 improved from class III to class II, 4 improved from class III to class I, and 8 improved from class II to class I (see Figure 13).

[0331] The KCCQ-CSS score improved by 7.3 (-1.0, 18.8) points from a baseline median (IQR) of 69.8 (56.8, 83.9), and 21 (54%) patients had an improvement of 5 points or more (Figures 14 and 15). Fourteen (34%) patients with symptomatic angina (SAQ-AF ≤80) at baseline experienced an improvement response to treatment, and the SAQ-AF increased by a mean (SD) change of 14.3 (±16.0) from baseline to week 10 (p = 0.005) (Figure 14).

Table 14

[0332] Intermediate safety 85% of the cohort achieved a dose of 15 mg by week 6 (see Figure 10). 66% of patients had at least 1 TEAE (see Table 15). There were no drug discontinuations due to AEs. At week 9, 1 patient had their dose reduced to 10 mg due to the AE fatigue. 1 patient interrupted their dose for 2 days (recovery) due to the AE palpitations. 3 patients had SAEs: bronchitis, new atrial fibrillation, cardiac arrest. None of these were judged by the principal investigator to be related to aficamten.

[0333] At the 10th week, 3 patients (7.3%) had an LVEF < 50%. Two occurred in patients with persistent atrial fibrillation, and one of them reported palpitations requiring adjustment of the heart rate control medication. No AE of heart failure was reported. All 3 patients had returned to their baseline LVEF by the 12th week.

Table 15

[0334] Second intermediate result Forty-one patients were enrolled. Baseline characteristics are shown in Table 16.

[0335] There was a moderate and reversible decrease in LVEF of -5.5% (9.9) from baseline to the 10th week (Figure 17). There were no treatment interruptions or tapering events related to LVEF < 50%, and no events at LVEF < 40%.

[0336] At the 10th week, the mean of KCCQ-CSS improved by 10.6 points (p < 0.0001 for the change from baseline to the 10th week) (Figure 18, data are shown as mean and standard deviation). The symptom burden clinically decreased in 58% of all patients, and nearly half of the patients reported moderate and large to very large improvements (Figure 19).

[0337] The NYHA class improved during treatment. 28% of the patients achieved NYHA class 1 (asymptomatic) by the 10th week (Figure 20), and 56% of all patients showed a functional improvement of NYHA class 1 or above. The change from baseline to the 10th week showed p = 0.011 compared with the assumed placebo effect of 37%.

[0338] Fourteen patients (34%) who had symptomatic angina (SAQ-AF ≤ 80) at baseline experienced an improvement response to the treatment, and the SAQ-AF increased by an average (SD) change of 14.3 (±16.0) from baseline to the 10th week (p = 0.005) (Figure 21).

[0339] The median NT-proBNP (IQR) decreased at each scheduled visit and the percentage change from baseline was highly statistically significant (see Figure 22, ***P < 0.0001). By the end of treatment (10 weeks), a significant mean (SE) decrease of -870 pg / mL (155.3), or 55% (p < 0.0001) was achieved. The median (IQR) of hs-cTnI also decreased significantly in proportion to baseline at each study visit (*p < 0.05, **p < 0.005) (see Figure 22). By the end of treatment (10 weeks), a significant mean (SE) decrease of -24.8 ng / L (11.8), or 21% (p < 0.05) was achieved. After a 2-week washout, both cardiac biomarkers recovered after stopping drug treatment (see Figure 22).

[0340] To consider treatment effects in specific patient subgroups, an exploratory responder analysis was performed. Responders were defined as those showing any of (a) a decrease of more than 50% in NT-proBNP, (b) an improvement of NYHA class 1 or more, (c) an improvement of KCCQ ≥ 5 points, or (d) a combination of the foregoing. A potential difference in treatment effect was observed in patients with BMI ≥ 30 compared to those with BMI < 30 (Figure 23A). Consistent treatment effects were also observed in other patient subgroups: patients receiving beta-blockers versus those not receiving beta-blockers (Figure 23B), patients with elevated TnI or E / e’ (>13) versus those without elevation of TnI or E / e’ (Figure 23C); patients with a genetic or family history of HCM versus those without a genetic or family history (Figure 23D).

[0341] Doppler measurements of the patient's diastolic function (lateral e’, lateral E / e’, septal E / e’) generally improved from baseline to week 10 (Figure 25, showing mean and 95% CI).

[0342] Of the 41 registered patients, 7 patients with mid-ventricular obstruction (MVO) were tested. MVO patients represent a subgroup of nHCM patients who are often excluded from other trials and are quite symptomatic with restrictive symptoms. All patients included in this subgroup showed improvement and reduction in symptoms in both NT-proBNP and hs-troponin I levels (Figure 24).

Table 16

[0343] Second interim safety Three (7.3%) patients experienced an LVEF < 50% at week 10 (EOT). An LVEF < 40% did not occur. After a 2-week washout (week 12), all LVEFs returned to normal and there were no related SAEs. Four (9.8%) patients experienced SAEs, one of whom died. None of the SAEs were due to aficamten.

[0344] Conclusion Aficamten was generally well tolerated and the LVEF decreased moderately on target as a response to 10 weeks of aficamten administration. During open-label therapy, the burden of heart failure improved significantly in most non-obstructive patients, along with improvement in cardiac biomarkers. A significant improvement in angina was also achieved. The mean decrease of 14.3 points in the angina frequency score means that the frequency of angina decreased from daily or weekly to weekly or monthly. The trend of diastolic function markers suggests that there may be favorable echocardiogram evidence of improved myocardial relaxation with longer exposure at the target dose.

[0345] Example 3 A non-blind, continuing clinical trial of CK-274 is conducted in patients with symptomatic nHCM or MVOHCM. The treatment period is expected to be several years. The primary objective of this trial was to determine the safety and tolerability of CK-274 over 5 years.

[0346] Approximately 25 patients may be enrolled in this trial. After screening for a maximum of 56 days, eligible patients will be administered a single daily dose of aficamten. The maximum tolerated dose will be notified by the conduct of other ongoing trials on aficamten. Each patient will start at a pre-specified minimum dose and adjust the dose up to the maximum tolerated dose (not exceeding the pre-specified maximum dose) under the guidance of echocardiogram. Dose adjustments cannot be made more than once every two weeks.

[0347] As described in Example 2, patients who had completed the trial and did not develop atrial fibrillation were eligible for enrollment in this trial. Dose adjustment under echocardiogram guidance based on site readings was managed by the principal investigator of the clinical trial and could be performed at any time during the trial as described below.

[0348] Trial Design On Day 1, each patient will undergo an echocardiogram examination, and each patient will be administered Dose 1 of CK-274 once daily for two weeks. At Week 2, each patient received a shortened echocardiogram two hours after dose administration. If the biplane LVEF was 55% or higher, the patient was then increased to Dose 2. Otherwise, the patient continued with 5 mg of CK-274. If the LVEF was <50%, treatment was discontinued.

[0349] At Week 4, Week 6, Week 12, and then every 12 weeks thereafter, to determine whether additional dose adjustments are necessary, two hours after dose administration, each patient underwent an echocardiogram or a shortened echocardiogram (shortened echocardiogram at Week 4 and Week 6, echocardiogram at Week 12 and every 12 weeks thereafter) (see Tables 17 and 18). Outpatient cardiac monitoring was performed at Weeks 48, 96, 144, 192, and 240. Cardiac magnetic resonance was monitored at Weeks 48, 144, and 240. (See Figure 8). If the patient's LVEF dropped below 40% after the visit at Week 2, an echocardiogram may be performed again (preferably within 24 hours) to confirm the initial findings. If the echocardiogram findings are confirmed, the patient will receive a drug holiday of more than two days. If LVEF ≧ 55% is demonstrated by local echocardiogram examination, the patient may continue to receive CK-274 at the reduced previous tolerated dose.

Table 17

Table 18

[0350] Echocardiogram The echocardiogram 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), left ventricular stroke volume), interventricular septal thickness and free wall thickness, E / e’, E / A, and LA volume.

[0351] Cardiac magnetic resonance In the cardiac magnetic resonance (CMR) imaging sub-study, the effects of long-term administration of aficamten on the cardiac morphology, function, and fibrosis are evaluated in HCM patients who are eligible and have selected to participate. CMR is performed at baseline at any time during the screening period and can be performed within 8 weeks before the first administration of aficamten administered on Day 1. Patients who fail the screening and are re-screened do not need to perform baseline CMR again. If the subject is enrolled in the CMR sub-study of Example 5, there is no need to repeat the baseline CMR. For patients with an eGFR of less than 30 mL / min / 1.73 m2 or patients allergic to gadolinium, only CMR without contrast agent is performed. Patients may also choose to have only non-contrast CMR evaluation for any other reason. Subsequent CMR tests are performed within ±30 days of the visits at Week 48 and Week 144, or within 60 days before the visit at Week 240 or end of treatment (EOT).

[0352] Record the NYHA functional classification. If available, patients answer the patient-reported outcome (PRO) questionnaires: Kansas City Cardiomyopathy Questionnaire (KCCQ) specified in Table 19, Seattle Angina Questionnaire-7 (SAQ-7), EuroQol 5-Dimension 5-Level Scale (EQ-5D-5L), Patient Global Impression of Change (PGI-C) scale, Clinical Global Impression (CGI) scale, SF-36 Physical Function Subscale (SF-36PFS). [Table 19]

[0353] Primary endpoint The primary endpoints are as follows: (i) the patient incidence of reported adverse events (AE), (ii) the patient incidence of reported serious adverse events (SAE); (iii) the patient incidence of left ventricular ejection fraction (LVEF) less than 50%.

[0354] Exploratory endpoint The exploratory objectives of this trial include the following. (i) C at 1-year intervals until the end of participation troughTo evaluate the steady-state pharmacokinetics of aficamten during long-term administration as monitored by [specific monitoring method]; (ii) To evaluate the long-term effects of aficamten on cardiac biomarkers, as evaluated by changes from baseline values of 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; (iv) For EQ-5D-5L, PGI-C, CGI, Kansas City Cardiomyopathy Questionnaire (KCCQ), SAQ-7, SF-36 Physical Function Subscale (SF-36PFS), evaluate the changes from baseline until the end of participation at 12-week intervals and assess the impact on the symptoms of nHCM; (v) To evaluate the pharmacodynamic effects of aficamten on cardiac function and structure. This is evaluated by changes from baseline until the end of participation in cardiac function and structure measurements by the following echocardiograms at 12-week intervals. Namely, LVEF; left ventricular fractional shortening (LVFS); left ventricular stroke volume (LVSV); left ventricular end-systolic and end-diastolic volumes (LVESV and LVEDV respectively); 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 aficamten on electrocardiogram indices of myocardial repolarization abnormalities by changes from baseline in the proportion of patients showing left ventricular strain patterns on electrocardiograms at 12-week intervals until the end of participation; (vii) To evaluate the effect of aficamten on cardiac structure. Evaluate the changes from baseline until 1 year, 3 years, 5 years, and the end of participation, and cardiac morphology and structure measurements evaluated by cardiac magnetic resonance (CMR) imaging: RV and LV mass; septum, free wall, and maximum wall thickness; left atrial volume; end-diastolic volume (EDV); end-systolic volume (ESV); (viii) To evaluate the effect of aficamten on cardiac function by changes from baseline at 1, 3, 5 years and until the end of participation, and biventricular function evaluated by CMR imaging: stroke volume (SV); ejection fraction (EF); cardiac output (CO); (ix) To evaluate the effect of aficamten on cardiac fibrosis.Evaluated by changes from baseline at 1 year, 3 years, 5 years, and until the end of participation, and evaluated by the following parameters with late gadolinium enhancement (LGE) after CMR: LGE mass (g); LGE mass % (% of LV mass).

[0355] Example 4 This is a phase 3, multi - center, randomized, double - blind, placebo - controlled trial for participants with symptomatic nHCM. This phase 3 trial is designed to further evaluate the effects of aficamten on quality of life, exercise capacity, heart failure symptoms, cardiac biomarkers, cardiac remodeling, and clinical outcomes. Additionally, the safety and tolerability of aficamten are evaluated in participants with nHCM.

[0356] Approximately 420 eligible participants are randomly assigned to aficamten or placebo in a 1:1 ratio. Doses of 5, 10, 15, or 20 mg or corresponding placebo are administered incrementally using echocardiography as a guide for dose adjustment. Randomization is stratified by the presence of persistent atrial fibrillation and intracavitary obstruction.

[0357] This trial consists of 2 parts. That is, part 1 is from day 1 to week 36, and part 2 is from week 36 to week 72. All participants complete part 1. When part 1 ends, participants proceed to part 2 until the last randomized participant completes part 1 (week 36). At that point, all remaining eligible study participants in part 2 attend a visit at the end of the study following the visit at the end of treatment.

[0358] Enrollment is restricted so that less than about 10% of participants have persistent or permanent atrial fibrillation and less than about 10% of participants have a BMI in the range of greater than 35 and less than 40 kg / m2. Participants who complete the trial have the option to roll over to an open - label long - term administration trial.

[0359] A cardiovascular magnetic resonance imaging sub - study is conducted on up to 100 participants.

[0360] Abbreviations: AE = adverse event; CGI = Clinical Global Impression; CPET = cardiopulmonary exercise testing; EQ-5D-5L = EuroQol 5-dimension 5-level instrument; hs-cTnI = high-sensitivity cardiac troponin I; KCCQ = Kansas City Cardiomyopathy Questionnaire; KCCQ-CSS = KCCQ-Clinical Summary Score; KCCQ-OSS = KCCQ-Overall Summary Score; LAVI = left atrial volume index; LVEF = left ventricular ejection fraction; LVMI = left ventricular mass index; MRI = magnetic resonance imaging; nHCM = non-obstructive hypertrophic cardiomyopathy; NT-proBNP = N-terminal pro-brain natriuretic peptide; NYHA = New York Heart Association; PGI-C = Patient's Global Impression of Change; PK = pharmacokinetics (plural possible); 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.

[0361] Eligibility Eligibility criteria: Participants who meet all of the following criteria at the time of screening can participate in the study: (1) Aged 18 to 85 years. (2) Body mass index < 40 kg / m 2. (3) Diagnosed with nHCM and meeting the following criteria in a screening echocardiogram: (i) Left ventricular end-diastolic wall thickness of 15 mm or more in one or more myocardial segments, or 13 mm or more in one or more wall segments, with a known disease-causing genetic mutation or a family history of HCM, and (ii) Resting LVOT-G < 30 mmHg and Valsalva LVOT-G < 50 mmHg, and (iii) LVEF ≧ 60%. Participants with a history of mid-cavity or apical obstruction without LVOT obstruction are eligible. (4) NYHA class II or III. (5) Respiratory exchange ratio of 1.00 or more at the time of screening by cardiopulmonary exercise testing (CPET) and predicted maximal oxygen uptake (pVO2) of 90% or less regardless of age and gender. (6) KCCQ-CSS score of 30 or more and 85 or less. (7) NT-proBNP: (a) In the case of atrial fibrillation or atrial flutter, NT-proBNP ≧ 300 pg / mL or NT-proBNP ≧ 900 pg / mL, or (b) In the case of black participants, in the case of atrial fibrillation or atrial flutter, NT-proBNP ≧ 225 pg / mL or NT-proBNP ≧ 675 pg / mL. (8) Hemoglobin level of 10 g / dL or more. (9) Participants taking beta-blockers, verapamil, diltiazem, or ranolazine are expected to have been taking a stable dose for at least 2 weeks before baseline CPET and to continue the same dosing regimen during the study period. (10) Male participants are eligible if they agree to the following: a) Refrain from sperm donation during the trial period and for at least 10 weeks after the final dose of IP, and b) During the trial period and for 4 weeks after the final dose of IP, (i) Refrain from heterosexual intercourse as part of their preferred normal lifestyle (abstain long-term and continuously), agree in writing to continue abstinence, or (ii) If the female partner is a woman with a potential for pregnancy, agree to use a male condom and have the female partner use a highly effective contraceptive method. (11) Female participants are eligible if they are not pregnant, not breastfeeding, and have no plans for egg donation and meet at least one of the following conditions.a) Not a pregnant woman, b) A WOCBP who has been using a highly effective method of contraception during the trial period and for at least 4 weeks after the last dose of the IP, and whose male partner has consented to condom use, c) The WOCBP must have a negative pregnancy test (urine or serum as required by local regulations) on the day before the first dose of the trial IP.

[0362] Exclusion Criteria: Participants who meet any of the following criteria will be excluded from the study: (1) Severe valvular disease (at the discretion of the treating physician): (a) Moderate or greater aortic stenosis or fixed subaortic obstruction, (b) Moderate or greater mitral regurgitation. (2) Known or suspected infiltrative, genetic, or storage diseases (e.g., Noonan syndrome, Fabry disease, amyloidosis) that cause cardiac hypertrophy similar to nHCM. (3) Known coronary artery stenosis of 70% or more. (4) History of left ventricular systolic dysfunction (left ventricular ejection fraction less than 45%) or stress cardiomyopathy. (5) Unable to exercise on a treadmill or bicycle (e.g., orthopedic limitations). (6) Recorded indoor air oxygen saturation less than 90% at screening or history of severe chronic obstructive pulmonary disease or severe / critical pulmonary hypertension. (7) History of syncope, symptomatic ventricular arrhythmia, or sustained ventricular tachycardia during exercise within 3 months prior to screening. (8) History of treatment-resistant hypertension (blood pressure continues to rise despite taking maximum doses of 3 or more antihypertensive medications). (9) Screening diastolic blood pressure exceeding 100 mmHg. (10) Previous treatment with amifampridine. (11) Treatment with mavacamten within 3 months prior to screening (consultation with a medical monitor is required prior to screening). (12) Received ventricular septal reduction therapy within 6 months prior to screening. (13) Consideration or potential consideration for registration on the heart transplant list or implantation of a left ventricular assist device during the study period. (14) Paroxysmal or persistent atrial fibrillation is excluded only if (a) rhythm restoration therapy (direct current cardioversion, atrial fibrillation ablation surgery, or antiarrhythmic therapy, etc.) was required up to 3 months prior to screening, or (b) heart rate control and anticoagulation therapy have not been achieved up to at least 3 months prior to screening.

[0363] Exclusion Criteria for the Cardiac MRI Substudy: (1) Unable to tolerate cardiac MRI. (2) Wearing an implantable cardioverter-defibrillator (ICD). (3) Wearing a cardiac pacemaker.

[0364] Procedure Participants randomly assigned to Aficamten may receive up to 4 gradually increasing IP administrations over the first 6 weeks of the trial, as outlined in Tables 20 and 21 below. For participants randomized to Aficamten, the initial dose of Aficamten is 5 mg (Dose 1). Each participant is administered Dose 1 once daily for 2 weeks. At the 2-week visit, participants undergo a cardiac echocardiogram approximately 2 hours after the administration of the investigational product (IP). If the left ventricular ejection fraction is 60% or greater on the cardiac echocardiogram, the participant is up-titrated to 10 mg (Dose 2). Otherwise, the participant maintains the same dose.

[0365] After administering the assigned dose for an additional 2 weeks (i.e., Week 4), each participant undergoes a cardiac echocardiogram approximately 2 hours after IP administration. If the LVEF is 60% or greater on the echocardiogram, the participant is up-titrated to the next higher dose. Otherwise, the participant maintains the same dose.

[0366] After administering the assigned dose for an additional 2 weeks (i.e., Week 6), each participant undergoes a cardiac echocardiogram approximately 2 hours after IP administration. If the LVEF is 60% or greater on the echocardiogram, the participant is up-titrated to the next higher dose. Otherwise, the participant maintains the same dose.

[0367] After administering the assigned dose for an additional 2 weeks, at the Week 8 visit, each participant undergoes a cardiac echocardiogram 2 hours after IP dose administration to confirm that the LVEF is 50% or greater. If the LVEF is less than 50% at Week 8, the participant is down-titrated to the next lower dose or, if the participant is taking 5 mg (Dose 1), down-titrated to placebo.

[0368] At any point during the trial, if the LVEF is less than 50% on echocardiogram, the participant is either returned to the previous dose level or, if the participant is on 5 mg, the IP is switched to placebo, in which case the participant continues to receive placebo for the remainder of the trial period. If it is consistently shown that the LVEF is less than 40% on the scheduled echocardiogram, the investigational drug is temporarily discontinued. If the LVEF recovers to 60% or more, treatment can be resumed at the next lower dose level in consultation with the medical monitor.

[0369] The treatment period is up to 72 weeks, with a 4-week follow-up period (weeks 72 to 76) after the last dose. All participants are followed for at least week 36 of the trial or until part 1. Participants who complete week 36 continue in the double-blind placebo-controlled trial until week 72 (followed by end of treatment [EOT] at week 76) or until the last participant randomized in part 1 completes week 36. When the last randomized participant completes week 36, all remaining active trial participants receive an end-of-treatment visit (within 4 weeks), followed by a 4-week follow-up end-of-trial visit. The schedule of activities is shown in Figure 16.

Table 20

Table 21

Table 22

Table 23

[0370] Pharmacokinetics As specified in Table 24, approximately 4 mL of blood samples are collected to measure the plasma concentration of aficamten. The samples are used to evaluate the PK of aficamten and its metabolites.

Table 24

[0371] Cardiac MRI Substudy In the Cardiac MRI Substudy, up to 100 nHCM participants who are eligible and have consented to participate will be evaluated for the effects of aficamten administration on cardiac morphology, function, and fibrosis. Cardiac MRI will be performed during screening and at 36 and 72 weeks. If the evaluations are performed on the same day, cardiac MRI must be performed after CPET. Patients with an eGFR < 30 mL / min / 1.73 m2 or who have an allergy to gadolinium may undergo non-contrast MRI. Participants who are ineligible at screening and are re-screened do not need to undergo cardiac MRI again.

[0372] Statistical Methods Assuming that the difference in the change from baseline in KCCQ-CSS between aficamten and placebo is 5 points, the standard deviation is 15, and 10% of the participants have an unknown change from baseline data for the primary evaluation item, a sample size of 420 participants (210 participants per treatment group) can detect the difference in the mean change in KCCQ-CSS from baseline to 36 weeks with a power of more than 90%, and the two-sided type I error will be 0.05.

[0373] During the trial, the pooled SD for the change from baseline in KCCQ-CSS at 36 weeks will be blindly and regularly monitored. If the pooled SD is larger than expected, the sample size may be increased to maintain the intended power.

[0374] Perform effectiveness analysis on the full analysis set (FAS). In the primary analysis, test the null hypothesis that there is no difference in the treatment effect at the primary endpoint between participants randomized to placebo or aficamten. The change from baseline in KCCQ-CSS was analyzed using a mixed model repeated measures model with fixed effects for the interaction between treatment group, randomization stratification factor, visit, between visit-baseline, and between visit-treatment group, and with the baseline KCCQ-CSS as a covariate. A two-sample t-test is performed to compare the composite z-scores between treatment groups for the first secondary endpoint. The proportion of responders is analyzed using the Cochran-Mantel-Haenszel (CMH) test stratified by the randomization stratification factor. Other changes from baseline endpoints are analyzed using the same model as for the primary endpoint. The time-to-event endpoint is analyzed using both Kaplan-Meier estimates and a Cox regression model.

[0375] Safety analysis is performed on the safety analysis set.

[0376] The number and percentage of participants reporting adverse events manifested by treatment are tabulated by the MedDRA preferred term and system organ class.

Table 25

[0377] Endpoint Primary endpoint: To evaluate the effect of aficamten on the health status of participants by comparing it with placebo, measuring the change in KCCQ-CSS from baseline to week 36.

[0378] Secondary endpoints: (1) To evaluate the effect of aficamten on maximal and peak exercise capacity compared to placebo, measured by the change in the composite of two Z-scores of CPET parameters from baseline to 36 weeks: pVO2 (maximal exercise capacity) and VE / VCO2 slope (peak exercise capacity); (2) To evaluate the effect of aficamten on NYHA functional classification, measured as the proportion of participants with an improvement of 1 class or more in NYHA functional class from baseline to 36 weeks, comparing aficamten to placebo; (3) To evaluate the effect of aficamten on biomarkers of cardiac wall stress, measured by the change in NT-proBNP from baseline to 36 weeks, comparing to placebo; (4) To evaluate the effect of aficamten on echocardiographic measurements of structural remodeling, measured by the change in LAVI from baseline to 36 weeks, comparing to placebo; (5) To evaluate the effect of aficamten on cardiovascular events, measured as the time to the first event of cardiovascular death, heart transplantation or left ventricular assist device, aborted sudden cardiac death, non-fatal stroke, hospitalization due to heart failure, or arrhythmia (atrial fibrillation or ventricular tachyarrhythmia) requiring treatment or hospitalization, comparing to placebo.

[0379] Safety endpoints: To compare and evaluate the safety and tolerability of aficamten with placebo in participants with nHCM, evaluating by (1) the incidence rate of AEs in participants; (2) the incidence rate of LVEF < 50% in combination with the following: (a) signs and symptoms of heart failure, and / or (b) an increase in NT-proBNP compared to baseline at the time of LVEF assessment; (3) the incidence rate of LVEF < 40%.

[0380] Exploratory endpoints: (1) To compare and evaluate the effect of aficamten on the exercise capacity and functional class of African Americans with placebo. Measured by the number of participants taking aficamten who achieved any of the following at week 36: (a) change in pVO2 from baseline of 1.0 mL / kg / min or more and improvement in NYHA functional class by 1 class or more, or (b) change in pVO2 from baseline of 2.0 mL / kg / min or more and no worsening of NYHA functional class; (2) To compare and evaluate the effect of aficamten on the health status reported by the participants with placebo. The evaluation is measured by (a) change in KCCQ-OSS from baseline to week 36 and week 72, (b) change in KCCQ-CSS from baseline to week 72, (c) proportion of participants with improvement in KCCQ-CSS and KCCQ-OSS of 5, 10, 15, and 20 points or more at week 36 and week 72, (d) time to improvement in KCCQ-CSS of 5 points or more from baseline, (e) change in SAQ-7 from baseline to week 36 and week 72; (3) To compare aficamten with placebo and evaluate the effect of aficamten on left ventricular structure, compliance, and echocardiographic values of the filled heart. The measurement items are (a) change in LVMI from baseline to week 36 and week 72, (b) change in mean medial and lateral wall e' from baseline to week 36 and week 72; (4) To compare aficamten with placebo and evaluate the effect of aficamten on left ventricular structure, compliance, and echocardiographic values of the filled heart. The measurement items are (a) change in LVMI from baseline to week 36 and week 72, (b) change in mean medial and lateral wall e' from baseline to week 36 and week 72; (5) To compare and evaluate the effect of aficamten on myocardial injury biomarkers with placebo. Measure the change in hs-cTnI from baseline to week 36 and week 72; (6) To compare and evaluate the effect of aficamten on exercise symptoms and CPET parameters with placebo.Measure the changes from baseline to week 36: (a) circulatory power (VO2 × SBP), (b) O2 pulse, (c) VAT, (d) total work load (watts), (e) heart rate response, (f) Borg scale; (7) Evaluate the effect of aficamten on health status and health-related quality of life measured by the PRO questionnaire compared to placebo. Measured by the change in individual responses to CGI, PGI-C, and EQ-5D-5L from baseline to week 36 and week 72; (8) Measure and evaluate the pharmacokinetics of aficamten and its metabolites with pharmacokinetic parameters up to 36 weeks; (9) To evaluate the effect of aficamten on myocardial remodeling by cardiac MRI, measure the following changes from baseline to week 36 and week 72: (a) LVMI, (b) septum, free wall, and maximum wall thickness, (c) myocardial fibrosis, (d) LAVI and left atrial function, (e) left ventricular end-systolic volume, (f) left ventricular end-diastolic volume.

[0381] Safety analysis is performed on the safety analysis set.

[0382] Pharmacokinetic endpoint: Plasma concentration of aficamten and PK parameters (maximum observed plasma concentration [C max and trough plasma concentration [C trough ) are summarized using descriptive statistics including mean, SD, geometric mean, coefficient of variation, median, and range.

[0383] Example 5 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 WO2021 / 011807.

Claims

1. A method for treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of CK-274 【Chemical Formula 2】 or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof is selected by adjusting the daily dose of CK-274 or a pharmaceutically acceptable salt thereof administered to the patient.

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

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

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

5. The method according to any one of claims 1 to 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 according to claim 5, wherein the daily dose is about 5 mg.

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

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

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

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

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

12. A method for treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient in need thereof, comprising administering to the patient a first daily dose of CK-274 【Chemical Formula 3】 or a pharmaceutically acceptable salt thereof over a first period, and based on components of a first echocardiogram of the patient obtained after the first period, administering to the patient a second daily dose of CK-274 or a pharmaceutically acceptable salt thereof over a second period, or terminating the administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient. The method as described above.

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

14. The method according to claim 12 or 13, wherein the component of the first echocardiogram includes biplane LVEF.

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

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

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

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

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

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

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

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

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

24. The method according to any one of claims 12 to 23, wherein the first period is about two weeks.

25. The method according to any one of claims 12 to 24, wherein the second period is about two weeks.

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

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

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

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

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

31. When the second daily dose of the CK-274 or a pharmaceutically acceptable salt thereof is more than the first daily dose of the CK-274 or a pharmaceutically acceptable salt thereof and the biplane LVEF of the second echocardiogram is below the predetermined biplane LVEF threshold value, the third daily dose of the CK-274 or a pharmaceutically acceptable salt thereof is the same as the first daily dose of the CK-274 or a pharmaceutically acceptable salt thereof. The method according to claim 29.

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

33. The component of the second echocardiogram includes a biplane LVEF. When the biplane LVEF of the second echocardiogram is equal to or higher than the predetermined biplane LVEF threshold value and lower than the second predetermined biplane LVEF, the third daily dose of the CK-274 or a pharmaceutically acceptable salt thereof is the same as the second daily dose of the CK-274 or a pharmaceutically acceptable salt thereof. The method according to any one of claims 26 to 28.

34. The component of the second echocardiogram includes a biplane LVEF. When the biplane LVEF of the second echocardiogram is equal to or higher than the second predetermined biplane LVEF threshold value, the third daily dose of the CK-274 or a pharmaceutically acceptable salt thereof is more than the second daily dose of the CK-274 or a pharmaceutically acceptable salt thereof. The method according to any one of claims 26 to 28.

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

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

37. The method according to any one of claims 26 to 36, further comprising measuring said components of the second echocardiogram.

38. The method according to any one of claims 26 to 37, wherein said third period is about two weeks.

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

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

41. The method according to claim 39 or 40, wherein said components of the third echocardiogram include biplane LVEF.

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

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

44. When the third daily dose of the CK-274 or a pharmaceutically acceptable salt thereof is more than the second daily dose of the CK-274 or a pharmaceutically acceptable salt thereof and the biplane LVEF of the third echocardiogram is below the predetermined biplane LVEF threshold value, the fourth daily dose of the CK-274 or a pharmaceutically acceptable salt thereof is the same as the second daily dose of the CK-274 or a pharmaceutically acceptable salt thereof, or When the third daily dose of the CK-274 or a pharmaceutically acceptable salt thereof is the same as the second daily dose of the CK-274 or a pharmaceutically acceptable salt thereof and the biplane LVEF of the third echocardiogram is below the predetermined biplane LVEF threshold value, the fourth daily dose of the CK-274 or a pharmaceutically acceptable salt thereof is the same as the first daily dose of the CK-274 or a pharmaceutically acceptable salt thereof, the method according to claim 42 or 43.

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

46. The component of the third echocardiogram includes a biplane LVEF. When the biplane LVEF of the third echocardiogram is equal to or higher than the predetermined biplane LVEF threshold value and lower than the second predetermined biplane LVEF, the fourth daily dose of the CK-274 or a pharmaceutically acceptable salt thereof is the same as the third daily dose of the CK-274 or a pharmaceutically acceptable salt thereof, the method according to any one of claims 39 to 41.

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

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

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

50. The method according to any one of claims 39 to 49, wherein the fourth period is about two weeks.

51. A method for treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient in need thereof, CK-274 [Chemical Formula 4] or administering a first daily dose of a pharmaceutically acceptable salt thereof to the patient over a first period, administering a second daily dose of CK-274 or a pharmaceutically acceptable salt thereof to the patient over a second period based on a first echocardiogram including the biplane LVEF of the patient obtained after the first period, or terminating the administration of the CK-274 to the patient, when the biplane LVEF of the first echocardiogram is below a first predetermined biplane LVEF threshold, the administration of the CK-274 or a pharmaceutically acceptable salt thereof to the patient is terminated. When the bipyplane LVEF is equal to or higher than the first predetermined bipyplane LVEF threshold value and lower than the second predetermined bipyplane LVEF threshold value, the second daily dose of the CK-274 or a pharmaceutically acceptable salt thereof is the same as the first daily dose of the CK-274 or a pharmaceutically acceptable salt thereof. The method according to claim 51, wherein when the bipyplane LVEF of the first echocardiogram exceeds the second predetermined bipyplane LVEF threshold value, the second daily dose of the CK-274 or a pharmaceutically acceptable salt thereof is higher than the first daily dose of the CK-274 or a pharmaceutically acceptable salt thereof.

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

53. The method according to embodiment 51 or 52, further comprising measuring the bipyplane LVEF for the first echocardiogram.

54. The method according to any one of claims 51 to 53, wherein the first period is about two weeks.

55. The method according to any one of claims 51 to 54, wherein the second period is about two weeks.

56. The method according to any one of claims 51 to 55, wherein the second daily dose of the CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient over the second period, and based on a second echocardiogram of the patient obtained after the second period, which includes the bipyplane LVEF of the patient, and the second daily dose of the CK-274 or a pharmaceutically acceptable salt thereof, administering a third daily dose of the CK-274 or a pharmaceutically acceptable salt thereof to the patient over a third period, or terminating the administration of the CK-274 or a pharmaceutically acceptable salt thereof to the patient. When the bipyplane LVEF of the second echocardiogram is lower than the first predetermined bipyplane LVEF threshold value and the second daily dose of the CK-274 or a pharmaceutically acceptable salt thereof is the same as the first daily dose of the CK-274 or a pharmaceutically acceptable salt thereof, the administration of the CK-274 or a pharmaceutically acceptable salt thereof to the patient is terminated. When the biplane LVEF of the second echocardiogram is below the first predetermined biplane LVEF threshold value and the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is more 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 less than the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof. When the biplane LVEF is equal to or higher than the first predetermined biplane LVEF threshold value and lower than the second predetermined biplane LVEF threshold value, 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. When the biplane LVEF of the second echocardiogram is higher than the second predetermined biplane LVEF threshold value, the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof is more than the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof, the method.

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

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

59. The method according to any one of claims 56 to 58, wherein the third period is about two weeks.

60. The method according to any one of claims 56 to 59, wherein a third daily dose of said CK-274 or a pharmaceutically acceptable salt thereof is administered to said patient over said third period, further comprising administering to said patient a fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof over a fourth period, or terminating the administration of said CK-274 to said patient, based on a third echocardiogram of said patient obtained after said third period and including the biplane LVEF of said patient, and said third daily dose of CK-274 or a pharmaceutically acceptable salt thereof. When the biplane LVEF of the third echocardiogram is below the first predetermined biplane LVEF threshold value 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, the 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 first predetermined biplane LVEF threshold value and the third 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, the fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof is less than the third daily dose of CK-274 or a pharmaceutically acceptable salt thereof. When the biplane LVEF is equal to or greater than the first predetermined biplane LVEF threshold value, 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. [

61. ] The method according to claim 60, wherein the first daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg of CK-274, the second daily dose of CK-274 or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg of 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 of 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, or about 20 mg of CK-274. [

62. ] The method according to claim 60 or 61, further comprising measuring the biplane LVEF for the third echocardiogram.

63. The method according to any one of claims 60 to 62, wherein the third period is about two weeks.

64. The method according to any one of claims 51 to 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, comprising: (1) administering to the patient a first daily dose ("dose 1") of CK-274 [Chemical Formula 5] or a pharmaceutically acceptable salt thereof over a first period; (2) after the first period, performing a first echocardiogram on the patient to determine the patient's biplane LVEF ("LVEF1"); (a) if the patient's LVEF1 is less than 50%, terminating the administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient; or (b) if the patient's LVEF1 is 55% or more, administering to the patient a second daily dose ("dose 2") of CK-274 or a pharmaceutically acceptable salt thereof over a second period, wherein dose 2 is greater than dose 1; (c) if the patient's LVEF1 is 50% or more and less than 55%, administering to the patient the same dose as the dose administered over the first period of CK-274 or a pharmaceutically acceptable salt thereof over a second period, and optionally (3) after the second period, performing a second echocardiogram on the patient to determine the patient's biplane LVEF ("LVEF2"); (a) if the patient has received dose 1 during the second period and the patient's LVEF2 is less than 50%, terminating the administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient; or (b) if the patient has received dose 2 during the second period and the patient's LVEF2 is less than 50%, administering dose 1 of CK-274 or a pharmaceutically acceptable salt thereof to the patient over a third period; (c) If the patient has received Dose 1 during the second period and the patient's LVEF2 is 55% or more, administering to the patient a higher daily dose of the CK-274 or a pharmaceutically acceptable salt thereof ("Dose 2") over a third period, or (d) If the patient has received Dose 2 during the second period and the patient's LVEF2 is 55% or more, administering to the patient a third daily dose of the CK-274 or a pharmaceutically acceptable salt thereof ("Dose 3") over a third period, where Dose 3 is higher than Dose 2, the administering, or (e) If the patient's LVEF2 is 50% or more and less than 55%, administering to the patient the same dose as the dose administered over the second period of the CK-274 or a pharmaceutically acceptable salt thereof over a third period, and optionally (4) After the third period, performing a third echocardiogram on the patient to determine the patient's biplane LVEF ("LVEF3"), (a) If the patient has received Dose 1 during the third period and the patient's LVEF3 is less than 50%, terminating the administration of the CK-274 or a pharmaceutically acceptable salt thereof to the patient, or (b) If the patient has received Dose 2 during the third period and the patient's LVEF3 is less than 50%, administering Dose 1 of the CK-274 or a pharmaceutically acceptable salt thereof to the patient over a fourth period, or (c) If the patient has received Dose 3 during the third period and the patient's LVEF3 is less than 50%, administering Dose 2 of the CK-274 or a pharmaceutically acceptable salt thereof to the patient over a fourth period, or (d) If the patient has received Dose 1 during the third period and the patient's LVEF3 is 55% or more, administering Dose 2 of the CK-274 or a pharmaceutically acceptable salt thereof to the patient over a fourth period, or (e) If the patient has received Dose 2 during the third period and the patient's LVEF3 is 55% or more, administering Dose 3 of the CK-274 or a pharmaceutically acceptable salt thereof to the patient over a fourth period, or (f) If the patient has received Dose 3 during the third period and the patient's LVEF3 is 55% or more, administering to the patient a fourth once-daily dose of the CK-274 or a pharmaceutically acceptable salt thereof ("Dose 4") over a fourth period, wherein Dose 4 is more than Dose 3, or (5) If the patient's LVEF3 is 50% or more and less than 55%, administering to the patient the same dose as the dose administered over the third period of the CK-274 or a pharmaceutically acceptable salt thereof over a fourth period, and The method comprising the above.

66. The method according to claim 65, wherein the first period is about two weeks.

67. The method according to any one of claims 65 to 66, wherein the second period is about two weeks, about ten weeks, about twelve weeks, about six months, about one year, about two years, about three years, about four years, or about five years, or indefinite.

68. The method according to any one of claims 65 to 67, wherein the third period is about two weeks, about ten weeks, about twelve weeks, about six months, about one year, about two years, about three years, about four years, or about five years, or indefinite.

69. The method according to any one of claims 65 to 68, wherein the fourth period is about two weeks, about ten weeks, about twelve weeks, about six months, about one year, about two years, about three years, about four years, or about five years, or indefinite.

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

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

72. The method according to any one of claims 65 to 71, wherein Dose 3 is about 15 mg.

73. The method according to any one of claims 65 to 72, wherein Dose 4 is about 20 mg.

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

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

76. If the patient has received the maximum tolerable dose and the patient's LVEF is 55% or more, the patient continues to receive the same maximum dose in the next period. The method according to any one of claims 1 to 75.

77. The method according to any one of claims 1 to 76, wherein the administration of said CK-274 or a pharmaceutically acceptable salt thereof is terminated or temporarily interrupted when the LVEF of said patient is less than 40%.

78. The method according to any one of claims 1 to 77, wherein the administration of said CK-274 or a pharmaceutically acceptable salt thereof is terminated or temporarily interrupted when an unscheduled echocardiogram shows an LVEF of less than 50% and the patient has symptoms of low cardiac output.

79. The method according to any one of claims 1 to 78, wherein the LVOT-G of said patient at rest and after Valsalva is less than 30 mmHg before the administration of CK-274 or a pharmaceutically acceptable salt thereof.

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

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

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

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

84. The method according to any one of claims 1 to 83, wherein the patient has received septal reduction therapy (SRT) before starting treatment with CK-274 or a pharmaceutically acceptable salt thereof.

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

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

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

88. The method according to any one of claims 1 to 87, which does not include collecting a blood sample from said patient.

89. The method according to any one of claims 1 to 87, which does not include analyzing a blood sample of the patient.

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

91. A method for treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient in need thereof, comprising 【Chemical Formula 6】 administering to the patient a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof.

92. A method for treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient in need thereof, comprising [Chemical Formula 7] administering to the patient a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, wherein the patient has a resting left ventricular ejection fraction of at least 60% prior to administration of CK-274 or a pharmaceutically acceptable salt thereof.

93. A method for treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient in need thereof, comprising 【Chemical 8】 administering to the patient a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, wherein the patient has a resting left ventricular ejection fraction of at least 60% and a left ventricular outflow tract pressure gradient (LVOT-G) at rest and after Valsalva of less than 30 mmHg prior to administration of CK-274 or a pharmaceutically acceptable salt thereof.

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

95. The method according to claim 94, wherein the dose is adjusted once during the course of treatment.

96. The method according to claim 94, wherein the dose is adjusted two or more times during the course of treatment.

97. The daily dose is administered to the patient in a constant amount for about two weeks before the amount of the daily dose is adjusted, according to any one of claims 95 to 96.

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

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

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

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

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

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

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

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

108. The method according to any one of claims 1 to 107, wherein administration of CK-274 results in a reduction in left ventricular wall stress.

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

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

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

112. A method of treating MVOHCM in a patient in need of treatment for midventricular obstructive (MVO) HCM, comprising CK-274 【Chemical Formula 9】 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 adjusting the daily dose of CK-274 or a pharmaceutically acceptable salt thereof administered to the patient, said method.

113. A method of treating mid-ventricular obstructive (MVO) hypertrophic cardiomyopathy in a patient in need of treatment for MVO hypertrophic cardiomyopathy, comprising: CK-274 【Chemical 10】 administering to the patient a first daily dose of CK-274 or a pharmaceutically acceptable salt thereof over a first period; and based on components of a first echocardiogram of the patient obtained after the first period, administering to the patient a second daily dose of CK-274 or a pharmaceutically acceptable salt thereof over a second period, or terminating administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient, said method.

114. The method according to any one of claims 1 to 113, wherein the method results in one or more of the following in the patient: a) an improvement of one class or more in NYHA functional classification, and / or b) a decrease in mean NT-proBNP, and / or c) a decrease in cardiac troponin I.

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

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

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

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

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

120. A method for treating non-obstructive hypertrophic cardiomyopathy (nHCM) in a patient in need thereof, comprising: (1) administering to the patient a first daily dose ( "dose 1") of CK-274 【Chemical Formula 11】 or a pharmaceutically acceptable salt thereof over a first period; (2) after the first period, performing a first echocardiogram on the patient to determine the biplane LVEF ( "LVEF1") of the patient; (a) if the patient's LVEF1 is less than 50%, terminating the administration of CK-274 or a pharmaceutically acceptable salt thereof to the patient; or (b) if the patient's LVEF1 is 60% or greater, administering to the patient a second daily dose ( "dose 2") of CK-274 or a pharmaceutically acceptable salt thereof over a second period, wherein dose 2 is greater than dose 1; (c) if the patient's LVEF1 is 50% or greater and less than 60%, administering to the patient the same dose as that administered over the first period of CK-274 or a pharmaceutically acceptable salt thereof over a second period, and optionally (3) after the second period, performing a second echocardiogram on the patient to determine the biplane LVEF ( "LVEF2") of the patient; (f) if the patient received dose 1 during the second period and the patient's LVEF2 is less than 50%, terminating the 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 less than 50%, administering dose 1 of CK-274 or a pharmaceutically acceptable salt thereof to the patient over a third period; or (h) if the patient received dose 1 during the second period and the patient's LVEF2 is 60% or greater, administering the second daily dose ( "dose 2") of CK-274 or a pharmaceutically acceptable salt thereof to the patient over a third period; or (i) If the patient has received Dose 2 during the second period and the patient's LVEF2 is 60% or more, administering to the patient a third once-daily dose of the CK-274 or a pharmaceutically acceptable salt thereof ("Dose 3") over a third period, wherein Dose 3 is more than Dose 2, said administering, or (j) If the patient's LVEF2 is 50% or more and less than 60%, administering to the patient the same dose as the dose administered over the second period of the CK-274 or a pharmaceutically acceptable salt thereof over a third period, and optionally (4) After the third period, performing a third echocardiogram on the patient to determine the patient's biplane LVEF ("LVEF3"), (a) If the patient has received Dose 1 during the third period and the patient's LVEF3 is less than 50%, terminating the administration of the CK-274 or a pharmaceutically acceptable salt thereof to the patient, or (g) If the patient has received Dose 3 during the second period and the patient's LVEF3 is less than 50%, administering Dose 1 of the CK-274 or a pharmaceutically acceptable salt thereof to the patient over a fourth period, or (h) If the patient has received Dose 3 during the third period and the patient's LVEF3 is less than 50%, administering Dose 2 of the CK-274 or a pharmaceutically acceptable salt thereof to the patient over a fourth period, or (i) If the patient has received Dose 1 during the second period and the patient's LVEF3 is 60% or more, administering Dose 3 of the CK-274 or a pharmaceutically acceptable salt thereof to the patient over a fourth period, or (j) If the patient has received Dose 2 during the third period and the patient's LVEF3 is 60% or more, administering Dose 3 of the CK-274 or a pharmaceutically acceptable salt thereof to the patient over a fourth period, or (k) If the patient has received Dose 3 during the third period and the patient's LVEF3 is 60% or more, administering to the patient a fourth once-daily dose of the CK-274 or a pharmaceutically acceptable salt thereof ("Dose 4") over a fourth period, wherein Dose 4 is more than Dose 3, said administering, or When the patient's LVEF3 is 50% or more and less than 60%, administering to the patient, over a fourth period, the same dosage as the dosage administered over the third period of the CK-274 or a pharmaceutically acceptable salt thereof; The method, comprising.

121. The method according to claim 120, wherein the first period is about two weeks.

122. The method according to any one of claims 120 to 121, wherein the second period is about two weeks, about ten weeks, about twelve weeks, about six months, about one year, about two years, about three years, about four years, or about five years, or indefinite.

123. The method according to any one of claims 120 to 122, wherein the third period is about two weeks, about ten weeks, about twelve weeks, about six months, about one year, about two years, about three years, about four years, or about five years, or indefinite.

124. The method according to any one of claims 120 to 123, wherein the fourth period is about two weeks, about ten weeks, about twelve weeks, about six months, about one year, about two years, about three years, about four years, or about five years, or indefinite.

125. The method according to any one of claims 120 to 124, wherein Dosage 1 is about 5 mg.

126. The method according to any one of claims 120 to 125, wherein Dosage 2 is about 10 mg.

127. The method according to any one of claims 120 to 126, wherein Dosage 3 is about 15 mg.

128. The method according to any one of claims 120 to 127, wherein Dosage 4 is about 20 mg.

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

130. The method according to any one of claims 120 to 128, wherein each of Dosage 1, Dosage 2, Dosage 3, and Dosage 4 is administered as two divided daily doses.

131. The method according to any one of claims 116 to 130, wherein when the patient has received the maximum tolerable dose and the patient's LVEF is 60% or more, the patient continues to receive the same maximum dose in the next period.

132. The method according to any one of claims 116 to 131, wherein the administration of the CK-274 or a pharmaceutically acceptable salt thereof ends or is temporarily interrupted when the patient's LVEF is less than 40%.

133. The administration of said CK-274 or a pharmaceutically acceptable salt thereof is terminated or temporarily interrupted when an unexpected echocardiogram shows an LVEF of less than 50% and the patient has symptoms of low cardiac output, according to any one of claims 116 to 132.

134. Before administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient's resting LVOT-G is less than 30 mmHg, according to any one of claims 116 to 133.

135. Before administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient's post-Valsalva LVOT-G is less than 50 mmHg, according to any one of claims 116 to 134.

136. Before administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient's left ventricular ejection fraction (LVEF) is 60% or more, according to any one of claims 116 to 135.

137. Before administration of CK-274 or a pharmaceutically acceptable salt thereof, the patient's NT-proBNP level is greater than 300 pg / mL, according to any one of claims 116 to 136.

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

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

140. The patient has received septal reduction therapy (SRT) before starting treatment with CK-274 or a pharmaceutically acceptable salt thereof, according to any one of claims 116 to 139.

141. The patient is a CYP2D6 poor metabolizer, according to any one of claims 116 to 140.

142. The patient is in a fasting state when administered CK-274 or a pharmaceutically acceptable salt thereof, according to any one of claims 116 to 141.

143. The patient is in a postprandial state when administered CK-274 or a pharmaceutically acceptable salt thereof, according to any one of claims 116 to 141.

144. The method according to any one of claims 116 to 143, which does not include collecting a blood sample of the patient.

145. The method according to any one of claims 116 to 143, which does not include analyzing a blood sample of the patient.

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

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

150. The method according to any one of claims 116 to 149, wherein administration of CK-274 results in a decrease in left ventricular wall stress.

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

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

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

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

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

156. The method according to any one of claims 1 to 153, wherein the obesity index of the patient is 30 or more.

157. The method according to any one of claims 1 to 153, wherein the obesity index of the patient is less than 30.

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

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

160. The method according to 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 tablet comprises (i) about 1% to about 50% by weight of the CK-274 or a pharmaceutically acceptable salt thereof, and (ii-1) about 10% to about 60% by weight of mannitol, and (ii-2) about 5% to about 45% by weight of microcrystalline cellulose, and (iii) about 0.1% to about 10% by weight of hydroxypropyl cellulose, and (iv) about 1% to about 10% by weight of croscarmellose sodium, and (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, provided that the % by weight excludes the weight thereof when a coating is present. The method according to claim 159.

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

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