CN117794535A - Method for treating hypertrophic cardiomyopathy - Google Patents

Method for treating hypertrophic cardiomyopathy Download PDF

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Publication number
CN117794535A
CN117794535A CN202280048360.1A CN202280048360A CN117794535A CN 117794535 A CN117794535 A CN 117794535A CN 202280048360 A CN202280048360 A CN 202280048360A CN 117794535 A CN117794535 A CN 117794535A
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compound
lvef
pharmaceutically acceptable
acceptable salt
biplane
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CN202280048360.1A
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Chinese (zh)
Inventor
F·马利克
S·库普弗
S·B·海特纳
L·A·罗伯逊
孟里心
A·奥斯穆希纳
Q·沃尔特曼
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Cytokinetics Inc
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Cytokinetics Inc
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Priority claimed from PCT/US2022/073808 external-priority patent/WO2023288324A1/en
Publication of CN117794535A publication Critical patent/CN117794535A/en
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Abstract

Methods for treating obstructive hypertrophic cardiomyopathy are described herein. The method of treatment comprises administration of a cardiac myosin inhibitor (CK-3773274, also known as CK-274 or aficonazole) and may comprise titrating the daily dose administered based on one or more components of the echocardiogram. The daily dose may be increased, maintained, decreased or terminated based on the echocardiography.

Description

Method for treating hypertrophic cardiomyopathy
Cross Reference to Related Applications
U.S. provisional application No. 63/203,333 filed on day 7 and 16 of 2021 is claimed; U.S. provisional application No. 63/299,753, filed on 1 month 14 of 2022; U.S. provisional application No. 63/305,609, filed on 1/2/2022; U.S. provisional application No. 63/331,197 filed on 14 th month 4 of 2022; and U.S. provisional application No. 63/343,975 filed on day 19 of 5 of 2022; the contents of said provisional application are hereby incorporated by reference in their entirety for all purposes.
Technical Field
The disclosure herein relates to the treatment of obstructive hypertrophic cardiomyopathy and compounds and compositions useful in the treatment of hypertrophic cardiomyopathy.
Background
Hypertrophic Cardiomyopathy (HCM) is a disease in which the myocardium (myocardium) becomes abnormally thick (hypertrophic). Myocardial thickening results in the left ventricle interior becoming smaller and stiffer, and thus the ventricle becoming less able to relax and fill with blood. Thus, patients with obstructive hypertrophic cardiomyopathy may suffer from diastolic abnormalities and Mitral Regurgitation (MR). This ultimately limits the pumping function of the heart, resulting in symptoms including chest pain, dizziness, shortness of breath, or syncope during physical activity. A subset of patients with HCM is at high risk of progressive disease that can lead to death from atrial tremors, strokes, and cardiac arrhythmias. Adverse cardiac remodeling of oHCM is a known risk factor for progression to arrhythmia and heart failure. Thus, therapies to address this condition are needed.
Disclosure of Invention
Methods and compositions for treating hypertrophic cardiomyopathy are described herein. Cardiac myosin inhibitors (CK-3773274, also known as CK-274 or aficostat (aficamten), and referred to herein as compound 1) or a pharmaceutically acceptable salt thereof) are useful in the treatment of hypertrophic cardiomyopathy, reducing the resting left ventricular outflow tract pressure gradient (LVOT-G) to less than 30mmHg in patients suffering from obstructive hypertrophic cardiomyopathy (oHCM), and/or reducing the left ventricular outflow tract pressure gradient (LVOT-G) to less than 50mmHg following a warburg event in patients suffering from obstructive hypertrophic cardiomyopathy (oHCM). As further set forth herein, the daily dose of compound 1 may be titrated based on the results of the echocardiography.
In one example, a method of reducing the resting left ventricular outflow tract pressure gradient (LVOT-G) to less than 30mmHg in a patient having obstructive hypertrophic cardiomyopathy (oHCM) comprises administering to the patient a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The reduction of resting LVOT-G to less than 30mmHg may occur within 10 weeks of starting treatment with compound 1 or a pharmaceutically acceptable salt thereof. The reduction of resting LVOT-G to less than 30mmHg may occur within two weeks of starting treatment with compound 1 or a pharmaceutically acceptable salt thereof. In some implementations, the decrease in resting LVOT-G persists for at least 10 weeks of treatment. In some embodiments, the decrease in resting LVOT-G occurs within 2 to 6 weeks of the end of dose titration. In some embodiments, the decrease in resting LVOT-G peaks within 2 to 6 weeks of the end of dose titration.
In some implementations, a method of reducing left ventricular outflow tract pressure gradient (LVOT-G) to less than 50mmHg after a warfare event in a patient with obstructive hypertrophic cardiomyopathy (oHCM) comprises administering to the patient a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The decrease in LVOT-G to less than 50mmHg following warrior action may occur within two weeks of starting treatment with compound 1 or a pharmaceutically acceptable salt thereof. The decrease in LVOT-G following warrior action may last for at least 10 weeks of treatment. In some embodiments, the decrease in LVOT-G after a warrior event occurs within 2 to 6 weeks of the end of dose titration. In some embodiments, the decrease in LVOT-G peaks within 2 to 6 weeks of end of dose titration after the warrior event.
A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof can comprise administering to the patient a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof, is selected by titrating the daily dose of compound 1, or a pharmaceutically acceptable salt thereof, administered to the patient. In some embodiments, the dose is titrated once during the course of treatment. In some embodiments, the dose is titrated two or more times during the course of treatment. The daily dose may be administered to the patient in a constant amount for about two weeks prior to titration of the daily dose amount.
In some implementations of the above methods, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a daily dose of about 5mg to about 30mg. In some embodiments, the daily dose is about 5mg. In some embodiments, the daily dose is about 10mg. In some embodiments, the daily dose is about 15mg. In some embodiments, the daily dose is about 20mg. In some embodiments, the daily dose is about 30mg.
In some implementations, the daily dose is administered daily as a single dose. In some implementations, the daily dose is administered in 2 divided doses.
In some embodiments, a method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof comprises: administering a first daily dose of compound 1, or a pharmaceutically acceptable salt thereof, to the patient for a first period of time; and administering a second daily dose of compound 1 or a pharmaceutically acceptable salt thereof to the patient for a second period of time, or terminating administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient, based on one or more components of the first echocardiogram of the patient taken after the first period of time. The method may comprise selecting a second daily dose of compound 1 or a pharmaceutically acceptable salt thereof based on one or more components of the first echocardiogram. In some embodiments, the one or more components of the first echocardiogram comprise biplane LVEF, post-warrior LVOT-G, or resting LVOT-G. In some embodiments, the one or more components of the first echocardiogram comprise biplane LVEF, post-warrior LVOT-G, and resting LVOT-G. In some embodiments, the one or more components of the first echocardiogram comprise biplane LVEF and post-warrior LVOT-G.
In some implementations of the above methods, the one or more components of the first echocardiogram comprise a biplane LVEF, and the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is lower than the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold. For example, the predetermined biplane LVEF threshold may be 50%.
In some implementations of the above methods, the one or more components of the first echocardiogram comprise a biplane LVEF and administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient is terminated when the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold. For example, the predetermined biplane LVEF threshold may be 50%.
In some implementations of the above methods, the one or more components of the first echocardiogram include a biplane LVEF, resting LVOT-G, and post-warrior action LVOT-G, and wherein the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the biplane LVEF of the first echocardiogram is equal to or above a predetermined biplane LVEF threshold, the resting LVOT-G of the first echocardiogram is below a predetermined resting LVOT-G threshold, and the post-warrior action LVOT-G of the first echocardiogram is below a predetermined post-warrior action LVOT-G threshold. In some embodiments, the predetermined biplane LVEF threshold is 50%, the predetermined resting LVOT-G threshold is 30mmHg, and the post-warrior action LVOT-G threshold is 50mmHg.
In some implementations of the above methods, the one or more components of the first echocardiogram comprise biplane LVEF, resting LVOT-G, and post-valot-G, and wherein the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is greater than the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the first echocardiogram satisfies any of the following conditions: (1) The biplane LVEF is equal to or above a predetermined biplane LVEF threshold and the resting LVOT-G is equal to or above a predetermined resting LVOT-G threshold, or (2) the biplane LVEF is equal to or above a predetermined biplane LVEF threshold, the resting LVOT-G is below a predetermined resting LVOT-G threshold and the post-warrior-action LVOT-G is equal to or above a predetermined post-warrior-action LVOT-G threshold. In some embodiments, the predetermined biplane LVEF threshold is 50%, the predetermined resting LVOT-G threshold is 30mmHg, and the post-warrior action LVOT-G threshold is 50mmHg.
In some implementations of the above methods, the one or more components of the first echocardiogram comprise biplane LVEF and post-valot-G, and wherein the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the first echocardiogram meets any of the following conditions: (1) The biplane LVEF is equal to or above a predetermined biplane LVEF threshold and below a second predetermined biplane LVEF threshold; or (2) the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold and the post-wag LVOT-G of the first echocardiogram is below a second predetermined post-wag LVOT-G threshold. In some embodiments, the predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the second predetermined post-warrior-action LVOT-G threshold is 30mmHg.
In some implementations of the above methods, the one or more components of the first echocardiogram comprise a biplane LVEF and post-warrior action lvet-G, and wherein the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is greater than the first daily dose of compound 1 when the biplane LVEF of the first echocardiogram is above a second predetermined biplane LVEF threshold and the post-warrior action lvet-G of the first echocardiogram is equal to or greater than a second predetermined post-warrior action lvet-G threshold. In some embodiments, the predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the second predetermined post-warrior-action LVOT-G threshold is 30mmHg.
In some implementations of the above methods, the first daily dose of compound 1, or a pharmaceutically acceptable salt thereof, is about 5mg of compound 1. In some embodiments, the second daily dose of compound 1, or a pharmaceutically acceptable salt thereof, is about 5mg or about 10mg of compound 1.
In some implementations of the above method, the method further comprises measuring one or more components of the first echocardiogram.
In some implementations of the above methods, the first period of time is about 2 weeks. In some embodiments, the second period of time is about 2 weeks.
In some implementations of the above methods, a second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient for a second period of time, and the method further comprises administering a third daily dose of compound 1 or a pharmaceutically acceptable salt thereof to the patient for a third period of time, or terminating administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient, based on the one or more components of the second echocardiogram of the patient taken after the second period of time and the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises selecting a third daily dose of compound 1 or a pharmaceutically acceptable salt thereof based on the one or more components of the second echocardiogram and the second daily dose. In some embodiments, the one or more components of the second echocardiogram comprise biplane LVEF, post-warrior LVOT-G, or resting LVOT-G. In some embodiments, the one or more components of the second echocardiogram comprise biplane LVEF, post-warrior LVOT-G, and resting LVOT-G. In some embodiments, the one or more components of the second echocardiogram comprise biplane LVEF and post-warrior LVOT-G.
In some embodiments of the above methods, the one or more components of the second echocardiogram comprise a biplane LVEF, and when the biplane LVEF of the second echocardiogram is below a predetermined biplane LVEF threshold, the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is lower than the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof, or administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient is terminated. In some embodiments, the predetermined biplane LVEF threshold is 50%.
In some embodiments of the above methods, administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient is terminated when the biplane LVEF of the second echocardiogram is below a predetermined biplane LVEF threshold and the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to or lower than the first daily dose of compound 1. In some embodiments, the predetermined biplane LVEF threshold is 50%.
In some embodiments of the above methods, the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is higher than the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof and the biplane LVEF of the second echocardiogram is lower than the predetermined biplane LVEF threshold. In some embodiments, the predetermined biplane LVEF threshold is 50%.
In some embodiments of the above methods, the one or more components of the second echocardiogram comprise a biplane LVEF, resting LVOT-G, and post-warrior action LVOT-G, and wherein the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the biplane LVEF of the second echocardiogram is equal to or above a predetermined biplane LVEF threshold, the resting LVEOT-G of the second echocardiogram is below a predetermined resting LVOT-G threshold, and the post-warrior action LVOT-G of the second echocardiogram is below a predetermined post-warrior action LVOT-G threshold. In some embodiments, the predetermined biplane LVEF threshold is 50%, the predetermined resting LVOT-G threshold is 30mmHg, and the post-warrior action LVOT-G threshold is 50mmHg.
In some embodiments of the above methods, the one or more components of the second echocardiogram comprise biplane LVEF, resting LVOT-G, and post-valot-G, and wherein the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is greater than the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the second echocardiogram meets any of the following conditions: (1) The biplane LVEF is equal to or above a predetermined biplane LVEF threshold and the resting LVEOT-G is equal to or above a predetermined resting lvet-G threshold, or (2) the biplane LVEF is equal to or above a predetermined biplane LVEF threshold, the resting lvet-G is below a predetermined resting lvet-G threshold and the post-warrior-action lvet-G is equal to or above a predetermined post-warrior-action lvet-G threshold. In some embodiments, the predetermined biplane LVEF threshold is 50%, the predetermined resting LVOT-G threshold is 30mmHg, and the post-warrior action LVOT-G threshold is 50mmHg.
In some embodiments of the above methods, the one or more components of the second echocardiogram comprise biplane LVEF and post-valot-G, and wherein the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the second echocardiogram meets any of the following conditions: (1) The biplane LVEF is equal to or above a predetermined biplane LVEF threshold and below a second predetermined biplane LVEF threshold; or (2) the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold and the post-warrior-action LVOT-G is below a second predetermined post-warrior-action LVOT-G threshold. In some embodiments, the predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the second predetermined post-warrior-action LVOT-G threshold is 30mmHg.
In some embodiments of the above methods, the one or more components of the second echocardiogram comprise a biplane LVEF and post-warrior action lvet-G, and wherein the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is greater than the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the biplane LVEF of the second echocardiogram is above a second predetermined biplane LVEF threshold and the post-warrior action lvet-G of the second echocardiogram is equal to or greater than a second predetermined post-warrior action lvet-G threshold. In some embodiments, the predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the second predetermined post-warrior-action LVOT-G threshold is 30mmHg.
In some embodiments of the above methods, the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg of compound 1, the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg or about 10mg of compound 1, and the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg, about 10mg or about 15mg of compound 1.
In some embodiments of the above methods, the method further comprises measuring one or more components of the second echocardiogram.
In some embodiments of the above methods, the third period of time is about 2 weeks.
In some embodiments of the above methods, administering a third daily dose of compound 1 or a pharmaceutically acceptable salt thereof to the patient for a third period of time, the method further comprises administering a fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof to the patient, for a fourth period of time, or terminating administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient based on the third daily dose of one or more components and compound or a pharmaceutically acceptable salt thereof of a third echocardiogram of the patient taken after the third period of time. In some embodiments, the method further comprises selecting a fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof based on the one or more components of the third echocardiogram and the third daily dose. In some embodiments, the one or more components of the third echocardiogram comprise biplane LVEF, post-warrior LVOT-G, or resting LVOT-G. In some embodiments, the one or more components of the third echocardiogram comprise biplane LVEF, post-warrior LVOT-G, and resting LVOT-G. In some embodiments, the one or more components of the third echocardiogram comprise biplane LVEF and post-warrior LVOT-G.
In some embodiments of the above methods, the one or more components of the third echocardiogram comprise a biplane LVEF, and when the biplane LVEF of the third echocardiogram is below a predetermined biplane LVEF threshold, the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is lower than the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof, or administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient is terminated. In some embodiments, administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient is terminated when the biplane LVEF of the third echocardiogram is below a predetermined biplane LVEF threshold and the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to or lower than the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the predetermined biplane LVEF threshold is 50%.
In some embodiments of the above methods, when the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is above the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof and the biplane LVEF of the third echocardiogram is below the predetermined biplane LVEF threshold, the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof; or when the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof and the biplane LVEF of the third echocardiogram is below the predetermined biplane LVEF threshold, the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the predetermined biplane LVEF threshold is 50%.
In some embodiments of the above methods, the one or more components of the third echocardiogram comprise a biplane LVEF, resting LVOT-G, and post-warrior action LVOT-G, and wherein the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the biplane LVEF of the third echocardiogram is equal to or above a predetermined biplane LVE threshold, the resting LVEOT-G of the third echocardiogram is below a predetermined resting LVOT-G threshold, and the post-warrior action LVOT-G of the third echocardiogram is below a predetermined post-warrior action LVOT-G threshold. In some embodiments, the predetermined biplane LVEF threshold is 50%, the predetermined resting LVOT-G threshold is 30mmHg, and the post-warrior action LVOT-G threshold is 50mmHg.
In some embodiments of the above methods, the one or more components of the third echocardiogram comprise biplane LVEF, resting LVOT-G, and post-valot-G, and wherein the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is greater than the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the third echocardiogram meets any of the following conditions: (1) The biplane LVEF is equal to or above a predetermined biplane LVEF threshold and the resting LVEOT-G is equal to or above a predetermined resting lvet-G threshold, or (2) the biplane LVEF is equal to or above a predetermined biplane LVEF threshold, the resting lvet-G is below a predetermined resting lvet-G threshold and the post-warrior-action lvet-G is equal to or above a predetermined post-warrior-action lvet-G threshold. In some embodiments, the predetermined biplane LVEF threshold is 50%, the predetermined resting LVOT-G threshold is 30mmHg, and the post-warrior action LVOT-G threshold is 50mmHg.
In some embodiments of the above methods, the one or more components of the third echocardiogram comprise biplane LVEF and post-valot-G, and wherein the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the third echocardiogram meets any of the following conditions: (1) The biplane LVEF is equal to or above a predetermined biplane LVEF threshold and below a second predetermined biplane LVEF threshold; or (2) the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold and the post-warrior-action LVOT-G is below a second predetermined post-warrior-action LVOT-G threshold. In some embodiments, the predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the second predetermined post-warrior-action LVOT-G threshold is 30mmHg.
In some embodiments of the above methods, the one or more components of the third echocardiogram comprise a biplane LVEF and post-warrior action lvet-G, and wherein the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is greater than the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the biplane LVEF of the third echocardiogram is above a second predetermined biplane LVEF threshold and the post-warrior action lvet-G of the third echocardiogram is equal to or greater than a second predetermined post-warrior action lvet-G threshold. In some embodiments, the predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the second predetermined post-warrior-action LVOT-G threshold is 30mmHg.
In some embodiments of the above methods, the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg of compound 1, the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg or about 10mg of compound 1, the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg, about 10mg or about 15mg of compound 1, and the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg, about 10mg, about 15mg or about 20mg of compound 1.
In some embodiments of the above methods, the method further comprises measuring one or more components of a third echocardiogram.
In some embodiments of the above methods, the fourth period of time is about 2 weeks.
In some implementations, a method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof comprises: administering a first daily dose of compound 1, or a pharmaceutically acceptable salt thereof, to a patient for a first period of time; and administering a second daily dose of compound 1 or a pharmaceutically acceptable salt thereof to the patient based on a first echocardiogram comprising biplane LVEF and post-warrior action lvet-G of the patient taken after the first period of time, for a second period of time, or terminating administration of compound 1 to the patient, wherein: terminating administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient if the biplane LVEF of the first echocardiogram is below a first predetermined biplane LVEF threshold; the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof if the first echocardiography meets any of the following conditions: (1) The biplane LVEF is equal to or above a first predetermined biplane LVEF threshold and below a second predetermined biplane LVEF threshold; or (2) the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold and the post-warrior-action LVOT-G is below a predetermined post-warrior-action LVOT-G threshold; and if the biplane LVEF of the first echocardiogram is above the second predetermined biplane LVEF threshold and the post-warrior-action LVOT-G of the first echocardiogram is equal to or above the predetermined post-warrior-action LVOT-G threshold, the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is greater than the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof.
In some embodiments of the above methods, the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg of compound 1 and the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg or about 10mg of compound 1.
In some embodiments of the above method, the method further comprises measuring biplane LVEF and post-wag LVOT-G of the first echocardiogram.
In some embodiments of the above methods, the first period of time is about 2 weeks.
In some embodiments of the above methods, the second period of time is about 2 weeks.
In some embodiments of the above methods, administering to the patient a second daily dose of compound 1 or a pharmaceutically acceptable salt thereof for a second period of time, the method further comprising administering to the patient a third daily dose of compound 1 or a pharmaceutically acceptable salt thereof for a third period of time, or terminating administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient based on a second echocardiogram of the patient comprising biplane LVEF and post-warfare agents, LVOT-G, obtained after the second period of time, and the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof, wherein: terminating administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient if the biplane LVEF of the second echocardiogram is below the first predetermined biplane LVEF threshold and the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof; if the biplane LVEF of the second echocardiogram is below the first predetermined biplane LVEF threshold and the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is higher than the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof, the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is lower than the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof; the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof if the second echocardiography meets any of the following conditions: (1) The biplane LVEF is equal to or above a first predetermined biplane LVEF threshold and below a second predetermined biplane LVEF threshold; or (2) the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold and the post-warrior-action LVOT-G is below a predetermined post-warrior-action LVOT-G threshold; and if the biplane LVEF of the second echocardiogram is above the second predetermined biplane LVEF threshold and the post-warrior-action LVOT-G of the second echocardiogram is equal to or above the predetermined post-warrior-action LVOT-G threshold, the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is greater than the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof.
In some embodiments of the above methods, the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg of compound 1, the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg or about 10mg of compound 1, and the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg, about 10mg or about 15mg of compound 1.
In some embodiments of the above method, the method further comprises measuring biplane LVEF and post-wag LVOT-G of the second echocardiogram.
In some embodiments of the above methods, the third period of time is about 2 weeks.
In some embodiments of the above methods, administering to the patient a third daily dose of compound 1 or a pharmaceutically acceptable salt thereof for a third period of time, the method further comprising administering to the patient a fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof for a fourth period of time, or terminating administration of compound 1 to the patient based on a third echocardiogram of the patient comprising biplane LVEF and post-valot-G, taken after the third period of time, and a third dose of compound 1 or a pharmaceutically acceptable salt thereof, wherein: terminating administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient if the biplane LVEF of the third echocardiogram is below the first predetermined biplane LVEF threshold and the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof; if the biplane LVEF of the third echocardiogram is below the first predetermined biplane LVEF threshold and the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is higher than the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof, the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is lower than the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof; the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof if the third echocardiogram satisfies any of the following conditions: (1) The biplane LVEF is equal to or above a first predetermined biplane LVEF threshold and below a second predetermined biplane LVEF threshold; or (2) the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold and the post-warrior-action LVOT-G is below a predetermined post-warrior-action LVOT-G threshold; and if the biplane LVEF of the third echocardiogram is above the second predetermined biplane LVEF threshold and the post-warrior-action LVOT-G of the third echocardiogram is equal to or above the predetermined post-warrior-action LVOT-G threshold, the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is greater than the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg of compound 1, the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg or about 10mg of compound 1, the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg, about 10mg or about 15mg of compound 1, and the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg, about 10mg, about 15mg or about 20mg of compound 1. In some embodiments, the method further comprises measuring biplane LVEF and post-warrior-action lvet-G of the second echocardiogram. In some embodiments, the third period of time is about 2 weeks.
In some embodiments of the above method, the first predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the LVOT-G threshold after the predetermined warrior event is 30mmHg.
In some embodiments of any of the above methods, prior to administration of compound 1 or a pharmaceutically acceptable salt thereof, the patient has (i) resting LVOT-G ≡50mmHg; or (ii) resting LVOT-G is greater than or equal to 30mmHg and after <50mmHg and Wash action LVOT-G is greater than or equal to 50mmHg.
In some embodiments of any of the above methods, the patient has a Left Ventricular Ejection Fraction (LVEF) > 60% prior to administration of compound 1 or a pharmaceutically acceptable salt thereof.
In some embodiments of any of the above methods, during treatment with compound 1, or a pharmaceutically acceptable salt thereof, the patient is not administered ciclopirox.
In some embodiments of any of the above methods, the patient is administered propidium amine during treatment with compound 1 or a pharmaceutically acceptable salt thereof.
In some embodiments of any of the methods above, the patient is not treated with propidium or an anti-arrhythmic drug having negative cardiotonic activity within 4 weeks prior to treatment with compound 1 or a pharmaceutically acceptable salt thereof.
In some embodiments of any of the methods above, the anti-arrhythmic agent is administered to the patient during treatment with compound 1 or a pharmaceutically acceptable salt thereof.
In some embodiments of any of the above methods, the patient is a CYP2D6 hypometabolizer.
In some embodiments of any of the above methods, the patient is fasted when compound 1 or a pharmaceutically acceptable salt thereof is administered.
In some embodiments of any of the above methods, the patient is fed when compound 1 or a pharmaceutically acceptable salt thereof is administered.
In some embodiments of any of the above methods, the method does not include collecting a blood sample from the patient.
In some embodiments of any of the above methods, the method does not include analyzing the blood sample of the patient.
In some embodiments of any of the above methods, the β -blocker is administered to the patient during treatment with compound 1 or a pharmaceutically acceptable salt thereof.
Also provided herein is a method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof.
In some embodiments of any of the methods above, the method results in one or more of the following: improved mitral regurgitation, improved cardiac relaxation, beneficial cardiac remodeling, reverse cardiac remodeling, beneficial cardiac structural remodeling, beneficial cardiac functional remodeling, adverse cardiac remodeling reversal, reduced average Left Ventricular Mass Index (LVMI), improved Left Ventricular (LV) filling pressure, reduced Left Atrial Volume Index (LAVI), reduced assessment of the category of pre-systole motion of the mitral valve leaflets, reduced frequency of eccentric mitral regurgitation, reduced lateral E/E', reduced lateral E/E, reduced Brain Natriuretic Peptide (BNP), and reduced N-terminal pro-hormone of brain natriuretic peptide (NT-proBNP).
In some embodiments, one or more results of the treatment occur within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks of starting the treatment with compound 1 or a pharmaceutically acceptable salt thereof.
In some embodiments of any of the above methods, the Left Ventricular Mass Index (LVMI) of the patient is decreased.
In some embodiments of any of the above methods, the Left Arterial Volume Index (LAVI) of the patient is decreased.
In some embodiments of any of the methods above, e' of the patient is reduced.
In some embodiments of any of the above methods, the lateral E/E' of the patient is reduced.
In some embodiments of any of the methods above, the likelihood of pre-systole movement of the mitral valve leaflet is reduced.
In some embodiments of any of the methods above, the likelihood of mitral regurgitation is reduced.
In some embodiments of any of the above methods, the level of brain natriuretic peptide or the N-terminal pro-hormone of brain natriuretic peptide (NT-proBNP) is reduced in the patient.
In some embodiments of any of the above methods, the level of cardiac troponin I in the patient is decreased.
In some embodiments of any of the methods above, the left ventricular wall stress of the patient is reduced.
In some embodiments of any of the above methods, the patient has reduced myocardial damage.
In some embodiments of any of the above methods, the patient's symptoms of heart failure are reduced, e.g., the method results in a reduction in the NYHA classification of the patient.
In some embodiments of any of the above methods, the method produces a sustained effect for at least 10 weeks, 12 weeks, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years.
In some embodiments of any of the methods above, the second, third, or fourth period of time may be, for example, about 2 weeks, about 10 weeks, about 12 weeks, about 6 months, about 1 year, about 2 years, about 3 years, about 4 years, or about 5 years, or indefinitely. The indefinite period of administration as used herein may indicate: administration until the patient no longer requires treatment; administration until no further therapeutic effect is present; or until no further therapeutic reasons are present.
Drawings
FIG. 1 illustrates an exemplary method for treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient, the method comprising titrating a daily dose of CK-274, or a pharmaceutically acceptable salt thereof.
FIG. 2 shows a schematic view of a phase 1 clinical study of CK-274 (also known as African). The studies included SAD cohorts, MAD cohorts, CYP2D6-PM cohorts, and food effect cohorts. MAD and CYP2D6-PM queues begin when a tolerable pharmacologically active dose (approximately 5% decrease in LVEF) is identified in the SAD queue. The food effect queue begins after the last SAD queue is completed. SAD 75-mg dose cohort meets the criteria for stopping dose escalation, and the remaining patients in this cohort receive 50mg. Subsequently, the final SAD queue was completed using 40mg of African. CYP2D6-PM = cytochrome P450 2D6 weak metaboliser phenotype; d = day; LVEF = left ventricular ejection fraction; MAD = multiple incremental doses; qd = once daily; SAD = single increment dose.
FIG. 3A shows the mean (SE) maximum plasma concentration (C) of African increased in a dose-proportional manner following a single oral administration between 1mg and 50mg max ). Figure 3B shows increased dose-scale exposure (AUC) of african following single oral administration between 1mg and 50mg 24 )(B)。AUC 24 Area under the plasma drug concentration-time curve for=0 to 24 h; c (C) max =maximum plasma concentration; SE = standard error.
Figure 4 shows plasma concentrations over time of multiple doses of alfukantan according to an exemplary clinical trial. Mean (SE) aficonazole plasma concentrations are shown. The data points are offset for clarity. The plasma concentration of alfukantan was increased between the 5-mg dose and 2 higher doses; however, by day 2, there was no difference between the average concentrations of 7.5-mg and 10-mg doses. The clearance rates for the 5-mg and 10-mg doses were similar, and the cumulative ratio for all 3 doses was similar. Only valley measurements are shown for day 7, day 8, day 10, day 11, day 12 and day 13. For the 5-mg and 10-mg cohorts, the dosing period was 14 days and follow-up was 3 days. For the 7.5-mg cohort, dosing was prolonged to 17 days and followed for 3 days, and steady state was confirmed after 10 to 12 days. SE = standard error.
Fig. 5A shows SAD queues for an exemplary african clinical trial and fig. 5B shows MAD queues for an exemplary african clinical trial. Mean (SE) change from baseline for LVEF is shown. The data points are offset for clarity. In the SAD and MAD queues, LVEF was observed to decrease (5% to 15% decrease) over the target range. In the SAD cohort, LVEF generally decreased slightly, and the average maximum decrease in the 50-mg group was 5.8% (1.5 h post-dose). In the MAD cohort, the greatest average decrease in LVEF from baseline occurred in the 10-mg group (average change of 5.0% 1.5h after day 14 dosing). LVEF = left ventricular ejection fraction; MAD = multiple incremental doses; qd, once a day; SAD = single increment dose; SE = standard error.
Fig. 6A shows analysis of SAD cohorts according to an exemplary clinical trial and shows that there is a decreasing trend in LVEF as the plasma concentration of african increases. Figure 6B shows an analysis of the MAD cohort for an exemplary clinical trial and shows minimal inhibition of LVEF by most participants at plasma alfukantan concentrations of 180 ng/ml. CI = confidence interval; LVEF = left ventricular ejection fraction; MAD = multiple incremental doses; SAD = single increment dose.
FIG. 7 shows resting LVOT-G in a treatment and placebo cohort according to an exemplary clinical trial of CK-274 (African).
FIG. 8 shows LVOT-G after Wash action in treatment and placebo cohorts according to an exemplary clinical trial of CK-274 (African).
FIG. 9 shows Left Arterial Volume Index (LAVI) changes in treatment and placebo queues according to an exemplary clinical trial of CK-274.
FIG. 10 shows the change in lateral E/E' ratio of treatment and placebo cohorts according to an exemplary clinical trial of CK-274 (African).
Fig. 11 shows changes in mitral valve characteristics including Mitral Regurgitation (MR), eccentric MR, and preshrinking motion (SAM) according to treatment and placebo arms of an exemplary clinical trial of CK-274 (african).
FIG. 12 shows the change in resting LVOT-G in treatment and placebo cohorts according to an exemplary clinical trial of CK-274 (African).
FIG. 13 shows the change in resting Wash action LVOT-G in treatment and placebo queues according to an exemplary clinical trial of CK-274 (African).
Figure 14 shows the change in LVEF for treatment and placebo cohorts according to an exemplary clinical trial of CK-274 (african).
Figure 15 shows NYHA functional class response of treatment and placebo cohorts according to an exemplary clinical trial of CK-274 (african).
FIG. 16 shows the variation of the average NT-proBNP in treatment and placebo queues according to an exemplary clinical trial of CK-274 (African).
FIG. 17 shows the change in resting LVOT-G in treatment and placebo cohorts according to an exemplary clinical trial of CK-274 (African).
FIG. 18 shows the change in resting Wash action LVOT-G in treatment and placebo queues according to an exemplary clinical trial of CK-274 (African).
Figure 19 shows the change in LVEF for treatment and placebo cohorts according to an exemplary clinical trial of CK-274 (african).
Figure 20 shows the hemodynamic response of treatment and placebo cohorts according to an exemplary clinical trial of CK-274 (african).
Figure 21 shows NYHA functional class response of treatment and placebo cohorts according to an exemplary clinical trial of CK-274 (african).
FIG. 22 shows the variation of the average NT-proBNP in treatment and placebo queues according to an exemplary clinical trial of CK-274 (African).
FIG. 23 shows hs-troponin in treatment and placebo cohorts according to an exemplary clinical trial of CK-274 (African).
Figure 24 shows NYHA functional class response of treatment and placebo cohorts according to an exemplary clinical trial of CK-274 (african).
Figure 25 shows NYHA functional class response of treatment and placebo cohorts according to an exemplary clinical trial of CK-274 (african).
FIG. 26 shows the design of an open marker extension for an exemplary clinical trial of CK-274 (African).
Figure 27 shows patient distribution over time at each dose in an open label extension of an exemplary clinical trial of CK-274 (african).
FIG. 28 shows resting LVOT-G in patients in an open label extension of an exemplary clinical trial of CK-274 (African).
FIG. 29 shows LVOT-G after Wash action in patients in an open marker extension of an exemplary clinical trial of CK-274 (African).
Figure 30 shows the LVEF change in patients in the open label extension of an exemplary clinical trial of CK-274 (african).
Figure 31 shows NYHA functional class distribution of patients at different time points in an open-label extension of an exemplary clinical trial of CK-274 (african).
FIG. 32 shows NYHA functional class responses of patients at different time points in an open label extension of an exemplary clinical trial of CK-274 (African).
FIG. 33 shows the mean NT-proBNP change in patients in an open-label extension of an exemplary clinical trial of CK-274 (African).
Figure 34 shows mean cardiac troponin I changes in patients in the open label extension of an exemplary clinical trial of CK-274 (aficonazole).
Fig. 35 shows the change in KCCQ score from baseline in the open label extension of an exemplary clinical trial of CK-274 (african).
Fig. 36 shows the proportion of patients with varying levels of KCCQ score from baseline in the open label extension of an exemplary clinical trial of CK-274 (africant).
Fig. 37 shows the percent change from baseline of hs-troponin I for treatment and placebo cohorts according to an exemplary clinical trial of CK-274 (afitaconate).
Detailed Description
Described herein are cardiac myosin inhibitors (CK-3773274, also known as CK-274 or aficonazole) and methods of using the cardiac myosin inhibitors to treat hypertrophic cardiomyopathy. The method of treatment may include adjusting the dose based on one or more measured left ventricular outflow tract pressure gradients (LVOT-G), biplane Left Ventricular Ejection Fraction (LVEF) measurements, and/or post-valgus-action LVOT-G measurements, e.g., to increase, decrease, or maintain the dose. These measurements may be made, for example, using echocardiography.
CK-3773274 (Compound 1) is a small molecule cardiac myosin inhibitor, which has the structure shown below.
The chemical name of CK-274 is
(R) -N- (5- (5-ethyl-1, 2, 4-oxadiazol-3-yl) -2, 3-dihydro-1H-inden-1-yl) -1-methyl-1H-pyrazole-4-carboxamide. The small molecule inhibitors may be administered, for example, orally to a patient to treat hypertrophic cardiomyopathy.
CK-274 has been described in WO 2019/144041, which is incorporated herein by reference. CK-274 or a pharmaceutically acceptable salt thereof can be obtained following the methods described herein. The CK-274 used in the disclosed methods may be present as a pharmaceutically acceptable salt, solvate, hydrate, polymorph or combination thereof, and may be formulated into any suitable pharmaceutical formulation. Polymorphs of CK-274 have been described in WO 2021/01807, which is incorporated herein by reference. Formulations of CK-274 are described in WO 2021/01808, which is incorporated herein by reference. CK-274 is designed to reduce hypercrinkage associated with Hypertrophic Cardiomyopathy (HCM). Without being limited by theory, in preclinical models, CK-274 reduces cardiac contractility by binding directly to cardiac troponin at unique and selected sex binding sites, thereby preventing the troponin from entering a productive state. CK-274 reduces the number of active actin-myosin cross-bridges per cardiac cycle and thus reduces myocardial contractility. This mechanism of action may be therapeutically effective in conditions characterized by excessive supercondensation, such as HCM (e.g., obstructive HCM, also known as oHCM).
Definition of the definition
As used in this specification, the following words and phrases are generally intended to have the meanings as set forth below, unless the context in which they are used indicates otherwise.
Reference herein to "about" a value or parameter includes (and sets forth) the value or parameter itself and any value or parameter that is 5% higher or 5% lower than the parameter. For example, a description of "about X" includes descriptions of "X" and "X+/-5%".
"NYHA class" or "NYHA class" refers to the New York heart Association heart failure symptom functional classification (New York Heart Association functional classification of heart failure symptoms). Descriptions of each of NYHA categories I, II, III and IV can be found in "Classes of Heart Failure", american Heart Association (American Heart Association), https:// www.heart.org/en/health-metrics/heart-failure/what-is-heart-failure/classification-of-heart-failure, adapted from: 1) Dolgin M, association NYH, fox AC, gorlin R, levin RI, new york heart society criterion com ittee, "Nomenclature and Criteria for diagnosis of diseases of the heart and great vessels", 9 th edition, boston, MA Lippincott Williams and Wilkins; 3 months 1 1994; and 2) Criteria Committee, new York heart society, inc. diseases of the Heart and Blood vehicles, nomendure and Criteria for diagnosis, 6 th edition, boston, little, brown and Co.1964, page 114. Briefly, NYHA class I indicates that the patient does not have physical activity limitations; common physical activity does not cause excessive fatigue, palpitations, dyspnea (shortness of breath). NYHA class II indicates that the patient has mild physical activity limitations; comfortable at rest; common physical activity can lead to fatigue, palpitations, and dyspnea (shortness of breath). NYHA class III indicates that the patient has significant physical activity limitations; comfortable at rest; less than normal physical activity can lead to fatigue, palpitations, or dyspnea. NYHA class IV indicates that the patient is unable to comfortably perform any physical activity; symptoms of heart failure at rest; if any physical activity is performed, discomfort may increase.
The term "pharmaceutically acceptable salt" refers to salts of any of the compounds herein that are known to be non-toxic and commonly used in the medical literature. In some embodiments, pharmaceutically acceptable salts of the compounds retain the biological effectiveness of the compounds described herein and are not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts can be found in Berge et al, pharmaceutical Salts, J.pharmaceutical Sciences, month 1 1977, 66 (1), 1-19. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts may be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts may 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-hydroxyethanesulfonic acid, p-toluenesulfonic acid, stearic acid and salicylic acid. Inorganic and organic bases may be utilized to form pharmaceutically acceptable base addition salts. Inorganic bases from which salts may be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines; substituted amines, including naturally occurring substituted amines; a cyclic amine; and a basic ion exchange resin. Examples of the organic base include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from the group consisting of ammonium, potassium, sodium, calcium, and magnesium salts.
If the compounds described herein are obtained in the form of acid addition salts, the free base may be obtained by basifying a solution of the acid salt. Conversely, if the compound is a free base, the addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds (see, e.g., berge et al Pharmaceutical Salts, j. Pharmaceutical Sciences,1977, 1 month, 66 (1), 1-19). Those skilled in the art will recognize a variety of synthetic methods that may be used to prepare pharmaceutically acceptable addition salts.
The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. The present invention encompasses its use in pharmaceutical compositions, except insofar as any conventional medium or agent is incompatible with the active ingredient. Supplementary active ingredients may also be incorporated into the pharmaceutical compositions.
The terms "patient", "individual" and "subject" refer to an animal, such as a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows, and humans. In some embodiments, the patient or subject is a human, e.g., a human that has become or is to become a subject of treatment, observation, or experiment. The compounds, compositions and methods described herein are useful for both human therapy and veterinary applications.
The term "therapeutically effective amount" or "effective amount" refers to an amount of a compound disclosed and/or described herein that is sufficient to affect treatment as defined herein when administered to a patient in need of treatment. A therapeutically effective amount of a compound may be an amount sufficient to treat a disease responsive to modulation of cardiac sarcomere. The therapeutically effective amount will vary depending on, for example, the following: the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound, the dosing regimen to be followed, the time of administration, the manner of administration, all of which can be readily determined by one of ordinary skill in the art. The therapeutically effective amount can be determined experimentally, e.g., by determining the blood concentration of a chemical entity or theoretically, by calculating bioavailability.
"Treatment" (and related terms such as "Treatment") include one or more of the following: inhibiting a disease or disorder; slowing or arresting the progression of clinical symptoms of the disease or disorder; and/or alleviating a disease or condition (i.e., causing remission or regression from clinical symptoms). The term encompasses situations where the patient has experienced a disease or disorder, as well as situations where no disease or disorder is currently experienced but is expected to occur. The term encompasses complete and partial reduction or prevention of a disorder or condition, or complete or partial reduction of a clinical symptom of a disease or condition. Thus, the compounds described and/or disclosed herein may prevent exacerbation of an existing disease or condition, help manage a disease or condition, or reduce or eliminate a disease or condition. When used in a prophylactic manner, the compounds disclosed and/or described herein can prevent the development of, or reduce the extent of, a disease or disorder that may develop.
Reference to any dosage amount of a compound described herein or a pharmaceutically acceptable salt thereof (e.g., 5mg, 10mg, 20mg, etc. of compound 1) refers to the amount of the compound that does not contain any salt (i.e., equivalent mass).
Treatment of hypertrophic cardiomyopathy
As further described herein, a therapeutically effective amount of CK-274 can be administered to a patient to treat hypertrophic cardiomyopathy. CK-274 can be administered at constant dosage levels. CK-274 can be administered at titrated dose levels. For example, the dosage of CK-274 can be adjusted based on the patient's response to the drug. That is, the dosage of CK-274 may be periodically increased, decreased, or maintained based on measurements of drug response, such as one or more of left ventricular outflow tract pressure gradient (LVOT-G), biplane Left Ventricular Ejection Fraction (LVEF), and/or LVOT-G measurements after a Watt event.
The results of the latest clinical trial (see example 1) showed that treatment with CK-274 for 10 weeks resulted in a substantial and statistically significant reduction of the mean resting left ventricular outflow tract pressure gradient (LVOT-G) (p=0.0003, p=0.0004, queue 1 and queue 2, respectively) and the mean post-warrior action LVOT-G (p=0.001, p <0.0001, queue 1 and queue 2, respectively) compared to baseline compared to placebo. Most patients treated with CK-274 (78.6% in cohort 1 and 92.9% in cohort 2) reached the therapeutic goal, defined as resting gradient <30mmHg and post-warrior action gradient <50mmHg at week 10 compared to placebo (7.7%). The decrease in LVOT-G occurred within two weeks of beginning treatment with CK-274, peaking within 2 to 6 weeks of end of dose titration, and continuing until 10 weeks of end of treatment. The observed decrease in LVOT-G was dose dependent and as the dose of CK-274 was increased, the patient reached a greater decrease in LVOT-G.
Treatment with CK-274 was well tolerated in clinical trials. In summary, the incidence of adverse events was similar between treatment groups. CK-274 did not cause serious adverse events and CK-274 did not experience treatment disruption. No new cases of atrial tremor were reported by the investigator. In this dose range finding trial, one patient experienced a transient decrease in Left Ventricular Ejection Fraction (LVEF), which required dose adjustment without interruption of the dose. LVEF returned to baseline within two weeks after treatment of both cohorts, confirming the reversibility of the effect using CK-274, similar to that observed in healthy participants in the CK-274 phase 1 study.
CK-274 is administered in a therapeutically effective dose (e.g., a dose sufficient to provide treatment of a disease state). For humans, the daily dose may be between about 1mg and about 50 mg. For example, the daily dose may be about 5mg, about 10mg, about 15mg, about 20mg, or about 30mg, or any amount therebetween. Daily dose is the total amount administered during a day. Daily doses may be, but are not limited to, administered daily, every other day, weekly, every 2 weeks, monthly, or at different intervals. In some embodiments, the daily dose is administered for a period ranging from one day to one lifetime of the subject. In some embodiments, the daily dose is administered once daily. In some embodiments, the daily dose is administered in multiple divided doses, e.g., in 2, 3, or 4 divided doses. In some embodiments, the daily dose is administered in 2 divided doses.
In one example, hypertrophic cardiomyopathy in a patient is treated by administering to the patient CK-274 in a daily dose of about 5mg to about 30 mg. In one example, hypertrophic cardiomyopathy in a patient is treated by administering to the patient a daily dose of CK-274 of about 5 mg. In one example, hypertrophic cardiomyopathy in a patient is treated by administering to the patient CK-274 in a daily dose of about 10 mg. In one example, hypertrophic cardiomyopathy in a patient is treated by administering to the patient CK-274 in a daily dose of about 15 mg. In one example, hypertrophic cardiomyopathy in a patient is treated by administering to the patient a daily dose of CK-274 of about 20 mg. In one example, hypertrophic cardiomyopathy in a patient is treated by administering to the patient CK-274 in a daily dose of about 25 mg. In one example, hypertrophic cardiomyopathy in a patient is treated by administering to the patient a daily dose of CK-274 of about 30 mg. In some embodiments of any of the foregoing, the treatment of hypertrophic cardiomyopathy further comprises administering propidium to the patient.
In some embodiments, methods for treating hypertrophic cardiomyopathy are provided, comprising administering CK-274, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising CK-274, or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent, wherein the second therapeutic agent is propidium. In some embodiments, the hypertrophic cardiomyopathy is obstructive hypertrophic cardiomyopathy and/or treatment refractory hypertrophic cardiomyopathy. In some embodiments, there is provided a method of treating obstructive hypertrophic cardiomyopathy, treating refractory hypertrophic cardiomyopathy, or treating refractory obstructive hypertrophic cardiomyopathy, comprising administering CK-274, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising CK-274, or a combination of a pharmaceutically acceptable salt thereof, and a second therapeutic agent, wherein the second therapeutic agent is propidium. In some embodiments, the combination of CK-274 or a pharmaceutically acceptable salt thereof and propidium bromide comprises simultaneous administration of CK-274 or a pharmaceutically acceptable salt thereof and propidium bromide. In some embodiments, the combination of CK-274 and propidium comprises sequentially administering CK-274 or a pharmaceutically acceptable salt thereof and propidium. In some embodiments, the combination of CK-274 or a pharmaceutically acceptable salt thereof and propidium amine comprises administering CK-274 or a pharmaceutically acceptable salt thereof to a patient who has been treated with propidium amine.
During the course of treatment of hypertrophic cardiomyopathy, the dosage of CK-274 administered to the patient can be titrated, for example, by increasing, decreasing or maintaining the dosage. Titration may be performed once during treatment or may be repeated at intervals. For example, in some implementations, a dose of CK-274 is titrated two or more times (e.g., 3, 4, 5, or more times) during the course of treatment. In some embodiments, the new daily dose is administered to the patient in a constant amount for about 1 week to about 8 weeks (or about 2 weeks to about 6 weeks, or about 4 weeks) prior to titration of the daily dose. In some embodiments, the new daily dose amount is administered to the patient in a constant amount for about 2 weeks prior to titration. For example, a first daily dose may be administered to a patient for about 2 weeks prior to a first titration, wherein the daily dose amount is increased, decreased, or maintained. A second titration may then be performed about 2 weeks after the first titration. Titration of the dose allows the dose to be personalized to the patient's response to the drug, thereby maximizing the potential therapeutic effect of the patient.
Titration of the dose may be based on one or more of left ventricular outflow tract pressure gradient (LVOT-G), biplane Left Ventricular Ejection Fraction (LVEF), and/or LVOT-G after a wag action measured in the patient. The one or more measurements may be determined, for example, using echocardiography. Echocardiography is performed after administration of a daily dose (e.g., from about 1 hour to about 3 hours after administration of the dose). In some embodiments, echocardiography is performed about 2 hours after administration of the daily dose.
In some embodiments, an initial daily dose of about 5mg, about 10mg, about 15mg, about 20mg, or about 30mg CK-274, or any amount therebetween, is administered to a patient. Resting LVOT-G, biplane LVEF and/or post-warrior LVOT-G is measured by echocardiography after a period of time (e.g., about 2 weeks), such as after administration (e.g., about 1-3 hours or about 2 hours after administration). The daily dose is increased if the resting LVOT-G is equal to or above a predetermined resting LVOT-G threshold (e.g., about 25mmHg or greater, about 30mmHg or greater, or about 35mmHg or greater) and the biplane LVEF is equal to or above a predetermined biplane LVEF threshold (e.g., about 40% or greater, about 45% or greater, about 50% or greater, about 55% or greater, or about 60% or greater). Alternatively, if the resting LVOT-G is not equal to or above the predetermined resting LVOT-G threshold, the dose may still be increased if the post-wag LVOT-G is equal to or above the predetermined post-wag LVOT-G threshold (e.g., about 40mmHg or greater, about 45mmHg or greater, about 50mmHg or greater, about 55mmHg or greater, or about 60mmHg or greater) and the biplane LVEF is equal to or above the predetermined biplane LVEF threshold. The dose may be maintained if the biplane LVEF is equal to or above the predetermined threshold, but the resting LVOT-G is below the resting LVOT-G threshold and the post-warrior-action LVOT-G is below the post-warrior-action LVOT-G threshold. If the biplane LVEF is below the biplane LVEF threshold, the dose may be reduced or terminated. For example, if the biplane LVEF is below the biplane LVEF threshold and the current dose is not the lowest (e.g., first) dose, the dose may be reduced. The dose may be terminated if the biplane LVEF is below the biplane LVEF threshold and the current dose is the lowest (e.g., first) dose. In some embodiments, the resting LVOT-G threshold is about 30mmHg, the biplane LVEF threshold is about 50%, and the post-warrior-action LVOT-G threshold is about 50mmHg. In some embodiments, titration of the dose of CK-274 includes maintaining the dose at the current dose; increasing the dose by about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, or about 10mg, or any amount therebetween; reducing the dose by about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, or about 10mg, or any amount therebetween; or terminate administration. In some embodiments, titration of the dose includes maintaining the dose at the current dose; increasing the dose by about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, or about 10mg, or any amount therebetween; or by reducing the dose by about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, or about 10mg, or any amount therebetween.
After a period of time (e.g., about 2 weeks) of the first titration dose is administered to the patient, the dose may be titrated (i.e., increased, decreased, or maintained) again based on the patient's resting LVOT-G, biplane LVEF, and/or post-warburg LVOT-G, e.g., using the same threshold parameters as discussed above. Exemplary dose titration schedules include: the first titration dose is administered for about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, about 10 weeks, or about 12 weeks or any amount of time therebetween, followed by dose titration based on the patient's resting LVOT-G, biplane LVEF, and/or post-warburg LVOT-G, e.g., using the same threshold parameters as discussed above. Other repetitions of administration and dose titration may be performed accordingly.
In some embodiments, the method may reduce the resting left ventricular outflow tract pressure gradient (LVOT-G) of the patient to less than a particular value. The reduction of resting LVOT-G to less than a particular value may occur within 10 weeks of starting treatment with compound 1 or a pharmaceutically acceptable salt thereof. The reduction of resting LVOT-G to less than a particular value may occur within 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 9 weeks, or 10 weeks of starting treatment with compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the decrease in resting LVOT-G persists for at least 10 weeks of treatment. In some embodiments, the decrease in resting LVOT-G occurs within 2 to 6 weeks of the end of dose titration. In some embodiments, the decrease in resting LVOT-G peaks within 2 to 6 weeks of the end of dose titration. In some embodiments, the specific resting LVOT-G value is: 60mmHg, 59mmHg, 58mmHg, 57mmHg, 56mmHg, 55mmHg, 54mmHg, 53mmHg, 52mmHg, 51mmHg, 50mmHg, 49mmHg, 48mmHg, 47mmHg, 46mmHg, 45mmHg, 44mmHg, 43mmHg, 42mmHg, 41mmHg, 40mmHg, 39mmHg, 38mmHg, 37mmHg, 36mmHg, 35mmHg, 34mmHg, 33mmHg, 32mmHg, 31mmHg, 30mmHg, 29mmHg, 28mmHg, 27mmHg, 26mmHg or 25mmHg.
In some embodiments, the method results in a decrease in left ventricular outflow tract pressure gradient (LVOT-G) to less than a particular value following a waffle action in the patient. The decrease in LVOT-G to less than a specified value following warrior action may occur within 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 9 weeks, or 10 weeks of starting treatment with compound 1 or a pharmaceutically acceptable salt thereof. The decrease in LVOT-G following warrior action may last for at least 10 weeks of treatment. In some embodiments, the decrease in LVOT-G after a warrior event occurs within 2 to 6 weeks of the end of dose titration. In some embodiments, the decrease in LVOT-G peaks within 2 to 6 weeks of end of dose titration after the warrior event. In some embodiments, the LVOT-G value after a particular warfare action is: 70mmHg, 69mmHg, 68mmHg, 67mmHg, 66mmHg, 65mmHg, 64mmHg, 63mmHg, 62mmHg, 61mmHg, 60mmHg, 59mmHg, 58mmHg, 57mmHg, 56mmHg, 55mmHg, 54mmHg, 53mmHg, 52mmHg, 51mmHg, 50mmHg, 49mmHg, 48mmHg, 47mmHg, 46mmHg, 45mmHg, 44mmHg, 43mmHg, 42mmHg, 41mmHg, 40mmHg, 39mmHg, 38mmHg, 37mmHg, 36mmHg, 35mmHg, 34mmHg, 33mmHg, 32mmHg, 31mmHg or 30mmHg.
Provided herein are methods of reducing the resting left ventricular outflow tract pressure gradient (LVOT-G) to less than a particular value in a patient suffering from obstructive hypertrophic cardiomyopathy (oHCM), comprising administering to the patient a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The reduction of resting LVOT-G to less than a particular value may occur within 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 9 weeks, or 10 weeks of starting treatment with compound 1 or a pharmaceutically acceptable salt thereof. The reduction of resting LVOT-G to less than a particular value may occur within two weeks of starting treatment with compound 1 or a pharmaceutically acceptable salt thereof. In some implementations, the decrease in resting LVOT-G persists for at least 10 weeks of treatment. In some embodiments, the decrease in resting LVOT-G occurs within 2 to 6 weeks of the end of dose titration. In some embodiments, the decrease in resting LVOT-G peaks within 2 to 6 weeks of the end of dose titration. In some embodiments, the specific resting LVOT-G value is: 60mmHg, 59mmHg, 58mmHg, 57mmHg, 56mmHg, 55mmHg, 54mmHg, 53mmHg, 52mmHg, 51mmHg, 50mmHg, 49mmHg, 48mmHg, 47mmHg, 46mmHg, 45mmHg, 44mmHg, 43mmHg, 42mmHg, 41mmHg, 40mmHg, 39mmHg, 38mmHg, 37mmHg, 36mmHg, 35mmHg, 34mmHg, 33mmHg, 32mmHg, 31mmHg, 30mmHg, 29mmHg, 28mmHg, 27mmHg, 26mmHg or 25mmHg.
Provided herein are methods of reducing left ventricular outflow tract pressure gradient (LVOT-G) to less than a particular value following a warfare event in a patient suffering from obstructive hypertrophic cardiomyopathy (oHCM), comprising administering to the patient a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The decrease in LVOT-G to less than a specified value following warrior action may occur within 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 9 weeks, or 10 weeks of starting treatment with compound 1 or a pharmaceutically acceptable salt thereof. The decrease in LVOT-G following warrior action may last for at least 10 weeks of treatment. In some embodiments, the decrease in LVOT-G after a warrior event occurs within 2 to 6 weeks of the end of dose titration. In some embodiments, the decrease in LVOT-G peaks within 2 to 6 weeks of end of dose titration after the warrior event. In some embodiments, the LVOT-G value after a particular warfare action is: 70mmHg, 69mmHg, 68mmHg, 67mmHg, 66mmHg, 65mmHg, 64mmHg, 63mmHg, 62mmHg, 61mmHg, 60mmHg, 59mmHg, 58mmHg, 57mmHg, 56mmHg, 55mmHg, 54mmHg, 53mmHg, 52mmHg, 51mmHg, 50mmHg, 49mmHg, 48mmHg, 47mmHg, 46mmHg, 45mmHg, 44mmHg, 43mmHg, 42mmHg, 41mmHg, 40mmHg, 39mmHg, 38mmHg, 37mmHg, 36mmHg, 35mmHg, 34mmHg, 33mmHg, 32mmHg, 31mmHg or 30mmHg.
Provided herein are methods of reducing the resting left ventricular outflow tract pressure gradient (LVOT-G) to less than a particular value and reducing the left ventricular outflow tract pressure gradient (LVOT-G) to less than a particular value after a warburg event in a patient suffering from obstructive hypertrophic cardiomyopathy (oHCM), the method comprising administering to the patient a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The reduction of resting LVOT-G to less than a particular value and the reduction of LVOT-G to less than a particular value following a warrior action may occur within 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 9 weeks, or 10 weeks of starting treatment with compound 1 or a pharmaceutically acceptable salt thereof. The reduction of resting LVOT-G to less than a specified value and the reduction of LVOT-G to less than a specified value following a warrior action may occur within two weeks of starting treatment with compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the decrease in resting LVOT-G and the decrease in LVOT-G following warrior action persist for at least 10 weeks of treatment. In some embodiments, both the decrease in resting LVOT-G and the decrease in LVOT-G following a warrior event may occur within 2 to 6 weeks of the end of dose titration. In some embodiments, both the decrease in resting LVOT-G and the decrease in LVOT-G following a warrior event peak within 2 to 6 weeks of the end of dose titration. In some embodiments, the specific resting LVOT-G value is: 60mmHg, 59mmHg, 58mmHg, 57mmHg, 56mmHg, 55mmHg, 54mmHg, 53mmHg, 52mmHg, 51mmHg, 50mmHg, 49mmHg, 48mmHg, 47mmHg, 46mmHg, 45mmHg, 44mmHg, 43mmHg, 42mmHg, 41mmHg, 40mmHg, 39mmHg, 38mmHg, 37mmHg, 36mmHg, 35mmHg, 34mmHg, 33mmHg, 32mmHg, 31mmHg, 30mmHg, 29mmHg, 28mmHg, 27mmHg, 26mmHg or 25mmHg. In some embodiments, the LVOT-G value after a particular warfare action is: 70mmHg, 69mmHg, 68mmHg, 67mmHg, 66mmHg, 65mmHg, 64mmHg, 63mmHg, 62mmHg, 61mmHg, 60mmHg, 59mmHg, 58mmHg, 57mmHg, 56mmHg, 55mmHg, 54mmHg, 53mmHg, 52mmHg, 51mmHg, 50mmHg, 49mmHg, 48mmHg, 47mmHg, 46mmHg, 45mmHg, 44mmHg, 43mmHg, 42mmHg, 41mmHg, 40mmHg, 39mmHg, 38mmHg, 37mmHg, 36mmHg, 35mmHg, 34mmHg, 33mmHg, 32mmHg, 31mmHg or 30mmHg. In some embodiments, the specified resting LVOT-G value is 30mmHg and the LVOT-G value after a specified Watt action is 50mmHg.
Provided herein are methods of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient eligible for diaphragmatic therapy (SRT), comprising administering to the patient a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. Also provided herein is a method of treating oHCM in a patient in need of SRT, the method comprising administering to the patient a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof, wherein the method does not require SRT in the patient. In some embodiments, the SRT is a myotomy. In some embodiments, the SRT is an alcohol septal ablation.
Further provided herein is a method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient having symptoms of heart failure, the method comprising administering to the patient a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof, wherein the method results in a reduction in symptoms of heart failure as assessed by NYHA classification. In some of the foregoing embodiments, the method increases heart failure symptoms in the patient by at least one NYHA class, e.g., by one or two NYHA classes. In some of the foregoing embodiments, the method converts the patient from NYHA class III to class II or class I. In some of the foregoing embodiments, the method converts the patient from NYHA class III to class II. In some of the foregoing embodiments, the method converts the patient from NYHA class III to class I. In some of the foregoing embodiments, the method converts the patient from NYHA class II to class I. In some of the foregoing embodiments, the reduction in symptoms of heart failure occurs within 10 weeks of starting treatment with compound 1 or a pharmaceutically acceptable salt thereof.
In some embodiments, titration of daily doses of CK-274 or a pharmaceutically acceptable salt thereof is based on results of echocardiography including biplane LVEF and LVOT-G after Wash action. For example, the daily dose of CK-274 or a pharmaceutically acceptable salt thereof may be increased, maintained or decreased (or terminated, e.g., if the subject has received the lowest (e.g., first) daily dose) based on the results of biplane LVEF and/or LVOT-G following a waffle action. For example, based on the results of biplane LVEF and/or LVOT-G following a waffle maneuver, the daily dose of CK-274 or a pharmaceutically acceptable salt thereof can be increased, maintained, or decreased (or terminated, e.g., if the subject has received the first daily dose). The first daily dose of CK-274, or a pharmaceutically acceptable salt thereof, is administered to the patient for a first period of time (e.g., about two weeks). The second daily dose of the subject, or termination of administration of CK-274 or a pharmaceutically acceptable salt thereof, is then selected based on the biplane LVEF and post-valot-G of the patient obtained after the first period of time. If the biplane LVEF of the echocardiogram is below a first predetermined biplane LVEF threshold (e.g., 50%), administration of CK-274 or a pharmaceutically acceptable salt thereof may be terminated. If the biplane LVEF of the echocardiogram is below a first predetermined biplane LVEF threshold (e.g., 50%) and the patient has received a minimum (e.g., first) daily dose, then administration of CK-274 or a pharmaceutically acceptable salt thereof may be terminated. If the biplane LVEF of the echocardiogram is below a first predetermined biplane LVEF threshold (e.g., 50%) and the patient has not received the lowest daily dose, the daily dose may be reduced (i.e., the second daily dose is less than the first daily dose). If the biplane LVEF is equal to or above the first predetermined biplane threshold and below the second predetermined biplane LVEF threshold (e.g., 55%), or if the biplane LVVEF is equal to or above the second predetermined biplane LVEF threshold and the post-warrior-action LVOT-G is below the post-predetermined warrior-action LVOT-G threshold (e.g., 30 mmHg), then the daily dose is maintained (i.e., the second daily dose is equal to the first daily dose). If the biplane LVEF is equal to or above the second predetermined biplane threshold and the post-warrior-action LVOT-G is above the predetermined post-warrior-action LVOT-G threshold, then the daily dose may be increased (i.e., the second daily dose is greater than the first daily dose).
A second daily dose may be administered to the patient for a second period of time (e.g., about two weeks) prior to re-titration based on results of a second echocardiogram of the patient including biplane LVEF and LVOT-G after a waffle action taken after the second period of time. For example, a third daily dose or termination of administration, may be selected based on the second echocardiogram and the second daily dose. Administration may be terminated if the second daily dose is equal to (or lower than) the first daily dose and the biplane LVEF of the second echocardiogram is lower than the first predetermined biplane LVEF threshold. If the second daily dose is higher than the first daily dose and the biplane LVEF of the second echocardiogram is lower than the first predetermined biplane LVEF threshold, the third daily dose may be reduced relative to the second daily dose, e.g., to the amount of the first daily dose. Administration may be terminated if the second daily dose is equal to (or lower than) the first daily dose (e.g., if the second daily dose is the lowest dose) and the biplane LVEF of the second echocardiogram is lower than the first predetermined biplane LVEF threshold. If the second daily dose is above the lowest (e.g., first) daily dose and the biplane LVEF of the second echocardiogram is below the first predetermined biplane LVEF threshold, the third daily dose may be reduced relative to the second daily dose, e.g., to the amount of the first daily dose. The daily dose may be maintained (i.e., the third daily dose is equal to the second daily dose) if the biplane LVEF is equal to or above the first predetermined biplane LVEF threshold and below the second predetermined biplane LVEF threshold, or if the biplane LVEF is equal to or above the second predetermined biplane LVEF threshold and the post-warrior-action LVOT-G is below the predetermined post-warrior-action LVOT-G threshold. If the biplane LVEF of the second echocardiogram is above a second predetermined biplane LVEF threshold and the post-warrior-action LVOT-G of the second echocardiogram is equal to or above the predetermined post-warrior-action LVOT-G threshold, a third daily dose may be increased relative to the second daily dose. A third daily dose is then administered to the patient for a third period of time (e.g., two weeks).
Titration of the daily dose may be repeated for additional rounds, if desired, to select the fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof or to terminate administration. For example, a third echocardiogram of the patient comprising biplane LVEF and post-warrior action LVOT-G may be acquired after a third period of time, and a fourth daily dose of CK-274 or a pharmaceutically acceptable salt thereof may be selected based on the third echocardiogram and 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 equal to (or below) the first daily dose, administration of CK-274 or a pharmaceutically acceptable salt thereof may be terminated. The fourth daily dose may be reduced relative to the third daily dose if the third daily dose is higher than the first daily dose and the biplane LVEF of the third echocardiogram is lower than the first predetermined biplane LVEF threshold. If the biplane LVEF of the third echocardiogram is below the first predetermined biplane LVEF threshold and the third daily dose is equal to (or lower than) the first daily dose (e.g., if the third daily dose is the lowest dose), administration of CK-274 or a pharmaceutically acceptable salt thereof may be terminated. The fourth daily dose may be reduced relative to the third daily dose if the third daily dose is above 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 may be equal to the third daily dose if the biplane LVEF of the third echocardiogram is equal to or above the predetermined biplane LVEF threshold and below the second predetermined biplane LVEF threshold, or the biplane LVEF of the third echocardiogram is equal to or above the second predetermined biplane LVEF threshold and the post-warrior-action lvet-G of the third echocardiogram is below the predetermined post-warrior-action lvet-G threshold. The fourth daily dose may be increased relative to the third daily dose if the biplane LVEF of the third echocardiogram is above the second predetermined biplane LVEF threshold and the post-warrior-action LVOT-G of the third echocardiogram is equal to or above the predetermined post-warrior-action LVOT-G threshold.
FIG. 1 illustrates an exemplary method for treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient, the method comprising titrating a daily dose of CK-274, or a pharmaceutically acceptable salt thereof. The exemplary method shown in fig. 1 provides four daily dosage levels, with the first daily dosage level being the lowest daily dosage level, but can be readily modified to include additional or fewer dosage levels. The exemplary method shown in fig. 1 may be further modified such that the first daily dosage level is not the lowest daily dosage level. At 102, CK-274, or a pharmaceutically acceptable salt thereof, is administered to the patient at a first daily dosage level (e.g., about 5 mg). After a first period of time, at 104, the daily dosage level is increased or maintained, or administration is terminated. The selection may be based on a first echocardiogram acquired for the patient after a first period of time. If the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold (e.g., 50%), administration 106 may optionally be terminated, wherein no further dose of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient. The first daily dose level (e.g., about 5 mg) may be optionally maintained when the first echocardiography meets any of the following conditions: (1) The biplane LVEF is equal to or above a predetermined biplane LVEF threshold (e.g., 50%) and below a second predetermined biplane LVEF threshold (e.g., 55%); or (2) the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold (e.g., 55%) and the post-warrior LVOT-G of the first echocardiogram is below a predetermined post-warrior LVOT-G threshold (e.g., 30 mmHg). Alternatively, the first daily dose level (e.g., about 5 mg) may be selected to be maintained when the biplane LVEF of the first echocardiogram is equal to or above a predetermined biplane LVEF threshold (e.g., 50%), the resting LVOT-G of the first echocardiogram is below a predetermined resting LVOT-G threshold (e.g., 30 mmHg), and the post-warrior-action LVOT-G of the first echocardiogram is below a predetermined post-warrior-action LVOT-G threshold (e.g., 50 mmHg). If maintenance is selected, then the patient is administered a first daily dose level of CK-274, or a pharmaceutically acceptable salt thereof, for a second period of time at 102, and optionally, the daily dose can be re-titrated at 104 after the second period of time. The daily dose level may be increased to a second daily dose level (e.g., 10 mg) when the first echocardiography meets any of the following conditions: (1) The biplane LVEF is equal to or above a predetermined biplane LVEF threshold (e.g., 50%) and below a second predetermined biplane LVEF threshold (e.g., 55%); or (2) the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold (e.g., 55%) and the post-wag LVOT-G of the first echocardiogram is below a second predetermined post-wag LVOT-G threshold (e.g., 30 mmHg). Alternatively, the daily dose level may be increased to a second daily dose level (e.g., 10 mg) when the first echocardiography meets any of the following conditions: (1) The biplane LVEF is equal to or above a predetermined biplane LVEF threshold (e.g., 50%) and the resting LVOT-G is equal to or above a predetermined resting LVOT-G threshold (e.g., 30 mmHg), or (2) the biplane LVEF is equal to or above a predetermined biplane LVEF threshold (e.g., 50%), the resting LVOT-G is below a predetermined resting LVOT-G threshold (e.g., 30 mmHg) and the post-warrior-action LVOT-G is equal to or above a predetermined post-warrior-action LVOT-G threshold (e.g., 50 mmHg). If an increase in the daily dosage level is selected, then CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient at 108 at a second daily dosage level for a second period of time.
If a second daily dose level of CK-274, or a pharmaceutically acceptable salt thereof (e.g., 10 mg), is administered to the patient at 108, the daily dose may be re-titrated (i.e., the daily dose is selected to be increased, decreased, or maintained) based on the echocardiogram at 110. If the biplane LVEF of the echocardiogram is below a predetermined biplane LVEF threshold (e.g., 50%), the daily dose may be reduced to a first daily dose level (e.g., 10mg to 5 mg). If the daily dose is reduced to the first daily dose level, the first daily dose level is administered to the patient at 102. The second daily dose level (e.g., about 10 mg) may be optionally maintained when the echocardiography meets any of the following conditions: (1) The biplane LVEF is equal to or above a predetermined biplane LVEF threshold (e.g., 50%) and below a second predetermined biplane LVEF threshold (e.g., 55%); or (2) the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold (e.g., 55%) and the post-wag LVOT-G of the echocardiogram is below a predetermined post-wag LVOT-G threshold (e.g., 30 mmHg). Alternatively, the second daily dose level (e.g., about 10 mg) may be selected to be maintained when the biplane LVEF of the echocardiogram is equal to or above a predetermined biplane LVEF threshold (e.g., 50%), the resting LVOT-G of the echocardiogram is below a predetermined resting LVOT-G threshold (e.g., 30 mmHg), and the post-warrior-action LVOT-G of the second echocardiogram is below a predetermined post-warrior-action LVOT-G threshold (e.g., 50 mmHg). If maintenance is selected, then a second daily dose level of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient at 108 for another period of time, and optionally, the daily dose may be re-titrated at 110 after the period of time. The daily dose level may be increased to a third daily dose level (e.g., 15 mg) when the echocardiography meets any of the following conditions: (1) The biplane LVEF is equal to or above a predetermined biplane LVEF threshold (e.g., 50%) and below a second predetermined biplane LVEF threshold (e.g., 55%); or (2) the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold (e.g., 55%) and the post-wag LVOT-G of the echocardiogram is below a second predetermined post-wag LVOT-G threshold (e.g., 30 mmHg). Alternatively, the daily dose level may be increased to a third daily dose level (e.g., 15 mg) when the echocardiography meets any of the following conditions: (1) The biplane LVEF is equal to or above a predetermined biplane LVEF threshold (e.g., 50%) and the resting LVOT-G is equal to or above a predetermined resting LVOT-G threshold (e.g., 30 mmHg), or (2) the biplane LVEF is equal to or above a predetermined biplane LVEF threshold (e.g., 50%), the resting LVOT-G is below a predetermined resting LVOT-G threshold (e.g., 30 mmHg) and the post-warrior-action LVOT-G is equal to or above a predetermined post-warrior-action LVOT-G threshold (e.g., 50 mmHg). If an increase in the daily dosage level is selected, then CK-274, or a pharmaceutically acceptable salt thereof, is administered to the patient at 112 at a second daily dosage level for the period of time.
If a third daily dose level of CK-274, or a pharmaceutically acceptable salt thereof (e.g., 10 mg), is administered to the patient at 112, the daily dose may be re-titrated (i.e., the daily dose is selected to be increased, decreased, or maintained) based on the echocardiogram at 114. If the biplane LVEF of the echocardiogram is below a predetermined biplane LVEF threshold (e.g., 50%), the daily dose may be reduced to a second daily dose level (e.g., 15mg to 10 mg). If the daily dose is reduced to a second daily dose level, a second daily dose level is administered to the patient at 108. The third daily dose level (e.g., about 15 mg) may be optionally maintained when the echocardiography meets any of the following conditions: (1) The biplane LVEF is equal to or above a predetermined biplane LVEF threshold (e.g., 50%) and below a second predetermined biplane LVEF threshold (e.g., 55%); or (2) the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold (e.g., 55%) and the post-wag LVOT-G of the echocardiogram is below a predetermined post-wag LVOT-G threshold (e.g., 30 mmHg). Alternatively, the third daily dose level (e.g., about 15 mg) may be selected to be maintained when the biplane LVEF of the echocardiogram is equal to or above a predetermined biplane LVEF threshold (e.g., 50%), the resting LVOT-G of the echocardiogram is below a predetermined resting LVOT-G threshold (e.g., 30 mmHg), and the post-warrior-action LVOT-G of the echocardiogram is below a predetermined post-warrior-action LVOT-G threshold (e.g., 50 mmHg). If maintenance is selected, then a third daily dose level of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient at 112 for another period of time, and optionally, the daily dose may be re-titrated at 114 after the period of time. The daily dose level may be increased to a fourth daily dose level (e.g., 20 mg) when the echocardiography meets any of the following conditions: (1) The biplane LVEF is equal to or above a predetermined biplane LVEF threshold (e.g., 50%) and below a second predetermined biplane LVEF threshold (e.g., 55%); or (2) the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold (e.g., 55%) and the post-wag LVOT-G of the echocardiogram is below a second predetermined post-wag LVOT-G threshold (e.g., 30 mmHg). Alternatively, the daily dose level may be increased to a fourth daily dose level (e.g., 20 mg) when the echocardiography meets any of the following conditions: (1) The biplane LVEF is equal to or above a predetermined biplane LVEF threshold (e.g., 50%) and the resting LVOT-G is equal to or above a predetermined resting LVOT-G threshold (e.g., 30 mmHg), or (2) the biplane LVEF is equal to or above a predetermined biplane LVEF threshold (e.g., 50%), the resting LVOT-G is below a predetermined resting LVOT-G threshold (e.g., 30 mmHg) and the post-warrior-action LVOT-G is equal to or above a predetermined post-warrior-action LVOT-G threshold (e.g., 50 mmHg). If an increase in the daily dosage level is selected, CK-274 or a pharmaceutically acceptable salt thereof at a fourth daily dosage level is administered to the patient at 116 for a second period of time.
In the exemplary method shown in fig. 1, the first daily dose level is the minimum dose and thus cannot be reduced further. However, in other embodiments, if the biplane LVEF of the echocardiogram is below a predetermined biplane LVEF threshold (e.g., 50%), the first daily dose level may not be the minimum dose and, thus, may be reduced to a lower dose level (e.g., 10mg to 5 mg).
In the exemplary method shown in fig. 1, the fourth daily dose level is the maximum dose and thus cannot be increased further. However, in other embodiments, other dosage levels may be obtained and the daily dosage may be further increased at 118. The method shown in fig. 1, at 118, selects to maintain the fourth daily dosage level or to reduce the daily dosage level based on the echocardiogram. If the biplane LVEF of the echocardiogram is below the predetermined biplane LVEF threshold (e.g., 50%), the daily dose may be reduced to a third daily dose level (e.g., 20mg to 15 mg). If the daily dose is reduced to the third daily dose level, a second daily dose level is administered to the patient at 112. The third daily dose level (e.g., about 20 mg) may be optionally maintained when the echocardiography meets any of the following conditions: (1) The biplane LVEF is equal to or above a predetermined biplane LVEF threshold (e.g., 50%) and below a second predetermined biplane LVEF threshold (e.g., 55%); or (2) the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold (e.g., 55%) and the post-wag LVOT-G of the echocardiogram is below a predetermined post-wag LVOT-G threshold (e.g., 30 mmHg). Alternatively, the third daily dose level (e.g., about 15 mg) may be selected to be maintained when the biplane LVEF of the echocardiogram is equal to or above a predetermined biplane LVEF threshold (e.g., 50%), the resting LVOT-G of the echocardiogram is below a predetermined resting LVOT-G threshold (e.g., 30 mmHg), and the post-warrior-action LVOT-G of the echocardiogram is below a predetermined post-warrior-action LVOT-G threshold (e.g., 50 mmHg). If maintenance is selected, then a third daily dose level of CK-274 or a pharmaceutically acceptable salt thereof is administered to the patient at 116 for another period of time, and optionally, the daily dose may be re-titrated at 118 after said period of time.
Exemplary daily dose increases include from about 5mg to about 10mg CK-274, from about 10mg to about 15mg CK-274, from about 10mg to about 20mg CK-274, or from about 20mg to about 30mg. Other dose increases are readily contemplated, such as an increase of about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, or about 10mg, or any amount therebetween, given an initial daily dose. Exemplary daily dose reductions include a reduction from about 30mg to about 20mg, a reduction from about 20mg to about 10mg, a reduction from about 15mg to about 10mg, or a reduction from about 10mg to about 5mg. Other dose reductions may be readily envisioned, such as a reduction of about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, or about 10mg, or any amount therebetween, given an initial daily dose.
Exemplary embodiments of the methods described herein include administering a first daily dose (e.g., between about 1mg and about 20mg (e.g., 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 15mg, or 20 mg) or any amount of the first daily dose therebetween) of CK-274 or a pharmaceutically acceptable salt thereof for a first period of time (e.g., about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 12 weeks, or any length of time therebetween), followed by maintaining the daily dose based on the resting LVOT-G, biplane LVEF, and/or the valv event of the patient, decreasing the daily dose (e.g., decreasing the daily dose by about 1mg to about 10mg, e.g., decreasing the daily dose by 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, or 10mg, or any amount therebetween), increasing the daily dose (e.g., increasing the daily dose by about 1mg to about 2mg, 3mg, 4mg, 5mg, 6mg, 8mg, or any amount therebetween), ending the daily dose (e.g., 1mg, 2mg, 8mg, 9mg, or any amount therebetween), or any length of time period of time therebetween. Another exemplary embodiment of the methods described herein comprises administering a first daily dose of CK-274, or a pharmaceutically acceptable salt thereof, for about two weeks, followed by maintenance of the daily dose, reduction of the daily dose by about 5mg, increase of the daily dose by about 5mg, or termination of administration to achieve a second daily dose based on resting LVOT-G, biplane LVEF, and/or post-warburg actions of the patient. Another exemplary embodiment of the methods described herein comprises administering a first daily dose of CK-274, or a pharmaceutically acceptable salt thereof, for about three weeks, followed by maintenance of the daily dose, reduction of the daily dose by about 5mg, increase of the daily dose by about 5mg, or termination of administration to achieve a second daily dose based on resting LVOT-G, biplane LVEF, and/or post-warburg actions of the patient. Another exemplary embodiment of the methods described herein comprises administering a first daily dose of CK-274, or a pharmaceutically acceptable salt thereof, for about two weeks, followed by maintenance of the daily dose, reduction of the daily dose by about 10mg, increase of the daily dose by about 10mg, or termination of administration to achieve a second daily dose based on resting LVOT-G, biplane LVEF, and/or post-warburg actions of the patient. Another exemplary embodiment of the methods described herein comprises administering a first daily dose of CK-274, or a pharmaceutically acceptable salt thereof, for about three weeks, followed by maintenance of the daily dose, reduction of the daily dose by about 10mg, increase of the daily dose by about 10mg, or termination of administration to achieve a second daily dose based on resting LVOT-G, biplane LVEF, and/or post-warburg actions of the patient. Another exemplary embodiment of the methods described herein comprises administering a first daily dose of CK-274, or a pharmaceutically acceptable salt thereof, for about 2 weeks to about 12 weeks, followed by maintaining the daily dose of LVOT-G, reducing the daily dose by about 10mg, increasing the daily dose by about 10mg, or terminating administration to achieve a second daily dose based on the patient's resting LVOT-G, biplane LVEF, and/or post-warburg actions.
Treatment of hypertrophic cardiomyopathy can improve motor performance and/or alleviate symptoms in patients with high dynamic ventricular contractions caused by hypertrophic cardiomyopathy. In some embodiments, the methods comprise administering to an individual having hypertrophic cardiomyopathy a therapeutically effective daily dose of CK-274, or a pharmaceutically acceptable salt thereof, thereby improving the motor ability of the individual. In some embodiments, the methods comprise administering a therapeutically effective daily dose of CK-274, or a pharmaceutically acceptable salt thereof, to an individual with hypertrophic cardiomyopathy, thereby alleviating one or more symptoms of high dynamic ventricular contractions. In some embodiments, the methods comprise administering to an individual having hypertrophic cardiomyopathy a therapeutically effective daily dose of CK-274, or a pharmaceutically acceptable salt thereof, in combination with propioamine, thereby improving the motor ability of the individual. In some embodiments, the methods comprise administering to an individual with hypertrophic cardiomyopathy a therapeutically effective daily dose of CK-274, or a pharmaceutically acceptable salt thereof, in combination with propidium, thereby alleviating one or more symptoms of high dynamic ventricular contractions.
In some embodiments, a therapeutically effective amount of CK-274, or a pharmaceutically acceptable salt thereof, is administered to a patient suffering from hypertrophic cardiomyopathy, thereby reducing resting LVOT-G in the patient. In some embodiments, the patient's baseline resting LVOT-G is about 30mmHg or greater, about 40mmHg or greater, or about 50mmHg or greater. In response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, resting LVOT-G can be reduced to less than 30mmHg, such as to about 25mmHg or less, about 20mmHg or less, or about 15mmHg or less. In some embodiments, the resting LVOT-G is reduced by about 10mmHg or more, about 15mmHg or more, about 20mmHg or more, about 25mmHg or more, about 30mmHg or more, or about 35mmHg or more in response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof. In some embodiments, resting LVOT-G is reduced by about 10mmHg to about 40mmHg in response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof. The decrease in resting LVOT-G may occur after about 1 week, after about 2 weeks, after about 3 weeks, after about 4 weeks, after about 5 weeks, after about 6 weeks, after about 8 weeks, or after about 10 weeks of daily dose administration.
In some embodiments, a therapeutically effective amount of CK-274, or a pharmaceutically acceptable salt thereof, is administered to a patient suffering from hypertrophic cardiomyopathy, thereby reducing LVOT-G after a patient's Wash action. In some embodiments, a therapeutically effective amount of CK-274, or a pharmaceutically acceptable salt thereof, is administered in combination with propidium to a patient suffering from hypertrophic cardiomyopathy, thereby reducing LVOT-G after a patient's warfarin action. In some embodiments, the LVOT-G after baseline warfare activity of the patient is about 30mmHg or greater, about 40mmHg or greater, 50mmHg or greater, about 60mmHg or greater, or about 70mmHg or greater. In response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, LVOT-G can be reduced to less than 50mmHg after a Wash event, for example to about 45mmHg or less, about 40mmHg or less, about 35mmHg or less, or about 30mmHg or less. In some embodiments, LVOT-G is reduced by about 10mmHg or more, about 15mmHg or more, about 20mmHg or more, about 25mmHg or more, about 30mmHg or more, or about 35mmHg or more following a warburg action in response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof. In some embodiments, LVOT-G is reduced by about 10mmHg to about 40mmHg after a Wash action in response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof. The decrease in LVOT-G following warrior action may occur after about 1 week, after about 2 weeks, after about 3 weeks, after about 4 weeks, after about 5 weeks, after about 6 weeks, after about 8 weeks, or after about 10 weeks of daily dose administration.
In some embodiments, a therapeutically effective amount of CK-274, or a pharmaceutically acceptable salt thereof, is administered to a patient suffering from hypertrophic cardiomyopathy to treat hypertrophic cardiomyopathy, wherein biplane LVEF is maintained at or above 50%. In some embodiments, a therapeutically effective amount of CK-274, or a pharmaceutically acceptable salt thereof, is administered in combination with propitiamine to treat hypertrophic cardiomyopathy in a patient suffering from hypertrophic cardiomyopathy, wherein biplane LVEF is maintained at or above 50%. In some embodiments, biplane LVEF is reduced by less than about 20%, less than about 15%, less than about 10%, or less than about 5% in response to administration of a therapeutically effective amount of CK-274, or a pharmaceutically acceptable salt thereof. The maintenance interval of the biplane LVEF 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 of daily dose administration.
In some embodiments, a therapeutically effective amount of CK-274, or a pharmaceutically acceptable salt thereof, is administered to a patient suffering from hypertrophic cardiomyopathy, thereby reducing the Left Ventricular Mass Index (LVMI) of the patient. LVMI can be reduced by about 1g/m in response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof 2 Or greater, about 1.5g/m 2 Or greater, about 2g/m 2 Or greater, about 2.5g/m 2 Or greater, about 3g/m 2 Or greater, about 3.5g/m 2 Or greater, or about 4g/m 2 Or larger. In some embodiments, LVMI is reduced by about 1g/m in response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof 2 To about 10g/m 2 mmHg, e.g. reduced by about 1g/m 2 To about 6g/m 2 Or about 2g/m 2 To about 5g/m 2 . The decrease in LVMI may occur after about 1 week, after about 2 weeks, after about 3 weeks, after about 4 weeks, after about 5 weeks, after about 6 weeks, after about 8 weeks, or after about 10 weeks of daily dose administration.
In some embodiments, a therapeutically effective amount of CK-274, or a pharmaceutically acceptable salt thereof, is administered to a patient suffering from hypertrophic cardiomyopathy, thereby reducing the Left Arterial Volume Index (LAVI) of the patient. In response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, LAVI may be reduced by about 0.5mL/m 2 Or greater, about 1mL/m 2 Or greater, about 1.5mL/m 2 Or greater, about 2mL/m 2 Or greater, or about 2.5mL/m 2 Or larger. In some embodiments, the LAVI is reduced by about 0.5mL/m in response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof 2 To about 5mL/m 2 mmHg, e.g. reduced by about 0.5mL/m 2 To about 4g/m 2 Or about 1mL/m 2 To about 3mL/m 2 . The decrease in LAVI may occur after about 1 week, after about 2 weeks, after about 3 weeks, after about 4 weeks, after about 5 weeks, after about 6 weeks, after about 8 weeks, or after about 10 weeks of daily dose administration.
In some embodiments, a therapeutically effective amount of CK-274, or a pharmaceutically acceptable salt thereof, is administered to a patient suffering from hypertrophic cardiomyopathy, thereby reducing the e' value of the patient. In response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, the e' value may be reduced by about 0.1cm/s or greater, about 0.15cm/s or greater, about 0.2cm/s or greater, or about 0.25cm/s or greater. In some embodiments, in response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof, the e' value is reduced by about 0.05cm/s to about 0.3cm/s, for example by about 0.1cm/s to about 0.25cm/s, or by about 0.15cm/s to about 0.25cm/s. The decrease in e' value may occur after about 1 week, after about 2 weeks, after about 3 weeks, after about 4 weeks, after about 5 weeks, after about 6 weeks, after about 8 weeks, or after about 10 weeks of daily dose administration.
In some embodiments, a therapeutically effective amount of CK-274, or a pharmaceutically acceptable salt thereof, is administered to a patient suffering from hypertrophic cardiomyopathy, thereby reducing the lateral E/E' ratio of the patient. The lateral E/E' ratio may be reduced by about 0.5 or greater, 1 or greater, about 1.2 or greater, about 1.5 or greater, or about 1.8 or greater in response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof. In some embodiments, the lateral E/E' ratio is reduced by about 0.5 to about 2, e.g., by about 1 to about 1.8, or about 1.5 to about 1.8, in response to administration of a therapeutically effective amount of CK-274 or a pharmaceutically acceptable salt thereof. The decrease in the lateral E/E' ratio may occur after about 1 week, after about 2 weeks, after about 3 weeks, after about 4 weeks, after about 5 weeks, after about 6 weeks, after about 8 weeks, or after about 10 weeks of daily dose administration.
In some embodiments, a therapeutically effective amount of CK-274, or a pharmaceutically acceptable salt thereof, is administered to a patient suffering from hypertrophic cardiomyopathy, thereby reducing the likelihood of pre-systole movement (SAM) of the mitral valve leaflet of the patient.
In some embodiments, a therapeutically effective amount of CK-274, or a pharmaceutically acceptable salt thereof, is administered to a patient suffering from hypertrophic cardiomyopathy, thereby reducing the likelihood of mitral regurgitation or eccentric mitral regurgitation in the patient.
In some embodiments, a therapeutically effective amount of CK-274, or a pharmaceutically acceptable salt thereof, is administered to a patient suffering from hypertrophic cardiomyopathy, thereby reducing the level of brain natriuretic peptide or the N-terminal pro-hormone of brain natriuretic peptide (NT-proBNP) in the patient. The reduction in the level of brain natriuretic peptide or the N-terminal pro-hormone of brain natriuretic peptide (NT-proBNP) in the patient may occur after about 1 week, after about 2 weeks, after about 3 weeks, after about 4 weeks, after about 5 weeks, after about 6 weeks, after about 8 weeks, or after about 10 weeks of daily dose administration. In some of the foregoing embodiments, the hypertrophic cardiomyopathy is obstructive hypertrophic cardiomyopathy (oHCM).
In some embodiments, a therapeutically effective amount of CK-274, or a pharmaceutically acceptable salt thereof, is administered to a patient suffering from hypertrophic cardiomyopathy, thereby reducing the level of cardiac troponin I. The reduction in cardiac troponin I levels in a patient may occur after about 1 week, after about 2 weeks, after about 3 weeks, after about 4 weeks, after about 5 weeks, after about 6 weeks, after about 8 weeks, or after about 10 weeks of daily dose administration. In some of the foregoing embodiments, the hypertrophic cardiomyopathy is obstructive hypertrophic cardiomyopathy (oHCM).
In some embodiments of any of the foregoing, when administration of CK-274 or a pharmaceutically acceptable salt thereof is initiated, the patient suffering from hypertrophic cardiomyopathy is classified as NYHA class III. In some embodiments, when CK-274 or a pharmaceutically acceptable salt thereof is initially administered, patients with hypertrophic cardiomyopathy are classified as NYHA class II.
In some embodiments of any of the foregoing, administering CK-274, or a pharmaceutically acceptable salt thereof, to a patient suffering from hypertrophic cardiomyopathy further reduces left ventricular wall stress in the patient and/or reduces myocardial damage in the patient. The reduction in left ventricular wall stress can be measured as a decrease in serum NT-proBNP levels. The reduction in myocardial damage can be measured in terms of changes in hs-troponin. The reduction in left ventricular wall stress and/or the reduction in myocardial damage in the patient may occur after about 1 week, after about 2 weeks, after about 3 weeks, after about 4 weeks, after about 5 weeks, after about 6 weeks, after about 8 weeks, or after about 10 weeks of daily dose administration. In some of the foregoing embodiments, the hypertrophic cardiomyopathy is obstructive hypertrophic cardiomyopathy (oHCM).
In some embodiments of any of the foregoing, administering CK-274, or a pharmaceutically acceptable salt thereof, to a patient suffering from obstructive hypertrophic cardiomyopathy can improve the motor ability of the patient. In some embodiments of any of the foregoing, administration of CK-274, or a pharmaceutically acceptable salt thereof, to a patient suffering from obstructive hypertrophic cardiomyopathy can improve the motor ability of the patient, e.g., as per peak oxygen uptake (pVO 2 ) Is a change in (pVO) or peak oxygen uptake by cardiopulmonary exercise testing (CPET) 2 ) Measured as a change in (c).
In some embodiments of any of the foregoing, administering CK-274, or a pharmaceutically acceptable salt thereof, to a patient suffering from obstructive hypertrophic cardiomyopathy can improve the overall workload during CPET.
In some embodiments of any of the foregoing, administration of CK-274, or a pharmaceutically acceptable salt thereof, to a patient suffering from obstructive hypertrophic cardiomyopathy can improve other CPET parameters, including (but not limited to) one or more of the following: (1) Ventilator efficiency (VE/VCO) 2 Slope); (2) Cycle power (VO) 2 X shrinkage BP); and (3) Ventilator Anaerobic Threshold (VAT).
In some embodiments of any of the foregoing, administering CK-274, or a pharmaceutically acceptable salt thereof, to a patient suffering from obstructive hypertrophic cardiomyopathy can improve the patient's health condition. In some embodiments of any of the foregoing, administration of CK-274, or a pharmaceutically acceptable salt thereof, to a patient suffering from obstructive hypertrophic cardiomyopathy can improve patient health, as determined by a change in the kansashimi cardiomyopathy questionnaire-total score (Kansas City Cardiomyopathy Questionnaire-Overall Summary Score, KCCQ-OSS). In some embodiments of any of the foregoing, administering CK-274, or a pharmaceutically acceptable salt thereof, to a patient suffering from obstructive hypertrophic cardiomyopathy can improve patient health, as determined by changes in the kansashimi cardiomyopathy questionnaire-clinical summary score (KCCQ-CSS). In some embodiments of any of the foregoing, administering CK-274, or a pharmaceutically acceptable salt thereof, to a patient suffering from obstructive hypertrophic cardiomyopathy can improve the patient's health condition, as determined by a change in the kansasa city myocardial questionnaire-total symptom score (KCCQ-TSS). In some embodiments of any of the foregoing, administering CK-274, or a pharmaceutically acceptable salt thereof, to a patient suffering from obstructive hypertrophic cardiomyopathy can improve patient health, as determined by changes in the kansashimi cardiomyopathy questionnaire-body limitation score (KCCQ-PLS). In some embodiments of any of the foregoing, administering CK-274, or a pharmaceutically acceptable salt thereof, to a patient suffering from obstructive hypertrophic cardiomyopathy can improve patient health, as determined by changes in the kansashimi cardiomyopathy questionnaire-social restriction score (KCCQ-SLS). In some embodiments of any of the foregoing, administering CK-274, or a pharmaceutically acceptable salt thereof, to a patient suffering from obstructive hypertrophic cardiomyopathy can improve the patient's health condition, as determined by a change in the kansasa cardiomyopathy questionnaire-quality of life (KCCQ-QoL). In some embodiments, administration of CK-274 or a pharmaceutically acceptable salt thereof to a patient suffering from obstructive hypertrophic cardiomyopathy can increase one or more KCCQ field scores (e.g., KCCQ-OSS, KCCQ-CSS, KCCQ-TSS, KCCQ-PLS, KCCQ-SLS, or KCCQ-QoL) by at least about 5 minutes, at least about 10 minutes, or at least about 20 minutes. In some embodiments, administration of CK-274 or a pharmaceutically acceptable salt thereof to a patient suffering from obstructive hypertrophic cardiomyopathy can increase one or more KCCQ scores (e.g., KCCQ-OSS, KCCQ-CSS, KCCQ-TSS, KCCQ-PLS, KCCQ-SLS, or KCCQ-QoL) by about 5 minutes to less than 10 minutes, about 10 minutes to less than 20 minutes, or at least 20 minutes. In some such embodiments, the increase in one or more KCCQ domain scores is an increase in KCCQ-OSS. In some embodiments, the increase in one or more KCCQ domain scores lasts for about 6 months. In some embodiments, administration of CK-274 or a pharmaceutically acceptable salt thereof to a patient suffering from obstructive hypertrophic cardiomyopathy can increase KCCQ-CSS by 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, or more than 5 minutes. In some embodiments of any of the foregoing, administration of CK-274, or a pharmaceutically acceptable salt thereof, to a patient suffering from obstructive hypertrophic cardiomyopathy can improve the patient's health and health-related quality of life as measured by the PRO questionnaire, as determined by a change in response to a EuroQol 5-dimensional 5 level instrument (EQ-5D-5L).
Combinations of the foregoing are also contemplated. In some embodiments of any of the foregoing, administration of CK-274, or a pharmaceutically acceptable salt thereof, to a patient suffering from obstructive hypertrophic cardiomyopathy can improve exercise capacity and functional class, e.g., as determined according to: (1) pVO 2 The change compared with the baseline is more than or equal to 1.5mL/kg/min and the NYHA functional class is improved by more than or equal to 1 class; or (2) pVO 2 The change from baseline was ≡3.0mL/kg/min and NYHA functional class was not worsened. In some embodiments of any of the foregoing, administering CK-274 or a pharmaceutically acceptable salt thereof to a patient suffering from obstructive hypertrophic cardiomyopathy produces resting LVOT-G in the patient<LVOT-G after 30mmHg and Wash action<50mmHg and NYHA functional class I. In some embodiments of any of the foregoing, the administration of CK-274, or a pharmaceutically acceptable salt thereof, to a patient suffering from obstructive hypertrophic cardiomyopathy causes the patient to rest LVOT-G<LVOT-G after 30mmHg and Wash action<The functional categories of 50mmHg and NYHA are improved by more than or equal to 1 category.
In some embodiments, administration of CK-274 or a pharmaceutically acceptable salt thereof to a patient suffering from hypertrophic cardiomyopathy produces a sustained effect of at least 10 weeks, 12 weeks, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, administration of CK-274 or a pharmaceutically acceptable salt thereof to a patient suffering from hypertrophic cardiomyopathy produces a sustained effect for at least 6 months. In some embodiments, administration of CK-274 or a pharmaceutically acceptable salt thereof to a patient suffering from hypertrophic cardiomyopathy produces a sustained effect for at least 1 year. In some embodiments, administration of CK-274 or a pharmaceutically acceptable salt thereof to a patient suffering from hypertrophic cardiomyopathy produces a sustained effect for at least 5 years. Persistent effects include, for example, one or more effects selected from the group consisting of: the resting LVOT-G is reduced to less than 30mmHg; LVOT-G decreased to less than 50mmHg after Wash action; improving mitral regurgitation; improving cardiac relaxation; beneficial cardiac remodeling; reverse cardiac remodeling; beneficial cardiac structural remodeling; beneficial cardiac remodeling; adverse cardiac remodeling reverses; decreasing the average Left Ventricular Mass Index (LVMI); improving Left Ventricular (LV) filling pressure; decreasing Left Atrial Volume Index (LAVI); a class assessment that reduces preshrinking motion of the mitral valve leaflet; reducing preshrinking motion of the mitral valve leaflets; reducing the frequency of eccentric mitral regurgitation; reducing mitral regurgitation; reducing lateral E/E'; reducing lateral E/E; lowering Brain Natriuretic Peptide (BNP) levels; lowering the N-terminal pro-hormone (NT-proBNP) level of brain natriuretic peptide; lowering cardiac troponin I levels; reducing left ventricular wall stress; reducing myocardial damage; and reducing symptoms of heart failure, such as decreasing NYHA classification.
Administration of the compounds and compositions disclosed and/or described herein may be via any accepted mode of administration of therapeutic agents, including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. In some embodiments, the compound or composition is administered orally or intravenously. In some embodiments, the compounds or compositions disclosed and/or described herein are administered orally.
Pharmaceutically acceptable compositions include solid, semi-solid, liquid and aerosol dosage forms, such as tablets, capsules, powders, liquids, suspensions, suppositories and aerosol forms. The compounds disclosed and/or illustrated herein may also be administered in the following forms: sustained or controlled release dosage forms (e.g., controlled/sustained release pellets, depot injections, osmotic pumps, or transdermal (including electrotransport) patch forms) for prolonged administration, and/or pulsed administration at a predetermined rate. In some embodiments, the compositions are provided in unit dosage forms suitable for single administration of precise dosages.
CK-274 may be administered alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical compositions may also contain minor amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate). Typically, the pharmaceutical composition will contain 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. Practical methods of preparing such dosage forms are known or apparent to those skilled in the art; see, for example, remington' sPharmaceutical Sciences, mack Publishing Company, easton, pennsylvania.
In some embodiments, CK-274 or a pharmaceutical composition containing CK-274 will take the form of a pill or tablet, and thus the composition may contain one or more of diluents (e.g., lactose, sucrose, dicalcium phosphate), lubricants (e.g., magnesium stearate) and/or binders (e.g., starches, gum acacia), polyvinylpyrrolidine, gelatin, cellulose derivatives) and compounds disclosed and/or described herein. Other solid dosage forms include powders, pellets (marume), solutions or suspensions encapsulated in gelatin capsules (e.g., in propylene carbonate, vegetable oils or triglycerides).
The pharmaceutically administrable liquid composition may be prepared, for example, by: the compounds disclosed and/or illustrated herein and optional pharmaceutical additives are dissolved, dispersed, or suspended, etc., in a carrier (e.g., water, saline, aqueous dextrose, glycerol, ethylene glycol, ethanol, etc.) to form a solution or suspension. The injectable formulations may be prepared in conventional form, in liquid solutions or suspensions, in emulsions, or in solid form suitable for dissolution or suspension in a liquid prior to injection. The percentage of the compound contained in such parenteral compositions depends on, for example, the physical properties of the compound, the activity of the compound, and the needs of the subject. However, the active ingredient may be employed in a solution at a percentage of 0.01% to 10%, and may be higher if the composition is a solid that will be subsequently diluted to another concentration. In some embodiments, the composition will comprise from about 0.2 to 2% of the compounds disclosed and/or described herein in solution.
Pharmaceutical compositions of the compounds disclosed and/or illustrated herein may also be administered to the respiratory tract as aerosols or solutions for nebulizers, or as fine powders for insufflation, alone or in combination with inert carriers such as lactose. In such a case, the particles of the pharmaceutical composition may have a diameter of less than 50 microns, or in some embodiments less than 10 microns.
In addition, the pharmaceutical compositions may include a compound disclosed and/or described herein and one or more additional agents, medicaments, adjuvants, and the like. Suitable medicaments and pharmaceutical agents include those described herein.
Medicine box
Also provided are articles of manufacture and kits containing any of the compounds or pharmaceutical compositions provided herein. The article may comprise a container having a label. Suitable containers include, for example, bottles, vials, and test tubes. The container may be formed from a variety of materials such as glass or plastic. The container may contain the pharmaceutical compositions provided herein. The label on the container may indicate that the pharmaceutical composition is for use in preventing, treating or inhibiting a disorder described herein, and may also indicate instructions for use in vivo or in vitro.
In one aspect, provided herein are kits comprising a compound or composition described herein and instructions for use. The kit may contain instructions for treating heart disease in an individual or subject in need thereof. The kit may additionally contain any material or device useful for administering the compound or composition, such as a vial, syringe, or IV bag. The kit may also contain a sterile package.
The illustrated embodiments
Embodiment 1. A method of reducing the resting left ventricular outflow tract pressure gradient (LVOT-G) to less than 30mmHg in a patient suffering from obstructive hypertrophic cardiomyopathy (oHCM), the method comprising administering to the patient a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof.
Embodiment 2. The method of embodiment 1 wherein the reduction of resting LVOT-G to less than 30mmHg occurs within 10 weeks of starting treatment with compound 1 or a pharmaceutically acceptable salt thereof.
Embodiment 3. The method of embodiment 1 wherein the reduction of resting LVOT-G to less than 30mmHg occurs within two weeks of starting treatment with compound 1 or a pharmaceutically acceptable salt thereof.
Embodiment 4. The method of any one of embodiments 1-3, wherein the decrease in resting LVOT-G is for at least 10 weeks of treatment.
Embodiment 5. The method of any one of embodiments 1-4, wherein the decrease in resting LVOT-G peaks within 2 to 6 weeks of end of dose titration.
Embodiment 6. A method of reducing left ventricular outflow tract pressure gradient (LVOT-G) to less than 50mmHg after a warrior event in a patient suffering from obstructive hypertrophic cardiomyopathy (oHCM), the method comprising administering to the patient a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof.
Embodiment 7. The method of embodiment 6, wherein the decrease in LVOT-G to less than 50mmHg after the warrior event occurs within two weeks of starting treatment with compound 1 or a pharmaceutically acceptable salt thereof.
Embodiment 8. The method of embodiment 6 or 7, wherein the decrease in LVOT-G after the warrior event is for at least 10 weeks of treatment.
Embodiment 9. The method of any one of embodiments 6-8, wherein the decrease in LVOT-G peaks within 2 to 6 weeks of end of dose titration after the warrior event.
Embodiment 10. A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof, is selected by titrating the daily dose of compound 1, or a pharmaceutically acceptable salt thereof, administered to the patient.
Embodiment 11. The method of embodiment 10, wherein the dose is titrated once during the course of treatment.
Embodiment 12. The method of embodiment 10, wherein the dose is titrated two or more times during the course of treatment.
Embodiment 13. The method of any one of embodiments 10-12, wherein the daily dose is administered to the patient in a constant amount for about two weeks prior to titrating the daily dose amount.
Embodiment 14. The method of any one of embodiments 1-13, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 5mg to about 30mg.
Embodiment 15. The method of embodiment 14, wherein the daily dose is about 5mg.
Embodiment 16. The method of embodiment 14, wherein the daily dose is about 10mg.
Embodiment 17. The method of embodiment 14, wherein the daily dose is about 15mg.
Embodiment 18. The method of embodiment 14, wherein the daily dose is about 20mg.
Embodiment 19. The method of embodiment 14, wherein the daily dose is about 30mg.
Embodiment 20. The method of any of embodiments 10-19, wherein the daily dose is administered daily as a single dose.
Embodiment 21. The method of any one of embodiments 10-19, wherein the daily dose is administered in 2 divided doses.
Embodiment 22. A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, the method comprising:
Administering a first daily dose of compound 1, or a pharmaceutically acceptable salt thereof, to the patient for a first period of time; and
administering a second daily dose of compound 1 or a pharmaceutically acceptable salt thereof to the patient for a second period of time, or terminating administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient, based on one or more components of the patient's first echocardiogram taken after the first period of time.
Embodiment 23. The method of embodiment 22, comprising selecting a second daily dose of compound 1 or a pharmaceutically acceptable salt thereof based on the one or more components of the first echocardiogram.
Embodiment 24. The method of embodiment 22 or 23, wherein the one or more components of the first echocardiogram comprise biplane LVEF, post-warrior-action lvet-G, or resting lvet-G.
Embodiment 25. The method of embodiment 22 or 23, wherein the one or more components of the first echocardiogram comprise biplane LVEF, post-warrior-action lvet-G, and resting lvet-G.
Embodiment 26. The method of embodiment 22 or 23, wherein the one or more components of the first echocardiogram comprise biplane LVEF and post-warrior-action lvet-G.
Embodiment 27 the method of any one of embodiments 22-26, wherein the one or more components of the first echocardiogram comprise a biplane LVEF and the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is lower than the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold.
The method of any one of embodiments 22-26, wherein the one or more components of the first echocardiogram comprise a biplane LVEF and administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient is terminated when the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold.
Embodiment 29. The method of embodiment 27 or 28, wherein the predetermined biplane LVEF threshold is 50%.
The method of any one of embodiments 22-29, wherein the one or more components of the first echocardiogram comprise biplane LVEF, resting LVOT-G, and post-valot-G, and wherein the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the biplane LVEF of the first echocardiogram is equal to or above a predetermined biplane LVEF threshold, the resting LVOT-G of the first echocardiogram is below a predetermined resting LVOT-G threshold, and the post-valot-G of the first echocardiogram is below a predetermined post-valot-G threshold.
Embodiment 31 the method of any one of embodiments 22-30, wherein the one or more components of the first echocardiogram comprise biplane LVEF, resting LVOT-G, and post-valot-G, and wherein the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is greater than the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the first echocardiogram satisfies any one of the following conditions: (1) The biplane LVEF is equal to or above a predetermined biplane LVEF threshold and the resting LVOT-G is equal to or above a predetermined resting LVOT-G threshold, or (2) the biplane LVEF is equal to or above a predetermined biplane LVEF threshold, the resting LVOT-G is below a predetermined resting LVOT-G threshold and the post-warrior-action LVOT-G is equal to or above a predetermined post-warrior-action LVOT-G threshold.
Embodiment 32 the method of embodiment 30 or 31 wherein the predetermined biplane LVEF threshold is 50%, the predetermined resting LVOT-G threshold is 30mmHg, and the post-warrior action LVOT-G threshold is 50mmHg.
Embodiment 33 the method of any one of embodiments 22-29, wherein the one or more components of the first echocardiogram comprise biplane LVEF and post-valot-G, and wherein the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the first echocardiogram satisfies any one of the following conditions: (1) The biplane LVEF is equal to or above a predetermined biplane LVEF threshold and below a second predetermined biplane LVEF threshold; or (2) the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold and the post-wag LVOT-G of the first echocardiogram is below a second predetermined post-wag LVOT-G threshold.
Embodiment 34 the method of any one of embodiments 22-29 and 33, wherein the one or more components of the first echocardiogram comprises biplane LVEF and post-warrior action lvet-G, and wherein the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is greater than the first daily dose of compound 1 when the biplane LVEF of the first echocardiogram is above a second predetermined biplane LVEF threshold and the post-warrior action lvet-G of the first echocardiogram is equal to or above a second predetermined post-warrior action LVOT-G threshold.
Embodiment 35 the method of embodiment 33 or 34 wherein the predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the second predetermined post-warrior action LVOT-G threshold is 30mmHg.
Embodiment 36 the method of any one of embodiments 22-35, wherein the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg of compound 1.
Embodiment 37 the method of embodiment 36, wherein the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg or about 10mg of compound 1.
Embodiment 38 the method of any one of embodiments 22-37, further comprising measuring the one or more components of the first echocardiogram.
Embodiment 39. The method of any one of embodiments 22-38, wherein the first period of time is about 2 weeks.
Embodiment 40. The method of any of embodiments 22-39, wherein the second period of time is about 2 weeks.
Embodiment 41 the method of any one of embodiments 22-40, wherein a second daily dose of compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient for a second period of time, the method further comprising administering a third daily dose of compound 1, or a pharmaceutically acceptable salt thereof, to the patient for a third period of time, or terminating administration of compound 1, or a pharmaceutically acceptable salt thereof, to the patient based on one or more components of the second echocardiogram of the patient taken after the second period of time and the second daily dose of compound 1, or a pharmaceutically acceptable salt thereof.
Embodiment 42. The method of embodiment 41, comprising selecting a third daily dose of compound 1 or a pharmaceutically acceptable salt thereof based on the one or more components of the second echocardiogram and the second daily dose.
Embodiment 43 the method of embodiment 41 or 42, wherein the one or more components of the second echocardiogram comprise biplane LVEF, post-warrior-action lvet-G, or resting lvet-G.
Embodiment 44 the method of embodiment 41 or 42, wherein the one or more components of the second echocardiogram comprise biplane LVEF, post-warrior-action lvet-G, and resting lvet-G.
Embodiment 45 the method of embodiment 41 or 42, wherein the one or more components of the second echocardiogram comprise biplane LVEF and post-warrior-action lvet-G.
Embodiment 46 the method of any one of embodiments 41-45, wherein the one or more components of the second echocardiogram comprise a biplane LVEF and when the biplane LVEF of the second echocardiogram is below a predetermined biplane LVEF threshold, the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is lower than the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof, or the administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient is terminated.
Embodiment 47 the method of embodiment 46, wherein administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient is terminated when the biplane LVEF of the second echocardiogram is below a predetermined biplane LVEF threshold, and the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to or lower than the first daily dose of compound 1.
Embodiment 48 the method of embodiment 46, wherein the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is higher than the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof and the biplane LVEF of the second echocardiogram is below a predetermined biplane LVEF threshold.
Embodiment 49 the method of any one of embodiments 46-48 wherein the predetermined biplane LVEF threshold is 50%.
Embodiment 50 the method of any one of embodiments 41-49, wherein the one or more components of the second echocardiogram comprise biplane LVEF, resting LVOT-G, and post-valot-G, and wherein the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the biplane LVEF of the second echocardiogram is equal to or above a predetermined biplane LVEF threshold, the resting LVEOT-G of the second echocardiogram is below a predetermined resting LVOT-G threshold, and the post-valot-G of the second echocardiogram is below a predetermined post-valot-G threshold.
Embodiment 51 the method of any one of embodiments 41-50, wherein the one or more components of the second echocardiogram comprise biplane LVEF, resting LVOT-G, and post-valot-G, and wherein the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is greater than the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the second echocardiogram satisfies any one of the following conditions: (1) The biplane LVEF is equal to or above a predetermined biplane LVEF threshold and the resting LVEOT-G is equal to or above a predetermined resting lvet-G threshold, or (2) the biplane LVEF is equal to or above a predetermined biplane LVEF threshold, the resting lvet-G is below a predetermined resting lvet-G threshold and the post-warrior-action lvet-G is equal to or above a predetermined post-warrior-action lvet-G threshold.
Embodiment 52 the method of embodiment 50 or 51 wherein the predetermined biplane LVEF threshold is 50%, the predetermined resting LVOT-G threshold is 30mmHg, and the post-warrior action LVOT-G threshold is 50mmHg.
Embodiment 53 the method of any one of embodiments 41-49, wherein the one or more components of the second echocardiogram comprise biplane LVEF and post-valot-G, and wherein the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the second echocardiogram satisfies any one of the following conditions: (1) The biplane LVEF is equal to or above a predetermined biplane LVEF threshold and below a second predetermined biplane LVEF threshold; or (2) the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold and the post-warrior-action LVOT-G is below a second predetermined post-warrior-action LVOT-G threshold.
Embodiment 54 the method of any one of embodiments 41-49 and 53, wherein the one or more components of the second echocardiogram comprises biplane LVEF and post-warrior action lvet-G, and wherein the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is greater than the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the biplane LVEF of the second echocardiogram is above a second predetermined biplane LVEF threshold and the post-warrior action lvet-G of the second echocardiogram is equal to or greater than a second predetermined post-warrior action LVOT-G threshold.
Embodiment 55 the method of embodiment 53 or 54, wherein the predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the second predetermined post-warrior action LVOT-G threshold is 30mmHg.
Embodiment 56 the method of any of embodiments 41-55, wherein the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg of compound 1, the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg or about 10mg of compound 1, and the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg, about 10mg or about 15mg of compound 1.
Embodiment 57 the method of any one of embodiments 41-56, further comprising measuring the one or more components of the second echocardiogram.
Embodiment 58 the method of any one of embodiments 41-57, wherein the third period of time is about 2 weeks.
Embodiment 59 the method of any one of embodiments 41-58, wherein a third daily dose of compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient for a third period of time, the method further comprising administering a fourth daily dose of compound 1, or a pharmaceutically acceptable salt thereof, to the patient, for a fourth period of time, or terminating administration of compound 1, or a pharmaceutically acceptable salt thereof, to the patient, based on the third daily dose of one or more components of the third echocardiogram of the patient taken after the third period of time, and the compound, or a pharmaceutically acceptable salt thereof.
Embodiment 60 the method of embodiment 59, comprising selecting a fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof based on the one or more components of the third echocardiogram and the third daily dose.
Embodiment 61 the method of embodiment 59 or 60, wherein the one or more components of the third echocardiogram comprise biplane LVEF, post-warrior-action lvet-G, or resting lvet-G.
Embodiment 62 the method of embodiment 59 or 60, wherein the one or more components of the third echocardiogram comprise biplane LVEF, post-warrior-action lvet-G, and resting lvet-G.
Embodiment 63 the method of embodiment 59 or 60, wherein the one or more components of the third echocardiogram comprise biplane LVEF and post-valot-G-wag motion
Embodiment 64 the method of any one of embodiments 59-63, wherein the one or more components of the third echocardiogram comprise a biplane LVEF and the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is lower than the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof, or the administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient is terminated when the biplane LVEF of the third echocardiogram is below a predetermined biplane LVEF threshold.
The method of embodiment 65, wherein administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient is terminated when the biplane LVEF of the third echocardiogram is below a predetermined biplane LVEF threshold, and the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to or lower than the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof.
Embodiment 66. The method of embodiment 64 or 65, wherein:
when the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is higher than the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof and the biplane LVEF of the third echocardiogram is below a predetermined biplane LVEF threshold, the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof; or (b)
When the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof and the biplane LVEF of the third echocardiogram is below a predetermined biplane LVEF threshold, the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof.
Embodiment 67. The method of any one of embodiments 64-66, wherein the predetermined biplane LVEF threshold is 50%.
Embodiment 68 the method of any one of embodiments 59-67, wherein the one or more components of the third echocardiogram comprise biplane LVEF, resting LVOT-G, and post-valot-G, and wherein the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the biplane LVEF of the third echocardiogram is equal to or above a predetermined biplane LVEF threshold, the resting LVEOT-G of the third echocardiogram is below a predetermined resting LVOT-G threshold, and the post-valot-G of the third echocardiogram is below a predetermined post-valot-G threshold.
Embodiment 69 the method of any one of embodiments 59-68, wherein the one or more components of the third echocardiogram comprise biplane LVEF, resting LVOT-G, and post-valot-G, and wherein the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is greater than the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the third echocardiogram satisfies any one of the following conditions: (1) The biplane LVEF is equal to or above a predetermined biplane LVEF threshold and the resting LVEOT-G is equal to or above a predetermined resting lvet-G threshold, or (2) the biplane LVEF is equal to or above a predetermined biplane LVEF threshold, the resting lvet-G is below a predetermined resting lvet-G threshold and the post-warrior-action lvet-G is equal to or above a predetermined post-warrior-action lvet-G threshold.
Embodiment 70 the method of embodiment 68 or 69 wherein the predetermined biplane LVEF threshold is 50%, the predetermined resting LVOT-G threshold is 30mmHg, and the post-warrior action LVOT-G threshold is 50mmHg.
Embodiment 71 the method of any one of embodiments 59-67, wherein the one or more components of the third echocardiogram comprise biplane LVEF and post-valot-G, and wherein the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the third echocardiogram satisfies any one of the following conditions: (1) The biplane LVEF is equal to or above a predetermined biplane LVEF threshold and below a second predetermined biplane LVEF threshold; or (2) the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold and the post-warrior-action LVOT-G is below a second predetermined post-warrior-action LVOT-G threshold.
Embodiment 72 the method of any one of embodiments 59-67 and 71, wherein the one or more components of the third echocardiogram comprise biplane LVEF and post-warrior action lvet-G, and wherein a fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is greater than a third daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the biplane LVEF of the third echocardiogram is above a second predetermined biplane LVEF threshold and the post-warrior action lvet-G of the third echocardiogram is equal to or greater than a second predetermined post-warrior action LVOT-G threshold.
Embodiment 73 the method of embodiment 71 or 72, wherein the predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the second predetermined post-warrior action LVOT-G threshold is 30mmHg.
Embodiment 74 the method of any of embodiments 59-73, wherein the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg of compound 1, the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg or about 10mg of compound 1, the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg, about 10mg or about 15mg of compound 1, and the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg, about 10mg, about 15mg or about 20mg of compound 1
Embodiment 75 the method of any one of embodiments 59-74, further comprising measuring one or more components of the third echocardiogram.
Embodiment 76 the method of any one of embodiments 59-75, wherein the fourth period of time is about 2 weeks.
Embodiment 77. A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, the method comprising:
administering a first daily dose of compound 1, or a pharmaceutically acceptable salt thereof, to the patient for a first period of time; and
administering a second daily dose of compound 1 or a pharmaceutically acceptable salt thereof to the patient for a second period of time, or terminating administration of compound 1 to the patient, based on a first echocardiogram comprising biplane LVEF and post-warrior action, of the patient taken after the first period of time, wherein:
terminating administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient if the biplane LVEF of the first echocardiogram is below a first predetermined biplane LVEF threshold;
the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof if the first echocardiogram satisfies any of the following conditions: (1) The biplane LVEF is equal to or above a first predetermined biplane LVEF threshold and below a second predetermined biplane LVEF threshold; or (2) the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold and the post-warrior-action LVOT-G is below a predetermined post-warrior-action LVOT-G threshold; and is also provided with
If the biplane LVEF of the first echocardiogram is above a second predetermined biplane LVEF threshold and the post-warrior action LVOT-G of the first echocardiogram is equal to or above a predetermined post-warrior action LVOT-G threshold, the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is greater than the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof.
The method of embodiment 78, wherein the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg of compound 1 and the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg or about 10mg of compound 1.
Embodiment 79 the method of embodiment 77 or 78, further comprising measuring biplane LVEF and post-wav motion lvet-G of said first echocardiogram
Embodiment 80 the method of any one of embodiments 77-79, wherein said first period of time is about 2 weeks.
Embodiment 81 the method of any one of embodiments 79-80 wherein the second period of time is about 2 weeks.
The method of embodiments 77-81, wherein administering to the patient a second daily dose of compound 1 or a pharmaceutically acceptable salt thereof for a second period of time further comprises administering to the patient a third daily dose of compound 1 or a pharmaceutically acceptable salt thereof for a third period of time, or terminating administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient based on a second echocardiogram comprising biplane LVEF and post-warrior action of the patient taken after the second period of time and a second daily dose of compound 1 or a pharmaceutically acceptable salt thereof, wherein:
Terminating administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient if the biplane LVEF of the second echocardiogram is below a first predetermined biplane LVEF threshold and the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof;
if the biplane LVEF of the second echocardiogram is below a first predetermined biplane LVEF threshold and the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is higher than the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof, the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is lower than the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof;
the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof if the second echocardiogram satisfies any of the following conditions: (1) The biplane LVEF is equal to or above a first predetermined biplane LVEF threshold and below a second predetermined biplane LVEF threshold; or (2) the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold and the post-warrior-action LVOT-G is below a predetermined post-warrior-action LVOT-G threshold; and is also provided with
If the biplane LVEF of the second echocardiogram is above a second predetermined biplane LVEF threshold and the post-warrior action LVOT-G of the second echocardiogram is equal to or above a predetermined post-warrior action LVOT-G threshold, the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is greater than the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof.
The method of embodiment 83, wherein the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg of compound 1, the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg or about 10mg of compound 1, and the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg, about 10mg or about 15mg of compound 1.
Embodiment 84 the method of embodiment 82 or 83, further comprising measuring biplane LVEF and post-warrior LVOT-G of the second echocardiogram.
Embodiment 85 the method of any one of embodiments 82-84, wherein said third period of time is about 2 weeks.
The method of any one of embodiments 82-85, wherein a third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient for a third period of time, the method further comprising administering a fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof to the patient for a fourth period of time, or terminating administration of compound 1 to the patient based on a third echocardiogram of the patient comprising biplane LVEF and post-valvular action, taken after the third period of time, and a second third dose of compound 1 or a pharmaceutically acceptable salt thereof, wherein:
Terminating administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient if the biplane LVEF of the third echocardiogram is below a first predetermined biplane LVEF threshold and the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof;
if the biplane LVEF of the third echocardiogram is below a first predetermined biplane LVEF threshold and the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is higher than the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof, the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is lower than the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof;
the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof if the third echocardiogram satisfies any of the following conditions: (1) The biplane LVEF is equal to or above a first predetermined biplane LVEF threshold and below a second predetermined biplane LVEF threshold; or (2) the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold and the post-warrior-action LVOT-G is below a predetermined post-warrior-action LVOT-G threshold; and is also provided with
If the biplane LVEF of the third echocardiogram is above a second predetermined biplane LVEF threshold and the post-warrior action LVOT-G of the third echocardiogram is equal to or above a predetermined post-warrior action LVOT-G threshold, the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is greater than the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof.
The method of embodiment 87, wherein the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg of compound 1, the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg or about 10mg of compound 1, the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg, about 10mg or about 15mg of compound 1, and the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg, about 10mg, about 15mg or about 20mg of compound 1.
Embodiment 88 the method of embodiment 86 or 87, further comprising measuring biplane LVEF and post-warrior LVOT-G of the third echocardiogram.
Embodiment 89 the method of any one of embodiments 86-88, wherein the third time period is about 2 weeks.
Embodiment 90 the method of any one of embodiments 77-89, wherein the first predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the post-predetermined warfarin LVOT-G threshold is 30mmHg.
Embodiment 91 the method of any one of embodiments 1-90, wherein prior to administration of compound 1 or a pharmaceutically acceptable salt thereof, the patient has (i) resting LVOT-G ≡50mmHg; or (ii) resting LVOT-G is greater than or equal to 30mmHg and after <50mmHg and Wash action LVOT-G is greater than or equal to 50mmHg.
Embodiment 92 the method of any one of embodiments 1-91, wherein the patient has a Left Ventricular Ejection Fraction (LVEF) of ≡60% prior to administration of compound 1 or a pharmaceutically acceptable salt thereof.
Embodiment 93 the method of any one of embodiments 1-92, wherein no propidium amine is administered to the patient during treatment with compound 1 or a pharmaceutically acceptable salt thereof.
Embodiment 94 the method of any one of embodiments 1-92, wherein propidium amine is administered to the patient during treatment with compound 1 or a pharmaceutically acceptable salt thereof.
Embodiment 95 the method of any one of embodiments 1-92, wherein the patient is not treated with propidium or an anti-arrhythmic drug having negative cardiotonic activity within 4 weeks prior to treatment with compound 1 or a pharmaceutically acceptable salt thereof.
Embodiment 96 the method of any one of embodiments 1-94, wherein an anti-arrhythmic agent is administered to the patient during treatment with compound 1 or a pharmaceutically acceptable salt thereof.
Embodiment 97 the method of any one of embodiments 1-96, wherein the patient is a CYP2D6 hypometabolizer.
Embodiment 98 the method of any one of embodiments 1-97, wherein the patient is fasted when compound 1 or a pharmaceutically acceptable salt thereof is administered.
Embodiment 99 the method of any one of embodiments 1-97, wherein the patient is fed when compound 1 or a pharmaceutically acceptable salt thereof is administered.
Embodiment 100. The method of any one of embodiments 1-99, wherein the method does not comprise collecting a blood sample of the patient.
Embodiment 101. The method of any one of embodiments 1-100, wherein the method does not comprise analyzing a blood sample of the patient.
Embodiment 102. The method of any one of embodiments 1-101, wherein the patient is administered a β -blocker during treatment with compound 1 or a pharmaceutically acceptable salt thereof.
Embodiment 103. A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof.
Embodiment 104. The method of any one of embodiments 1-103, wherein the method results in one or more of the following: improved mitral regurgitation, improved cardiac relaxation, beneficial cardiac remodeling, reverse cardiac remodeling, beneficial cardiac structural remodeling, beneficial cardiac functional remodeling, adverse cardiac remodeling reversal, reduced average Left Ventricular Mass Index (LVMI), improved Left Ventricular (LV) filling pressure, reduced Left Atrial Volume Index (LAVI), reduced assessment of the category of pre-systole motion of the mitral valve leaflets, reduced frequency of eccentric mitral regurgitation, reduced lateral E/E', reduced lateral E/E, reduced Brain Natriuretic Peptide (BNP), and reduced N-terminal pro-hormone of brain natriuretic peptide (NT-proBNP).
Embodiment 105 the method of any one of embodiments 1-103, wherein the method results in one or more of: peak oxygen uptake (pVO 2) improvement by cardiopulmonary exercise testing (CPET), kansashimi cardiomyopathy questionnaire clinical summary score (KCCQ-CSS) improvement, NYHA functional classification improvement of one or more categories, left ventricular outflow tract gradient (LVOT-G) improvement after warrior action, and total workload improvement during CPET.
Embodiment 106. The method of embodiment 105, wherein the method results in a change from baseline of pVO of ≡1.5mL/kg/min and an increase in NYHA functional class by one or more classes.
Embodiment 107 the method of embodiment 105 wherein the method is such that the change from baseline of pVO is ≡3.0mL/kg/min and the NYHA functional class is not worsened.
Embodiment 108. The method of embodiment 105, wherein the method increases KCCQ-CSS by 5 minutes or more.
Embodiment 109. The method of embodiment 105, wherein the method produces resting LVOT-G <30mmHg, LVOT-G <50mmHg after Watt action, and NYHA functional class I.
Embodiment 110 the method of embodiment 105, wherein the method increases resting LVOT-G <30mmHg, post-warrior LVOT-G <50mmHg, and NYHA functional class by one or more classes.
Embodiment 111 the method of any one of embodiments 104-110, wherein one or more results of the treatment occur within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks of starting treatment with compound 1 or a pharmaceutically acceptable salt thereof.
Embodiment 112. A method of reducing the resting left ventricular outflow tract pressure gradient (LVOT-G) to less than 30mmHg and reducing the left ventricular outflow tract pressure gradient (LVOT-G) to less than 50mmHg in a patient suffering from obstructive hypertrophic cardiomyopathy (oHCM), the method comprising administering to the patient a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof.
Embodiment 113 the method of embodiment 112 wherein the resting left ventricular outflow tract pressure gradient (LVOT-G) is reduced to less than 30mmHg and the left ventricular outflow tract pressure gradient (LVOT-G) is reduced to less than 50mmHg after a wag event occurs within 10 weeks of starting treatment with compound 1 or a pharmaceutically acceptable salt thereof.
Embodiment 114. The method of embodiment 113, wherein the resting left ventricular outflow tract pressure gradient (LVOT-G) is reduced to less than 30mmHg and the left ventricular outflow tract pressure gradient (LVOT-G) is reduced to less than 50mmHg after a wag event occurs within two weeks of starting treatment with compound 1 or a pharmaceutically acceptable salt thereof.
Embodiment 115 the method of any one of embodiments 112-114, wherein the decrease in LVOT-G after resting LVOT-G and warrior action is for at least 10 weeks of treatment.
Embodiment 116 the method of any one of embodiments 112-114 wherein the therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof is selected by titrating the daily dose of compound 1 or a pharmaceutically acceptable salt thereof administered to the patient.
Embodiment 117 the method of embodiment 116, wherein the dose is titrated once during the course of treatment.
Embodiment 118 the method of embodiment 116, wherein the dose is titrated two or more times during the course of treatment.
Embodiment 119 the method of any one of embodiments 116-118, wherein the daily dose is administered to the patient in a constant amount for about two weeks prior to titrating the daily dose.
Embodiment 120 the method of any one of embodiments 116-118, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 5mg to about 30mg.
Embodiment 121. The method of embodiment 120, wherein the daily dose is about 5mg.
Embodiment 122 the method of embodiment 120, wherein the daily dose is about 10mg.
Embodiment 123 the method of embodiment 120, wherein the daily dose is about 15mg.
Embodiment 124. The method of embodiment 120, wherein the daily dose is about 20mg.
Embodiment 125 the method of embodiment 120 wherein the daily dose is about 30mg.
Embodiment 126 the method of any one of embodiments 116-125, wherein the daily dose is administered daily as a single dose.
Embodiment 127 the method of any one of embodiments 116-125, wherein said daily dose is administered in 2 divided doses.
Embodiment 128 the method of any one of embodiments 116-127, wherein the decrease in LVOT-G peaks within 2 to 6 weeks of end of dose titration after resting LVOT-G and warrior action.
Embodiment 129. A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof, wherein the patient has a resting left ventricular outflow tract pressure gradient (LVOT-G) of at least 50mmHg prior to administration of compound 1, or a pharmaceutically acceptable salt thereof.
Embodiment 130. A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof, wherein the patient has a resting left ventricular outflow tract pressure gradient (LVOT-G) of at least 30mmHg and less than 50mmHg and a post-warfare left ventricular outflow tract pressure gradient (LVOT-G) of at least 50mmHg prior to administration of compound 1, or a pharmaceutically acceptable salt thereof.
Embodiment 131. A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof, wherein the patient is eligible for diaphragmatic reduction therapy (SRT).
Embodiment 132 the method of embodiment 131, wherein the method does not require diaphragmatic reduction therapy in the patient.
Embodiment 133 the method of embodiment 131 or 132, wherein the diaphragmatic reduction therapy is myotomy.
Embodiment 134 the method of embodiment 131 or 132, wherein the diaphragmatic reduction therapy is alcohol diaphragmatic ablation.
Embodiment 135 a method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient having symptoms of heart failure, the method comprising administering to the patient a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof, wherein the method results in a reduction in symptoms of heart failure as assessed by NYHA classification.
The method of embodiment 136, wherein the method converts a patient from NYHA class III to class II or class I.
Embodiment 137 the method of embodiment 135 wherein the method converts a patient from NYHA class II to class I.
The method of embodiment 138, wherein the method converts a patient from NYHA class III to class I.
The method of embodiment 139, wherein the method converts the patient from NYHA class III to class II.
The method of any of embodiments 135-139, wherein the reduction in symptoms of heart failure occurs within 10 weeks of starting treatment with compound 1 or a pharmaceutically acceptable salt thereof.
The method of embodiment 141, wherein the method increases the patient by at least one NYHA class.
Embodiment 142. The method of embodiment 141, wherein the method results in an increase in one NYHA class.
Embodiment 143 the method of embodiment 141, wherein the method results in an increase in two NYHA classes.
The method of any one of embodiments 135-143, wherein the reduction in symptoms of heart failure occurs within 10 weeks of starting treatment with compound 1 or a pharmaceutically acceptable salt thereof.
Embodiment 145. A method of reducing the level of NT-proBNP in a patient, the method comprising administering to the patient a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof.
Embodiment 146 the method of embodiment 145, wherein the patient has obstructive hypertrophic cardiomyopathy (oHCM).
Embodiment 147 a method of reducing cardiac troponin I levels in a patient, comprising administering to the patient a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof.
Embodiment 148 the method of embodiment 147, wherein the patient has obstructive hypertrophic cardiomyopathy (oHCM).
Embodiment 149. The method of any one of embodiments 129-148, wherein the therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof is selected by titrating the daily dose of compound 1 or a pharmaceutically acceptable salt thereof administered to the patient.
Embodiment 150. The method of embodiment 149, wherein the dose is titrated once during the course of treatment.
Embodiment 151 the method of embodiment 149, wherein the dose is titrated two or more times during the course of treatment.
The method of any one of embodiments 149-151, wherein the daily dose is administered to the patient in a constant amount for about two weeks prior to titrating the daily dose.
The method of any one of embodiments 149-152, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 5mg to about 30 mg.
Embodiment 154 the method of embodiment 153, wherein the daily dose is about 5mg.
Embodiment 155 the method of embodiment 153, wherein the daily dose is about 10mg.
Embodiment 156. The method of embodiment 153, wherein the daily dose is about 15mg.
Embodiment 157 the method of embodiment 153, wherein the daily dose is about 20mg.
Embodiment 158 the method of embodiment 153, wherein the daily dose is about 30mg.
Embodiment 159 the method of any one of embodiments 154-158, wherein said daily dose is administered daily as a single dose.
The method of any one of embodiments 154-158, wherein the daily dose is administered in 2 divided doses.
Embodiment 161 the method of any of embodiments 1-160, wherein when administration of compound 1 or a pharmaceutically acceptable salt thereof is initiated, the patient is classified as NYHA class III.
Embodiment 162 the method of any one of embodiments 1-160, wherein when administration of compound 1, or a pharmaceutically acceptable salt thereof, is initiated, the patient is classified as NYHA class II.
The method of any one of embodiments 1-162, wherein the method reduces left ventricular wall stress in the patient.
Embodiment 164 the method of any one of embodiments 1-163, wherein the method reduces myocardial damage to the patient.
Embodiment 165 the method of any one of embodiments 1-164, wherein administering compound 1 or a pharmaceutically acceptable salt thereof has a sustained effect for at least 6 months.
Embodiment 166. The method of any one of embodiments 1-164, wherein administering compound 1 or a pharmaceutically acceptable salt thereof has a sustained effect for at least 5 years.
Embodiment 167. The method of any of embodiments 1-164, wherein administering compound 1 or a pharmaceutically acceptable salt thereof has a sustained effect for at least 10 weeks, 12 weeks, 1 year, 2 years, 3 years, or 4 years.
Embodiment 168. A method of reducing left ventricular wall stress in a patient, the method comprising administering to the patient a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein the patient has obstructive hypertrophic cardiomyopathy (oHCM).
Embodiment 169 the method of embodiment 168, wherein the therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof is selected by titrating the daily dose of compound 1 or a pharmaceutically acceptable salt thereof administered to the patient.
Examples
The present application may be better understood by reference to the following non-limiting examples, which are provided as exemplary embodiments of the present application. The following examples are presented to more fully illustrate the embodiments, however, should in no way be construed as limiting the broad scope of the application. While certain embodiments of the present application have been shown and described herein, it should be understood that such embodiments are provided by way of example only. Many alterations, modifications and substitutions may be made by those having ordinary skill in the art without departing from the spirit and scope of the invention. It should be understood that various alternatives to the embodiments described herein may be employed in practicing the methods described herein.
Example 1
This first human study of alfukantan (also known as CK-274) was performed to evaluate its safety, pharmacokinetic and pharmacodynamic profiles, including effects of food or CYP2D6 weak metaboliser (CYP 2D 6-PM) phenotypes. African is a selective cardiac myosin inhibitor that reduces the measurement of preclinical left ventricular contractility in vitro and in vivo, and thus can have therapeutic potential for managing hypertrophic cardiomyopathy. This phase 1, double blind, randomized, placebo controlled study received healthy adults aged 18 to 55 years to receive single or multiple escalated doses (14 or 17 days) of either alfukantan or placebo. In addition to standard safety and pharmacokinetic assessments, pharmacodynamic effects were assessed by echocardiography. The study received 102 participants (57 in single dose cohorts, 24 in multi-dose cohorts, 9 in CYP2D6-PM cohorts, and 12 in food effect cohorts). Adverse events were generally mild and not more frequent than placebo at single-dose.ltoreq.50 mg and multiple-dose.ltoreq.10 mg of African. In a single increment dose cohort, the plasma concentration of alfukantan was increased in a dose-proportional manner; the half-life of alfukantan is 75 to 85 hours. Neither food nor CYP2D6-PM phenotype has a clinically significant impact on pharmacokinetics. With a single 50-mg dose, the average Left Ventricular Ejection Fraction (LVEF) was reduced by 5.5% (p=0.0001) from baseline. With multiple doses, a 5.0% decrease in average LVEF was observed after 10mg of african lasting 14 days once a day. At the doses evaluated, alfukantan appeared to be safe and well tolerated. Shows the pharmacodynamic effect on LVEF, which provides support for further clinical studies of alfukantan.
Method
Summary of the study and ethics. The study used randomized, placebo controlled, single dose (SAD) and multiple dose (MAD) designs (fig. 2). Design studies are not to identify the maximum tolerated dose, but rather to identify a pharmacologically active dose range, which is defined as giving an absolute decrease in Left Ventricular Ejection Fraction (LVEF) from baseline (e.g., a decrease in baseline LVEF value from 70% to between 55% and 65%) ranging from 5% to 15%. When this range is reached, or when a non-tolerated dose is identified (if earlier), early dose escalation should be stopped.
Participants and treatments. To qualify for the present study, the participants should be healthy adults aged 18 to 55 years with a body mass index of 18.0 to 32.0kg/m 2 With normal Electrocardiography (ECG) and clinical laboratory values, or with only minor abnormalities that are considered clinically insignificant. Participants must also have normal cardiac structure and function, LVEF being ≡60% for the first 4 SAD queues, LVEF being ≡65% for the subsequent SAD queues, all MAD queues and food effect queues, and LVEF being ≡55% for the CYP2D6-PM queues. No prescription drugs were allowed to be used by the participants for 14 days, no over-the-counter drugs (except acetaminophen) for 7 days, or tobacco or nicotine for 3 months prior to the study; in addition, it was not allowed to consume alcohol, caffeine or grapefruit within 48 hours prior to study registration.
A randomized schedule is generated centrally for each queue and treatment session. In all cohorts, the alfukantan or matched placebo was administered in the form of granules in capsules containing about 240ml of water. Study medication was administered after an overnight fast, except during the feeding period in the food effect cohort.
Single increment dose (SAD) queue. The SAD portion of the study used randomized, double-blind, placebo-controlled, sequential, ascending dose design, wherein participants received a single ascending oral dose of study drug. The 7 queues were administered sequentially (fig. 2). Of the 8 participants in each cohort, the first 2 were randomly assigned (1:1) to either avibactam or placebo and follow-up for a minimum of 2 days, then the remaining participants of the group were dosed. The remaining 6 participants were then randomly assigned (5:1) to receive either oral single doses of african tan (1 mg, 3mg, 10mg, 25mg, 40mg, 50mg or 75 mg) or placebo.
Initial doses of African were selected using standards based on the guidelines of the United states food and drug administration (United States Food and Drug Administration) of previous animal studies and employing safety margins of > 10 times. Dose escalation will cease when the results identify a pharmacologically active dose range or non-tolerogenic dose (whichever occurs first) that reduces LVEF by 5% to 15%.
Dose escalation recommendations for SAD cohorts and MAD cohorts described below were made by treatment researchers who were blind to the treatment group and approved or disapproved by the non-blind dose level review board (Dose Level Review Committee, DLRC). Decisions were made when No. 6 participants had been treated and the follow-up was No. 3 days, including collection of clinical, laboratory, ECG and telemetry data and suitability for assessment of maximum plasma drug concentration (C max ) Echocardiography of LV function at time. The increasing criteria included the occurrence of LVEF in no more than 2 participants in the dose group<50% and no individuals present LVEF<45%. Dose escalation criteria were as follows: (1) The individual did not continuously develop cardiac serious adverse events associated with the study drug; (2) 2 individuals did not experience similar non-cardiac serious adverse events in the same organ system that appeared to be associated with study drug; (3) With the last pre-dose value (by dose level review Committee [ DLRC ]]Assay) did not experience a decrease in Left Ventricular Ejection Fraction (LVEF) in 2 individuals treated with alfukantan>15%; (4) Individuals do not develop LVEF<45% (unless DLRC and treatment investigator determined to be not related to study drug); and (5) treatment investigators and DLRC approve ascending and next level doses based on their clinical judgment.
Multiple Ascending Dose (MAD) cohorts. MAD cohorts were also designed using randomization, double-blind, placebo-controlled, sequential. The MAD cohort was initiated when the SAD cohort identified a single oral dose that was well tolerated and correlated with the observed PD effect. Each of the 3 MAD queues included 8 participants, which were randomized (6:2) to either african or placebo. Participants received once daily oral doses of study drug for 14 days (in a 5 or 10mg avibactam to placebo cohort) or 17 days (for a 7.5mg avibactam to placebo cohort).
CYP2D6 poor metaboliser cohort. A separate cohort was enrolled to evaluate the potential effect of CYP2D6 genetic variants on PK properties of alfukantan. The CYP2D6 gene encodes a cytochrome P450 2D6 enzyme, which is elaborated as the most widely characterized polymorphic drug metabolizing enzyme, and previous in vitro studies have suggested that CYP2D6 is a potential metabolizing enzyme of African.
Determining CYP2D6 genotype at the time of screening all study participants; participants identified as CYP2D6-PM are excluded from the SAD and MAD queues, but are invited to participate in the CYP2D6-PM queue. Following the SAD 25-mg cohort, the first individual in the CYP2D6-PM cohort was dosed (FIG. 2). Each participant received a single dose of african tan (10 mg) or placebo. The 9 participants were randomized (7:2) and the whistle dosing group consisted of the first 2 participants of the treatment.
Food effect queue. To evaluate the effects of food on PK of alfukantan, separate cohorts were enrolled after completion of the last SAD cohort, with 8 to 12 participants scheduled to be enrolled. In the open-label, 2-factor crossover design, participants received 2 single doses of 10mg of african, spaced at > 14 days. Participants were randomly grouped into 1 of 2 sequences at a 1:1 ratio: fasted/fed or fed/fasted. In the fasted period, the african is administered after overnight fasted; in the feeding period, the african is administered 30 minutes after the onset of a high fat breakfast.
Evaluation of
Safety and tolerability. Safety is assessed in terms of the incidence of Adverse Events (AEs) and the incidence of reduced LVEF. Treatment Emergency AE (TEAE) is defined as AE that begins or increases after administration of the study drug. All AEs were coded using regulatory activity medical dictionary (Medical Dictionary for Regulatory Activities) version 21.1 and rated using the american national cancer institute AE common terminology standard (National Cancer Institute Common Terminology Criteria for AE) (version 4.03) 5 score severity scale. Each AE was judged by the treatment investigator to be related or unrelated to the study drug. Clinical laboratory tests were obtained at regular intervals in all queues.
For safety monitoring, participants in all cohorts performed periodic echocardiography assessed by cardiologists. Echocardiography was also reviewed by the echocardiography core laboratory for PD assessment in SAD and MAD queues, as described below. In addition, participants in all cohorts were monitored with a 12 lead ECG recording using a Holter monitor (Holter monitor). For safety monitoring, single 12 lead ECG was periodically extracted at screening, pre-dose and throughout the follow-up and interpreted by the investigator. In SAD, MAD and CYP2D6-PM cohorts, cardiac kinetic ECGs (10 second, 12 lead ECG recordings in triplicate) were obtained prior to the corresponding PK blood and ECG intervals quantified by qualified readers.
Pharmacokinetic analysis. For all study groups, blood samples were obtained for PK assessment prior to dosing, up to 12 times daily on day 1, and then at regular intervals throughout the study. Blood samples were collected according to the following schedule: SAD queues: day 1: pre-and post-dosing 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h, 48h, 72h, 96h and 216h. MAD cohort (14 days of dosing): day 1: pre-and post-dosing 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h and 12h; day 2, day 4, day 5, day 6 and day 9: pre-dose (corresponding to the trough samples after dosing on days 1, 3, 4, 5 and 8) and 1.5h post-dose; day 3, day 7, day 8, day 10, day 11, day 12, and day 13: pre-dosing (corresponding to the trough samples after dosing on days 2, 6, 7, 9, 10, 11 and 12); day 14: pre-and post-dosing 0.25h, 0.5h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h, 48h, 72h and 168h. MAD cohort (17 days of dosing): day 1: pre-and post-dosing 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h and 12h; day 2, day 4, day 5, day 6 and day 9: pre-dose (corresponding to the trough samples after dosing on days 1, 3, 4, 5 and 8) and 1.5h post-dose; first, the Day 3, day 7, day 8, day 10, day 11, day 12, day 13, day 14, day 15, and day 16: pre-dosing (corresponding to the trough samples dosed after day 2, day 6, day 7, day 9, day 10, day 11, and day 12); day 17: pre-and post-dosing 0.25h, 0.5h, 1.5h, 2h, 2.5h, 3h, 5h, 7h, 9h, 12h, 24h, 36h, 48h, 72h and 168h. CYPD6-PM queue: day 1: pre-and post-dosing 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h, 48h, 72h, 96h, 216h, 312h and 552h. Food effect queue: day 1: pre-and post-dosing 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h, 48h, 72h, 96h, 144h and 216h. UsingVersion 7.0 uses standard non-compartmental methods to calculate PK parameters; the actual sample collection time was used.
Plasma concentrations of alfukantan were measured using high performance liquid chromatography-tandem mass spectrometry methods, the accuracy, precision, linearity, sensitivity and specificity of which were verified in Celerion (Lincoln, nebraska). The analytical range (lower limit of quantification to upper limit) of African is 1.00ng/ml to 500ng/ml.
Echocardiography. For the PD evaluation of LVEF, the echocardiograms of the SAD and MAD queues were interpreted by the echocardiogram core laboratory and used for all data analysis and dose level review decisions while an immediate local interpretation of the echocardiogram was performed for safety monitoring. Echocardiography was obtained on day-1, before day 1, and 1.5h, 4h, and 24h after dosing in SAD cohorts receiving 1mg, 3mg, or 10mg of african. Echocardiography was obtained on day-1, before day 1 dosing, and 1.5h, 6h, and 24h after dosing for SAD queues receiving 25mg, 40mg, 50mg, or 75mg of african. If 24h LVEF has not returned to near or above baseline, as determined by the investigator, echocardiography is only obtained on day 3 (48 h post-dose). Echocardiography was obtained on day-1, 1.5h before and after dosing on days 2, 4 and 9, and 1.5h, 24h and 72h after dosing on day 14 (for 5-mg and 10-mg cohorts) or 1.5h, 24h and 72h after dosing on day 17 (for 7.5-mg cohorts) in the MAD cohort. If the participant's previous LVEF was not near or above baseline, as determined by the investigator, echocardiography was obtained only 3 days after the last dose (day 17 or day 20).
And (5) carrying out statistical analysis. The sample size selected for this study was based on a precedent set of other first human PK studies with similar properties and was not calculated based on assay force. All participants receiving ≡1 dose of study drug (either African or placebo) were included in the safety analysis. The PK analysis set included all participants who received > 1 dose of study drug and had > 1 evaluable PK plasma profile.
PK analysis was aimed at assessing the effects of single dose kinetics, multi-dose (steady state) kinetics, CYP2D6 phenotype on the absorption and elimination of alfukantan, and the effects of food on the absorption and elimination of alfukantan. For the SAD cohort, the dose ratio of african was evaluated on day 1 using a verification force model. For the MAD cohort, dose ratios were evaluated using the assay force model on day 1 and day 14 or day 17. Several considerations are taken into account when assessing the dose proportion of the drug, such as results from statistical analysis of the assay force model (e.g., slope estimate and 2-sided 95% confidence interval [ CI ]]Is included), the qualitative assessment of PK specificity against the drug, and the clinical relevance. For the SAD cohort, the parameter used to evaluate the dose ratio was the area under plasma drug concentration-time curve (AUC) (AUC Last time ) AUC (AUC) extrapolated to infinity at time 0 inf ) AUC (AUC) over time 0 to 24h 24 ) And maximum plasma concentration (C max ). For MAD queues, the parameter is AUC 24 And C on day 1 max AUC at the end of dosing period (AUC tau ) And C on day 14 or day 17 max . By involving a second (ln dose) 2 And three times (ln dose) 3 The effect was used to verify the statistically linear relationship between ln-transformed PK parameters and ln-transformed doses. If a 5% significance level is used, the secondary and tertiary effects are not statistically significant, or ifThe effect is statistically significant but with said small magnitude that it is clinically irrelevant, a statistically linear relationship is established. UsingPROC MIXED was subjected to dose-scale analysis. If a statistically linear relationship is shown and if the 2-sided 95% CI around the slope estimation parameter includes a value of 1 for the dose dependent parameter, then a dose scale is established.
In the MAD cohort, helmert contrast (Helmert contrast) was used to convert ln to plasma trough concentration (C Valley value ) Values were analyzed for stability of alfukantan. Separately performing a variance (ANOVA) model analysis for each dose level; the days were included as a fixation effect. A hermite comparison was developed so that the average value at each time point was compared with the average value at the subsequent time point. Steady state was established at the time point where no statistical difference (α=5%, side 2) was observed with the subsequent time points.
PD analysis concentrations included all participants who received 1 dose of study drug and had 1 dose or more pre-and 1 dose or more post-echocardiographic measurements. Descriptive analysis included absolute decrease in LVEF from baseline and category LVEF response (LVEF decrease from baseline ≡5%,. Gtoreq.10% and ≡10%)>15% participant ratio and LVEF<50% and<45% of the proportion of participants). UsingVersion 9.3 or higher generates descriptive statistics of echocardiographic parameters.
Dose-response analysis was performed using analysis of covariance (ANCOVA) to identify the least squares mean difference (african minus placebo). To analyze the effect of drug dose on echocardiographic parameters in SAD and MAD cohorts, a linear hybrid model of repeated measures covariance analysis (ANCOVA) was used to perform inference analysis on the PD analysis set. ANCOVA uses baseline values as covariates, including treatment, time point, and time point-treatment interactions as fixed effects, and changes from baseline as dependent variables. Unstructured variance-covariance structures are used and the model takes into account the point in time repeat measurements. ANCOVA analysis was performed separately for each study portion and for each PD parameter. The least squares mean, the difference of the least squares mean (active minus placebo) and the relevant 2-sided 95% CI are presented for each comparison.
Analysis of concentration 'bins' and exposure-response was also performed using ANCOVA. UsingPROC MIXED performed all comparative analyses. Another inference analysis was performed in SAD and MAD queues to evaluate the relationship between concentration of alfukantan and LVEF of participants in the PK/PD analysis set. Concentration bin ANCOVA was performed using a linear hybrid model of the repeated measure analysis, using concentration bin sets as fixed effects, baseline PD parameters as covariates, changes compared to baseline as dependent variables, and random intercepts for adjusting the repeated measure. An unstructured variance-covariance structure is used. Plasma concentrations of african were paired with consistent PD parameters. ANCOVA compares the change in PD parameters between each bin versus the pooled placebo group. The least squares mean, the difference of the least squares mean (bin minus placebo) and the relevant 2-sided 95% CI are presented for each comparison. ANCOVA analysis was performed separately for each study portion. For all time points where PK data and PD metrics are available, the time points are pooled for analysis. In each part of the study, the concentration of african with time-matched PD data was pooled and ordered in ascending order. The data were then divided from minimum to maximum into 5 sets of observations ('bins'), each set consisting of 20% data points. Each bin is treated as a separate group. Concentration bins consisted of a placebo group and 5 bin groups pooled based on concentrations at all time points of the african treatment.
The above analysis was then repeated using the concentration as a continuous variable to estimate the exposure-reaction trend. The random intercept effect and the random concentration effect were added to ANCOVA. Estimates of concentration slopes and corresponding 2-sided 95% CI and ANCOVA analysis are presented for each study portion.
For all time points where PK data and PD metrics are available, the time points are pooled for analysis. The nominal significance level of 5% was used for statistical comparison, without adjusting for multiplexing.
Results
Study population. A total of 102 participants were enrolled: 57 out of SAD queues, 24 out of MAD queues, 9 out of CYP2D6-PM queues and 12 out of food effect queues. All participants completed the study. The mean age of each cohort was between 32 and 40 years old, and most participants were males (table 1).
Table 1: baseline characteristics
Values are mean (range), n (%) or mean ± SD. BMI = body mass index; LVEF = left ventricular ejection fraction; MAD = multiple incremental doses; CYP2D6-PM = cytochrome P450 2D6 hypometabolizer; SAD = single increment dose; sd=standard deviation.
For the SAD cohort, there is no safety issue prohibiting dose escalation between 1mg and 25 mg. With the next planned dose (50 mg), 1 participant had a LVEF <50% (46.2%) after dosing; however, this did not meet the up-dosing stop rule and a 75-mg cohort was started. Sentinel participants in the 75-mg cohort had a LVEF <45% after dosing; thus, the other participants were not dosed at 75 mg. Thus, the 50-mg group was expanded and the other 5 participants in this queue were dosed. After expansion, 1 participant in the 50-mg dose group experienced a LVEF <45%, which was also reduced by >15%. Therefore, no more than 50mg was administered to the other participants. The DLRC determines the dose for the final single dose cohort to be 40mg.
Following the results of the 1-mg to 25-mg SAD cohort, the first MAD cohort was started with 5mg african once a day for 14 days. There was no safety problem and the next queue was started with 10mg once daily for 14 days. In this queue, 2 participants met the stopping criteria based on echocardiographic results. DLRC determines that the next therapeutic level should be 7.5mg to better characterize PK at steady state; thus, the dosing period was extended from 14 days to 17 days to ensure that PK reached steady state by the last day of dosing.
Safety and tolerability. There was no severe AE and no participants discontinued the study due to AE. For single and multi-dose administration, TEAE was observed to be generally mild (grade 1) and not more frequently with alfukantan than with placebo (tables 2 and 3). In summary, the most common TEAE in both SAD and MAD queues is headache (tables 2 and 3).
Table 2: treatment of emergency adverse events in SAD queue
The value is n (%). The most common TEAE based on priority is reported among ≡2 participants in the total queue. * The 'left chest foamy feel' is consistent with gastrointestinal correlations rather than cardiac correlations.Beginning about 60 hours after administration. SAD = single increment dose; TEAE = treatment emergency adverse event.
Table 3: treatment of Emergency adverse events in MAD queue
The value is n (%). Priority-based TEAE was reported among ≡1 participant in the total queue. MAD = multiple incremental doses; qd = once daily; TEAE = treatment emergency adverse event.
Echocardiographic related AEs with <45% reduction in ejection fraction based on study echocardiography expert evaluation were reported among 3 participants: there were 1 in each of the SAD 40-mg, 50-mg and 75-mg queues (Table 4). All AEs were grade 1 and were resolved at the next echocardiographic evaluation (within 2.5h to 4.6 h). A single participant receiving 75mg of african had a LVEF of 34.6% 1.5h after dosing, which was reduced by 31.5% and concluded that the dose of the SAD portion of the study was ascending as discussed above. At the subsequent evaluation after 2.5h, LVEF had returned to 51.9%. No <45% AE reduction in ejection fraction was reported in MAD, CYP2D6-PM or food effect cohorts.
In all queues, the average safety ECG parameters at the estimated time points are within normal limits. No clinically significant change from baseline was observed in any of the parameters. The QT interval (QTcF) of the heart rate was corrected using the friericia's formula, no more than 450ms at baseline or at any evaluation during the dosing interval, except 2 individuals with baseline QTcF ≡440ms and QTcF values increased by 3ms and 13ms, respectively. In all the cohorts, QTcF interval of >30ms did not increase, except 1 participant whose QTcF interval increased by 33ms (427 ms vs. baseline 394 ms) at day 5 in the SAD placebo group. In cardiac kinetic assessment, class analysis of ECG parameters did not reveal cardiac safety issues and there was no evidence of positive QT effects following single or multiple doses of african.
At the time point after dosing, all vital signs were within normal limits. No clinically significant serum chemistry, hematology or urinalysis results were observed during the study.
Table 4: echocardiographic related AEs with <45% reduction in ejection fraction
* The time after administration of the drug.LVEF values for safety assessment were determined by study cardiologists. />In the SAD cohort, post-dose echocardiography was performed at 1.5h, 4h, 6h, 24h, and 48h post-dose. AE = adverse event; LVEF = left ventricular ejection fraction; SAD = single increment dose.
Pharmacokinetics of drugs
Single dose kinetics. The plasma african profile at all dose levels is generally well characterized, except for the lowest dose of 1mg (due to the concentration approaching the lower limit of quantification) and the highest dose of 75mg (administered only 1 participant), as discussed above. In the dosage range of 1mg to 50mg, the mean maximum plasma concentration and exposure are increased in a dose-proportional manner, e.g. C max And plasma concentration versus time curve area under time (AUC) of time 0 to 24h 24 ) As shown by the increase in dose (figures 3A-3B and table 5). The average clearance and the distribution volume at each dose were similar. The median time to maximum concentration was observed to occur between 0.5h and 2.8h, and the maximum time for all participants was 4.0h. The average half-life ranges from 75h to 85h.
Table 5: summary of plasma African pharmacokinetics following Single oral dose administration
Multiple dose kinetics. With once daily dosing, mean plasma concentrations increased between 5-mg dose and 2 higher doses (7.5 mg and 10 mg); however, by day 2 there was little difference between the average concentrations of 7.5-mg and 10-mg doses (FIG. 4). Plasma PK parameters are shown in table 6. By the end of the treatment period (day 14 or day 17), the mean plasma concentration is between 2 and 2.5 times the day 1 plasma concentration. The terminal elimination half-life of each dose was estimated to be consistent, between 77h and 86 h. The clearance rates for the 5-mg and 10-mg doses were similar, and the cumulative ratio of 3 doses was similar. Consistent with the observed end elimination half-life estimates, steady state was reached after 10 to 12 days (fig. 4).
Table 6: summarization of plasma African pharmacokinetics following multiple oral dose administration
CYP2D6 poor metaboliser cohort. In CYP2D6-PMs, the average half-life is prolonged to 110h compared to 85h in broad metabolizers (i.e., 10-mg SAD cohort); however, no increase in AUC was observed in this group, and the geometric mean AUC compared to 679ng h/ml (geometric CV% 35) in a broad population of metabolizers (Table 5) 24 Is 495ng h/ml (coefficient of geometric variation% [ CV ]]19 (table 7). CYP2D6-PM does not appear to have reduced clearance, resulting in clinically significant exposure differences.
Table 7: summary of plasma African pharmacokinetics in CYP2D6 poor metabolizer cohort
The dose of African was 10mg. AUC and C max Values are presented as geometric mean and geometric CV, T max Values are presented as median (range) and all other parameters are presented as arithmetic mean ± standard deviation. AUC (AUC) 24 Area under the plasma drug concentration-time curve =time 0 to 24 h; AUC (AUC) inf AUC extrapolated to infinity =time 0; CL/F = apparent total body clearance; c (C) max =maximum plasma concentration; CV% = coefficient of variation; PK = pharmacokinetics; t is t 1/2 =half-life; t (T) max Time to maximum plasma concentration; vz/F = apparent distribution volume.
Effects of food. PK parameters for alfukantan in the food effect cohort are shown in table 8. African C when taken with food max Increase by about 30% and decrease in time to the observed maximum concentration (1.5 vs. 2.3 h). However, the food has a AUC ofMinimal effects, and geometric mean AUC of fasted state 24 (geometric CV%) was 601 (33) ng.h/ml vs. 631 (25) ng.h/ml for the fed state.
Table 8: summary of plasma African pharmacokinetics in food Effect cohorts
The dose of aficonazole was 10mg in each cohort. * For AUC inf 、t 1/2 CL/F and Vz/F, n=4.For AUC inf 、t 1/2 CL/F and Vz/F, n=7. AUC and C max Values are presented as geometric mean and geometric CV, T max Median (range) is presented and all other parameters are presented as arithmetic mean ± standard deviation. AUC (AUC) 24 Area under the plasma drug concentration-time curve for=0 to 24 h; AUC (AUC) inf AUC extrapolated to infinity =time 0; CL/F = apparent total body clearance; c (C) max =maximum plasma concentration; CV% = coefficient of variation; t is t 1/2 =half-life; t (T) max Time to maximum plasma concentration; vz/F = apparent distribution volume.
Pharmacodynamics of medicine
Left ventricular ejection fraction. At baseline, the mean LVEF range for each cohort was 61.0% to 67.5% (table 1). In the SAD cohort, an average decrease in LVEF was observed in the group receiving the highest dose of african (fig. 5A). A maximum average decrease from baseline (minimum square average difference 5.5%, p=0.0001) was seen at 1.5h post-dose in the 50-mg cohort. LVESV and LVEDV were statistically significantly increased by 8.1mL and 6.6mL, respectively (table 9). Other echocardiographic parameters (e.g., stroke volume, cardiac output, cardiac time interval, and metrics reflecting diastolic function) do not change significantly (table 9). Single participants receiving 75mg of african showed a 31.5% decrease in LVEF at 1.5h post-dose, which was resolved at 2.5h post-start but concluded that the dose was increasing in the SAD portion of the study, as discussed above. In the MAD cohort, there was a significant decrease in LVEF with continued dosing in the 10-mg cohort (FIG. 5B). A maximum average maximum% reduction of 5.0% from baseline was seen at day 14 at 1.5h post-dosing in the 10-mg cohort (fig. 5B). The 3.2% reduction in placebo correction (least squares mean difference) did not reach statistical significance (p=0.21), which may be due to the lack of statistical verification force in this panel comparison.
Table 9: echocardiographic parameters
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The table compares placebo data for echocardiographic parameters with 50mg of african (highest well-tolerated single dose) at baseline and 1.5h (time of echocardiography closest to peak plasma concentration of african). A = peak a wave velocity, bpm = heart beat per minute, CFB = change from baseline, CO = cardiac output, E = peak E wave velocity, EDV = end-systolic volume, ESV = end-systolic volume, ET = ejection time, E' lateral = tissue doppler velocity of the sidewall, IVCT = isovolumetric contraction time, IVRT = isovolumetric relaxation time, LAV = left atrial volume, LVEF = left ventricular ejection fraction, NS = insignificant (p > 0.05), SD = standard deviation, SV = cardiac output
Class LVEF reactions. In the SAD cohort, an absolute decrease of.gtoreq.5% from baseline was observed in 1 of 15 participants in the placebo cohort (7%), 1 of 6 participants in the 3-mg cohort (17%), 2 of 6 participants in the 40-mg cohort (33%), 7 of 11 participants in the 50-mg cohort (64%), and 1 of 1 participant in the 75-mg cohort (100%), whereas no participant decrease of.gtoreq.5% in the 1-mg, 10-mg, or 25-mg cohorts. An absolute decrease of.gtoreq.10% occurs in 1 out of 6 participants in the 40-mg queue (17%), 2 out of 11 participants in the 50-mg queue (18%), and 1 out of 75-mg queue (100%). A decrease in LVEF to <50% was observed for 2 out of 11 participants in the 50-mg queue (18%) (48.2% and 45.5% according to the core laboratory evaluation) and 1 out of 1 participant in the 75-mg queue (100%). Only participants in the 75-mg cohort experienced LVEF <45%.
In the MAD cohort, an absolute decrease in LVEF from baseline of ≡5% was observed in 4 participants: 1 of 6 participants receiving placebo (17%), 1 of 6 participants receiving 7.5mg of african once a day (17%) and 2 of 6 participants receiving 10mg of african once a day (33%). Of these participants, 2 participants in the 10-mg cohort decreased by ≡10%. No reduction in LVEF to <50% was observed in any MAD cohort according to the core laboratory evaluation.
Relationship of plasma concentration to LVEF variation. The PK/PD relationship of african is illustrated by plotting the change in plasma concentration of african versus LVEF for the SAD and MAD queues (fig. 6A and 6B). In the SAD cohort, there is a trend towards decreasing LVEF as the plasma concentration of alfukantan increases. In the bin concentration analysis (122 ng/ml to 524ng/ml, p < 0.0001) and concentration-slope analysis (p=0.0027) of the highest plasma concentration bin, the relationship of LVEF to african plasma concentration was statistically significant. In the MAD cohort, the relationship of LVEF to plasma aficonazole did not reach statistical significance in either bin concentration analysis or linear regression analysis, possibly due to the more limited range of plasma concentrations and smaller group sizes investigated.
Discussion of
This phase 1, first human study has established that alfukantan is physiologically effective in reducing LVEF and tolerates good doses (up to 50mg as a single oral dose or up to 10mg after multiple administrations) in healthy participants, thereby identifying the pharmacologically active dose to be used as the starting dose for patient studies with HCM. In addition, a single oral dose of 10mg was well tolerated in individuals with the CYP2D6-PM phenotype and food had no significant effect on PK of alfukantan. Together these observations support the continued development of alfukantan for patients with HCM and provide a roadmap for phase 2 studies.
Safety of African. No severe AE was observed in the study and all participants completed the intended dosing as planned. In general, AEs were mild and similar in frequency between participants treated with alfukantan and placebo. Importantly, participants with LVEF falling below 50% had no adverse changes in the relevant symptoms or vital signs, and LVEF for these cases returned to baseline within 24 hours. The present study did not aim to find the maximum tolerated dose, and thus dose escalation was stopped immediately as soon as significant PD effects were observed in the SAD and MAD portions of the study; thus, no intolerable doses due to AE were identified.
Effects on LVEF. In the SAD cohort, a dose of 50mg produced a 5.8% decrease in average LVEF, while in the MAD cohort, 10mg once a day for 14 days produced a 5% decrease in average absolute LVEF. The proportion of participants whose absolute decrease in LVEF from baseline was ≡5% increased with increasing dose; the absolute decrease in LVEF from baseline is ≡10% for up to 64% of the participants in the 50-mg SAD cohort and 33% of the participants in the 10-mg MAD cohort. In the SAD cohort, LVEF was statistically significantly reduced as the plasma concentration of african was increased when the widest exposure range of african was explored. Thus, the study achieves its secondary objective, namely to identify pharmacologically active doses and elucidate their PK/PD relationship.
The LVEF of three participants was reduced to <50% which was rapidly reversed after discontinuation of study drug. After a single dose of 50mg, 2 (18%) participants experienced LVEF <50% (48.2% and 45.5%). After a single dose of 75mg, 1 participant experienced a decrease in LVEF to 34.1%. In all cases, events were noted about 1.5 hours after dosing, and lvef recovered to >50% by 4 to 6 hours post dosing. SAD results provide information for dose selection for other parts of the study, and no echocardiography AE in MAD, CYP2D6-PM or food effect cohorts.
Meaning of PK results. African exhibits linear kinetics over a dose range of 1mg to 50 mg; half-life is independent of concentration and clearance is independent of dose. Steady state was reached with 10-mg dose by day 10 end and with 5-mg and 7.5-mg dose by day 12 end. There is no effect indicating that a change in the administered food is required. These study results support once daily dosing in the fasted or fed state.
The relationship between plasma concentration and LVEF suggests a broad therapeutic index that will facilitate optimization of individual doses in patients with HCM that are expected to be titrated via increasing ranges of doses until the desired PD effect is achieved. In addition, the half-life of alfukantan (75 h to 85h after a single dose; 77h to 86h after multiple doses) and the observed reversibility of the effect provide the potential advantage of reaching steady state within 2 weeks and easily reversing the excessive effects on LVEF.
Conclusion (d). African shows a favorable safety profile in healthy participants, no serious AE or meaningful changes in laboratory tests, ECG or health assessment. Any decrease in LVEF to a value <50% was reversible within 6 hours after single dosing. Pharmacologically active doses of avibactam were identified that can be used as the starting dose for the study of patients with HCM.
Example 2
Multicenter, randomized, placebo-controlled, double-blind, dose-finding phase 2 clinical trials of CK-274 were performed in patients with symptomatic obstructive HCM (oHCM). The main objective of the test was to determine the safety and tolerability of CK-274. The secondary objective was to elucidate the concentration-response relationship of CK-274 on the left ventricular outflow tract gradient during 10 weeks of treatment as measured by echocardiography and post-valvular action, elucidate the dose-response relationship of CK-274, and evaluate the plasma concentration of CK-274 in patients with oHCM. 17 studies in north america and europe were on-site screening patients for recruitment in cohorts 1 and 2. The third cohort (cohort 3) was also studied to evaluate the safety and efficacy of the combination of CK-274 and the class IA antiarrhythmic drug propidium.
The first two cohorts (cohort 1 and cohort 2) did not include patients receiving propineb. Cohort 3 included patients receiving propitiamine. Within each of the first two cohorts, patients were randomized to active or placebo treatment at 2:1 and received up to three ascending doses of CK-3773274 or placebo based on echocardiographic guidelines. In the third cohort, all patients received up to three ascending doses of CK-3773274 based on echocardiographic guidelines. In summary, the duration of treatment was 10 weeks, followed by a 4 week follow-up period following the last dose.
Because patient characteristics were substantially altered in this disease, personalized dose titration for Pharmacodynamic (PD) response (LVOT-G reduced to <30mmHg and LVEF maintained > 50%) was employed to maximize efficacy and safety.
Patients were eligible for inclusion in the study only if all of the following criteria were applicable: 1. being able to understand and willing to sign Informed Consent (ICF) and to follow all study procedures and limitations for the duration specified in the activity schedule; 2. men and women between 18 and 85 years of age at screening; 3. the weight of the screening is more than or equal to 45kg;4. diagnosis of oHCM was made according to the following criteria: (a) Having LV hypertrophy and non-dilated LV chambers in the absence of other heart diseases; and (b) a minimum wall thickness of 15mm or more (a minimum wall thickness of 13mm or more is acceptable for a positive family history of HCM or known pathogenic gene mutation); 5. a sufficient echocardiographic acoustic window; 6. during screening, LVOT-G for queues 1 and 2 was as follows: (a) resting gradient is more than or equal to 50mmHg; or (b) a resting gradient of not less than 30mmHg and less than 50mmHg and a LVOT-G of not less than 50mmHg after a Wash action; or LVOT-G for queue 3 as follows: persistent resting LVOT obstruction (. Gtoreq.30 mmHg) and stimulated LVOT obstruction (. Gtoreq.50 mmHg); 7. the Left Ventricular Ejection Fraction (LVEF) is more than or equal to 60% during screening; 8. the New York Heart Association (NYHA) class II or III at the time of screening; 9. patients taking β -blockers, verapamil, dithiin (dithiem) or ranolazine should have taken stable doses for >4 weeks prior to the randomization and are expected to still use the same drug regimen during the study period; 10. male patients were eligible to participate in the study if they agreed to the following conditions during the study and for at least 10 weeks after the last dose: (a) does not donate sperm; adding (b) (i) does not treat the sexuality as its preferred and usual lifestyle (long-term and long-lasting abstinence) and agrees to maintain abstinence; or (b) (i) must agree to use a male condom, and if its female partner is a woman with fertility potential, allowing its female partner to use an efficient contraceptive method; 11. female patients are eligible for participation in the study if they are not pregnant or are not lactating, and at least one of the following conditions apply: (a) (i) a female not having fertility potential, or (a) (ii) a female having fertility potential, and using a high-efficiency contraceptive method during the study and for at least 4 weeks after the last administration; and (b) females with fertility potential must undergo a negative pregnancy test (urine or serum required by local regulations) within 3 days prior to the first dose of study intervention; 12. all screening procedures can be completed; stable doses of propineb were taken for >4 weeks (queue 3 only) prior to screening.
Patients were excluded from the study if any of the following criteria apply: 1. aortic stenosis or fixed sub-aortic obstruction; 2. invasive or storable conditions known to cause cardiac hypertrophy (e.g., noonan syndrome, fabry disease, amyloidosis) that mimic oHCM; 3. history of Left Ventricular (LV) contractile dysfunction (LVEF) at any time during its clinical course<45%); 4. with a recorded history of the current obstructive coronary artery disease (one or more epicardial coronary stenosis)>70%) or a recorded history of myocardial infarction; 5. treatment with diaphragmatic reduction therapy (surgical myotomy or percutaneous alcohol diaphragmatic ablation) or planning either treatment during the study period; 6. previous treatment with cardiotoxic agents such as doxorubicin or similar drugs; 7. for queues 1 and 2: treatment with propitiamine or an anti-arrhythmic drug with negative cardiotonic activity had been performed within 4 weeks prior to screening and for cohort 3: treatment with antiarrhythmic drugs having negative cardiotonic activity other than propidium during the 4 weeks prior to screening; 8. any ECG abnormalities that have a risk that researchers consider to be safe to the patient (e.g., secondary type II atrioventricular block); 9. there were recorded paroxysmal atrial tremors or flutters during the screening period; 10. paroxysmal or permanent atrial fibrillation requiring a heart rhythm recovery therapy (e.g., direct current heart beat recovery, ablation procedure, or antiarrhythmic therapy) less than or equal to 6 months prior to screening, except if atrial fibrillation has been treated with anticoagulation and adequate control of heart rate >For 6 months, then this term is not applicable; 11. a history of syncope or sustained ventricular tachyarrhythmia exercise during the first 6 months of screening; 12. placement of implantable artificial cardiac defibrillators (ICDs) within 3 months prior to screening or planned placement of ICDs during the study;13. a history of ICD shock appropriate for life threatening ventricular arrhythmias within 6 months prior to screening; 14. receiving a major organ transplant (e.g., heart, lung, liver, bone marrow, kidney) or a transplant expected within 12 months from randomization); 15. liver damage, defined as Total Bilirubin (TBL) 1.5×upper normal limit (ULN) at screening, or alanine Aminotransferase (ALT) or aspartate Aminotransferase (AST) 3×ULN, except patients who were allowed to have documented Belbert syndrome and had TBL 1.5×ULN without other liver disease due to unbound hyperbilirubinemia; 16. any other clinically significant condition, malignancy, active infection, other condition or history or evidence of the disease that would, in the view of a researcher or medical monitor, constitute a risk to patient safety or interfere with research evaluation, procedure or completion; 17. hemoglobin during screening<10.0g/dL;18. glomerular filtration rate (eGFR) estimated at screening <30mL/min/1.73m 2 (improvement of diet (Modification of Diet in Renal Disease) equation by modified kidney disease); 19. currently being engaged in another research setting or drug study or prior to screening<1 month (or 5 half-lives of the drug, whichever is longer) to receive the study device or drug; 20. previously received treatment with CK-3773274 or currently receiving Ma Waka (mavacamten); 21. has a known high sensitivity to any excipient in CK-3773274 film coated tablets.
In each cohort, patients received up to three ascending doses of CK-3773274, as shown in table 11. Each patient received dose 1 once a day for 2 weeks. At week 2, the patient was echocardiographically performed 2 hours after administration of the drug. The patient titrated up to dose 2 if the echocardiography meets any of the following conditions: (1) The rest LVOT-G is more than or equal to 30mmHg and the biplane LVEF is more than or equal to 50 percent; or (2) the rest LVOT-G is less than 30mmHg, the LVOT-G is more than or equal to 50mmHg after the W-shaped action, and the biplane LVEF is more than or equal to 50 percent. Otherwise, the patient still takes dose 1. If LVEF is <50% at week 2, the patient titrates down to placebo. The dose adjustment algorithm is shown in table 10 below.
After taking the divided dose for another 2 weeks (i.e. week 4), each patient had echocardiographic images taken 2 hours after administration of the dose. If the echocardiography meets any of the following conditions, the patient is incremented to the next higher dose: (1) The rest LVOT-G is more than or equal to 30mmHg and the biplane LVEF is more than or equal to 50 percent; or (2) the rest LVOT-G is less than 30mmHg, the LVOT-G is more than or equal to 50mmHg after the W-shaped action, and the biplane LVEF is more than or equal to 50 percent. Otherwise, the patient still takes the same dose. If LVEF <50% at week 4, the patient is returned to the previous dose level, or if the patient is taking dose 1, the patient is returned to placebo.
After taking the divided dose for another 2 weeks (i.e. week 6), each patient had echocardiographic images taken 2 hours after administration of the dose. If LVEF <50% at week 6, the patient is titrated down to the previous dose level, or if the patient is taking dose 1, the patient is returned to placebo.
Table 10: dose adjustment algorithm
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If at any time the patient's dose titrated down to placebo, it still took placebo for the duration of the study.
Table 11: dosing regimen
Queues Dose 1 Dose 2 Dose 3
Queue 1 5mg 10mg 15mg
Queue 2 10mg 20mg 30mg
Queue 3 5mg 10mg 15mg
Baseline characteristics of patients in cohorts 1, 2, and 3 are shown in tables 12 and 13.
Table 12: baseline characteristics of patients in phase 2 clinical trials
Table 13: baseline demographics and clinical features of patients in phase 2 clinical trial cohorts 1 and 2
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* =from individual investigator field echocardiography evaluation. BMI = body mass index; CV = coefficient of variation; LVEF = left ventricular ejection fraction; LA = left atrium; LVED = left ventricular end diastole size; LVOT = left ventricular outflow tract; NT-probnp=n-terminal pro-B type natriuretic peptide; NYHAFC = new york heart society of function category.
Several key structural and physiological measures of echocardiography obtained every 2 weeks and 2 weeks after the last dose, as well as the N-terminal pro-hormone of brain natriuretic peptide (NT-proBNP) were analyzed.
Initial results of the clinical study included data from two sequentially performed cohorts, cohort 1 (n=21) and cohort 2 (n=20), which randomly group patient treatment to CK-274 or placebo at 2:1. Patients received up to three ascending doses of CK-274 (5 mg, 10mg, 15mg in cohort 1 and 10mg, 20mg, 30mg in cohort 2) or placebo once a day. The patient was echocardiographically treated two weeks after treatment at each dose to determine the potential upward titration to the next higher dose. In summary, the duration of treatment for each patient in the study was 10 weeks, and echocardiography was performed 2 weeks after the last dose.
For patients taking CK-274 in cohort 1 (n=14), the average resting LVOT-G changed from 53.8mmHg at baseline to 13.4mmHg at 10 weeks; for patients taking CK-274 in cohort 2 (n=14), the average resting LVOT-G changed from 58.2mmHg at baseline to 15.1mmHg at 10 weeks; and for patients in the combined placebo group (n=13), the average resting LVOT-G changed from 52.1mmHg at baseline to 44.0mmHg at 10 weeks (fig. 7, p=0.0003 for cohort 1 and p=0.0004 for cohort 2 compared to placebo at 10 weeks).
For patients taking CK-274 in cohort 1 (n=14), the mean warrior action LVOT-G changed from 77.4mmHg at baseline to 38.1mmHg at 10 weeks; for patients taking CK-274 in cohort 2 (n=14), the mean warrior action LVOT-G changed from 82.3mmHg at baseline to 29.8mmHg at 10 weeks; and for patients in the combined placebo group (n=13), the mean warrior action LVOT-G changed from 84.6mmHg at baseline to 76.0mmHg at 10 weeks (fig. 8; p=0.001 for cohort 1 and p <0.0001 for cohort 2 compared to placebo at 10 weeks).
The average ejection fraction of patients in cohort 1 who took CK-274 (n=14) changed from 72.8% at baseline to 67.3% at 10 weeks; for patients taking CK-274 in cohort 2 (n=14), the average ejection fraction changed from 75.4% at baseline to 64.1% at 10 weeks, and for patients in the combined placebo group (n=13), the average ejection fraction changed from 74.5% at baseline to 74.9% at 10 weeks (p=0.01 for cohort 1 versus p= <0.0001 for cohort 2 compared to placebo at 10 weeks).
In summary, the incidence of adverse events was similar between treatment groups. Treatment with CK-274 was well tolerated in the study and the severity of adverse events was reported as mild or moderate. The investigator did not report treatment-related serious adverse events.
Patients in cohort 1 who received CK-274 did not have LVEF <50%. In cohort 2, one patient with a baseline LVEF of 58% titrated up to 20mg CK-274 and experienced a decrease in instantaneous LVEF to <50% (kept above 40%) requiring downward titration. No interruption or discontinuation of treatment with CK-274 occurred in any of the patients in both cohorts.
Patient distribution at each dose of CK-274 in the study (cohorts 1 and 2) is shown in Table 14. Patient distribution at each dose of CK-274 in study cohort 3 is shown in Table 15.
TABLE 14
TABLE 15
Secondary results of the clinical study included data from cohort 3 (n=13). All patients received up to three ascending doses of CK-274 (5 mg, 10mg, 15 mg) once a day. The patient was echocardiographically treated two weeks after treatment at each dose to determine the potential upward titration to the next higher dose. In summary, the duration of treatment for each patient in the study was 10 weeks, and echocardiography was performed 2 weeks after the last dose. Efficacy endpoints included resting and stimulating LVOT gradients, NYHA class and NT-proBNP.
In cohort 3, 13 patients (aged 59±14 years; 54% women) with NYHA categories II (n=5) and III (n=8) were enrolled. Patients in cohort 3 have similar demographics, LVEF, and ileus severity, but are more symptomatic and have a higher baseline NT-proBNP compared to cohorts 1 and 2. Patients in cohort 3 had symptomatic obstructive HCM and left ventricular outflow tract gradient (LVOT-G) of ≡50mmHg after resting or warfarin activity and had been previously treated with propidium and in most cases with β -adrenergic blockers. All patients received up to three ascending doses of african (5 mg, 10mg, 15 mg) once a day, titrated based on an echocardiographic guideline, as discussed above. In summary, the duration of treatment was 10 weeks, followed by a 4 week follow-up period following the last dose. A total of 13 patients were enrolled and all patients completed the study at the time of treatment.
The results of cohort 3 showed that a substantial decrease in average resting LVOT-G and post-warrior action LVOT-G was achieved (defined as resting gradient <30mmHg and post-warrior action gradient <50 mmHg). These clinically relevant pressure gradient decreases are achieved and the average Left Ventricular Ejection Fraction (LVEF) is only moderately reduced; the patient's LVEF does not drop below the 50% predetermined safety threshold. The new york heart society of function class was improved in most patients participating in trial cohort 3. Pharmacokinetic data were similar to those observed in cohorts 1 and 2. In addition, the safety and tolerability of alfukantan are consistent with the absence of treatment interruption and serious adverse events reported by researchers due to treatment.
The combination of CK-274 with propidium amine may present a treatment option for the most severe and treatment-refractory oHCM patients.
Results after 10 weeks of therapy
At baseline, there was no significant difference in key echocardiographic measurements and NT-proBNP values between African and placebo. Patients taking African had a tendency to decrease the average Left Ventricular Mass Index (LVMI) compared to placebo (-4.8 g/m) 2 (+ -2.4) vs. 3.3g/m 2 (±3.6) The method comprises the steps of carrying out a first treatment on the surface of the Average difference: 8.1g/m 2 P=0.063 value). From baseline to week 10, the index of Left Ventricular (LV) filling pressure was improved in the African treated group, including Left Atrial Volume Index (LAVI) (-2.9 mL/m) 2 (+ -1.5) vs. 2.2mL/m 2 (±1.5), p=0.004) (fig. 9); e '(0.5 cm/s (+ -0.4) pair-0.5 cm/s (+ -0.3), p=0.03) and lateral E/E' (-2.0 (+ -1.1) pair 1.8 (+ -0.8), p=0.006) (fig. 10). Similarly, in the African versus placebo at week 10, a categorical assessment of pre-systole movement of the mitral valve leaflets (SAM; -50% versus-17.3%) (FIG. 11) and frequency of eccentric mitral regurgitation (MR; -35.8% versus +13.3%) (FIG. 11) were observed, respectively, reduced relative to baseline. At week 10, there was a significantly greater reduction in NT-proBNP (geometric mean square ratio 0.38 (0.25-0.56), p=0.0002) with alfukantan versus placebo.
Figure 12 shows the change in resting LVOT-G for the treatment and placebo cohorts. Fig. 13 shows the change in resting warfare LVOT-G for the treatment and placebo cohorts. The effect of CK-274 treatment on LVOT-G was generally reduced in patients treated with propitiamine (cohort 3) compared to cohort 1 patients (same CK-274 dose). Fig. 14 shows the change in LVEF for the treatment and placebo cohorts. Figure 15 shows NYHA functional class response for treatment and placebo cohorts. FIG. 16 shows the variation of the mean NT-proBNP in the treatment and placebo queues.
The safety profile of all three treatment cohorts is presented in table 16, with 6 moderate adverse events recorded in cohort 3, including pneumonia, pertussis, pulmonary mass, back pain, shortness of breath, and sitting up breath. An asymptomatic atrial tremor adverse event is recorded in patients with a known prior medical history. The remaining adverse events included gastrointestinal symptoms (known side effects of propidium) and other adverse events seen in queues 1 and 2 (headache, dizziness). The overall security profile in queue 3 supports the combined use of CK-274 and propidium.
Table 16: safety profile of patients treated with CK-274 in phase 2 clinical trials
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These findings indicate that the treatment with alfukantan resulted in beneficial early cardiac remodeling, which is associated with LVMI, LAVI, lateral E/E ', SAM, eccentric mitral regurgitation and a decrease in brain natriuretic peptide and an increase in E' velocity, and further that alfukantan favorably affects cardiac remodeling in oHCM.
Results of queue 1 and queue 2
Referring to cohorts 1 and 2, complete hemodynamic responses occurred in 11 of 14 patients (79%) in the african cohort 1 and 13 of 14 patients (93%) in the african cohort 2 (resting LVOT gradient <30mmHg and warrior action gradient <50mmHg at week 10) compared to only 1 of 12 patients (8%) in the pooled placebo group (fig. 17, fig. 18, fig. 20).
Within the treatment period, EF in the alfukantan cohort 1 was reduced from 73% ± 6% to 67% ± 9% (LSMean with respect to placebo, p=0.007), and EF in the alfukantan cohort 2 was reduced from 75% ± 6% to 64% ± 8% (LSMean difference with respect to placebo, p < 0.001), with no change in the placebo group (75% ± 6% to 75% ± 4%; p=0.5) (fig. 19). Analysis of the relationship between the dose of african and EF over time revealed a dose-dependent decrease, with an average EF decrease of-0.6% (SE 0.084) per mg of african.
In the pooled african treatment group (cohorts 1 and 2), 15 of the 28 patients (53%) underwent one or more categories of NYHA class changes (fig. 21), including: 6 patients increased from class III to class II,8 patients increased from class II to class I, and one patient increased from class III to class I (fig. 24).
African treatment was associated with a 62% decrease in NT-proBNP levels (p < 0.001) compared to placebo at week 10. Importantly, 25 of the 27 patients taking alfukantan (93%) experienced at least some reduction in NT-proBNP levels compared to only 6 of the 12 placebo-treated patients (50%).
The baseline level of hs-Trop for the pooled African group was 17ng/L (CV% 290) and the baseline level of hs-Trop for the pooled placebo was 17ng/L (CV% 290) (FIG. 23). At week 10, patients in cohort 1 received an 18% relative decrease (p=0.29) from the pooled placebo, and patients in cohort 2 received a 26% relative decrease (p=0.097) from the pooled placebo. The changes in hs-troponin I levels in the pooled placebo group are shown in figure 37 for patients receiving alfukantan in cohorts 1, 2 and 3.
Early and sustained hemodynamic effects of alfukantan are accompanied by significant clinical benefit of heart failure symptoms in most patients. Symptom improvement of one or more of the NYHA classes, including 64% in cohort 2, occurs in more than half of patients treated with alfukantan, with most of the improvement resulting in a transition from class II to completely asymptomatic (class I) patients. It should be noted that aficonazole converts 7 patients from the symptoms of advanced heart failure (class III) to a less symptomatic state (class II or I).
This robust hemodynamic response is particularly pronounced because alfukantan converts most obstructive HCM patients to gradient levels below the current threshold for which diaphragmatic reduction therapy (e.g., myotomy or alcohol diaphragmatic ablation) is considered. This is a particularly relevant point, as one advantage of diaphragmatic reduction therapy is the opportunity to convert patients with advanced limiting symptoms (category III) to an asymptomatic or mild symptomatic state.
African is also associated with significant reduction of NT-proBNP and hs-troponin, which underscores that compounds may produce other potential downstream pathophysiological benefits, including reduced LV wall stress and reduced myocardial damage.
Example 3
Open label extended clinical trials of CK-274 were initiated in patients with symptomatic oHCM. The main objective of the test was to determine the safety and tolerability of CK-274 over a 5 year period.
Patients who completed the study as described in example 2 and had not had atrial tremor were eligible to be enrolled in the study. Echocardiographic guided dose titration based on field readings is administered by the researcher and can be performed at any time during the trial, as described below.
Study design
Each patient received dose 1 of CK-274 once a day for 2 weeks. At week 2, each patient performed an intercepted echocardiogram 2 hours after administration of the drug. The patient titrated up to dose 2 if the echocardiography meets any of the following conditions: (1) The rest LVOT-G is more than or equal to 30mmHg and the biplane LVEF is more than or equal to 50 percent; or (2) the rest LVOT-G is less than 30mmHg, the LVOT-G is more than or equal to 50mmHg after the W-shaped action, and the biplane LVEF is more than or equal to 50 percent. Otherwise, the patient still took 5mg of CK-274. If LVEF <50%, the treatment is discontinued. If LVEF <40%, the treatment is discontinued.
At weeks 4, 6, 12 and every 12 weeks thereafter, each patient underwent echocardiography or truncated echocardiography 2 hours after administration of the drug (truncated echocardiography at weeks 4 and 6; and echocardiography at weeks 12 and every 12 weeks thereafter) to determine if additional dose titration was required (see tables 17 and 18). Dynamic cardiac monitoring was performed at week 48, week 96, week 144, week 192 and week 240. Cardiac magnetic resonance was monitored at week 48, week 144 and week 240. (see FIG. 26). Baseline characteristics of patients enrolled in the open-label extension study are shown in table 19.
Table 17: dose adjustment algorithm
Table 18: dosing regimen
Dose 1 Dose 2 Dose 3 Dose 4
5mg 10mg 15mg 20mg
Table 19: baseline characteristics of open marker extension studies
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Preliminary results
Preliminary results are shown in FIGS. 27-34. Figure 27 shows patient distribution over time at each dose. At the time of data collection, 38 patients had been enrolled in the trial, and all 38 patients had reached at least week 2 dosing; 37 of the 38 patients had reached at least week 6 dosing; 30 of the 38 patients had reached at least week 12 dosing; and 19 of the 38 patients had reached at least 24 weeks of dosing. The percentage of patients receiving each dose level (5 mg, 10mg or 15 mg) at each time point is shown in figure 27. Based on echocardiographic data from on-site readings of these patients, significant resting LVOT-G and a decrease in the warrior action LVOT-G over time are shown in fig. 28 and 29; significant and sustained decreases in LVOT gradient were identified at weeks 2-24. In addition, minimal and steady decrease in LVEF was noted up to week 24, as shown in figure 30.
At baseline, 53% of patients were NYHA class III and 47% of patients were NYHA class II.
In patients who have reached at least week 12 dosing: at week 12, only 7% of patients were NYHA class III;52% of patients are NYHA class II; and 41% of patients were NYHA class I (fig. 31). Relative to baseline, 72% of patients have experienced an increase of one NYHA class, and 7% of patients have increased two NYHA classes (fig. 32).
In patients who have reached at least week 24 dosing: at week 24, only 6% of patients were NYHA class III;39% of patients are NYHA class II; and 56% of patients were NYHA class I (fig. 31). Relative to baseline, 61% of patients have undergone an increase of one NYHA class, and 17% of patients have undergone an increase of two NYHA classes (fig. 32).
Patients in the study did not show deterioration of NYHA class compared to baseline.
Preliminary security
Table 20
N＝38
Patient with at least one TEAE 28(74％)
Patient with at least one associated TEAE 8(21％)
Patient with at least one TESAE 2(5％)
Patient with at least one severe TEAE 1(3％)
Patients with TEAE resulting in drug disruption 1(3％)
Patients with TEAE resulting in reduced dose 2(5％)
TEAE: treatment of emergency adverse events
TESAE: treatment of emergency serious adverse events
Cardiac AE: atrial tremor (2); angina (1); bradycardia (1); ejection fraction reduction (1); mitral stenosis (1); QTc prolongation (1)
One patient with LVEF <50% and TESAE had a history of alcohol-induced atrial tremor and LVEF decrease <50% prior to the study. Repeated episodes of alcohol-induced atrial tremor with similar LVEF reduction to 47% when 15mg CK-274 was taken; CK-274 was titrated downward. The patient then suffers from worsening atrial tremor and failed recovery from the heart beat; interrupt CK-274. This patient recovered sinus rhythm when taking amiodarone (amiodarone) (abstaining from alcohol), had evidence of LVEF 60% and obstruction and had restarted dose 1 (5 mg) of CK-274.
Because researchers worry about QTc prolongation in subjects with abnormal baseline EKG, one patient underwent a temporary downward titration. A temporary downward titration of alfukantan was performed while waiting for core laboratory QTc interpretation. QTc was confirmed to be normal and then alfukantan was increased.
One subject with severe TESAE showed altered mental status prior to planning cardiac arrest due to exacerbation of atrial fibrillation by administration of dotc (direct acting oral anticoagulant), resulting in hospitalization. MRI shows a presumed embolic stroke. The patient was then diagnosed with an congenital heart abnormality (secondary hole atrial septal defect). No down titration or interruption of CK-274 is required.
Kansas City Cardiomyopathy Questionnaire (KCCQ)
KCCQ was used to assess the health of the participants before the start of the african in OLE and at 12 and 24 weeks of treatment. The change from baseline in KCCQ score was determined, including oss=total summary score, css=clinical summary score, tss=total symptom score, pls=physical limitation score, sls=social limitation score, qol=quality of life. Patients were classified as worsening (. Ltoreq.5 min), unchanged (. Ltoreq.5 min to <5 min), small improvement (5 min to <10 min), medium to large improvement (10 min to <20 min) and large to large improvement (. Gtoreq.20 min) relative to baseline.
The results show that at 12 weeks, the KCCQ scores of OLE participants improved significantly, lasting up to 24 weeks. The proportion of participants with clinically significant improvement (. Gtoreq.5 score in total) was 72.7% at week 12 and 72.0% at week 24. A significant clinical improvement of 36.4% (20 min.) was seen at week 12 and a significant clinical improvement of 40.0% was seen at week 24 (fig. 35, fig. 36). Treatment with CK-274 resulted in significant and sustained improvement of all KCCQ field scores for up to 6 months.
Conclusion(s)
In this open label extension study of patients treated for obstructive HCM with background medical therapy (including propidium in some cases): CK-274 was associated with a significant and sustained LVOT gradient decrease (fig. 28 and 29) and a substantial improvement in heart failure symptoms (about 80% of patients had one or more categories of NYHA category increase) (fig. 31 and 32) as well as a significant decrease in cardiac biomarkers (NT-proBNP and hs-cTnI) (fig. 33 and 34). CK-274 is well tolerated and there are no events of LVEF <50% caused by CK-274. These data demonstrate that the therapeutic effect of CK-274 can last for up to 6 months.
Example 4
The following examples illustrate phase 3, multicentric, randomized, double blind, placebo-controlled trials to evaluate the efficacy and safety of CK-3773274 (also known as CK-274 or alfukantan) in adults with symptomatic hypertrophic cardiomyopathy and left ventricular outflow tract obstruction. This test evaluates the effect of CK-3773274 treatment on cardiopulmonary performance and health status of patients with symptomatic oHCM over a 24 week period. This test was aimed at establishing the efficacy and safety of CK-3773274 in improving motor capacity and patient symptoms in patients with oHCM and in reducing left ventricular outflow tract gradient (LVOT-G).
This is a phase 3 randomized, placebo controlled, double blind, multi-center trial in patients with symptomatic oHCM. Approximately 270 eligible patients were randomized at a 1:1 ratio to receive either CK-3773274 or placebo. Dose titration was conducted using echocardiography to administer doses of 5mg, 10mg, 15mg, or 20mg in increments or matched placebo. Randomization was stratified by using β -blocker and CPET movement patterns.
The test included three time periods. The screening period lasted up to 6 weeks. The double-blind placebo-controlled treatment period lasted 24 weeks. The final administration of CK-3773274 was followed by a 4 week safety follow-up period. CK-3773274 is administered orally once daily. The CK-3773274 dose was titrated individually at weeks 2, 4 and 6 using echocardiography during the initial six weeks of the treatment period. Only patients with LVOT-G.gtoreq.30 mmHg and biplane LVEF.gtoreq.55% after Wash action will have dose escalation at week 2, week 4 and week 6 visits. Echocardiography was performed at each subsequent visit during the trial and doses were titrated down as needed. pVO was measured by CPET at screening and at the end of treatment (week 24) 2 Is the primary endpoint of (c). Patients continued to take background HCM medications consistent with regional clinical practice guidelines during the trial, if applicable.
CMR imaging sub-studies were opened to approximately 40 patients who agreed to participate.
The primary mitigation strategy is facilitated by a personalized dose titration regimen based on the PD response of each patient to CK-3773274 and applying predetermined echocardiographic criteria (including the LVEF threshold for dose escalation, downward titration, and drug discontinuation).
Patients enrolled in this trial were required to have LVEF ≡60% prior to randomization, as confirmed by the central echocardiography laboratory. A low initial dose of 5mg and a maximum dose of 20mg were chosen, as these doses were found to be well tolerated in the phase 2 study (CY 6021) of patients with oHCM and effectively lowered LVOT-G without adversely affecting overall LVEF. Personalized dose escalation is only performed if the following criteria are met: LVOT-G is more than or equal to 30mmHg and biplane LVEF is more than or equal to 55% after the Wash action. Importantly, the lower LVEF limit for dose escalation was increased from 50% to 55% compared to CY 6021 to provide a safe limit compared to the LVEF threshold (< 50%), which would trigger dose reduction. If LVEF is <50% at any time, the dose of CK-3773274 will be titrated downward, and if LVEF is <40% at any time, CK-3773274 will be temporarily discontinued.
The main objective of this test was to evaluate the effect of CK-3773274 on motor capacity of patients with symptomatic oHCM. The indicated endpoint was peak oxygen uptake (pVO) as determined by cardiopulmonary exercise test (CPET) 2 ) Change from baseline to week 24.
A secondary objective of this trial was to evaluate the effect of CK-3773274 on patient health as determined from the change in the kansashimi cardiomyopathy questionnaire-clinical summary score (KCCQ-CSS) from baseline to week 12 and 24.
Another secondary objective of this trial was to evaluate the effect of CK-3773274 on New York Heart Association (NYHA) functional classification, as determined by the proportion of patients with an increase of > 1 class from baseline to week 12 and 24 NYHA functional classes.
Another secondary objective was to evaluate the effect of CK-3773274 on left ventricular outflow tract gradient (LVOT-G) after W-action, as determined by the change in LVOT-G from baseline to week 12 and week 24 after W-action and the proportion of patients with LVOT-G <30mmHg after week 12 and week 24 Shi Washi action.
Another secondary objective was to evaluate the effect of CK-3773274 on exercise capacity as determined from the change in total workload from baseline to week 24 during CPET.
To evaluate the safety and tolerability profile of CK-3773274 in patients with symptomatic oHCM, the following were recorded: (1) The incidence of reported major adverse cardiac events (cardiovascular [ CV ] death, cardiac arrest, non-fatal stroke, non-fatal myocardial infarction, CV hospitalization); (2) incidence of new onset persistent atrial tremor; (3) The incidence of sudden cardiac death due to discharge and abortion of an appropriately implantable defibrillator (ICD); (4) a Left Ventricular Ejection Fraction (LVEF) <50% incidence; and (5) treating the incidence of emergency adverse events.
One exploratory goal of this test was to evaluateThe effect of CK-3773274 on motor capacity and functional class, as determined by the number of patients reached at week 24 compared to baseline: (1) pVO 2 The change compared with the baseline is more than or equal to 1.5mL/kg/min and the NYHA functional class is improved by more than or equal to 1 class; or (2) pVO 2 The change from baseline was ≡3.0mL/kg/min and NYHA functional class was not worsened.
Another exploratory goal of this trial was to evaluate the effect of CK-3773274 on patient response over time, as determined according to the following: (1) KCCQ-CSS improved patient proportion >5 points at week 12 and 24; (2) Patient ratios with resting LVOT-G <30mmHg, LVOT-G <50mmHg after warrior action and NYHA functional class I at week 12 and 24; and (3) patient ratios with resting LVOT-G <30mmHg, LVOT-G <50mmHg and NYHA functional class increase of > 1 class after Wash action at weeks 12 and 24.
Another exploratory goal of this trial was to evaluate the effect of CK-3773274 on other CPET parameters, as determined from the following change from baseline to week 24: (1) Ventilator efficiency (VE/VCO) 2 Slope); (2) Cycle power (VO) 2 X shrinkage BP); and (3) Ventilator Anaerobic Threshold (VAT).
Another exploratory goal of this test was to evaluate the effect of CK-3773274 on health status and health-related quality of life as measured by the PRO questionnaire, as determined by the change from baseline to week 24 in the subject's response to the EuroQol 5-dimensional 5 level instrument (EQ-5D-5L).
Another exploratory goal of this test was to evaluate the effect of CK-3773274 on cardiac function and structure, as determined from the change from baseline to week 24 of echocardiographic measurements of cardiac structure and contractile function, including: LVEF, left ventricular end systole and end diastole volumes (LVESV and LVEDV, respectively) and left atrial volume.
Another exploratory goal of this assay was to evaluate the effect of CK-3773274 on biomarker levels, as determined by the change in NT-pro-BNP, hs-heart-TnI, and other biomarkers from baseline values up to week 24.
Another exploratory goal of this test was to evaluate CK-3773274 effects on left ventricular mass, function and structure by Cardiac Magnetic Resonance (CMR) imaging, as determined from the change from baseline to week 24 of CMR measurements of Left Ventricular (LV) mass index, LVEF, septum and free wall thickness, left arterial volume index, LVESV and LVEDV.
Another exploratory goal of this assay was to evaluate the pharmacokinetics of CK-3773274 and its metabolites, as determined by pharmacokinetic parameters up to week 24.
Overall design. This is a phase 3 randomized, placebo controlled, double blind, multi-center trial in patients with symptomatic oHCM. Approximately 270 eligible patients were randomized at a 1:1 ratio to receive either CK-3773274 or placebo. Randomization was layered by using beta-blockers (yes or no) and CPET exercise patterns (treadmill or bicycle) and implemented in an interactive website reaction system (Interactive Web Response System, IWRS). The number of patients taking the beta-blocker was capped and did not exceed about 70% of the total number enrolled. The number of patients with persistent atrial tremor at the time of screening will also be capped at about 15% and the number of patients using the bicycle CPET exercise mode will also be capped at about 50%.
CK-3773274 is administered orally once daily with or without food. The CK-3773274 dose was titrated individually at weeks 2, 4 and 6 using echocardiography during the initial six weeks of the treatment period. Only patients with a Wash maneuver LVOT-G > 30mmHg and biplane LVEF > 55% will an up-dosing occur at weeks 2, 4 and 6. Echocardiography was performed at each subsequent visit during the trial and doses were titrated down as needed. pVO was measured by CPET at screening and at the end of treatment (week 24) 2 Is the primary endpoint of (c). Patients continued to take background HCM medications consistent with regional clinical practice guidelines during the trial, if applicable.
All patients were followed according to the activity schedule (SoA) from random grouping to their final visit date, whether or not the patient continued to receive CK-3773274, unless the patient had previously discontinued the trial or withdrawn the consent. Early discontinuation visits were performed on patients who had previously discontinued trials.
This trial was designed to provide data supporting clinical efficacy and safety of CK-3773274 in patients with symptomatic oHCM and post-warburg LVOT-G >50 mmHg. LVOT-G reduction is expected to be associated with improvements in patient symptoms, health and exercise capacity. Because patient characteristics were substantially altered in this disease, personalized dose titration for PD response (LVOT-G decreased to <30mmHg and LVEF.gtoreq.55% was maintained) was employed to maximize efficacy and safety. Qualification criteria are designed to enable recruitment of patient populations representing a general population of patients with oHCM, while ensuring patient safety in this trial. Placebo-controlled and double-blind methods were employed in this trial to avoid bias in data collection, including safety assessment and PD metrics including primary and secondary endpoints.
Only if all of the following criteria apply, the patient is eligible for inclusion in the trial: (1) It is understood and willing to sign an ICF and to adhere to all trial procedures and constraints for the duration specified in the activity schedule. (2) Men and women between 18 and 85 years of age (including 18 and 85 years of age) were screened. (3) Body mass index<35kg/m 2 . (4) diagnosing HCM according to the following criteria: (a) Having LV hypertrophy and non distended LV chambers in the absence of other heart diseases, and (b) having the following end diastole LV wall thicknesses as measured by the echocardiographic core laboratory: one or more myocardial segments ≡15mm, or one or more wall segments ≡13mm, and a family history of known pathogenic gene mutations or positive HCM. (5) LVOT-G was at rest at 30 mmHg.gtoreq.30 mmHg during screening and at 50mmHg after W action as determined by the echocardiographic core laboratory. (6) LVEF was 60% or more at the time of screening as determined by the echocardiographic core laboratory. (7) New York Heart Association (NYHA) functional class II or III at the time of screening. And (8) the hemoglobin is more than or equal to 10g/dL during screening. (9) Respiratory Exchange Rate (RER) predicted at CPET screening according to core laboratory. Gtoreq.1.05 and pVO2<80%. (10) Patients taking beta-blockers, verapamil or ditafan should have undergone a stabilization regimen prior to randomization >For 6 weeks, and the same drug regimen was expected to be used during the trial. (11) If a male patientThe following conditions were agreed during the trial and at least 4 weeks after the last administration of CK-3773274 and were eligible to participate in the trial: (a) Not donate sperm, plus (b) (i) not treat the sexual intercourse as its preferred and usual lifestyle (long-term and long-lasting abstinence) and agree to maintain abstinence, or (ii) must agree to use a male condom and allow its female partner to use an efficient contraceptive method when it is a woman with fertility potential. (12) Female patients are eligible for participation in the study if they are not pregnant, are nursing or are scheduled to donate eggs and at least one of the following conditions apply: (a) Women with fertility potential (WOCBP), or WOCBP and using a high-efficiency contraceptive method during the trial and at least 4 weeks after the last administration of CK-3773274 and male partners agree to use a condom, and (b) WOCBP must be subjected to a negative pregnancy test (urine or serum required by local regulations) on day 1, prior to the first dose of study CK-3773274. (13) all screening procedures can be completed.
Patients will be excluded from the trial if any of the following criteria apply: (1) Significant heart valve disease (at the discretion of the investigator) includes moderate-to-severe valve aortic stenosis and/or regurgitation, or moderate-to-severe mitral regurgitation that is not caused by pre-systole motion of the mitral valve. (2) There is a recorded history of the current obstructive coronary artery disease (one or more epicardial coronary stenosis > 70%) or a recorded history of myocardial infarction. (3) The simulation of oHCM is known or suspected to cause invasive, hereditary or storable disorders of cardiac hypertrophy (e.g. noonan syndrome, fabry's disease, amyloidosis). (4) Previously treated with cardiotoxic agents such as doxorubicin or similar drugs. (5) History of LV contractile dysfunction (LVEF < 45%) or stress cardiomyopathy at any time during its clinical course. (6) Any ECG abnormalities (e.g., secondary type II atrioventricular block) that have been considered by researchers to be at risk to patient safety. (7) There was a recorded paroxysmal atrial tremor during the screening period. (8) Less than or equal to 6 months prior to screening, paroxysmal or permanent atrial fibrillation in need of cardiac rhythm recovery therapy (e.g., direct current heart beat recovery, atrial tremor ablation procedure, or anti-arrhythmic therapy). (this term does not apply if atrial tremor has been treated with anticoagulation and heart rate is adequately controlled for >6 months) (9) a history of syncope or sustained ventricular tachyarrhythmia exercise during the first 6 months of screening. (10) ICDs were placed within 3 months prior to screening or planned during the trial. (11) A history of appropriate ICD discharge was received within 6 months prior to screening due to life threatening ventricular arrhythmias. (12) Either treatment has been treated with diaphragmatic reduction therapy (surgical myotomy or percutaneous alcohol diaphragmatic ablation) or planned during the trial period. (13) No exercise (e.g., orthopedic limitations) is possible on the treadmill or bicycle. (14) The indoor air oxygen saturation reading recorded at screening was <90%. (15) Liver damage, defined as Total Bilirubin (TBL) 1.5×upper normal limit (ULN), or alanine Aminotransferase (ALT) or aspartate Aminotransferase (AST) 3×ULN at the time of screening. Patients with documented strapdown syndrome and no other liver lesions with TBL.gtoreq.1.5XULN due to unbound hyperbilirubinemia are allowed. (16) A major organ transplant (e.g., heart, lung, liver, bone marrow, kidney) is received or is expected to be transplanted within 12 months of randomization. (17) Any other clinically significant condition, malignancy, active infection, other condition or history or evidence of the disease that would, in the view of a researcher or medical monitor, constitute a risk to patient safety or interfere with the evaluation, procedure or completion of the test; (18) The glomerular filtration rate (eGFR) estimated at screening was <30mL/min/1.73m2 (by modified renal disease diet improvement equation). (19) Currently engaged in another research device or drug trial or receiving a research device or drug <1 month (or 5 half-lives of drug, whichever is longer) prior to screening; no other study procedure was allowed while participating in this trial. (20) Treatment with CK-3773274 or Ma Waka has been previously accepted. (21) Any known high sensitivity to excipients in research drug tablets.
Exclusion criteria for CMR sub-studies included (1) intolerant CMR, (2) with ICD, or (3) with cardiac pacemaker.
Dose modification and scheduled dose titration. Patients randomly grouped into CK-3773274 received up to four ascending doses of CK-3773274 within the initial 6 weeks of the trial, as summarized in table 21. The initial dose for a patient receiving CK-3773274 is 5mg once a day (dose 1), and may be escalated to doses of 10mg, 15mg and 20mg once a day if it continues to meet the escalation criteria, or will cease its current dose when the escalation criteria is not met.
Table 21: echocardiographic criteria for scheduled dose titration
a Once the patient's CK-3773274 dose is titrated downward, no further escalation is allowed. LVEF if taken at 5mg<50% the patient will receive placebo.
After randomization, each patient received dose 1 (5 mg) once a day for two weeks. At week 2 visit, patients underwent echocardiography 2 hours after their dose of CK-3773274. The patient will titrate up to dose 2 (10 mg) if the echocardiography meets the following conditions: LVOT-G is more than or equal to 30mmHg after the Wash action, and biplane LVEF is more than or equal to 55%. Otherwise, the patient still took dose 1, unless if LVEF at week 2 <50%, the IWRS would assign the patient to placebo.
Two additional weeks after taking the distributed dose, each patient was echocardiographically performed 2 hours after administration of his dose of CK-3773274 at visit 4. The patient will titrate upward to the next higher dose if the echocardiography meets the following conditions: LVOT-G is more than or equal to 30mmHg after the Wash action, and biplane LVEF is more than or equal to 55%. Otherwise, the patient still takes the same dose, unless if LVEF at week 4 is <50%, the IWRS will assign the patient to the previous dose level, or to the placebo if the patient is taking dose 1.
After taking the allocated dose for another 2 weeks, each patient was echocardiographically performed 2 hours after administration of his dose of CK-3773274 at visit 6. The patient will titrate upward to the next higher dose if the echocardiography meets the following conditions: LVOT-G is more than or equal to 30mmHg after the Wash action, and biplane LVEF is more than or equal to 55%. Otherwise, the patient still takes the same dose, unless if LVEF at week 6 is <50%, the IWRS will assign the patient to the previous dose level, or to the placebo if the patient is taking dose 1.
Two additional weeks after taking the allocated dose, each patient was echocardiographically administered 2 hours after administration of his dose of CK-3773274 at visit 8 to ensure LVEF was ≡50%. If LVEF <50% at week 8, the IWRS will either assign the patient to the next lower dose or to placebo if the patient is taking dose 1.
After week 6, no other dose escalation could be performed. During the course of the study, dose reduction may be performed at scheduled or unscheduled visits for safety reasons. The dose reduction is determined by the IWRS system based on the echocardiographic results. After week 8, the dose reduction is based on echocardiographic results of the initial scheduled or unscheduled visit. If LVEF <50%, the IWRS will either assign the patient to the next lower dose, or to the placebo if the patient is taking dose 1. The IWRS does not further decrease the dose for at least 7 days after the previous decrease.
Cardiopulmonary exercise testing (CPET). All patients were subjected to CPET and gas exchange analysis, and the method will be standardized at all participating sites as described in the CPET manual. The test involves continuous ECG monitoring by trained personnel and is conducted in areas equipped with cardiopulmonary resuscitation devices. Running machines are the preferred mode of exercise testing. For CPET laboratories that do not conduct treadmill testing, bicycles are an acceptable alternative. Two modes of exercise regimen are provided in the CPET manual. For all exercise tests during the trial, the patient must use the same test pattern. CPET is administered by the same tester using the same equipment and after other test procedures on the visit date (including echocardiography, KCCQ, EQ-5D-5L, CGI, PGI-C, NYHA category, SAQ-7, vital signs, ECG, blood sampling, IP administration) whenever possible. During screening, patients not undergoing exercise protocols will be familiar with the technique.
All CPET tests are symptomatically limited and will strongly encourage patients to achieve maximum effort and RER.gtoreq.1.05. The reason for terminating the next largest movement test will be recorded. If RER is greater than or equal to 1.05, the test identifies the best effort.
Week 24 CPET should be administered at screening at about the same time of day (e.g., morning, noon, afternoon), at a time consistent with the last dose of beta-blocker and IP as baseline CPET. Wherever possible, the patient should conduct exercise testing between 3 hours and 10 hours after administration of the beta-blocker.
If the researcher identifies life threatening cardiac arrhythmias, early ischemia, severe hypotension or other serious findings during CPET, the patient is required to stop the exercise test and his/her physician is informed of the results. If the patient is conducting a screening test, she/he will not be randomly grouped into trials. Depending on the researcher, the enrolled patient with a non-life threatening event or finding to stop testing may restart testing at the time of safety and after appropriate treatment.
Echocardiography. Echocardiography was performed during screening and prior to day 1 dosing. Echocardiography was also performed at weeks 2, 4, 6, 8, 12, 16, 20, 24 and 28, 2 hours after out-patient dosing.
An authenticated sonographer will use standard high quality, high fidelity machines to perform echocardiography. The same sonographer will conduct all studies of a single patient whenever possible. Echocardiography will be performed according to the echocardiographic manual after the patient has rested supine for at least 10 minutes. Instructions for performing the Wash action and imaging LVOT-G will also be included in the echocardiographic manual.
When the echocardiogram is collocated with the blood draw, vital signs and/or ECG, the evaluation sequence will be vital signs, ECG, blood draw and echocardiogram. Blood should be drawn at a scheduled time point and an echocardiogram will be subsequently performed.
In addition to the right heart function metric detailed in the echocardiographic protocol, the echocardiographic parameters to be measured include at least left ventricular parameters (resting left ventricular outflow tract pressure gradient (LVOT-G), post-valsalva LVOT-G, LVEF, LVFS, global Longitudinal Strain (GLS), left ventricular end-diastolic diameter (LVEDD), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic diameter (LVESD), left ventricular end-systolic volume (LVESV), left Ventricular Cardiac Output (LVCO), LV cardiac output, LVOT velocity interval (VTI), inter-ventricular membrane thickness (IVST), isovolumetric contraction time (IVCT), IVRT, E/E ratio (septum and lateral), and Left Atrial Volume (LAV)).
When clinically indicated, unscheduled echocardiograms may be obtained, for example, to evaluate AEs or to follow-up clinically significant changes in the previous echocardiogram, as determined by the researcher. The results will be interpreted by an blinded ultrasound cardiologist at the site of the study.
All echocardiography (including unscheduled) will be sent to the core laboratory for interpretation. Site interpretations of LVEF and LVOT-G will be used for dose escalation and reduction decisions via IWRS. Core laboratory quantification of echocardiography will be used for all statistical analyses.
Cardiac magnetic resonance. CMR imaging sub-studies will evaluate the effect of CK-3773274 administration on heart morphology, function and fibrosis in approximately 40 oHCM patients eligible and consented to participate. CMR will be implemented between the screening period and 24 th period. Non-contrast CMR may be performed for patients with eGFR <30mL/min/1.73m2 or allergic to gadolinium.

Claims (87)

1. In a patient suffering from obstructive hypertrophic cardiomyopathy (oHCM), a method of reducing (a) a resting left ventricular outflow tract pressure gradient (LVOT-G) to less than 30mmHg, or (b) a post-valvular action left ventricular outflow tract pressure gradient (LVOT-G) to less than 50mmHg, or (c) a resting left ventricular outflow tract pressure gradient (LVOT-G) to less than 30mmHg and a post-valvular action left ventricular outflow tract pressure gradient (LVOT-G) to less than 50mmHg, the method comprising administering to the patient a therapeutically effective amount of compound 1,
Or a pharmaceutically acceptable salt thereof.
2. The method of claim 1, wherein the reduction of resting LVOT-G to less than 30mmHg, the reduction of left ventricular outflow tract pressure gradient (LVOT-G) to less than 50mmHg after a wag's action, or the reduction of resting left ventricular outflow tract pressure gradient (LVOT-G) to less than 30mmHg and the reduction of left ventricular outflow tract pressure gradient (LVOT-G) to less than 50mmHg after a wag's action occurs within 10 weeks of starting treatment with compound 1 or a pharmaceutically acceptable salt thereof.
3. The method of claim 2, wherein the reduction of resting LVOT-G to less than 30mmHg, the reduction of left ventricular outflow tract pressure gradient (LVOT-G) to less than 50mmHg after a wag's action, or the reduction of resting left ventricular outflow tract pressure gradient (LVOT-G) to less than 30mmHg and the reduction of left ventricular outflow tract pressure gradient (LVOT-G) to less than 50mmHg after a wag's action occurs within two weeks of starting treatment with compound 1 or a pharmaceutically acceptable salt thereof.
4. The method of any one of claims 1-3, wherein the resting LVOT-G is reduced to less than 30mmHg, the left ventricular outflow tract pressure gradient (LVOT-G) is reduced to less than 50mmHg after a wag motion, or the resting left ventricular outflow tract pressure gradient (LVOT-G) is reduced to less than 30mmHg and the left ventricular outflow tract pressure gradient (LVOT-G) is reduced to less than 50mmHg for at least 10 weeks of treatment.
5. The method of any one of claims 1-4, wherein the resting LVOT-G decreases to less than 30mmHg, the left ventricular outflow tract pressure gradient (LVOT-G) decreases to less than 50mmHg after a wag action, or the resting left ventricular outflow tract pressure gradient (LVOT-G) decreases to less than 30mmHg and the left ventricular outflow tract pressure gradient (LVOT-G) decreases to less than 50mmHg peaking within 2 to 6 weeks after a wag action.
6. A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of compound 1,
or a pharmaceutically acceptable salt thereof, wherein the patient has a resting left ventricular outflow tract pressure gradient (LVOT-G) of at least 50mmHg prior to administration of compound 1 or a pharmaceutically acceptable salt thereof.
7. A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of compound 1,
or a pharmaceutically acceptable salt thereof, wherein the patient has a resting left ventricular outflow tract pressure gradient (LVOT-G) of at least 30mmHg and less than 50mmHg and a post-valvular action left ventricular outflow tract pressure gradient (LVOT-G) of at least 50mmHg prior to administration of compound 1 or a pharmaceutically acceptable salt thereof.
8. A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of compound 1,
or a pharmaceutically acceptable salt thereof, wherein the patient is eligible for diaphragmatic reduction therapy (SRT).
9. The method of claim 8, wherein the method does not require diaphragmatic reduction therapy in the patient.
10. The method of claim 8 or 9, wherein the diaphragmatic reduction therapy is myotomy or alcohol diaphragmatic ablation.
11. A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient having symptoms of heart failure, the method comprising administering to the patient a therapeutically effective amount of compound 1,
or a pharmaceutically acceptable salt thereof, wherein the method results in a reduction in heart failure symptoms as assessed by NYHA classification.
12. The method of claim 11, wherein the method results in the patient increasing one NYHA class or two NYHA classes.
13. The method of claim 11 or 12, wherein the reduction in symptoms of heart failure occurs within 10 weeks of starting treatment with compound 1 or a pharmaceutically acceptable salt thereof.
14. A method of reducing NT-proBNP levels in a patient, said method comprising administering to said patient a therapeutically effective amount of compound 1,
Or a pharmaceutically acceptable salt thereof.
15. A method of reducing cardiac troponin I levels in a patient, the method comprising administering to the patient a therapeutically effective amount of Compound 1,
or a pharmaceutically acceptable salt thereof.
16. The method of claim 14 or 15, wherein the patient has obstructive hypertrophic cardiomyopathy (oHCM).
17. The method of any one of claims 1-16, wherein the method reduces left ventricular wall stress in the patient.
18. A method of reducing left ventricular wall stress in a patient, the method comprising administering to the patient a therapeutically effective amount of compound 1,
or a pharmaceutically acceptable salt thereof, wherein the patient has obstructive hypertrophic cardiomyopathy (oHCM).
19. The method of any one of claims 1-18, wherein the therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof is selected by titrating the daily dose of compound 1 or a pharmaceutically acceptable salt thereof administered to the patient.
20. A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof, wherein compound 1,
The therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof, is selected by titrating the daily dose of compound 1, or a pharmaceutically acceptable salt thereof, administered to the patient.
21. The method of claim 19 or 20, wherein the dose is titrated once during the course of treatment.
22. The method of claim 19 or 20, wherein the dose is titrated two or more times during the course of treatment.
23. The method of any one of claims 19-22, wherein the daily dose is administered to the patient in a constant amount for about two weeks prior to titrating the daily dose amount.
24. The method of any one of claims 1-23, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered at a daily dose of about 5mg to about 30mg.
25. The method of claim 24, wherein the daily dose is about 5mg, about 10mg, about 15mg, about 20mg, or about 30mg.
26. A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, the method comprising:
administering to the patient a first daily dose of compound 1,
or a pharmaceutically acceptable salt thereof, for a first period of time; and
administering a second daily dose of compound 1 or a pharmaceutically acceptable salt thereof to the patient for a second period of time, or terminating administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient, based on one or more components of the patient's first echocardiogram taken after the first period of time.
27. The method of claim 26, comprising selecting the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof based on the one or more components of the first echocardiogram.
28. The method of claim 26 or 27, wherein the one or more components of the first echocardiogram comprise (a) a biplane LVEF, (b) a post-warrior-action lvet-G, (c) a resting lvet-G, (d) a biplane LVEF and a post-warrior-action lvet-G, or (e) a biplane LVEF, a post-warrior-action lvet-G, and a resting lvet-G.
29. The method of any one of claims 26-28, wherein the one or more components of the first echocardiogram comprise a biplane LVEF, and compound 1 when the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold,
or a pharmaceutically acceptable salt thereof, is lower than the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof.
30. The method of any one of claims 26-28, wherein the one or more components of the first echocardiogram comprise a biplane LVEF and administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient is terminated when the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold.
31. The method of any one of claims 26-28, wherein the one or more components of the first echocardiogram comprise biplane LVEF, resting LVOT-G, and post-valvular action LVOT-G, and wherein the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the biplane LVEF of the first echocardiogram is equal to or above the predetermined biplane LVEF threshold, the resting LVOT-G of the first echocardiogram is below a predetermined resting LVOT-G threshold, and the post-valvular action LVOT-G of the first echocardiogram is below a predetermined post-valvular action LVOT-G threshold.
32. The method of any one of claims 26-28, wherein the one or more components of the first echocardiogram comprise biplane LVEF, resting LVOT-G, and post-valot-G, and wherein the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is greater than the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the first echocardiogram satisfies any one of the following conditions: (1) The biplane LVEF is equal to or above the predetermined biplane LVEF threshold and the resting lvet-G is equal to or above the predetermined resting lvet-G threshold, or (2) the biplane LVEF is equal to or above the predetermined biplane LVEF threshold, the resting lvet-G is below the predetermined resting lvet-G threshold and the post-warrior-action lvet-G is equal to or above the predetermined post-warrior-action lvet-G threshold.
33. The method of any one of claims 26-28, wherein the one or more components of the first echocardiogram comprise biplane LVEF and post-warfare LVOT-G, and wherein the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the first echocardiogram meets any one of the following conditions: (1) The biplane LVEF is equal to or above the predetermined biplane LVEF threshold and below a second predetermined biplane LVEF threshold; or (2) the biplane LVEF is equal to or above the second predetermined biplane LVEF threshold and the post-warrior LVOT-G of the first echocardiogram is below a second predetermined post-warrior LVOT-G threshold.
34. The method of any one of claims 26-28, wherein the one or more components of the first echocardiogram comprise biplane LVEF and post-warrior action lvet-G, and wherein the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is greater than the first daily dose of compound 1 when the biplane LVEF of the first echocardiogram is above the second predetermined biplane LVEF threshold and the post-warrior action lvet-G of the first echocardiogram is equal to or above the second predetermined post-warrior action LVOT-G threshold.
35. The method of any one of claims 26-34, wherein the first daily dose of compound 1, or a pharmaceutically acceptable salt thereof, is about 5mg of compound 1.
36. The method of claim 35, wherein the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg or about 10mg of compound 1.
37. The method of any one of claims 26-36, further comprising measuring the one or more components of the first echocardiogram.
38. The method of any one of claims 26-37, wherein the first period of time is about 2 weeks.
39. The method of any one of claims 26-38, wherein the second period of time is about 2 weeks.
40. The method of any one of claims 26-39, wherein the second daily dose of compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient for the second period of time, the method further comprising administering a third daily dose of compound 1, or a pharmaceutically acceptable salt thereof, to the patient for a third period of time, or terminating administration of compound 1, or a pharmaceutically acceptable salt thereof, to the patient based on one or more components of a second echocardiogram of the patient taken after the second period of time and the second daily dose of compound 1, or a pharmaceutically acceptable salt thereof.
41. The method of claim 40, comprising selecting the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof based on the one or more components of the second echocardiogram and the second daily dose.
42. The method of claim 40 or 41, wherein the one or more components of the second echocardiogram comprise (a) a biplane LVEF, (b) a post-warrior-action lvet-G, (c) a resting lvet-G, (d) a biplane LVEF and a post-warrior-action lvet-G, or (e) a biplane LVEF, a post-warrior-action lvet-G, and a resting lvet-G.
43. The method of any one of claims 40-42, wherein the one or more components of the second echocardiogram comprise a biplane LVEF, and the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is lower than the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof, or administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient is terminated when the biplane LVEF of the second echocardiogram is below the predetermined biplane LVEF threshold.
44. The method of any one of claims 40-42, wherein administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient is terminated when the biplane LVEF of the second echocardiogram is below the predetermined biplane LVEF threshold and the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to or lower than the first daily dose of compound 1.
45. The method of any one of claims 40-42, wherein the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is higher than the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof and the biplane LVEF of the second echocardiogram is lower than the predetermined biplane LVEF threshold.
46. The method of any one of claims 40-42, wherein the one or more components of the second echocardiogram comprise biplane LVEF, resting LVOT-G, and post-warrior action LVOT-G, and wherein the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the biplane LVEF of the second echocardiogram is equal to or above the predetermined biplane LVEF threshold, the resting LVEOT-G of the second echocardiogram is below the predetermined resting LVOT-G threshold, and the post-warrior action LVOT-G of the second echocardiogram is below the predetermined post-warrior action LVOT-G threshold.
47. The method of any one of claims 40-42, wherein the one or more components of the second echocardiogram comprise biplane LVEF, resting LVOT-G, and post-valot-G, and wherein the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is greater than the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the second echocardiogram satisfies any one of the following conditions: (1) The biplane LVEF is equal to or above the predetermined biplane LVEF threshold and the resting LVEOT-G is equal to or above the predetermined resting lvet-G threshold, or (2) the biplane LVEF is equal to or above the predetermined biplane LVEF threshold, the resting lvet-G is below the predetermined resting lvet-G threshold and the post-warrior-action lvet-G is equal to or above the predetermined post-warrior-action lvet-G threshold.
48. The method of any one of claims 40-42, wherein the one or more components of the second echocardiogram comprise biplane LVEF and post-valot-G-warrior action, and wherein the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the second echocardiogram meets any one of the following conditions: (1) The biplane LVEF is equal to or above the predetermined biplane LVEF threshold and below the second predetermined biplane LVEF threshold; or (2) the biplane LVEF is equal to or above the second predetermined biplane LVEF threshold and the post-warrior-action LVOT-G is below the second predetermined post-warrior-action LVOT-G threshold.
49. The method of any one of claims 40-42, wherein the one or more components of the second echocardiogram comprise biplane LVEF and post-warrior action lvet-G, and wherein the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is greater than the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the biplane LVEF of the second echocardiogram is above the second predetermined biplane LVEF threshold and the post-warrior action lvet-G of the second echocardiogram is equal to or above the second predetermined post-warrior action LVOT-G threshold.
50. The method of any one of claims 40-49, wherein the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg of compound 1, the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg or about 10mg of compound 1, and the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg, about 10mg or about 15mg of compound 1.
51. The method of any one of claims 40-50, further comprising measuring the one or more components of the second echocardiogram.
52. The method of any one of claims 40-51, wherein the third period of time is about 2 weeks.
53. The method of any one of claims 40-52, wherein the third daily dose of compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient for the third period of time, the method further comprising administering a fourth daily dose of compound 1, or a pharmaceutically acceptable salt thereof, to the patient for a fourth period of time, or terminating administration of compound 1, or a pharmaceutically acceptable salt thereof, to the patient based on the third daily dose of one or more components of the patient's third echocardiogram taken after the third period of time and compound, or a pharmaceutically acceptable salt thereof.
54. The method of claim 53, comprising selecting the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof based on the one or more components of the third echocardiogram and the third daily dose.
55. The method of claim 53 or 54, wherein the one or more components of the third echocardiogram comprise (a) a biplane LVEF, (b) a post-warrior-action lvet-G, (c) a resting lvet-G, (d) a biplane LVEF and a post-warrior-action lvet-G, or (e) a biplane LVEF, a post-warrior-action lvet-G, and a resting lvet-G.
56. The method of any one of claims 53-55, wherein the one or more components of the third echocardiogram comprise a biplane LVEF, and the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is lower than the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof, or administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient is terminated when the biplane LVEF of the third echocardiogram is below the predetermined biplane LVEF threshold.
57. The method of any one of claims 53-55, wherein administration of compound 1 or a pharmaceutically acceptable salt thereof to the patient is terminated when the biplane LVEF of the third echocardiogram is below the predetermined biplane LVEF threshold and the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to or lower than the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof.
58. The method of any one of claims 53-55, wherein:
when the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is above the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof and the biplane LVEF of the third echocardiogram is below the predetermined biplane LVEF threshold, the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof; or (b)
When the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof and the biplane LVEF of the third echocardiogram is below the predetermined biplane LVEF threshold, the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof.
59. The method of any one of claims 53-55, wherein the one or more components of the third echocardiogram comprise biplane LVEF, resting LVOT-G, and post-warrior action LVOT-G, and wherein the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the biplane LVEF of the third echocardiogram is equal to or above the predetermined biplane LVEF threshold, the resting LVOT-G of the third echocardiogram is below the predetermined resting LVOT-G threshold, and the post-warrior action LVOT-G of the third echocardiogram is below the predetermined post-warrior action LVOT-G threshold.
60. The method of any one of claims 53-55, wherein the one or more components of the third echocardiogram comprise biplane LVEF, resting LVOT-G, and post-valot-G, and wherein the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is greater than the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the third echocardiogram satisfies any one of the following conditions: (1) The biplane LVEF is equal to or above the predetermined biplane LVEF threshold and the resting lvet-G is equal to or above the predetermined resting lvet-G threshold, or (2) the biplane LVEF is equal to or above the predetermined biplane LVEF threshold, the resting lvet-G is below the predetermined resting lvet-G threshold and the post-warrior-action lvet-G is equal to or above the predetermined post-warrior-action lvet-G threshold.
61. The method of any one of claims 53-55, wherein the one or more components of the third echocardiogram comprise biplane LVEF and post-valot-G-warrior action, and wherein the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is equal to the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the third echocardiogram meets any one of the following conditions: (1) The biplane LVEF is equal to or above the predetermined biplane LVEF threshold and below the second predetermined biplane LVEF threshold; or (2) the biplane LVEF is equal to or above the second predetermined biplane LVEF threshold and the post-warrior-action LVOT-G is below the second predetermined post-warrior-action LVOT-G threshold.
62. The method of any one of claims 53-55, wherein the one or more components of the third echocardiogram comprise biplane LVEF and post-warrior action lvet-G, and wherein the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is greater than the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof when the biplane LVEF of the third echocardiogram is above the second predetermined biplane LVEF threshold and the post-warrior action lvet-G of the third echocardiogram is equal to or above the second predetermined post-warrior action LVOT-G threshold.
63. The method of any one of claims 53-62, wherein the first daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg of compound 1, the second daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg or about 10mg of compound 1, the third daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg, about 10mg or about 15mg of compound 1, and the fourth daily dose of compound 1 or a pharmaceutically acceptable salt thereof is about 5mg, about 10mg, about 15mg or about 20mg of compound 1.
64. The method of any one of claims 53-63, further comprising measuring the one or more components of the third echocardiogram.
65. The method of any one of claims 53-64, wherein the fourth period of time is about 2 weeks.
66. The method of any one of claims 29-65, wherein
(a) The predetermined biplane LVEF threshold is 50%;
(b) The predetermined biplane LVEF threshold is 50%, the predetermined resting LVOT-G threshold is 30mmHg, and the predetermined post-warfarin LVOT-G threshold is 50mmHg; or (b)
(c) The predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the second predetermined post-warfarin LVOT-G threshold is 30mmHg.
67. The method of any one of claims 1-66, wherein, prior to administration of compound 1 or a pharmaceutically acceptable salt thereof, the patient has (i) resting LVOT-G ≡50mmHg; or (ii) resting LVOT-G is greater than or equal to 30mmHg and after <50mmHg and Wash action LVOT-G is greater than or equal to 50mmHg.
68. The method of any one of claims 1-67, wherein the patient has a Left Ventricular Ejection Fraction (LVEF) > 60% prior to administration of compound 1 or a pharmaceutically acceptable salt thereof.
69. The method of any one of claims 1-68, wherein no propidium amine is administered to the patient during treatment with compound 1 or a pharmaceutically acceptable salt thereof.
70. The method of any one of claims 1-68, wherein the patient is administered propidium amine during treatment with compound 1 or a pharmaceutically acceptable salt thereof.
71. The method of any one of claims 1-68, wherein the patient is not treated with propidium or an anti-arrhythmic drug having negative cardiotonic activity within 4 weeks prior to treatment with compound 1 or a pharmaceutically acceptable salt thereof.
72. The method of any one of claims 1-68 or 70, wherein an anti-arrhythmic drug is administered to the patient during treatment with compound 1 or a pharmaceutically acceptable salt thereof.
73. The method of any one of claims 1-72, wherein the patient is a CYP2D6 hypometabolizer.
74. The method of any one of claims 1-73, wherein the patient is fasted when compound 1 or a pharmaceutically acceptable salt thereof is administered.
75. The method of any one of claims 1-73, wherein the patient is fed when compound 1 or a pharmaceutically acceptable salt thereof is administered.
76. The method of any one of claims 1-75, wherein the method does not comprise collecting a blood sample of the patient.
77. The method of any one of claims 1-76, wherein the method does not comprise analyzing a blood sample of the patient.
78. The method of any one of claims 1-77, wherein a β -blocker is administered to the patient during treatment with compound 1 or a pharmaceutically acceptable salt thereof.
79. The method of any one of claims 1-78, wherein the method results in one or more of: improved mitral regurgitation, improved cardiac relaxation, beneficial cardiac remodeling, reverse cardiac remodeling, beneficial cardiac structural remodeling, beneficial cardiac functional remodeling, adverse cardiac remodeling reversal, reduced average Left Ventricular Mass Index (LVMI), improved Left Ventricular (LV) filling pressure, reduced Left Atrial Volume Index (LAVI), reduced assessment of the category of pre-systole motion of the mitral valve leaflets, reduced frequency of eccentric mitral regurgitation, reduced lateral E/E', reduced lateral E/E, reduced Brain Natriuretic Peptide (BNP), and reduced N-terminal pro-hormone of brain natriuretic peptide (NT-proBNP).
80. The method of any one of claims 1-79, wherein the method results in one or more of: improvement in exercise capacity, improvement in peak oxygen uptake (pVO 2) by cardiopulmonary exercise testing (CPET), improvement in kansase's cardiomyopathy questionnaire total score (KCCQ-OSS), improvement in kansase's cardiomyopathy questionnaire clinical total score (KCCQ-CSS), improvement in quality of life as measured by PRO questionnaire, improvement in NYHA functional classification by one or more categories, improvement in left ventricular outflow tract gradient (LVOT-G) after warrior's action, and improvement in total workload during CPET.
81. The method of claim 80, wherein the method results in:
(a) pVO2 from baseline changes of > 1.5mL/kg/min and NYHA functional class improvement by one or more classes;
(b) pVO 2.gtoreq.3.0 mL/kg/min from baseline and NYHA functional class did not deteriorate.
82. The method of claim 80 or 81, wherein the method increases KCCQ-OSS or KCCQ-CSS by at least 5 minutes, at least 10 minutes, or at least 20 minutes.
83. The method of any one of claims 80-82, wherein the method increases resting LVOT-G <30mmHg, post-warrior action LVOT-G <50mmHg, and NYHA functional class by one or more classes.
84. The method of any one of claims 1-83, wherein the method reduces myocardial damage in the patient.
85. The method of any one of claims 1-84, wherein (a) the daily dose is administered daily as a single dose or (b) the daily dose is administered in 2 divided doses.
86. The method of any one of claims 1-85, wherein administering compound 1 or a pharmaceutically acceptable salt thereof has a sustained effect of at least 10 weeks, 12 weeks, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years.
87. The method of any one of claims 79-86, wherein the one or more results of the treatment occur within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks of starting treatment with compound 1 or a pharmaceutically acceptable salt thereof.
CN202280048360.1A 2021-07-16 2022-07-15 Method for treating hypertrophic cardiomyopathy Pending CN117794535A (en)

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